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					Microbiology
   Chapter 16
Immune Dysfunction
     Part I
Overview of Immune
    Dysfunction
Immune Dysfunctional Responses
   Immunopathology
       Disease states associated with underactivity or
        overactivity of the immune response
   Four common diseases
       Allergies and hypersensitivity
            An exaggerated misdirected expression of immune
             responses to an allergen (antigen)
       Autoimmunity
            Abnormal responses to “self”
       Immunodeficiency
            Deficiency or loss of immunity
       Cancer
            Both a cause and effect of immune dysfunction
     Under reaction                                           Over reaction
    Loss of Immunity            Antigen                      Hypersensitivities



                                                         B              Type I       Allergies &
                                                                                     Anaphylaxis
                                                                                   Involves IgE and
                                          Tc                                          Mast cells

      Cancer
Lack of surveillance
    by T cells




                                               Type IV




                                                             Type III
                                                                                    Blood Type
                                                                                 Incompatibilities
                                                                                  Involves IgG and
                                                                                    Complement
   Immunodeficiency             TC cell mediated
 Involves dysfunction to          First exposure
Either T or B cells or both   involves activation of
  Agammaglobulinemia             cytotoxic T cells.
   DiGeorge syndrome            Second exposure              Immune Complex
           SCID                results in cell killing   Involves large amounts of
           AIDS                    by TC. Also,          IgG, IgM, or IgA deposited
                                   important in           on basement membranes.
                                  graft rejection        Initiates immune response
                                                          resulting in tissue damage
                    Hypersensitivity States
                    Systems and Mechanisms
      Type                                                   Examples
                           Involved
        I           IgE mediated; involves mast      Anaphylaxis, allergies such
                    cells, basophils, and allergic   as hay fever, asthma
   Immediate
                    mediators
 hypersensitivity
                    IgG, IgM antibodies act upon     Blood group incompatibility;
       II           cells with complement and        myasthenia gravis
Antibody Mediated   cause cell lysis; includes
                    some autoimmune diseases
                    Antibody-mediated                Systemic lupus; rheumatoid
                    inflammation; circulating IgG    arthritis, serum sickness;
       III          complexes deposited in           rheumatic fever
Immune Complex      basement membranes of
                    target organs; includes some
                    autoimmune diseases
                    Delayed hypersensitivity and     Infection reaction; contact
       IV           cytotoxic reactions in tissues   dermatitis; graft rejection;
 T cell mediated                                     some type of autoimmunity
   Part II
Type I Reactions
Type I Allergic Reactions
   Two Levels of severity

       Atopy
            Any chronic local allergy such as hay fever or asthma


       Anaphylaxis
            A systemic often explosive reaction that involves
             airway obstruction and circulatory collapse
Who Has Allergies
 Generalized familial predisposition to
  allergies; not to a specific allergy
 Allergic responses are affected by age,
  infection, and geographic area
 Atopic allergies may be lifelong or may be
  “outgrown”
 Atopic allergies may also develop later in
  life in response to moving or lifestyle
  changes
Characteristics of Allergens
 Allergens are immunogenic
 Classified according to their portal of entry
       Ingestant
            Milk, peanuts, shellfish, soybeans, wheat, food
             additives, drugs such as penicllin
       Injectants
            Venom from bees or wasps, vaccines, serum from
             donor, drugs, hormones
       Contactants
            Cosmetics, detergents, rubber, solvents, dyes
Mechanism of Action of Type I
   Sensitizing dose
       Allergen penetrates portal of entry
       Lymphatics carry allergen to lymph nodes
       B cell activation forming plasma cell
            Class switching leads to IgE production
            Fc region of IgE high affinity for mast cells and basophils
   Provocative dose (Secondary Exposure)
       Allergen binds to IgE bound to mast cells and basophils
       Degranulation of mast cells and basophils
            Releases mediators with physiological effects, such as
             vasodilatation and bronchoconstriction
       Symptoms are rash, itching, redness, increased musous
        discharge, pain, swelling, and difficulty breathing
   Sensitization/IgE Production                                        Secondary Exposure
                 Allergen particles enter
                           Mucous membrane                         Allergen is encountered again


                      Lymphatic vessel
                                                                                      Allergen
                            Carries to
                                                                                      Attaches to
B cell                                                                                IgE causing
                  Lymph Node                                                          degranulation
                  T – B conjugate
                  Activates B cell


                              Proliferates
                                  Into                                              Systemic
                                                                                    distribution
                           Plasma Cell                                              of mediators in
                                                                                    bloodstream
                                                       Granules with
TH2                                                    Inflammatory
Cell                          IgE                      Mediators

                                                              End result: symptoms in various organs

                                             Mast cell in tissue
         Fc region                           Primed with IgE
          binds to                                                      Red, itchy eyes
         mast cells                                                                 Hives     Runny
                                                                                              nose
Cytokines, Target Organs, & Allergic
Symptoms
   Act alone or in combination: account for scope of
    allergic symptoms
       Histamine, serotonin, leukotriene, platelet activating
        factor, prostaglandins, bradykinin

   General targets include: skin, upper respiratory
    tract, GI tract, & conjunctiva
       Responses: rashes, itching, redness, rhinitis, sneezing,
        diarrhea, shedding tears


   Systemic targets: smooth muscles, mucous
    glands, and nervous tissues
       Responses: vascular dilation and constriction resulting
        in a change in blood pressure and respiration
Histamine
   Histamine
       Most profuse and fastest acting
   Stimulates
       Smooth muscle, glands, and eosinophils
   Response to chemical depends on the
    muscle location
       Constricts
            Smooth muscle of small bronchi & intestines
       Relaxes
            Vascular smooth muscles
                Constricted         Headache        Spectrum of inflammatory cytokines
Dilated blood   bronchioles
                                                    released by mast cells, common
    vessel                                          symptoms and target organs & tissues
                                                                        Wheal and flare
                                                        Dilated         reaction, itching
                                                      Blood vessel

                                                                       Increased blood flow
                                                                  Constricted
      Prostaglandin                                               bronchiole


                         Histamine                   Sm. muscle
                                                                          Wheezing, difficult
                          Serotonin                                       Breathing, coughing

                          Bradykinin                                 Increased peristalsis of
                                                                     intestine; diarrhea,
                                               Glands                vomiting


        Leukotriene
Slow acting
Involved in
asthma                        Prolonged
response.                     Constriction of
Increases                     Bronchioles &              Excessive mucus, tear formation
Mucous                        Airway constriction        Glandular secretions
secretion
Diseases Associated With Type I
   Atopic disease – hay fever, rhinitis, seasonal,
    inhaled plant pollen or mold
       Asthma – severe bronchoconstriction: inhaled allergen
       Eczema – dermatitis; ingestion, inhalation, skin contact
   Food allergy – intestinal portal can affect skin and
    respiratory tract
       Vomiting, diarrheas, abdominal pain
       Eczema hives, rhinitis, asthma, (infrequent) anaphylaxis
   Drug allergy – common side effect of treatment;
    any tissue can be affected
       Reactions range from mild atopy to fatal anaphylaxis
Treatment and Prevention
   Three common methods
       Avoiding allergen
       Drugs that block the action of cytokines
            Antihistamines
            Epinephrine
       Desensitization therapy
            Injected allergens
            Stimulate formation of high levels of allergen specific
             IgG
            IgG’s then prevent allergen from binding to IgE
            No degranulation
 Desensitization Therapy




Also, be aware that antihistamines interfere with histamine activity by binding to
receptors on target organs. People with chronic asthma may carry epinephrine
which causes rapid bronchiole relaxation. Finally, corticosteroids prevent plasma
cell from synthesizing IgE and may inhibit T cells
   Part II
Type II Reactions
Type II Reactions
   Transfusion reactions
       IgG antibodies from recipient bind to RBCs of
        incorrect donor leading to activation of
        complement and foreign cell lysis
   Myasthenia Gravis
       Auto IgG antibodies bind to receptors for
        acetylcholine
       Immune attack severely damages muscle cells
        leading to blocked synaptic transmissions and
        paralysis
                                                                                  α-B
 Blood Types                                                      Type A
                                                                                        B    B
      Characteristics of ABO Blood Groups


 Genotype
             Blood      Antigen on       Ab in                    Type B          α-A
             Type     RBC membrane      Plasma
                                                                                        A    A
  AA, AO        A            A           α-B
                                                                                   No α – A
  BB, BO        B            B           α-A                     Type AB           or α – B

     AB        AB         A and B        No Ab


                          Neither
                                         α–A                      Type O
    OO          O                        and
                          A nor B
                                         α-B                                  A      A B         B
Anti A and anti B IgG antibodies develop in early infancy due to exposure to antigens that are
widely distributed in nature. These antigens are surface molecules on bacteria and plant cells
that mimic the structure of A and B blood groups. Of course type A blood will not make anti A
and type B blood will not make anti B, due to self tolerance during clonal selection of B cells.
These anti A and B antibodies are the bases for transfusion reactions. However, these sort of
transfusion reactions are very rare due to the diligence of blood banks
Blood Compatibility
   Transfusing wrong blood
    type causes various rxn’s                           A antigens
                                                                         α–A
                                                                      in plasma
   Mild                                                             of recipient
       Fever, anemia, jaundice
   Severest
       Massive hemolysis of donor
        blood
       Systemic shock and kidney
        failure
       Blockage of the glomeruli
Of course with whole blood the plasma of the
Donor also contains α – B IgG antibodies. These
Antibodies could in theory agglutinate the recipients
Blood. However, this reaction is of no concern due
To the dilution of the donor’s blood into recipient
Hemolytic Disease of the Newborn
   Rh factor
       Protein expressed on RBCs of an Rh+ person
   Hemolytic Disease of Newborn (HDN)
       Rh- mother develops IgG antibodies to Rh+
        fetus during placental detachment and fetal
        blood mixing with maternal blood
            Known as sensitization of the mother
       If the next child is Rh+ the antibodies cross
        the placenta and cause complement mediated
        lysis of fetal RBCs
            potentially fatal
Prevention of HDN
   Passive immunization
       IgG antibodies which bind to Rh antigen
       Prevents sensitization of the mother
       RhoGAM
       Injection
   This disease can only occur if the mother
    is Rh- and the father is Rh+
Myasthenia Gravis
   Myasthenia Gravis
   Caused by
       Blocking antibodies
       Prevents ACh binding and
        muscle contraction
       Complement activation and
        degradation of muscle cell
        membranes
   Symptoms
       Early weakening of muscles
        of eyes and throat
       Complete loss of muscle
        function and death
Type I Diabetes
   Type I diabetes
       Autoantibodies target β cells of pancreas
            Complement activation
       Also involves TH1, activated Tc, and activated
        macrophages
       Complex immune reaction greatly reduces the
        amount of insulin secreted
       Associated with infection by Coxsackievirus & others
        Islet of Langerhans w/ β cells                Note the
                                                      lymphocyte
                                                      infiltration and
                                                      loss of
                                                      islet tissue


        Normal                           Diabetes
Rheumatic Fever
   Rheumatic Fever
       Caused by GAS – Streptococcus pyogenes
       In some cases mimicry occurs
            Ab formed during immune response cross react to
             molecules in the host that are similar to bacterial
             antigens
       Heart
            The Ab cross reactions trigger inflammation and
             injury of cardiac tissues
Autoimmunities of the Endocrine
Glands – Type II Reactions
   Hashimoto’s thyroiditis
       Hyptothyroidism
            AutoAb’s and T cells are reactive to the thyroid gland
            Stimulate an immune response which destroys
             thyroid tissue decreasing the release of thyroxin
             hormone
   Graves disease
       Hyperthyroidism
            In this case AutoAb’s do not lead to tissue destruction
            AutoAb’s bind to and activate receptors which secrete
             the thyroxin hormone
        Part III
      Type III Reactions
And Immune Complex Diseases
                                               Source of immune complexes varies


Type III Hypersensitivity                   Neutophils
                                                            Basement membrane
                                                            with immune complexes


   Antibody complexes are
    deposited in the basement
    membranes of epithelial
    tissues
       Incites a damaging
        inflammatory response
   Similarities to type II
       IgG and IgM Ab’s are
        involved
   Differences from type II        Blood vessels Heart   Joints    Skin     Kidney
       Antigens are not attached
        to cell surfaces



                                                Major Organ Targets
              Usually systemic autoimmune diseases
              Immune complexes activate complement




    Degranulation of mast cells   MAC contributes to tissue destruction




     Chemotactic factors for          Tissue damage and vascular
     neutrophils are released         damage lead to a continued
                                      immune response




Much damage stems from release of lytic
enzymes by neutrophils as they attempt
to ingest adhering immune complex
Systemic Lupus Erythematosus
   SLE
       Antoantibodies against a great variety of
        organs and tissues are produced
       Autoantibody-autoantigen complexes are
        deposited in the basement membranes of
        various organs
            Kidneys, bone marrow, skin, nervous system, joints,
             muscles, heart & GI
       How such a generalized loss of self tolerance
        arises is unknown
Rheumatoid Arthritis
   Rheumatoid Arthritis
       Immune complexes
        bind to synovial
        membranes of joints
       Activates phagocytes
        and release of cytokines
       Chronic inflammation
        leads to scar tissue and
        joint destruction
       Thickens membrane,
        erodes articular
        cartilage, and fuses the
        joint
   Part IV
Type IV Reactions
Type IV Hypersensitivity
   Type IV Hypersensitivity
       T cell mediated delayed response
       First Exposure
            Activation of TH1 and resting CD8 cells
            TH1 cells activated cytotoxic T cells
       Second Exposure causes tissue damage due to
            Activated TH1 cells releasing cytokines
            Brings macrophages to the area and activates them
               Increased concentration of destructive enzymes and
                local inflammation
            Now when “activated” cytotoxic T cells “sees” the
             same antigen it releases perforins resulting in
             localized cell killing
                                                                     Blister


                 Chemical antigens                       Inflammation
  Skin
  Layer                                                                          Kills skin
                                                                                   Cells



Dendritic Cell



                                                                      Formerly activated
                                                  Macrophage          Tc cell releases
                                                                      killing enzymes when
                                                                      antigen binds to it
                                                                      during a second
                                                                      exposure


 This picture illustrates the second exposure. During the first exposure a resting CD4 cell
 matured into an active TH1 cell which activated a Tc cell. Now, during the second exposure
 binding of the activated TH1causes release of TNF, IL, and IFN which bring macrophages to
 the area and stimulate a local immune response. Also during the second exposure the active
 Tc will bind to antigen which stimulates release of perforins.
Host Rejection of Graft
   T-Cell Mediated rejection of transplanted
    Tissues
       Host T cells bind to foreign class I MHC
        markers
       Release IL 2 as part of a general immune
        response
       As TH1 are activated Tc are activated
       Late in the process Antibodies are also formed
        against foreign tissue
         Part VI
Origins of Autoimmune Disease
Origins of Autoimmune Disease
   Sequestered antigen theory              Theory of immune
       Certain tissues develop              deficiency
        behind anatomical barriers              Inappropriate expression
        and cannot be scanned by                 of MHC II on cells which
        immune system                            do not normally express
       Eventually these tissues                 them can activate T and B
        become exposed by means                  cells to self
        of infection, trauma, or            Molecular mimicry
        deterioration leading to an
                                                Microbial antigens bear
        immune response
                                                 molecular similarities to
   Forbidden clones                             human cells causing cross
       Not all “self” reacting clones           reactions
        are destroyed
  Part VII
Immunodeficiency
Immunodeficiency Diseases
 Components of the immune response
  system are absent
 Deficiencies involve B cells, T cells, both B
  and T cells, phagocytes, and complement
 Two categories
       Primary immunodeficiency
            Congenital genetic errors
       Secondary disease
            Acquired after birth caused by natural or artificial
             agents, such as HIV, radiation or chemotherapy
Primary Immunodeficiency
   Primary immunodeficiency
       Lack of B-cell and/or T cell activity
       B cell defect
            agammaglobulinemia – patient lacks antibodies
       T cell defect
            thymus is missing or abnormal
            DiGeorge syndrome
       Severe combined immunodeficiency (SCID)
            Immature lymphocytes fail to mature properly
            Adenosine deaminase deficiency


                                                             41
                                           Adenosine Deaminase
                                           Deficiency ADA – autosomal
                                           recessive defect in metabolism
                                           of adenosine. Build up of this
                                           metabolic product is toxic to
                          DiGeorge         cells & kills them
                          Syndrome

  SCID No         Pre T cell
lymphocytes
  develop


                                                T cell


          Lymphoid
          Stem Cell



                  Pre B cell                    B cell


                          Congenital           hypogammaglobulinema
                      agammaglobulinemia           ADA deficiency
The Immune System and Cancer
 New growth of abnormal cells
 Tumors may be benign (nonspreading)
  self-contained; or malignant that spreads
  from tissue of origin to other sites
 Appear to have genetic alterations that
  disrupt the normal cell division cycle
 Possible causes include: errors in mitosis,
  genetic damage, activation of oncogenes,
  or retroviruses
 Immune surveillance, immune system
  keeps cancer “in check”
                                          43

				
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