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					    Pathophysiology
• JP Advis DVM, Ph.D.                                                                                     04
  Bartlett Hall, Animal Sciences, Cook,
  932 - 9240, advis@aesop.rutgers.edu

• Course website: rci.rutgers.edu/~advis
• Lectures, tests, grades, office hours, textbook,
                                    Lectures 1-2: Introduction to Pathophysiology (2)
                                    Lectures 3-4: Mechanisms of Self-Defense and Stress (2)
• Material to                       Lectures 5-8: Endocrine and Nervous System Dysfunctions (4)
                                    Lecture    9: Alterations of Skeletal Muscle Function (1)
  be covered:                                                 REVIEW AND TEST #1
                                    Lectures 12-18: Cardiovascular, Respiratory and Renal Dysfunctions (7)
                                                              REVIEW AND TEST #2
                                    Lectures 21-24: Alterations of Digestive Function and Intermediary Metabolism (4)
                                    Lectures 25-26: Alterations of the Reproductive System (2)
                                                              REVIEW AND TEST #3
• About
  lecture       •   There are not intended to be the sole source for studying the course material !!!!!!!!!!!!!!!!
                •   Slides are good to review the course material after you have study your course textbook
  slides:
                •   Slides are a good indicator of the relative importance of lecture topics (see slide # per topic
                •   Group slides by titles when using them to review course material. Match lectures and text.




                                    Hypersensitivities
                                           HYPERSENSITIVITIES (autoimmunity, alloimmunity, allergy):
    Hypersensitivities                     Hypersensitivity is an inappropriate immune response mis-
       mechanisms                          directed against the host’s own tissues (autoimmunity), or
       antigenic targets                   directed against beneficial foreign tissues such as transfu-
    Infection                              sions or transplants (alloimmunity), or it can be exagerated
       infectious microorganim             responses against enviromental agents (allergy). They are
       defense mechanisms
       infection and injury                classified as: type I (IgG mediated); type II (tissue specific);
       clinical manifestations             type III (immune complex mediated) & type IV (cell mediated)
       countermeasures
                                           reactions (immediate, min / hrs, or delayed, hrs / days). The
    Immune Deficiency                      most rapid immediate hypersensitivity reaction, anaphylaxis,
       clinical presentation               occurs within minutes of reexposure (can lead to CV shock).
       primary deficiency
       secondary deficiency
       evaluation and care                 Type I, Ag reacts with mast cell’s IgE & elicits degranulation.
       replacement therapy                 Type II, caused by complement mediated lysis, opsonization
    Stress Response                        and phagocytosis, Ab-dependent cell-mediated cytotoxity, &
       general adaptation synd.            modulation of cellular function. Type III, caused by formation
       neuroendocrine control              of immune complexes deposited in target tissues where they
       role of immune system
                                           activate complement cascade, generating chemotactic frag-
    Aging                                  ments that attract neutrophils. Type IV, caused by specifical-
       in general, and its effect
       on specific endocrine               ly sensitized T-cells to kill target cells directly or to release
       organss, as an example              chemokines that activate other cells, such as macrophages.
                                              Hypersensitivity is an inappropriate immune response




                                                        Page 1
                                     Hypersensitivities
     Hypersensitivities                             RELATIVE INCIDENCE AND EXAMPLES OF
        mechanisms                                      HYPERSENSITIVITY DISEASES
        antigenic targets
     Infection
                                       Ag target           Tyoe I              Type II          Type III         Type IV
        infectious microorganim
        defense mechanisms                                 (IgE –              (tissue         (immune            (cell
        infection and injury                              mediated)           specific)        complex)         mediated)
        clinical manifestations
        countermeasures                Allergy environ-   ++++               +                +                 ++
                                       mental Ag          Hay fever          Hemolysis in     Gluten (wheat)    Poison ivy
     Immune Deficiency                                                       drug allergies   allergy           allergy
        clinical presentation
        primary deficiency             Auto-immunity,     +                  ++               +++               ++
        secondary deficiency           self-Ag            May contribute     Autoimmune       Systemic lupus    Hashimoto
        evaluation and care                               to some type III   thrombocyto-     erythematosus     thyroiditis
        replacement therapy                               reactions          penia
     Stress Response
        general adaptation synd.       Alloimmunity,      +                  ++               +                 ++
        neuroendocrine control         another’s Ag       May contribute     Hemolysis        Anaphylactic      Graft rejection
        role of immune system                             to some type III   disease in the   response to
                                                          reactions          newborn          IgA , if IgA is
     Aging                                                                                    not made
        in general, and its effect
        on specific endocrine
        organss, as an example

                                            Hypersensitivity is an inappropriate immune response




                    RELATIVE INCIDENCE AND EXAMPLES OF
                        HYPERSENSITIVITY DISEASES

Ag target                     Tyoe I                     Type II                          Type III                   Type IV
                        (IgE – mediated)            (tissue specific)                    (immune                 (cell mediated)
                                                                                         complex)


Allergy environ-        ++++                       +                               +                            ++
mental Ag               Hay fever                  Hemolysis in                    Gluten (wheat)               Poison ivy allergy
                                                   drug allergies                  allergy


Auto-immunity,          +                          ++                              +++                          ++
self-Ag                 May contribute to          Autoimmune                      Systemic lupus               Hashimoto
                        some type III              thrombocyto-                    erythematosus                thyroiditis
                        reactions                  penia


Alloimmunity,           +                          ++                              +                            ++
another’s Ag            May contribute to          Hemolysis                       Anaphylactic                 Graft rejection
                        some type III              disease in the                  response to IgA ,
                        reactions                  newborn                         if IgA is not made




                                                          Page 2
                                      Hypersensitivities
      Hypersensitivities                     IMMUNOLOGIC MECHANISMS OF TISSUE DESTRUCTION
         mechanisms                     Type       Name       Time       Ab           Cell           C*    (e.g.)
         antigenic targets
      Infection                         I          IgE-       Imme-      IgE          Mast cell      No    Seasonal
                                                   mediated   diate                                        allergy rhinitis,
         infectious microorganim                                                                           asthma
         defense mechanisms
         infection and injury
         clinical manifestations        II         Tissue     Imme-      IgG, IgM     Macro-         Yes   Autoimmune
         countermeasures                           specific   diate                   phage in             thrombocyto-
                                                                                      tissue               penia purpura.
      Immune Deficiency                                                                                    Graves disease
         clinical presentation                                                                             Autoimmune
         primary deficiency                                                                                hemolytic
         secondary deficiency                                                                              anemia
         evaluation and care
         replacement therapy            III        Immune     Imme-      IgG, IgM     Neutro-        Yes   Systemic lupus
      Stress Response                              complex    diate                   phils                erythematosus
         general adaptation synd.
         neuroendocrine control         IV         Cell       Delayed    none         Lympho-        No    Contact sensi-
         role of immune system                     mediated                           cytes,               tivity to ivy and
                                                                                      Macro-               metals
      Aging                                                                           phages               (jewelry)
         in general, and its effect
         on specific endocrine                                 (* Participation of complement)
         organss, as an example

                                              Hypersensitivity is an inappropriate immune response




        IMMUNOLOGIC MECHANISMS OF TISSUE DESTRUCTION

Type              Name                Time            Ab                Cell                    C*         (e.g.)

I                 IgE-                Imme-diate      IgE               Mast cell               No         Seasonal allergy
                  mediated                                                                                 rhinitis, asthma



II                Tissue              Imme-diate      IgG, IgM          Macro-                  Yes        Autoimmune
                  specific                                              phage in                           thrombocyto-
                                                                        tissue                             penia purpura.
                                                                                                           Graves disease
                                                                                                           Autoimmune
                                                                                                           hemolytic anemia


III               Immune              Imme-diate      IgG, IgM          Neutro-                 Yes        Systemic lupus
                  complex                                               phils                              erythematosus

IV                Cell                Delayed         none              Lympho-                 No         Contact sensi-
                  mediated                                              cytes,                             tivity to ivy and
                                                                        Macro-                             metals (jewelry)
                                                                        phages

                                                               (* Participation of complement)




                                                        Page 3
                                      Hypersensitivities
      Hypersensitivities                       SAME EXAMPLES OF AUTOIMMUNE DISORDERS
         mechanisms                      System disease              Organ or tissue          Probable self-Ag
         antigenic targets
      Infection                          Endocrine system
                                                Graves disease       Hyperthyroidism          TSH-R in thyroid gland
         infectious microorganim             Hashimoto disease       Hypothyroidism           Thyroid cell surface Ag, TG
         defense mechanisms                   Diabetes mellitus      Pancreas                 Islet cell, Ins, Ins-R in ß cell
         infection and injury                  Addison disease       Adrenal hypofunction     Surface Ag, microsomal Ag
         clinical manifestations                  Male infertility   Testis                   Surface Ag in spermatozoa
         countermeasures
                                         Neuromuscular tissue
      Immune Deficiency                        Multiple sclerosis    Neural tissue            Surface Ag of nerve cells
         clinical presentation                Myasthenia gravis      Neuromuscular junction   Ach-R, striations skeleta;/cardiac m.
         primary deficiency                    Rheumatic fever       Heart                    Cardiac Ag that react w/Strep-Ag
         secondary deficiency            Gastrointestinal system
         evaluation and care                    Ulcerative colitis   Colon                    Mucosal cells
         replacement therapy                  Pernicious anemia      Stomach                  Surface Ag parietal cells, intrinsic f.
      Stress Response                    Connective tissue
         general adaptation synd.           Rheumatoid arthritis     Joints                   Collagen, IgG
         neuroendocrine control                Systemic Lupus        Multiple sites           Ag in nuclei, organells, EC matrix
         role of immune system
                                         Renal system
      Aging                                  Glomerulonephritis      Kidney                   Multiple immune complexes
         in general, and its effect      Respiratory system
         on specific endocrine             Goodpasture disease       Lung, kidney             Basal membrane, alveoli, glomeruli
         organss, as an example

                                             Hypersensitivity is an inappropriate immune response




                             SAME EXAMPLES OF AUTOIMMUNE DISORDERS


System disease                        Organ or tissue                             Probable self-Ag

Endocrine system
          Graves disease              Hyperthyroidism                             TSH-R in thyroid gland
       Hashimoto disease              Hypothyroidism                              Thyroid cell surface Ag, TG
         Diabetes mellitus            Pancreas                                    Islet cell, Ins, Ins-R in ß cell
         Addison disease              Adrenal hypofunction                        Surface Ag, microsomal Ag
            Male infertility          Testis                                      Surface Ag in spermatozoa
Neuromuscular tissue
        Multiple sclerosis Neural tissue                                          Surface Ag of nerve cells
       Myasthenia gravis Neuromuscular junction                                   Ach-R, striations skeleta;/cardiac m.
        Rheumatic fever Heart                                                     Cardiac Ag that react w/Strep-Ag
Gastrointestinal system
          Ulcerative colitis Colon                                                Mucosal cells
        Pernicious anemia Stomach                                                 Surface Ag parietal cells, intrinsic f.
Connective tissue
     Rheumatoid arthritis Joints                                                  Collagen, IgG
          Systemic Lupus Multiple sites                                           Ag in nuclei, organells, EC matrix
Renal system
       Glomerulonephritis Kidney                                                  Multiple immune complexes
Respiratory system
     Goodpasture disease Lung, kidney                                             Basal membrane, alveoli, glomeruli




                                                          Page 4
                                     Hypersensitivities
     Hypersensitivities                         CAUSES OF CLINICAL ALLERGIC REACTIONS
        mechanisms                       Typical allergen           Mechanism           Clinical manifestation
        antigenic targets
     Infection                           ingestants
                                                          Foods     Type I              Gastrointestinal allergy
        infectious microorganim                           Drugs     Tyoes I, II, III    Urticaria, immediate drug reaction,
        defense mechanisms                                                              hemolytic anemia, serum sickness
        infection and injury
        clinical manifestations          Inhalants
        countermeasures                       Pollen, dust, molds   Type I              Allergic rhinitis, bronqial asthma
                                           Aspergillus fumigatus    Types I, III        Allergic bronchpulm. Aspergillosis
     Immune Deficiency                              Thermophilic    Types III, IV       Extrinsic allergic alveolitis
        clinical presentation                     acetinolycetes*
        primary deficiency
        secondary deficiency             Injectants
        evaluation and care                               Drugs     Types I, II, III    Immediate drug reaction, hemolytic
        replacement therapy                                                             anemia, serum sicknes
     Stress Response                                  Bee venom     Type I              Anaphylaxis
                                                        Vaccines    Type III            Localized Arthus reaction
        general adaptation synd.                          Serum     Types I, III        Anaphylaxis, serum sickness
        neuroendocrine control
        role of immune system
                                         Contactans
     Aging                                    Poison ivy, metals    Type IV             Contact dermatitis
        in general, and its effect
        on specific endocrine          (* an order of fungi that is stimulated to grow by warmth)
        organss, as an example

                                            Hypersensitivity is an inappropriate immune response




                            CAUSES OF CLINICAL ALLERGIC REACTIONS


Typical allergen                     Mechanism                        Clinical manifestation

ingestants
                         Foods Type I                                 Gastrointestinal allergy
                         Drugs Tyoes I, II, III                       Urticaria, immediate drug reaction, hemolytic
                                                                      anemia, serum sickness
Inhalants
       Pollen, dust, molds Type I                                     Allergic rhinitis, bronqial asthma
     Aspergillus fumigatus Types I, III                               Allergic bronchpulm. Aspergillosis
              Thermophilic Types III, IV                              Extrinsic allergic alveolitis
           acetinolycetes*

Injectants
                         Drugs Types I, II, III                       Immediate drug reaction, hemolytic anemia,
                                                                      serum sicknes
                 Bee venom Type I                                     Anaphylaxis
                   Vaccines Type III                                  Localized Arthus reaction
                     Serum Types I, III                               Anaphylaxis, serum sickness

Contactans
        Poison ivy, metals Type IV                                    Contact dermatitis

                                       (* an order of fungi that is stimulated to grow by warmth)




                                                        Page 5
                Hypersensitivities – Type I
  Hypersensitivities
     mechanisms
                                                                        MECHANISM OF TYPE I
     antigenic targets                                                  IGG – MEDIATED REACTION:
  Infection
                                                                        First response to an allergen
     infectious microorganim
                                                                        stimulates B-lymphocytes to mature
     defense mechanisms                                                 into plasma cells that produce IgE,
     infection and injury                                               which is adsorbed to the surface of
     clinical manifestations                                            mast cell by binding to specific Fc-R
     countermeasures
                                                                        to “sensitize” it.
  Immune Deficiency
                                                                        In a 2nd exposure, allergens cross-link
     clinical presentation                                              surface bound IgE causing
     primary deficiency                                                 degranulation.
     secondary deficiency
     evaluation and care                                                The initial phase is characterized by
     replacement therapy                                                vasodilation, vascular leakage, and
                                                                        smooth muscle spasm or glandular
  Stress Response                                                       secretions, usually within 5-30 min
     general adaptation synd.                                           after Ag exposure.
     neuroendocrine control
     role of immune system                                              The late phase occurs 208 hr later
                                                                        without additional exposure to Ag and
  Aging                                                                 results from infiltration of tissue with
     in general, and its effect                                         inflammatory cells, like eosinophils,
     on specific endocrine                                              neutrophils, and basophils.
     organss, as an example

                                       Hypersensitivity is an inappropriate immune response




Allergen                                 FIRST
                                       EXPOSURE
                                                                                  MECHANISM OF TYPE I
                                  B-Lymphocyte        Plasma cell                 IGG – MEDIATED REACTION:

                                                                                  First response to an allergen
                                                                                  stimulates B-lymphocytes to
                                                                                  mature into plasma cells that
     Macrophage                                                                   produce IgE, which is adsorbed
                                                                                  to the surface of mast cell by
                                                                                  binding to specific Fc-R to
                                                               IgE                “sensitize” it.
 SECOND                                          Fc receptor                      In a 2nd exposure, allergens
EXPOSURE                                                                          cross-link surface bound IgE
                                                 Sensitized mast cell             causing degranulation.

                                                                                  The initial phase is
                                                                                  characterized by vasodilation,
                                                                                  vascular leakage, and smooth
                                                                                  muscle spasm or glandular
                                                                                  secretions, usually within 5-30
                                                                                  min after Ag exposure.
                                                               Allergic
                                                               reaction           The late phase occurs 208 hr
                                                                                  later without additional
                          Degranulated mast cell                Histamine         exposure to Ag and results
                                                                                  from infiltration of tissue with
                      EDEMA                                                       inflammatory cells, like
                                                                                  eosinophils, neutrophils, and
                                                                                  basophils.


           Blood vessel




                                                 Page 6
                   Hypersensitivities – Type I
     Hypersensitivities
        mechanisms
                                                                       MECHANISM OF TYPE I
        antigenic targets                                              IGG – MEDIATED REACTION:
     Infection
                                                                       First response to an allergen
        infectious microorganim
                                                                       stimulates B-lymphocytes to mature
        defense mechanisms                                             into plasma cells that produce IgE,
        infection and injury                                           which is adsorbed to the surface of
        clinical manifestations                                        mast cell by binding to specific Fc-R
        countermeasures
                                                                       to “sensitize” it.
     Immune Deficiency
                                                                       In a 2nd exposure, allergens cross-link
        clinical presentation                                          surface bound IgE causing
        primary deficiency                                             degranulation.
        secondary deficiency
        evaluation and care                                            The initial phase is characterized by
        replacement therapy                                            vasodilation, vascular leakage, and
                                                                       smooth muscle spasm or glandular
     Stress Response                                                   secretions, usually within 5-30 min
        general adaptation synd.                                       after Ag exposure.
        neuroendocrine control
        role of immune system                                          The late phase occurs 208 hr later
                                                                       without additional exposure to Ag and
     Aging                                                             results from infiltration of tissue with
        in general, and its effect                                     inflammatory cells, like eosinophils,
        on specific endocrine                                          neutrophils, and basophils.
        organss, as an example

                                     Hypersensitivity is an inappropriate immune response




                                               itching

                                                                                  MECHANISM OF TYPE I
          conjunctivitis                                                          IGG – MEDIATED REACTION:
                   rhinitis                   angioedema                          First response to an allergen
      laryngeal edema                                                             stimulates B-lymphocytes to
                                                                                  mature into plasma cells that
      urticaria                                          hypotension              produce IgE, which is adsorbed
                                                                                  to the surface of mast cell by
                                                                                  binding to specific Fc-R to
                                                                                  “sensitize” it.
bronchiospasm
   (asthma}                                                                       In a 2nd exposure, allergens
                                                                                  cross-link surface bound IgE
 dysrhytmias                                                                      causing degranulation.

                                                                                  The initial phase is
                                                                                  characterized by vasodilation,
                                                                                  vascular leakage, and smooth
                                                                                  muscle spasm or glandular
                                                           gastrointestinal       secretions, usually within 5-30
                                                                                  min after Ag exposure.
                                                           cramps and
                                                           malabsorption          The late phase occurs 208 hr
                                                                                  later without additional
                                                            angioedema
                                                                                  exposure to Ag and results
                                                                                  from infiltration of tissue with
                                                                                  inflammatory cells, like
                                                                                  eosinophils, neutrophils, and
                                                                                  basophils.




                                             Page 7
              Hypersensitivities – Type I
Hypersensitivities
   mechanisms
                                                                  MECHANISM OF TYPE I
   antigenic targets                                              IGG – MEDIATED REACTION:
Infection
                                                                  First response to an allergen
   infectious microorganim
                                (A) Angioedema                    stimulates B-lymphocytes to mature
   defense mechanisms                                             into plasma cells that produce IgE,
   infection and injury         (B) Allergic urticaria.           which is adsorbed to the surface of
   clinical manifestations          Skin lesions with             mast cell by binding to specific Fc-R
   countermeasures
                                    raised edges de-              to “sensitize” it.
Immune Deficiency                   veloped in min-hr
                                    with resolution               In a 2nd exposure, allergens cross-link
   clinical presentation            after 12 hr.                  surface bound IgE causing
   primary deficiency                                             degranulation.
   secondary deficiency
   evaluation and care                                            The initial phase is characterized by
   replacement therapy                                            vasodilation, vascular leakage, and
                                                                  smooth muscle spasm or glandular
Stress Response                                                   secretions, usually within 5-30 min
   general adaptation synd.                                       after Ag exposure.
   neuroendocrine control
   role of immune system                                          The late phase occurs 208 hr later
                                                                  without additional exposure to Ag and
Aging                                                             results from infiltration of tissue with
   in general, and its effect                                     inflammatory cells, like eosinophils,
   on specific endocrine                                          neutrophils, and basophils.
   organss, as an example

                                     Hypersensitivity is an inappropriate immune response




 (A)Angioedema                                                                 MECHANISM OF TYPE I
                                                                               IGG – MEDIATED REACTION:
 (B)Allergic
                                                                               First response to an allergen
   urticaria. Skin
                                                                               stimulates B-lymphocytes to
   lesions with                                                                mature into plasma cells that
   raised edges                                                                produce IgE, which is adsorbed
   de-veloped in                                                               to the surface of mast cell by
                                                                               binding to specific Fc-R to
   min-hr with                                                                 “sensitize” it.
   resolution after
                                                                               In a 2nd exposure, allergens
   12 hr.                                                                      cross-link surface bound IgE
                                                                               causing degranulation.

                                                                               The initial phase is
                                                                               characterized by vasodilation,
                                                                               vascular leakage, and smooth
                                                                               muscle spasm or glandular
                                                                               secretions, usually within 5-30
                                                                               min after Ag exposure.

                                                                               The late phase occurs 208 hr
                                                                               later without additional
                                                                               exposure to Ag and results
                                                                               from infiltration of tissue with
                                                                               inflammatory cells, like
                                                                               eosinophils, neutrophils, and
                                                                               basophils.




                                                  Page 8
                   Hypersensitivities – Type II
    Hypersensitivities                                             MECHANISM OF TYPE II
                                                                   TISSUE SPECIFIC REACTION:
         mechanisms
         antigenic targets                                         Ab binds to Ag in cell surface and
    Infection                                                      destroys or prevents the cell from
                                                                   functioning by:
         infectious microorganim
         defense mechanisms                                        (A) Complement mediated lysis (RBC
         infection and injury                                          target is depicted in this figure)
         clinical manifestations
         countermeasures
                                                                   (B) Phagocytosis by macrophages in
    Immune Deficiency                                                  the tissue

         clinical presentation                                     (C) Neutrophil mediated destruction of
         primary deficiency                                            the RBC
         secondary deficiency
         evaluation and care                                       (D) Ab dependent cell-mediated
         replacement therapy                                           cytotoxicity (ADCC), or
    Stress Response                                                (E) Modulation or blocking the normal
         general adaptation synd.                                      function of receptors by antirecep-
         neuroendocrine control                                        tors antibodies
         role of immune system
    Aging                                                          C1, complement component C1
         in general, and its effect                                C3b, complement fragment produced
         on specific endocrine                                         from C3, which acts as opsonin.
         organss, as an example

                                      Hypersensitivity is an inappropriate immune response




  C1
                          antibody
                                                                               MECHANISM OF TYPE II
                                                                               TISSUE SPECIFIC REACTION:

                                                                               Ab binds to Ag in cell surface
                                                                               and destroys or prevents the
                                                                               cell from functioning by:

COMPLEMENT MEDIATED LYSIS              PHAGOCYTOSIS BY                         (A)Complement mediated lysis
                                       EXTRAVASCULAR MACROPHAGE                   (RBC target is depicted in
                                                                                  this figure)
                  C1
            IgG                                                                (B)Phagocytosis by
                                                                                  macrophages in the tissue
       antigen
                                                                               (C)Neutrophil mediated
                                                                                  destruction of the RBC

                                                                               (D)Ab dependent cell-mediated
                                          C3b                                     cytotoxicity (ADCC), or
 NEUTROPHIL MEDIATED DAMAGE
                                                                               (E)Modulation or blocking the
                                                                                  normal function of receptors
                                                                                  by antirecep-tors antibodies


                                                                               C1, complement component C1
                                                                               C3b, complement fragment
                                                                                  produced from C3, which
                                                                                  acts as opsonin.


ANTIBODY DEPENDENT CELL                    RECEPTOR BLOCKAGE
MEDIATED CYTOTOXICITY




                                              Page 9
            Hypersensitivities – Type III
Hypersensitivities
   mechanisms
                                                             MECHANISM OF TYPE III
   antigenic targets                                         IMMUNE COMPLEX MEDIATED
Infection                                                    REACTION:
   infectious microorganim
                                                             (1) Immune complex form in the blood
   defense mechanisms                                             from circulating Ag and Ab and
   infection and injury
   clinical manifestations                                   (2) are deposited in certain target
   countermeasures
                                                                 tissues
Immune Deficiency
                                                             (3) The complexes activate
   clinical presentation                                         complement through C1 and
   primary deficiency                                            generate fragments that are
   secondary deficiency                                          chemotactic for neutrophils
   evaluation and care
   replacement therapy                                       (4) The neutrophils attached to the
                                                                 IgG and C3b in the immune
Stress Response                                                  complexes and
   general adaptation synd.
   neuroendocrine control                                    (5) release a variety of degradative
   role of immune system                                         enzymes that destroy the healthy
                                                                 tissues.
Aging
   in general, and its effect
   on specific endocrine
   organss, as an example

                                Hypersensitivity is an inappropriate immune response




                                                                          MECHANISM OF TYPE III
                                                                          IMMUNE COMPLEX MEDIATED
                                                                          REACTION:

                                                                          (1) Immune complex form in the
                                                                               blood from circulating Ag
                                                                               and Ab and

                                                                          (2) are deposited in certain
                                                                              target tissues

                                                                          (3) The complexes activate
                                                                              complement through C1 and
                                                                              generate fragments that are
                                                                              chemotactic for neutrophils

                                                                          (4) The neutrophils attached to
                                                                              the IgG and C3b in the
                                                                              immune complexes and

                                                                          (5) release a variety of
                                                                              degradative enzymes that
                                                                              destroy the healthy tissues.




                                       Page 10
            Hypersensitivities – Type IV
Hypersensitivities
   mechanisms
                                                             MECHANISM OF TYPE IV
   antigenic targets                                         CELL MEDIATED REACTION:
Infection
                                                             Antigens from target cells stimulate T-
   infectious microorganim
                                                             cells to differentiate into T cytotoxic
   defense mechanisms                                        cells (Tc) which have direct cytotoxic
   infection and injury                                      activity, and T helper cells (Th) which
   clinical manifestations                                   produce cytotoxins (mainly interferon
   countermeasures
                                                             gamma) that activate macrophages).
Immune Deficiency
                                                             The macrophages can attach to
   clinical presentation                                     targets and release enzymes and
   primary deficiency                                        reactive oxygen (O2) species that
   secondary deficiency                                      induce apoptosis of the target.
   evaluation and care
   replacement therapy
Stress Response
   general adaptation synd.
   neuroendocrine control
   role of immune system
Aging
   in general, and its effect
   on specific endocrine
   organss, as an example

                                Hypersensitivity is an inappropriate immune response




                                                                         MECHANISM OF TYPE IV
                                                                         CELL MEDIATED REACTION:

                                                                         Antigens from target cells
                                                                         stimulate T-cells to differentiate
                                                                         into T cytotoxic cells (Tc) which
                                                                         have direct cytotoxic activity,
                                                                         and T helper cells (Th) which
                                                                         produce cytotoxins (mainly
                                                                         interferon gamma) that activate
                                                                         macrophages).

                                                                         The macrophages can attach to
                                                                         targets and release enzymes
                                                                         and reactive oxygen (O2)
                                                                         species that induce apoptosis
                                                                         of the target.




                                       Page 11
                    Hypersensitivities – targets
     Hypersensitivities
          mechanisms
          antigenic targets
     Infection
          infectious microorganim
          defense mechanisms
          infection and injury
          clinical manifestations
          countermeasures
     Immune Deficiency
          clinical presentation
          primary deficiency
          secondary deficiency
          evaluation and care
          replacement therapy
     Stress Response
          general adaptation synd.
          neuroendocrine control         DEVELOPMENT OF ALLERGIC CONTACT DERMATITIS:
          role of immune system          Left: development of allergy to poison ivy. The primary contact with the Ag sensitizes
                                         (produce reactive T cells) the individual but does not produce a rash (dermatitis). The
     Aging                               secondary contact activates a Type IV cell-mediated reaction that causes dermatitis.
          in general, and its effect
          on specific endocrine          Right: contact dermatitis caused by a delayed hypersensitivity reaction leading to
          organss, as an example         vesicles scaling of the sites of contact.

                                               Hypersensitivity is an inappropriate immune response




                                catechol                      skin
                                molecules                   proteins




                    7 – 10 days                                        1 – 2 days


T cells    T memory cells                                         T memory cells many active cells


     no dermatitis                     cathecols combined                                   dermatitis
                                        with skin proteins

      PRIMARY                                                                   SECONDARY
      CONTACT                                                                    CONTACT
 DEVELOPMENT OF ALLERGIC CONTACT DERMATITIS:
 Left: development of allergy to poison ivy. The primary contact with the Ag sensitizes (produce reactive T
 cells) the individual but does not produce a rash (dermatitis). The secondary contact activates a Type IV cell-
 mediated reaction that causes dermatitis.

 Right: contact dermatitis caused by a delayed hypersensitivity reaction leading to vesicles scaling of the
 sites of contact.




                                                          Page 12
                        Hypersensitivities – targets
         Hypersensitivities
              mechanisms
              antigenic targets
         Infection
              infectious microorganim
              defense mechanisms
              infection and injury
              clinical manifestations
              countermeasures
         Immune Deficiency
              clinical presentation
              primary deficiency
              secondary deficiency
              evaluation and care
              replacement therapy             ABO BLOOD TYPES:
         Stress Response                      The relationship of antigens and antibodies associated with the ABO blood groups.
              general adaptation synd.        (A) The surface of RBC of individuals with blood group A have A antigen carbohydrate
              neuroendocrine control              and their blood have IgM antibodies against the B antigen.
              role of immune system           (B) The surface of RBC of individuals with blood group B have B antigen carbohydrate,
                                                  and their blood contain IgM antibodies against the A antigen.
         Aging                                (C) The surface of RBC of individuals with blood group AB have both A and B antigens,
              in general, and its effect          and their blood have antibodies to neither A nor B antigens.
              on specific endocrine           (D) The surface of RBC of individuals with blood group O have neither A nor B antigens,
              organss, as an example              and their blood contains antibodies to both A and B antigens.

                                                     Hypersensitivity is an inappropriate immune response




 BLOOD TYPE                       A                               B                          AB                                O
                              antigen A                       antigen B                antigen A and B                  neither antigen




 ERYTHROCYTES
     (RBC)




   ANTIBODIES




                               anti B                          Anti A                         neither                      anti A and B
                              antibody                        antibody                       antibody                       antibodies
ABO BLOOD TYPES:
The relationship of antigens and antibodies associated with the ABO blood groups.
(A) The surface of RBC of individuals with blood group A have A antigen carbohydrate and their blood have IgM antibodies against the B antigen.
(B) The surface of RBC of individuals with blood group B have B antigen carbohydrate, and their blood contain IgM antibodies against the A antigen.
(C) The surface of RBC of individuals with blood group AB have both A and B antigens, and their blood have antibodies to neither A nor B antigens.
(D) The surface of RBC of individuals with blood group O have neither A nor B antigens, and their blood contains antibodies to both A & B antigens.




                                                                Page 13
             Hypersensitivities – targets
Hypersensitivities
   mechanisms                   Chromosome 6: site of genes that encodes HLA antigens
   antigenic targets
Infection
   infectious microorganim
   defense mechanisms
   infection and injury
   clinical manifestations
   countermeasures
Immune Deficiency
   clinical presentation
   primary deficiency
   secondary deficiency
   evaluation and care
   replacement therapy
Stress Response
   general adaptation synd.
   neuroendocrine control
   role of immune system
                                HUMAN LEUKOCYTES ANTIGENS (HLA):
Aging                           The major histocompatibility complex (MHC) is located in
   in general, and its effect
   on specific endocrine        chromosome 6 and contains genes that code for class I antigens
   organss, as an example       and class III proteins (e.g. complement proteins and cytokines).
                                     Hypersensitivity is an inappropriate immune response




                                        Infection
Hypersensitivities
   mechanisms                      INFECTION:
   antigenic targets
Infection                          Bacteria injure cells by producing exotoxins (enzymes that
   infectious microorganim         damage host plasma membranes or inactivate enzymes
   defense mechanisms              critical to protein synthesis), and endotoxins (activate the
   infection and injury
   clinical manifestations         inflammatory response and produce fever). In septicemia,
   countermeasures                 endotoxins release vasoactive enzymes that increase
Immune Deficiency                  blood vessel permeability, hypotension, and septic shock.
   clinical presentation
   primary deficiency              Viruses may low protein synthesis, disrupt lysosomal
   secondary deficiency            membranes, form inclusion bodies where synthesis of
   evaluation and care
   replacement therapy             viral nucleic acid occurs, fuse with cells to produce giant
Stress Response                    cells, alter antigenic properties of the host cell, and
   general adaptation synd.        transform host cells into cancerous cells.
   neuroendocrine control
   role of immune system
                                   Fungi cause mycosis that occurs as yeasts (spheres) or
Aging                              molds (filaments or hypheae). They release toxins and
   in general, and its effect      enzymes that are damaging to tissue.
   on specific endocrine
   organss, as an example

                                   Most infections might be bacterial, viral or fungal in origin




                                            Page 14
                    Infection - microorganisms
    Hypersensitivities
          mechanisms                       CLASSES OF HUMAN INFECTIOUS MICRO-ORGANISMS
          antigenic targets
                                         Class             Size               e.g. disease
    Infection
          infectious microorganim        Viruses           20-30 nm           Measels, Heparitis B, Pneumonitis
          defense mechanisms
          infection and injury
          clinical manifestations
                                         Bacteria          0.8-15 m           Sthaphyloccocal wound infection, Cholera,
          countermeasures
                                                                              Streptoccocal pneumonia
    Immune Deficiency
          clinical presentation          Chlamidia         20-1000 nm         Trachoma
          primary deficiency             Ricketsiae        300-1200 nm        Rocky Mountain spotted fever
          secondary deficiency           Mycoplasma        125-350 nm         Mycoplasma pneumonia
          evaluation and care            Mycobacterium     1-10 m             Tuberculosis
          replacement therapy            Fungi             2-200 m            Tinea pedis (athlet’s foot)
                                                                              Thrush (candida)
    Stress Response                                                           Histoplasmosis
          general adaptation synd.
          neuroendocrine control         Protozoa          1-360 m            Giardasis
          role of immune system                                               Malaria
    Aging
          in general, and its effect     Helminths         3 mm – 10 m        Trichinosis
          on specific endocrine                                               Filariasis
          organss, as an example

                                           Most infections might be bacterial, viral or fungal in origin




              CLASSES OF HUMAN INFECTIOUS MICRO-ORGANISMS
Class                             Size                          e.g. disease

Viruses                           20-30 nm                      Measels, Heparitis B, Pneumonitis



Bacteria                          0.8-15 m                      Sthaphyloccocal wound infection, Cholera,
                                                                Streptoccocal pneumonia


Chlamidia                         20-1000 nm                    Trachoma
Ricketsiae                        300-1200 nm                   Rocky Mountain spotted fever
Mycoplasma                        125-350 nm                    Mycoplasma pneumonia
Mycobacterium                     1-10 m                        Tuberculosis
Fungi                             2-200 m                       Tinea pedis (athlet’s foot)
                                                                Thrush (candida)
                                                                Histoplasmosis


Protozoa                          1-360 m                       Giardasis
                                                                Malaria


Helminths                         3 mm – 10 m                   Trichinosis
                                                                Filariasis




                                                         Page 15
                                Infection - defense
    Hypersensitivities               PATHOGENS THAT DIRECTLY CAUSE TISSUE DAMAGE
       mechanisms
       antigenic targets            Infectious agent                       Disease
    Infection                       Produce exotoxins
       infectious microorganim                Streptococcus pyrogenes      Tonsilitis, Scarlet fever
       defense mechanisms                       Staphylococcus aureus      Boils, toxic shock syndrome, food poisoning
       infection and injury                  Corynbacterium diphteriae     Diphteria
       clinical manifestations                        Clostridium tetani   Tetanus
       countermeasures                                   Vibrio cholera    Cholera

    Immune Deficiency               Produce endotoxins
                                                      Escherichia coli     Gram-negative sepsis
       clinical presentation                     Haemophilus influenza     Meningitis, pneumonia
       primary deficiency                            Salmonella typhi      Typhoid
       secondary deficiency                                   Shigella     Bacillary dysentery
       evaluation and care                     Pseudomona aeruginosa       Wound infection
       replacement therapy                             Yersinia pestis     Plague
    Stress Response                 Cause direct damage by invasion
       general adaptation synd.                                  Variola   Smallpox
       neuroendocrine control                           Varicella zoster   Chicken pox, shingles
       role of immune system                           Hepatitis B virus   Hepatitis
                                                               Polyvirus   Poliomyelitis
    Aging                                                 Measles virus    Measles, subacute sclerosing panencephalitis
       in general, and its effect                        Influenza virus   Influenza
       on specific endocrine                       Herpes simplex virus    Cold sores
       organss, as an example

                                     Most infections might be bacterial, viral or fungal in origin




            PATHOGENS THAT DIRECTLY CAUSE TISSUE DAMAGE

Infectious agent                                   Disease

Produce exotoxins
            Streptococcus pyrogenes                Tonsilitis, Scarlet fever
              Staphylococcus aureus                Boils, toxic shock syndrome, food poisoning
           Corynbacterium diphteriae               Diphteria
                    Clostridium tetani             Tetanus
                       Vibrio cholera              Cholera
Produce endotoxins
                        Escherichia coli           Gram-negative sepsis
                   Haemophilus influenza           Meningitis, pneumonia
                       Salmonella typhi            Typhoid
                                Shigella           Bacillary dysentery
                 Pseudomona aeruginosa             Wound infection
                         Yersinia pestis           Plague
Cause direct damage by invasion
                               Variola             Smallpox
                      Varicella zoster             Chicken pox, shingles
                     Hepatitis B virus             Hepatitis
                             Polyvirus             Poliomyelitis
                        Measles virus              Measles, subacute sclerosing panencephalitis
                       Influenza virus             Influenza
                Herpes simplex virus               Cold sores




                                                  Page 16
                                   Infection - injury
   Hypersensitivities
      mechanisms                     PATHOGENS THAT INDIRECTLY CAUSE TISSUE DAMAGE
      antigenic targets
   Infection                        Infectious agent                                     Disease
      infectious microorganim       Produce immune complex
      defense mechanisms                                             Hepatitis B virus   Kidney disease
      infection and injury                                                     Malaria   Vascular deposits
      clinical manifestations                                           S. Pyogenes      Glomerulonephritis
      countermeasures
                                                                 Treponema pallidum      Kidney damage in 2ndary syphilis
   Immune Deficiency                                             Most acute infections   Transient renal deposits

      clinical presentation
      primary deficiency            Produce autoantibodies
      secondary deficiency                                              s. Pyogenes      Rheumatic fever
      evaluation and care                                     Mycoplasma pneumonia       Hemolytic anemia
      replacement therapy
   Stress Response                  Cause cell – mediated immunity
                                                          Mycobacterium tuberculosis     Tuberculosis
      general adaptation synd.                                Mycobacterium leprae       Tuberculoid leprosy
      neuroendocrine control                       Lymphocytic choriomeningitis virus    Aseptic meningitis
      role of immune system                                      Borrelia burgdorferi    Lyme arthritis
   Aging                                                       Schistosoma mansori       Schistosomiasis
                                                                Herpes simplex virus     Herpes stromal keratitis
      in general, and its effect
      on specific endocrine
      organss, as an example

                                     Most infections might be bacterial, viral or fungal in origin




        PATHOGENS THAT INDIRECTLY CAUSE TISSUE DAMAGE

Infectious agent                                                         Disease


Produce immune complex
                                          Hepatitis B virus              Kidney disease
                                                    Malaria              Vascular deposits
                                             S. Pyogenes                 Glomerulonephritis
                                      Treponema pallidum                 Kidney damage in secondary syphilis
                                      Most acute infections              Transient renal deposits


Produce autoantibodies
                                            S. Pyogenes Rheumatic fever
                                   Mycoplasma pneumonia Hemolytic anemia


Cause cell – mediated immunity
                        Mycobacterium tuberculosis                       Tuberculosis
                            Mycobacterium leprae                         Tuberculoid leprosy
                 Lymphocytic choriomeningitis virus                      Aseptic meningitis
                               Borrelia burgdorferi                      Lyme arthritis
                             Schistosoma mansori                         Schistosomiasis
                              Herpes simplex virus                       Herpes stromal keratitis




                                                  Page 17
                 Infection - countermeasures
                                        EXAMPLES OF MECHANISMS USED BY PATHOGENS TO
     Hypersensitivities                           RESIST THE IMMUNE SYSTEM
        mechanisms
        antigenic targets
                                     Mechanism                     Effect on immunity                   Example
     Infection
        infectious microorganim      Destroys or blocks
        defense mechanisms                          Make toxins    Kills phagocyte, block chemotaxis    Staphylococcus,
        infection and injury                                       Blocks phagocytosis                  Streptococcus
        clinical manifestations               Make anti-oxidant    Blocks kill by O2-radicals           Mycobacterium sp.,
        countermeasures               Make proteases digest IgA                                         Salmonella thypi
                                       Make “Fc-R” like surface    Promotes bacterial attachment        Neisseria gonorrohea,
     Immune Deficiency                   molecules that bind Ab    Blocks complement activation &       Haemophilus influenza
                                                                   Ab functioning as opsonins           Streptococcus
        clinical presentation                                                                           pneumoniae
        primary deficiency
        secondary deficiency
        evaluation and care          Mimics self-antigens
        replacement therapy           Make surface Ag as self-Ag   Pathogen resembles own tissue        Group A sterptococcus
                                                                   Forms Ab against self-Ag leading     (M prot), Mycoplasma
     Stress Response                                               to hypersensitivity disease          pneumoniae (red cell
        general adaptation synd.                                                                        Ag)
        neuroendocrine control
        role of immune system
                                     Change antigenic profile
     Aging                               Undergo Ag mutation or    Immune response delayed              Influenza, HIV, some
        in general, and its effect    activate genes that change   because of failure to recognize      parasites
        on specific endocrine                  surface molecules   new antigen
        organss, as an example

                                       Most infections might be bacterial, viral or fungal in origin




       EXAMPLES OF MECHANISMS USED BY PATHOGENS TO
                 RESIST THE IMMUNE SYSTEM

Mechanism                             Effect on immunity                                             Example

Destroys or blocks
                 Make toxins Kills phagocyte, block chemotaxis                                       Staphylococcus,
                              Blocks phagocytosis                                                    Streptococcus
            Make anti-oxidant Blocks kill by O2-radicals                                             Mycobacterium sp.,
   Make proteases digest IgA                                                                         Salmonella thypi
     Make “Fc-R” like surface Promotes bacterial attachment                                          Neisseria gonorrohea,
       molecules that bind Ab Blocks complement activation & Ab                                      Haemophilus influenza
                              functioning as opsonins                                                Streptococcus
                                                                                                     pneumoniae

Mimics self-antigens
   Make surface Ag as self-Ag Pathogen resembles own tissue                                          Group A sterptococcus
                              Forms Ab against self-Ag leading to                                    (M prot), Mycoplasma
                              hypersensitivity disease                                               pneumoniae (red cell Ag)


Change antigenic profile
      Undergo Ag mutation or Immune response delayed because                                         Influenza, HIV, some
   activate genes that change of failure to recognize new antigen                                    parasites
            surface molecules




                                                     Page 18
                        Immune deficiencies
                                DEFICIENCIES IN IMMUNITY:
Hypersensitivities
   mechanisms                   Failure of mechanisms of self-defense. It can be congenital
   antigenic targets            (primary, fail lymphocyte development) or acquired (secon-
Infection                       dary to disease or other physiological failure). Its hallmark is
   infectious microorganim      propensity to unusual or recurrent severe infections.
   defense mechanisms
   infection and injury
   clinical manifestations      Most defects of cell-mediated responses are fungal / viral,
   countermeasures
                                while humoral / complement defects elicit bacterial infection.
Immune Deficiency               Severe Combined Immunodeficiency (SCID) is a total lack of
   clinical presentation        T-cell function & severe (partial/ total) lack of B-cell function.
   primary deficiency
   secondary deficiency
   evaluation and care          Congenital thymic aplasia or hypoplasia is characterized by
   replacement therapy          complete or partial lack of T-cell immunity, and parathyroid
Stress Response                 (hypocalcemia) and cardiac anomalies.
   general adaptation synd.
   neuroendocrine control       Defects in B-cell function span from lack of B-cell matura-
   role of immune system
                                tion to selective immunoglobulin deficiency (e.g. IgA).
Aging
   in general, and its effect
   on specific endocrine        AIDS is an acquired dysfunction caused by a retrovirus that
   organss, as an example       infects and destroy CD4 lymphocytes (Th cells).
                                Immune deficiency is a failure of mechanisms of self-defense.




                        Immune deficiencies
                                     EXAMPLES OF PRIMARY DEFICIENCIES IN IMMUNITY
Hypersensitivities
   mechanisms                   Classification                 Deficiency                      Outcome
   antigenic targets
                                B-lymphocyte deficiency
Infection                                 In bone marrow       No B-cells, no Ab made          Recurrent bacterial infection
   infectious microorganim                 In class switch     Limited or no IgA only          Mild GI, respiratory infection
   defense mechanisms
   infection and injury
                                T-lymphocyte deficiency
   clinical manifestations
                                                In thymus      No T-cells                      Recurrent viral/fungi infect.
   countermeasures
                                          To a specific Ag     No T-cell response to           Recurrent and disseminated
Immune Deficiency                                              Candida                         infection with Candida

   clinical presentation
   primary deficiency           Combined deficiency
   secondary deficiency                    In B and T cells    No cell / humoral immunity      Various recurrent infections
   evaluation and care             Interaction of B,T, APC     No class I or II MHC            Various recurrent infections
   replacement therapy                              Others     Cytoskeletal, defect, low IgM   Various recurrent infections

Stress Response
                                Complement deficiency
   general adaptation synd.                          C3        Little or no C3 produced        Recurrent bacterial infection
   neuroendocrine control                            C6        Little or no C6 produced        Recurrent disseminated
   role of immune system                                                                       infection with Nisseria
Aging                           Phagocyte deficiency
   in general, and its effect                 Neutrophils      Lack of neutrophils             Recurrent bacterial infection
   on specific endocrine                   Bacterial killing   Lack of O2 radicals             Recurrent bacterial infection
   organss, as an example                                      produced                        sensitive to O2 radicals

                                Immune deficiency is a failure of mechanisms of self-defense.




                                                Page 19
             EXAMPLES OF PRIMARY DEFICIENCIES IN IMMUNITY

Classification                           Deficiency                               Outcome
B-lymphocyte deficiency
                In bone marrow No B-cells, no Ab made                             Recurrent bacterial infection
                 In class switch Limited or no IgA only                           Mild GI, respiratory infection

T-lymphocyte deficiency
                       In thymus No T-cells                                       Recurrent viral/fungi infect.
                 To a specific Ag No T-cell response to Candida                   Recurrent and disseminated
                                                                                  infection with Candida

Combined deficiency
                 In B and T cells No cell / humoral immunity                      Various recurrent infections
         Interaction of B,T, APC No class I or II MHC                             Various recurrent infections
                          Others Cytoskeletal, defect, low IgM                    Various recurrent infections

Complement deficiency
                                     C3 Little or no C3 produced                  Recurrent bacterial infection
                                     C6 Little or no C6 produced                  Recurrent disseminated infection
                                                                                  with Nisseria
Phagocyte deficiency
                       Neutrophils Lack of neutrophils                            Recurrent bacterial infection
                    Bacterial killing Lack of O2 radicals produced                Recurrent bacterial infection
                                                                                  sensitive to O2 radicals




                                      Stress - general
     Hypersensitivities
        mechanisms
        antigenic targets
     Infection
        infectious microorganim
        defense mechanisms
        infection and injury
        clinical manifestations
        countermeasures
     Immune Deficiency
        clinical presentation
        primary deficiency
        secondary deficiency
        evaluation and care
        replacement therapy
     Stress Response
        general adaptation synd.
        neuroendocrine control
        role of immune system
     Aging
        in general, and its effect
        on specific endocrine
        organss, as an example           The alarm reaction includes increased Cortisol, Epi and Nepi secretion.
                                          The stress axis is the main inhibitor of the immune system.




                                                     Page 20
                                            Adrenal gland



                                         Nerve
                                         signal                                      Kidney

                                  ACTH
                                                         medulla

                        cortex

                                    Glucocorticoids
                                                                      Adrenaline
                                       (cortisol)
                                                                     (epinephrine)


                                                                          Increased HR,
THE STRESS                               Liver releases                   breathing rate,
                                            glucose                      and blood sugar
 RESPONSE




                                 Stress - general
 Hypersensitivities
    mechanisms
    antigenic targets
 Infection
    infectious microorganim
    defense mechanisms
    infection and injury
    clinical manifestations
    countermeasures
 Immune Deficiency
    clinical presentation
    primary deficiency
    secondary deficiency
    evaluation and care
    replacement therapy
 Stress Response
    general adaptation synd.
    neuroendocrine control
    role of immune system
 Aging
    in general, and its effect
    on specific endocrine                            The stress response
    organss, as an example

                                  The stress axis is the main inhibitor of the immune system.




                                           Page 21
                                                    stressor




                                                      CRH


                           sympathetic nervous                 posterior pituitary     anterior pituitary
                                 system




                                                                                        cortisol




Vasoconstriction
Vascular growth factor
Angiogenic factors

                                                                                    Anti-           Immuno-
  THE STRESS                                                                          or
                                                                                     Pro-
                                                                                                   supression
                                                                                                       or
   RESPONSE                                      Increased blood
                                                                                 Inflamma-         Enhanced
                                                                                     tory           humoral
                                                     glucose                                        immunity




                                      Stress - general
      Hypersensitivities
         mechanisms
         antigenic targets
      Infection
         infectious microorganim
         defense mechanisms
         infection and injury
         clinical manifestations
         countermeasures
      Immune Deficiency
         clinical presentation
         primary deficiency
         secondary deficiency
         evaluation and care
         replacement therapy
      Stress Response
         general adaptation synd.      CRH – Mast cells – Histamine axis on Th1 / Th2 balance, and
         neuroendocrine control        cellular / humoral immunity:
         role of immune system         Humoral immunity protects against multicellular parasites,
      Aging                            extracellular bacteria, some viruses, soluble toxins, and
         in general, and its effect    allergenes. Cell immunity protects against intracellular bac-
         on specific endocrine
         organss, as an example
                                       teria, fungi, protozoa and several viruses.

                                        The stress axis is the main inhibitor of the immune system.




                                                 Page 22
                                       post ganglionic nerve terminals
  STRESSORS                                                                                       STRESSORS

                                                                          Cortisol
                                        CRH      NE            NE       Epinephrine

                                                                                                   blood
blood    Cortisol                          MAST CELL                             MONOCYTE          vessel
vessel Epinephrine
                                                  histamine




                                  histamine                    Th1                    Th1



                                                  IL-12                                           IL-10
                                                            cytokines               cytokines



                          Increased acute
                                                       Decreased cellular               Increased humoral
                            inflammation
                                                            immunity                   Immunity (Th2 shift)
                          allergic reaction
                                                        allergic reaction              B lymphocytes (Ab)
                                                      TC, NK, macrophage              eosinophils, mast cells
CRH – Mast cells – Histamine axis on Th1 / Th2 balance, &cellular / humoral immunity:
Humoral immunity protects against multicellular parasites, extracellular bacteria, some viruses, soluble toxins, and
allergenes. Cell immunity protects against intracellular bacteria, fungi, protozoa and several viruses.




                         Stress - neuroendocrine
      Hypersensitivities
          mechanisms                                             stress and / or
          antigenic targets                                    circadian rhythms
      Infection
          infectious microorganim
          defense mechanisms
          infection and injury
          clinical manifestations
          countermeasures
                                                                 Nervous system
      Immune Deficiency
          clinical presentation
          primary deficiency
          secondary deficiency
          evaluation and care
          replacement therapy
      Stress Response
          general adaptation synd.            Endocrine system                        Immune system
          neuroendocrine control
          role of immune system
      Aging
          in general, and its effect
          on specific endocrine
          organss, as an example

                                           The stress axis is the main inhibitor of the immune system.




                                                      Page 23
                         Stress - neuroendocrine
      Hypersensitivities
          mechanisms
          antigenic targets
      Infection
          infectious microorganim
          defense mechanisms
          infection and injury
          clinical manifestations
          countermeasures
      Immune Deficiency
          clinical presentation
          primary deficiency
          secondary deficiency
          evaluation and care
          replacement therapy
                                        Health outcome determinants in stressful life situations is moderated
                                        by numerous factors. Whether a life – challanged individual
      Stress Response                   experiences distress or illness depends on the subject’s appraisal of
          general adaptation synd.      the event and the coping strategies used during the stressful period.
          neuroendocrine control        Models (A) and (B) reflect possible outcomes in stressed healthy and
          role of immune system
                                        symptomatic individuals. Model (C) illustrates the dynamic clinical
      Aging                             setting in which the diagnosis of a serious illness and subsequent
          in general, and its effect    medical interventions may be perceived as stressful challenges & have
          on specific endocrine         potential detrimental influences on physical outcome.
          organss, as an example

                                            The stress axis is the main inhibitor of the immune system.




  POTENTIAL EFFECTS IN HEALTHY INDIVIDUALS


                       stressful life event


                                                                             POTENTIAL EFFECTS
                                         Ef opi




                                                                        DURING MEDICAL INTERVENTIONS
                                           fe ng
                                            c
                                             ct
                                               iv
                                                 e




                                                                        (--)          symptoms               (+)
      Significant stress                Transient response
           response                    Return to steady state
       Distress / illness
                                                                                      diagnosis          If perceived
  POTENTIAL EFFECTS IN SYMPTOMATICAL INDIVIDUALS                                                           as stress

                         stressful life event
                                                                                      treatment
                                        Ef o p i
                                          fe ng
                                           c
                                            ct
                                               iv
                                                 e




    Exacerbation of illness            Little of no effect on symptoms
Health outcome determinants in stressful life situations is moderated by numerous factors. Whether a life – challanged
individual experiences distress or illness depends on the subject’s appraisal of the event and the coping strategies used
during the stressful period. Models (A) and (B) reflect possible outcomes in stressed healthy and symptomatic
individuals. Model (C) illustrates the dynamic clinical setting in which the diagnosis of a serious illness and subsequent
medical interventions may be perceived as stressful challenges & have potential detrimental influences on physical
outcome.




                                                     Page 24
                                Aging in general
Hypersensitivities
   mechanisms
   antigenic targets
                                          Although it is doubtful that a single theory
Infection
                                          would explain all the mechanisms of aging,
   infectious microorganim                three of them have retained their appeal:
   defense mechanisms
   infection and injury
   clinical manifestations                Cellular changes produced by genetic and
   countermeasures
                                          environmental lifestyle factors
Immune Deficiency
   clinical presentation                  Changes in cellular regulatory, or control
   primary deficiency
   secondary deficiency                   mechanisms, especially in cells of the neuro-
   evaluation and care
   replacement therapy                    endocrine, immune, and central nervous
Stress Response                           system
   general adaptation synd.
   neuroendocrine control                 Degenerative extracellular and vascular
   role of immune system
Aging
                                          alterations
   in general, and its effect
   on specific endocrine
   organs, as an example                 Three non-exclusive theories of aging supported by
                                                           experimental data




                                Aging in general
Hypersensitivities
   mechanisms
                                  1.-     Cellular changes produced by genetic and
   antigenic targets
                                          environmental lifestyle factors
Infection
   infectious microorganim       Cells are damaged during replication from the inside (e.g.
   defense mechanisms
   infection and injury          DNA, proteins) or from the outside (e.g. ionizing radiation).
   clinical manifestations       Cells might also be programmed to age and thus have a
   countermeasures
                                 finite life span in which to replicate. For example, it has
Immune Deficiency                been suggested that an intrinsic genomic program
   clinical presentation         progressively slows or shut down physiological events (e.g.
   primary deficiency            mitosis).
   secondary deficiency
   evaluation and care
   replacement therapy           Experiments do not support that aging is the result of
Stress Response                  somatic mutations.
   general adaptation synd.
   neuroendocrine control        Accumulation of altered proteins in aging may result from
   role of immune system
                                 an increased production or a decreased ability of aged cells
Aging                            to degrade their cellular proteins, or both.
   in general, and its effect
   on specific endocrine
   organss, as an example                Three non-exclusive theories of aging supported by
                                                           experimental data




                                          Page 25
                                Aging in general
Hypersensitivities
   mechanisms                       2.-    Changes in cellular regulatory, or control
   antigenic targets
                                           mechanisms, especially in cells of neuro-
Infection                                  endocrine, immune, & central nervous system
   infectious microorganim
   defense mechanisms            A genetic program for aging is encoded in the brain and is
   infection and injury          controlled and relayed to peripheral tissues through hormonal and
   clinical manifestations
   countermeasures               neuronal agents.
Immune Deficiency
                                 Possible neuro-endocrine mechanisms include:
   clinical presentation
   primary deficiency
                                 (1) increase hormonal degradation; (2) decreased rate of hormonal
   secondary deficiency          synthesis/secretion; and (3) decreased target-organ sensitivity
   evaluation and care           related to number of cellular receptors for hormonal ligands,
   replacement therapy
                                 ligand receptor binding, or ligand internalization.
Stress Response
   general adaptation synd.
   neuroendocrine control
                                 Immune mechanisms have been suggested since:
   role of immune system          (1) immune function declines with age; (2) this decline is related
Aging                            to some diseases (e.g. cancer); and (3) number of auto-antibodies
   in general, and its effect    increase with age.
   on specific endocrine
   organss, as an example                 Three non-exclusive theories of aging supported by
                                                            experimental data




                                Aging in general
Hypersensitivities
   mechanisms                       3.-    Degenerative extracellular and vascular
   antigenic targets                       alterations
Infection                         Extracellular factors affecting aging include binding of
   infectious microorganim        collagen; increase in free radicals’ effect on cells; structural
   defense mechanisms             alterations of fascia, tendons, ligaments, bones and joints; and
   infection and injury           peripheral vascular disease, particularly arteriosclerosis.
   clinical manifestations
   countermeasures
Immune Deficiency                 Increased cross-linking in ECF matrix leads to less elastin and
                                  soluble collagen, decreased cell permeability, dehydration, skin
   clinical presentation
   primary deficiency             wrinkling, and skeletal muscle alterations (loss of contractility).
   secondary deficiency
   evaluation and care
   replacement therapy            Free radicals from O2 resulting from oxidative cell metabolism
                                  damage tissue during aging. These include superoxide radical,
Stress Response
   general adaptation synd.
                                  hydroxyl radical and hydrogen peroxide.
   neuroendocrine control
   role of immune system          Vascular deposition of lipids, Ca and plasma proteins due to
Aging                             alterations in ECF matrix affects vessel integrity, basal memb.
   in general, and its effect     thickening and smooth muscle alterations (e.g.arteriosclerosis).
   on specific endocrine
   organss, as an example                 Three non-exclusive theories of aging supported by
                                                            experimental data




                                            Page 26
                Aging and endocrinology
                                 AGING, ITS EFFECTS ON SPECIFIC ENDOCRINE ORGANS:
Hypersensitivities
   mechanisms
   antigenic targets             Age-related endocrine changes include alterations in
                                 secretion, circulating levels, metabolism, and biologic activity
Infection
                                 of hormones. There is also a loss of circadian (a 24-hour
   infectious microorganim
   defense mechanisms            period) control of hormone secretion. Although most glands
   infection and injury          decrease their levels of secretion, normal aging usually does
   clinical manifestations
   countermeasures               not lead to a deficiency state.
Immune Deficiency
   clinical presentation
   primary deficiency
                                 The general changes in the endocrine glands that occur with
   secondary deficiency          older age include:
   evaluation and care
   replacement therapy
                                 a) atrophy and weight loss with vascular changes,
Stress Response
   general adaptation synd.
   neuroendocrine control
                                 b) decreased secretion and clearance of hormones, and
   role of immune system
Aging                            c) variable changes in receptor binding and intracellular
   in general, and its effect       responses.
   on specific endocrine
   organss, as an example         Atrophy, hormone hyposecretion, and binding alterations are
                                                        linked to aging




                Aging and endocrinology
                                  AGING, ITS EFFECTS ON SPECIFIC ENDOCRINE ORGANS:
Hypersensitivities
   mechanisms                   For example, while adrenal cortex decreases its secretion of cortisol, negative
   antigenic targets            feedback mechanisms maintain normal plasma levels. As thyroid function ebb
Infection                       there is a decrease in T3-T4 which lead to a decrease in the metabolic rate and
                                an unawareness of temperature (e.g. cold intolerance and hot days will not be
   infectious microorganim
   defense mechanisms           noticed, thereby increasing the risk of heat stroke). A decrease in the
   infection and injury         secretion of GH causes a decrease in muscle mass and an increase in the
   clinical manifestations      storage of fat. Blood and tissue concentrations of many other hormones
   countermeasures              remain unchanged (e.g. TSH, thyroid hormones, ADH, PTH, prolactin, and
Immune Deficiency               glucocorticoids).
   clinical presentation
   primary deficiency
                                Despite unchanging hormone levels, some endocrine tissues become less
   secondary deficiency         responsive to stimulation. For example, there is less GH (growth hormone)
   evaluation and care          and insulin secreted after a carbohydrate-rich meal or during a glucose
   replacement therapy          tolerance test.
Stress Response
   general adaptation synd.     Peripheral tissues become less responsive to hormones, particularly gluco-
   neuroendocrine control       corticoids and ADH. The failure to produce enough cortisol can affect meta-
   role of immune system        bolism and the stress response. In addition, a decline in cortisol production
Aging                           will also reduce the anti-inflammatory and immunosuppressive qualities that
                                they give. This means that the elderly are more prone to pain and infections.
   in general, and its effect
   on specific endocrine
   organss, as an example         Atrophy, hormone hyposecretion, and binding alterations are
                                                        linked to aging




                                              Page 27
                       Your third Case Study
Hypersensitivities              SUMMARY:
   mechanisms                   You are presented with a 4-week-old Arab filly for depression,
   antigenic targets            coughing and nasal discharge. The foal was born with no
Infection                       apparent problems. Immunoglobulin levels were checked and
   infectious microorganim      were normal. However, the foal has been unhealthy and seems
   defense mechanisms           to be repeatedly sick with skin and respiratory infection. On
   infection and injury
   clinical manifestations      examination, the foal has a temperature of 38.8°C (102°F)
   countermeasures              (elevated), and a respiratory rate of 48 beats per min (elevated).
Immune Deficiency               On auscultation the foal has both crackles and wheezes
   clinical presentation        (abnormal lung sounds). The capillary refill time (CRT) is
   primary deficiency           prolonged, and the mucous membranes are darker pink than
   secondary deficiency         normal. The foal also has some abrasions and cellulitis in
   evaluation and care
   replacement therapy          those areas of the skin.
Stress Response
   general adaptation synd.
   neuroendocrine control       TENTATIVE DIAGNOSIS:
   role of immune system        LAB TESTS:
Aging                           FINAL DIAGNOSIS:
   in general, and its effect   TREATMENT:
   on specific endocrine
   organss, as an example              A 4-week-old Arab filly with depression, coughing, and
                                                          nasal discharge.




                       Your third Case Study
Hypersensitivities              DEFICIENCIES IN IMMUNITY:
   mechanisms
   antigenic targets            Failure of mechanisms of self-defense. It can be congenital (primary,
Infection                       fail lymphocyte development) or acquired (secon-dary to disease or
                                other physiological failure). Its hallmark is propensity to unusual or
   infectious microorganim
   defense mechanisms           recurrent severe infections.
   infection and injury
   clinical manifestations      Most defects of cell-mediated responses are fungal / viral, while
   countermeasures              humoral / complement defects elicit bacterial infection. Severe
Immune Deficiency               Combined Immunodeficiency (SCID) is a total lack of T-cell function &
                                severe (partial/ total) lack of B-cell function.
   clinical presentation
   primary deficiency
   secondary deficiency         Congenital thymic aplasia or hypoplasia is characterized by complete
   evaluation and care          or partial lack of T-cell immunity, and parathyroid (hypocalcemia) and
   replacement therapy          cardiac anomalies.
Stress Response
                                Defects in B-cell function span from lack of B-cell matura-tion to
   general adaptation synd.
   neuroendocrine control       selective immunoglobulin deficiency (e.g. IgA).
   role of immune system
Aging                           AIDS is an acquired dysfunction caused by a retrovirus that infects
                                and destroy CD4 lymphocytes (Th cells).
   in general, and its effect
   on specific endocrine
   organss, as an example              A 4-week-old Arab filly with depression, coughing, and
                                                          nasal discharge.




                                             Page 28

				
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