Docstoc

Disorders of Immunity_ Inflammation

Document Sample
Disorders of Immunity_ Inflammation Powered By Docstoc
					        The Immune Response:
• Introduction to Immunity
• Part I: Innate Immunity: Major Cells
• Part II: Innate Immunity: The Inflammatory
  Response
• Part III: Treatment of Inflammation
• Part IV: Adaptive Immunity


                                               1
Introduction to
    Immunity



                  2
Functions of the Immune
       Response




                          3
The Immune Response

   The Immune Response: A collective and coordinated
     response of cells of the immune system

   1. Protects host from invasion of anything foreign
   • Ex. foreign pathogens, bacteria, parasites, viruses, the environment in general

  2. Distinguishes “self” from non-self
   • Ex. cancer, autoimmune reactions
   • The immune system has a surveillance mechanism to identify itself
        – When it recognizes something that is nonself, the immune system has mechanisms to
          kill the cell
        – When the surveillance system breaks down or is over-challenged, disease occurs


   3. Mediates healing
   • Modulate inflammatory process and wound repair
   • Immunity and inflammation are wrapped up together to make healing more
     efficient

                                                                                         4
   Results of Immune
Dysfunction or Deficiency




                            5
 Results of Immune Dysfunction
          or Deficiency
• Immunodeficiency
  – Do not have the requisite amount of immunological ability
     • Cannot keep up with what is going on


• Allergies/Hypersensitivities
  – The response to something is exaggerated


• Transplantation pathology

• Autoimmunity

                                                                6
Innate Immunity




                  7
                Innate Immunity
• Natural resistance that a person is born with
   – Do not need anything else special

• Comprises physical, chemical, and cellular barriers that
  keep the self and the nonself apart

• First line of defense

• Ex. skin, mucosa
   – When radiator heat comes on, it dries out the mucosal
     membranes and makes you more susceptible to microorganisms
   – A person in the healthcare system needs to take care of the skin
     because dry skin makes a person more susceptible to invasion

                                                                    8
Adaptive Immunity




                    9
              Adaptive Immunity
• Acquired
   – When you are born and come into contact with antigens in the
     environment, your body mounts a response
      • Are able to recognize the pathogen in the future


• Specific

• Amplified response with memory
   – Has a recognition system
   – There is a molecular memory in the body about what happened
   – Able to respond more quickly to the pathogen when interact with
     it in the future



                                                                    10
Components of the Adaptive
   Immune Response




                             11
   Components of the Adaptive
      Immune Response
• Divided into two major components:

1. Cell-mediated adaptive immunity
   - T cells

2. Antibody-mediated (humoral immunity)
   - Circulating antibodies
   - B cells produce the antibodies for humoral immunity

   a. Antibody-mediated immunity is triggered by encounters with
      Antigens (Ags)

   b. Antibodies are also known as Immunoglobulins (Igs)

                                                                   12
     Part I:
Innate Immunity


                  13
Primary Immune Cells of
    Innate Immunity




                          14
Primary Immune Cells of Innate
          Immunity
•   Monocytes, macrophages, dendritic cells
•   Neutrophils
•   Eosinophils
•   Basophils
•   Mast cells
•   Natural killer cells


                                              15
Monocytes, Macrophages,
   and Dendritic cells




                          16
    Monocytes, Macrophages, and
           Dendritic cells
•   Phagocytic cells that are located in different areas of the body
•   While macrophages are important cells of the innate immunity, they also
    play key role in adaptive immunity

•   Monocytes in blood  Macrophages in tissues:

•   Dendritic cells are phagocytic cells in the nervous system

•   Include Kupffer, Langerhans, alveolar, peritoneal oligodendrocytes etc

•   Phagocytize antigen  present antigen (APC-antigen presenting cell)
     –   Internalize and consume pathogens with lysosomes and peroxisomes
     –   Process the antigen out of the substance that is foreign
           •   Takes the antigen, sticks it outside of itself, and presents it


•   When activated, secrete cytokines (tumor necrosis factor, interleukin-1, and
    others), oxygen radicals, proteolytic enzymes, arachidonic acid metabolites,
    prostaglandins
     –   Release molecules that are very important in inflammation

•   Macrophages are phagocytes
                                                                                 17
Neutrophils




              18
                    Neutrophils
• AKA Polymorphonuclear leukocytes (PMN)

• Antigen binding and non-specific phagocytosis

• Inflammatory response: First-line defender
  against bacterial invasion, colonization, and
  infection

• Important in innate immunity
  – Responsible for antigen binding and phagocytosis


                                                       19
Eosinophils




              20
                   Eosinophils
• Inflammatory response

• Fight parasites (worms especially)

• May release chemicals in respiratory tract during
  allergic asthma
  – Release chemical mediators




                                                  21
Basophils




            22
                       Basophils
• Release potent mediators during allergic
  responses (e.g. histamine)

• Have binding sites for IgE antibodies (Type 1
  Hypersensitivity)
  – The antibody will bind to antigen, and the basophil will release
    the inflammatory substances


• Reside in blood



                                                                       23
Mast Cells




             24
               Mast Cells
• Also from bone marrow and share
  characteristics with basophils

• Located in tissues; not blood

• Releases histamine which is the hallmark
  of tissue inflammatory response.



                                             25
Natural Killer Cells




                       26
              Natural Killer Cells
   Natural Killer Cells: an effector cell important in innate immunity.
• Small % of lymphocytes
   – Part of the lymphocyte population but are a small amount
• Can bind with antibody coated target cell  Antibody
  dependent cell-mediated cytotoxicity (ADCC)
   – Can recognize the antibody and destroy the cell
• Can attack virus-infected cells or cancer cells without help or
  activation first
   – Important in immunosurveillance
• Can recognize antigen without MHC restrictions
   – Major histamine compatibility
• NO MEMORY
   – Lives by the minute by doing what it does
• Regulated by cytokines, prostaglandins and thromboxane
• Release NK perforins, enzymes, and toxic cytokines to
  destroy target cells                                                    27
Outline of Immunity




                      28
29
Cytokines and the Immune
        Response




                           30
      Cytokines and the Immune
              Response
• Small, low molecular weight proteins (hormone-like) which are
  produced during all phases of the immune response.
   – They are released form one area, move, and act on another area
   – Short half-life
   – Work in a parocrine system (acts locally) rather than an endocrine
     system
       • This is characteristic of many of the immunological cytokines



• Primarily made by T cells and macrophages (lymphokines/
  monokines) and act primarily on immune cells
   – Lymphokines – a cytokine released from a lymphocyte (T cell)
   – Monokines – a cytokine released from a macrophage

                                                                          31
Processes that Cytokines are
        Involves in




                               32
  Processes that Cytokines are
          Involves in
• Innate immunity

• Adaptive immunity

• Hematopoiesis




                                 33
Cytokines and Innate
     Immunity




                       34
 Cytokines and Innate Immunity
• IL-1, IL-6, TNF (tumor necrosis factor) are
  important in the early inflammatory response.

• Derived mainly from macrophages,endothelial,
  and dendritic cells, and lymphocytes (T cells)

• Processes
  – Stimulate acute phase protein production by the liver
  – Stimulate the hypothalamus for a fever response
  – Increase adhesion molecules on the vascular
    endothelium
                                                            35
 Acute Phase Protein
Production by the Liver




                          36
Acute Phase Protein Production
         by the Liver
• Overlaps with the ESR

• Increases cytokine release in the body-
  sensed by the liver-liver increases amount
  of acute-phase proteins (complement,
  clotting factors)
  – Increased cytokines due to inflammation
    causes liver to produce more proteins, which
    increases ESR
                                                   37
Stimulate Hypothalamus for
     Fever Response




                             38
   Stimulate Hypothalamus for
        Fever Response
• Hypothalamus in the base of the brain
  thermoregulates the body

• One of the main reasons that you get a fever is
  because a cytokine burden increases enough to
  pass through the vasculature of the hypothalamus
  and resets the temperature of the body
  – Reason why anti-inflammatory decrease fever –
    decrease the burden of the cytokine production,
    which decreases the reason that the hypothalamus
    causes fever

                                                       39
Increase in Adhesion
     Molecules




                       40
Increase in Adhesion Molecules
• Cytokines trigger the endothelium to put out
  adhesion molecules so that when a macrophage
  comes by it sticks to it and squeezes between
  the endothelium cells out into the tissue to fight
  infection




                                                   41
Cytokines and Adaptive
       Immunity




                         42
      Cytokines and Adaptive
             Immunity
• Activate immune cells to proliferate and
  differentiate into effector and memory
  cells.




                                             43
Cytokines and Hematopoiesis




                              44
 Cytokines and Hematopoiesis
• Cytokines that stimulate bone marrow
  pluripotent stem cells, progenitor cells and
  precursor cells to produce large numbers
  of platelets, erythrocytes, lymphocytes,
  neutrophils, monocytes, eosinophils,
  basophils and dendritic cells are termed
  Colony Stimulation Factors (CSFs)


                                             45
     PART II
 Innate Immunity:
THE INFLAMMATORY
     RESPONSE



                    46
Inflammation




               47
                            Inflammation
Reaction of vascularized tissue to local injury (cellular) manifesting as
    redness, swelling, heat, pain, loss of function

•   Non-specific, chain of events similar regardless of injury type and extent
     – Stereotypic no matter the size of the injury

•   Includes vascular and cellular changes

•   Triggered when FIRST LINE OF Defense's integrity has been breached
    (skin, mucus membranes and damaged the endothelium or gotten to a vessel)
     – May be from the outside into the body or from the inside of the body out (ex.
       vacularitis)

•   Unpleasant and uncomfortable, but essential for survival
•   May lead to inflammatory diseases


                                                                                       48
Acute Inflammation




                     49
         Acute Inflammation
• 1. vascular phase

• 2. cellular phase




                              50
Acute Inflammation
 Vascular Phase




                     51
                 Acute Inflammation
                  Vascular Phase
•       After injury or insult, inflammation initiates a rapid vasoconstriction
        of small vessels in the local area
    –      The same thing as the rapid vasoconstriction that occurs in hemostasis


•     This vasoconstriction is then followed by a rapid vasodilatation of
      arterioles and venules (vasoactive hyperemia) that supply the
      local area.
    –     Results in the erythema (redness) and warmth in the area due
          to the increased blood flow to the area

•       Capillary permeability increases and fluid moves into the tissues
        (edema) causing swelling and pain.
    –      Due to cytokines that are released
    –      The capillaries become more permeable – cells that make up the cell wall
           become looser, allowing fluids and proteins to move out of the capillaries and
           into the tissue
                                                                                        52
 Vascular Phase
Possible Scenarios




                     53
                  Vascular Phase
                 Possible Scenarios
1. Immediate transient response to minor injury
•      Ex. very small, sterile cut (ex. razor cut, paper cut)
     •     At first you do not notice the blood because of the rapid vasoconstriction
           but then after rapid vasoconstriction the vasodilation occurs

2. Immediate sustained response (several days; results in damaged vessels)
     •   More of a traumatic event and possibly a less sterile field
     •   Ex. step on a garden hose
     •   The issue cannot resolve quickly and due to the hemostasis and clotting
         necessary, the several day response results in extra damage to the skin
         and vessels

3. Delayed hemodynamic response (increase in capillary permeability 4-24 hours
      after injury ; e.g., radiation burns, sun burns)
    •      Have an insult but do not realize an effect until 4-24 hours after an injury
    •      Ex. sunburn cooks the cells and damages them but they take a while to
           build up the response and the damage so that the response takes a while
           to show                                                                     54
    •      Redness is the vasodilation, vascular permeability leads to the edema
Acute Inflammation
 Vascular Phase




                     55
Acute Inflammation
  Cellular Phase




                     56
               Acute Inflammation
                 Cellular Phase
•     Ex. step on a garden rake and bacteria enters the site of injury
•     Characterized by the movement of phagocytic cells into the site of
      injury
    •      Need to remove them by recycling them
•     Release of chemical mediators by sentinel cells in the tissue
      (mast cells, basophils, macrophages)
    •      Sentinel cells in the tissues release cytokines, the endothelial
           cells recognize them, stick out adhesion molecules to allow
           phagocytic cells to stick to them
         •      Chemotaxis of the phagocytic cells from the vessels to
                the tissue because the cells of moving to the area of high
                signaling
•     Increases capillary permeability and allows leukocytes to migrate
      to the local area.
    •      Water wants to leave the vasculature, making it easier for the
           cells to get out of the blood and into the tissue where they can
                                                                          57
           fight infection
Acute Inflammation
  Cellular Phase




                     58
Inflammatory Mediators




                         59
        Inflammatory Mediators
•   Histamine
•   Plasma proteases
•   Arachidonic acid metabolites
•   Platelet aggregating factors
•   Cytokines




                                   60
Histamine




            61
                 Histamine
• One of the first mediators of inflammation
  causing dilatation and increased capillary
  permeability.

• Histamine high concentration in platelets,
  basophils, and mast cell
  – Allows there to be a cross talk between the
    clotting cascade and platelet plug

• In mast cells histamine is released in
  response to binding of IgE Antibodies
                                                  62
Plasma Proteases




                   63
          Plasma Proteases
• Kinins, activated complement, clotting
  proteins

• Bradykinin causes increased capillary
  permeability and pain.
  – Byproduct of plasma proteases
  – Causes pain by binding to nociceptors



                                            64
Arachidonic Acid Metabolites




                               65
    Arachidonic Acid Metabolites
•    Metabolism of arachidonic acid into prostaglandins
     via the cyclooxygenase pathway

•    Metabolism of arachidonic acid into leukotrienes via
     the lipoxygenase pathway




                                                            66
  Metabolism of Arachidonic
 Acid into Prostaglandins via
the Cyclooxygenase Pathway



                                67
      Metabolism of Arachidonic Acid into
Prostaglandins via the Cyclooxygenase Pathway

•       Arachidonic metabolics are very, very important inflammatory
        mediators
•       PGE1(prostaglandin E1) and PGE2, prostaglandin intermediates,
        are important in inducing inflammation
    –       Promoting the inflammatory pathways
    –       Induces vasodilation and bronchoconstriction
    –       Inhibits inflammatory cell function
    –       Prostaglandins released during the pulsatile flow are important in making blood
            not stick
    –       Control of acid production in the stomach
    –       Some are pro-inflammatory and some are pro-other things that are important
            and beneficial to the body

•       TXA2 (Thromboxane A2) promotes platelet aggregation and
        vasoconstriction
    –       Promotes branchoconstriction

•       Non-steroidals (aspirin etc) inhibit the first enzyme in the
        cyclooxygenase pathway.
    –       Used pharmacologically to reduce inflammation



                                                                                          68
Metabolism of Arachidonic
 Acid into Leukotrienes via
the Lipoxygenase Pathway




                              69
   Metabolism of Arachidonic Acid into
Leukotrienes via the Lipoxygenase Pathway
•    Leukotrienes are critically important in
    the generalized response of anaphlaxis
     •   C4, D4, E4: the slow releasing substances of anaphylaxis
         (SRA’s). They cause slow sustained contraction of
         bronchiole smooth muscle. Are important in asthma and
         anaphylaxis.


•    Target of the newer anti-asthma drugs,
    e.g., montelukast (Singulair), which act as
    leukotriene inhibitors


                                                                    70
Arachidonic Acid
    Diagram




                   71
72
Platelet Aggregating Factor




                              73
    Platelet Aggregating Factor
• Induced platelet aggregation
   – Pathways that are important for hemostasis are also important in
     the immune and inflammatory pathways


• Neutrophil activation

• Eosinophil chemotaxis




                                                                   74
Complement System




                    75
         Complement System
• Functionally analogous to the clotting cascade in
  hemostasis
• Primary mediator of the innate and adaptive
  humoral immune response. Produce inflammatory
  response, lyse foreign cells, increase
  phagocytosis
• About 20 plasma proteins. Circulate in inactive
  form much like clotting factors (C1, C4, C2, C3,
  C5C9). Proteins must be activated in the proper
  sequence in order to have their end effect (as with
  the clotting factors)
• Non-specific and no memory
                                                      76
Complement Pathways for
      Activation




                          77
      Complement Pathways for
            Activation
• Classical pathway depends on:
  1. Binding of IgG or IgM to invading organisms
       - antibodies bind to invading organisms
  2. Binding of complement to circulating antigen-antibody complex
     (complement fixation)
       - undergoes molecular change that promotes the activation
       complement
       - complement sees this and there is a molecular recognition

• Alternate pathway is triggered by interactions between complement
  and polysaccharides on microbes

• Lectin pathway is activated by binding proteins interacting with cell
  surface proteins in bacteria and yeast
    – Lectin can be recognized by complement and activates it
    – Lection is located inside cells and is seen when cells lyse
                                                                      78
Results of Complement




                        79
           Results of Complement
• MAC (membrane attack complex) insertion into target cell
  membrane  holes in cell membrane (lysis)
   – Form a pore that sticks into a cell and causes the cell to die through
     membrane depolarization

• Opsonization - C3b coats Ag-Ab complexes
   – Helps out neutrophils and macrophages with phagocytosis
   – Opsonization is when an antibody binds to bacteria
         • Complement binds to the antigen-antibody complex and opsonizes it so that the
           phagocytes want to phagocytize the complex even more

• Chemotaxis - C3a stimulates mast cells and basophils to
  release histamine and attract neutrophils and others
• C3a and C5a produce anaphylatoxin inducing histamine
  release in mast cells and basophils:
   •   Leads to contraction of smooth muscle,  vascular permeability, edema
   •   Complement, if activated, will bind to these cells and cause them to release histamine



                                                                                           80
Complement Pathways
      Diagram




                      81
82
Chronic Inflammation
 Persistent Irritants




                        83
            Chronic Inflammation
             Persistent Irritants
• Ex. talc, silica, asbestos that are breathed deeply into the
  respiratory tract, surgical sutures
   – The chronic inflammation causes persistent problems that results in
     disease

• Some bacteria (tuberculosis, syphilis)
   – Can be in the body for a long time, escape surveillance, and cause
     inflammation

• Injured tissue surrounding healing fracture
   – Keep stressing the healing fracture, leading to inflammation

• Inflammatory process lasts a prolonged amount of time
   – Sustained types of response


                                                                           84
Chronic Inflammation
      Patterns




                       85
              Chronic Inflammation
                    Patterns
•   Non-specific diffuse accumulation of macrophages and lymphocytes leading
    to fibroblast proliferation and scar tissue formation
     – Relsease cytokines and mediators that lead to the fibroblast proliferation
         and scar tissue formation
     – Ex. in the respiratory tract of smokers the epithelium begins dying and
         as the body goes to replace it, it says that the epithelium is difficult to
         replace so it replaces it with less ciliated, good cells, and then a scar
         tissue and fibroblasts

•   Granulomatous lesion  epitheloid cells form granuloma:
     – Lesions are very discrete
         • Ex. splinters, foreign bodies
         • After a couple of days, a granulomatous lesion forms and
           encapsulates the splinter
         • Eventually fibroblasts form around it and the nodule stays there for
           a long time
     – Ex. Tuberculosis tubercle
         • Waiting for the immune system to decrease so that the tuberculosis
           can come back
                                                                                 86
  Chronic Inflammation
Causes and Characteristics




                             87
   Chronic Inflammation
 Causes and Characteristics
Due to:
• Recurrent or progressive acute inflammation
  (smoking), OR
• Low-grade responses that fail to evoke acute
  responses (talc, silica, asbestos, tb)

Characteristics:
• Infiltration by mononuclear cells (Macs and Lymphs);
  not Neutrophils like in acute inflammation.
• Proliferation of fibroblasts ( scarring) ; not exudates



                                                         88
Manifestations of Inflammation
          Exudation




                                 89
 Manifestations of Inflammation
           Exudation
• Local manifestation of inflammation
• Extra vascular influx of fluid with high concentration of
  proteins, salts, cells (WBC) and cell debris
   – The fluid from the vessel leaves the vessel and enters into the
     tissues
• Fluid dilutes injurious chemicals
• Fluid brings in complement, Abs, and other chemotactic
  substances to injured areas in the tissues due to osmotic
  gradient
• The extra vascular proteins also act to pull water out of
  plasma   blood viscosity  clotting because water is taken
  out and cells are left behind (increase hemotocrit);
  containment of pathogens  cellular phase begins

                                                                       90
Manifestations of Inflammation
      Types of Exudate




                                 91
 Manifestations of Inflammation
       Types of Exudate
• Serous watery; low in protein
   – Early exudate
• Fibrinous large amounts of fibrinogen in the exudate
• Membranous necrotic debris in fibrinous matrix on
  mucus membrane surfaces
   – Forms a muscosy sheen on certain membranous surfaces
• Purulent    degraded white cells, protein, tissue debris
   – Ex. white looking acne blemish
• Hemorrhagic severe leakage of red cells from
  capillaries
   – Blood leaves the vasculature and enters the tissue
   – Ex. petechiae, purpura
                                                             92
Systemic Manifestations of
      Inflammation




                             93
      Systemic Manifestations of
            Inflammation
• Most all of the inflammatory mediators have very short
  half lives so autocrine and paracrine signaling
  predominates.
    – Mechanisms whereby cells secrete substances and they act very, very
      locally
        • Compared to endocrine systems



• If the site of inflammation is large enough or robust enough of if the
  inflammation is in the circulation, systemic manifestations can be
  evident in addition to the local manifestations

• Acute phase response

• Lymphadenitis                                                         94
Acute Phase Responses




                        95
        Acute Phase Responses
   Acute-Phase Response (hours-days after onset)
• Increase in plasma proteins (e.g., C-reactive protein)
   – Increased erythrocyte sedimentation rate (ESR)
• Fever (IL-1, IL-6 and TNF effects on hypothalamus)
   – Drive the hypothalamus to increase body temeprature
• Leukocytosis (presence of immature neutrophils; “band cells”)
   – Are consuming leukocytes to significant amounts and are trying to
     replace them
   – Similar to the reticulocytes in red blood cells
   – Band cells are indicative are immature neutrophils
• Skeletal muscle catabolism (mobilize amino acids for protein
  synthesis)
   – When there is active inflammation, individuals do not feel well, lose the
     drive to eat, do not take in enough nutrition, ask the liver to make a
     bunch of proteins
       • Break down the skeletal muscle to increase amino acid pool and make more
         proteins
   –   Negative nitrogen balance                                                    96
            –   Skeletal muscle is wasting
Lymphadenitis




                97
                 Lymphadenitis
• Regional swelling of lymph nodes, painful upon
  palpation

• A swollen lymph node is indicative of an
  inflammatory event in a local area or regional
  area
  – The regional swelling is an indication of systemic inflammation




                                                                      98
         Part III:
Treatment of Inflammation




                            99
Types of Treatment of
    Inflammation




                        100
       Types of Treatment of
           Inflammation
• Focus: Prevent the synthesis and release
 of pro-inflammatory mediators, such as
 prostaglandins

• NSAIDs

• Steroids

                                          101
Treatment of Inflammation
       Diagram




                            102
Treatment of Inflammation
       Diagram




                            103
Treatment of Inflammation
        NSAIDs




                            104
      Treatment of Inflammation
              NSAIDs
• NSAIDS: nonsteroidal anti-inflammatory drugs
  inhibit cyclooxygenase (COX), the enzyme that
  converts arachidonic acid to prostaglandins and
  thromboxane (e.g., aspirin, et al.) through the
  cyclooxygenase pathway
  •   Inhibit the enzymatic conversion




                                                105
Treatment of Inflammation
       Steroids




                            106
    Treatment of Inflammation
           Steroids
• Steroids: given systemically or topically

• Have a multiplicity of actions, many of which
  impair immune cell proliferation or cytokine
  release.

• Stop the metabolism of arachidonic acid from
  cell membrane phospholipids


                                                  107
COX-1 and COX-2




                  108
         COX-1 and COX-2
• Both produce prostaglandins and
  thromboxane (TXA) and convert
  arachidonic acid into prostaglandins




                                         109
COX-1




        110
                                  COX-1
•   Found in many different tissues

•   Inhibition of COX-1 is responsible for the adverse effects of
    NSAID’s because the drug works on all COX-1 tissue types
    •   COX-1 inhibition impairs the gastrointestinal mucosal barrier and
        gastric erosion and ulceration may result


    •   COX-1 inhibition impairs renal function so that sodium and water
        retention can result
        •   Leads to edema and hypertension


    •   COX-1 inhibition decreases the creation of thromboxane, which
        prevents platelet aggregation, which may produce bleeding.
        •   Such inhibition may also prevent myocardial infarction or ischemic (thrombotic)
                                                                                         111
            stroke in patients with overactive coagulation pathways.
COX-2




        112
                                  COX-2
• COX-2 is predominantly in immune cells.
•   Inhibiting COX-2 results in the therapeutically desirable effects of
    NSAID’s:
    •   If you are targeting inflammation, you should really be targeting COX-2
        because it is more specific

    •   Suppression of inflammation

    •   Decreasing systemic side effects
        •   Alleviation of pain

        •   Reduction of fever

•   However, many of the non-steroidals inhibit both COX-1 and COX-2
                                                                                  113
Contraindications




                    114
           Contraindications
• NSAIDs

• Hypersensitivity syndrome




                               115
NSAIDs




         116
                                 NSAIDs
•       NSAIDs should be avoided in mid to late pregnancy
        since:

•       They may cause premature closure of the ductus
        arteriosus.
    •      A shunt in the heart in the developing fetus that allows proper blood flow
    •      Important in maternal-fetal circulation and oxygenation of the fetus



•       They might also cause prolonged bleeding following
        delivery because of their effects on platelets.


                                                                                        117
Hypersensitivity Syndrome




                            118
        Hypersensitivity Syndrome
•       Hypersensitivity syndrome caused by COX inhibition:

•       This is not an allergic response because there are no
        antibodies to the NSAID; in susceptible individuals,
        any NSAID can trigger the reaction.
    •      Certain people are more sensitive to NSAIDs just because


•       Symptoms are similar to those of anaphylaxis.

•       Susceptible individuals should avoid all NSAIDS

                                                                      119
Aspirin




          120
                        Aspirin
•   An irreversible inhibitor of both COX-1 and COX-2 (it is
    nonselective).

•   Metabolized (with a half-life of ~20 minutes) to salicylic
    acid, which inhibits both COXs reversibly and has a
    longer half-life than aspirin

•   The anti-inflammatory activity is due to both the
    irreversible inhibition of both COXs by aspirin and
    reversible inhibition by salicylic acid.



                                                            121
Uses of Aspirin




                  122
                    Uses of Aspirin
•       Anti-inflammatory
•       Anti-pyretic (suppression of fever)
•       Analgesic

•       Dysmenorrhea
    •      Menstrual cramps are due to the production of prostaglandins

    •      Aspirin decreases smooth muscle cramping

•       Suppression of platelet aggregation



                                                                     123
   Uses of Aspirin
Suppression of Platelet
    Aggregation



                          124
             Uses of Aspirin
    Suppression of Platelet Aggregation
•    This use is usually accomplished by administration of an 81-mg
     enteric-coated tablet each morning.
    –       Allows the drug to pass through the stomach and be absorbed in the intestine
    –       Do not want aspirin to dissolve in the stomach because it affects gastric pH



•    The aspirin irreversibly inhibits COX-1 in platelets it encounters in the
     portal circulation, but in its 81 mg form it is completely metabolized on
     first pass and has no systemic effects.
    –       When aspirin is taken, any platelets in circulation are irreversibly inhibited but on
            the second time, the aspirin is converted to salicyclic acid and reversibly inhibit
            platelets
        •        Taking the small dose allows it to be that only the platelets in the circulation
                 are irreversibly affected (because of the short life of the platelets)



•    Over time, a substantial portion of platelets are affected by the low                      125
     dose aspirin without undue systemic side effects.
       Adverse Effects
Common to all Aspirin Formulations




                                     126
           Adverse Effects
    Common to all Aspirin Formulations
•       Salicylism: tinnitus, headache and dizziness caused by high
        doses such as the doses that are used in rheumatoid arthritis.
        Respiratory alkalosis may also result.

•       Reye’s syndrome: a fatal syndrome of liver failure in children
        suffering from chickenpox or influenza who use aspirin. For this
        reason, it is recommended that children be only given
        acetaminophen or ibuprofen for febrile illness. With this
        recommendation, the incidence of Reye’s syndrome has
        plummeted.

•       Poisoning: before childproof caps were mandated by law,
        aspirin poisoning was a common cause of illness and death in
        children. This is no longer such a problem
    •       The toxicity of aspirin in children is what prompted the mandation of
            childproof safety caps
                                                                                    127
Aspirin Formulation




                      128
                 Aspirin Formulation
•       Plain aspirin tablets.

•       Buffered aspirin: includes sodium bicarbonate to neutralize
        stomach acid and prevent gastric irritation.
    •       The sodium bicarbonate acts as the buffer
    •       Inhibit the prostaglandins, allowing the gastric mucosa to temporarily go
            down but you are also buffering the aspirin so you are helping it out

•       Enteric coated aspirin: remains intact in the stomach and
        dissolves in the duodenum; prevents gastric irritation.
•       Timed released: makes no sense for an irreversible drug that is
        completely metabolized on first pass
•       Rectal suppositories: Not recommended due to inconsistent
        absorption and rectal ulceration.

                                                                                   129
Aspirin Dosage




                 130
                        Aspirin Dosage
•       Is commonly available in:
•       regular strength (327 mg)
•       extra-strength (500 mg)
•       low-dose (81 mg) tablets
    •        Used by adults for the inhibition of platelets
    •        There is no evidence that taking more than 81 mg leads to further
             platelet aggregation

•       Adults: 650-1000 mg in one dose can be repeated every 4
        hours.

•       Children: aspirin is not recommended unless specifically requested by the
        child’s physician.


•       Inhibition of platelets: 81 mg per day.
                                                                                 131
Other Non-Selective NSAIDs




                             132
  Other Non-Selective NSAIDs
• Non-specific COX-1 and COX-2 inhibitors

• Specific COX-2 inhibitors




                                        133
Non-specific COX-1 and COX-
        2 Inhibitors




                          134
Non-specific COX-1 and COX-2
           Inhibitors
•   Nonspecific COX-1 and -2 inhibitors
    (aspirin, Ibuprofen, naproxen, etc.):

•   All have interactions with warfarin
    (Coumadin); they may potentiate bleeding
    tendencies produced by warfarin

•   Coagulation studies should be obtained
    frequently and warfarin dosage adjusted in
    patients who take both an NSAID and
    warfarin

                                               135
Specific COX-2 Inhibitors




                            136
          Specific COX-2 Inhibitors
•       Have recently been associated with increased risk of heart attacks.
    •       A result of clinical trials but many of the reasons are not known
    •       Could inhibit prostacycline, which is a positive mediator


•       Purported to produce fewer adverse effects in some individuals, such
        as GI irritation, bleeding, and sodium/water retention. However, data
        in the general population to support this contention is shaky.

•       Much more expensive than nonselective NSAIDS
    •       A nonselective NSAID is equally effective as a COX-2 inhibitor


•       Include:
    –      Rofecoxib (withdrawn from the market)
    –      Valdecoxib (withdrawn from the market)
    –      Celecoxib (Celebrex) is still available


                                                                                137
Acetaminophen




                138
                    Acetaminophen
•       Does not inhibit COX in the periphery; MOA is unclear
    •      Is not a COX inhibitor

•       Has no anti-inflammatory activity.
    •      Does not decrease inflammatory mediators

•       No side effects of gastric ulceration, sodium and water
        retention.
•       No effect on platelets or coagulation.
•       Uses
    –      Antipyretic
    –      Analgesic                                         139
Acetaminophen
Adverse Effects




                  140
            Acetaminophen
            Adverse Effects
•   Adverse effects: Hepatoxicity
•   Usually occurs because of overdose
•   Decreases liver function and may
    increase toxicity
•   Greatly exacerbated by concurrent alcohol
    use; so, hepatoxicity may occur at
    therapeutic doses in heavy drinkers.
•   Hepatotoxicity from acetaminophen has
    resulted in deaths from liver failure.
                                             141
Acetaminophen
Drug Interactions




                    142
          Acetaminophen
          Drug Interactions
• May affect warfarin metabolism because it
  is metabolized by the liver to increase
  levels of warfarin and increase its
  anticoagulant effects.




                                          143
Acetaminophen
   Dosages



                144
            Acetaminophen
               Dosages
•   Available in 327 mg and 500 mg tablets.

•   Adult dose is 650 mg to 1000 mg every
    4-6 hours with a daily limit of 3 g (3000
    mg).

•   Dosage is reduced depending on the age
    of the child


                                                145
Formulations of NSAIDs and
     Acetaminophen




                             146
NSAIDS and acetaminophen are found in
         many formulations
             Be careful !




                                   147
    Part IV:
Adaptive Immunity

                148
Active Adaptive Immunity




                           149
     Active Adaptive Immunity
• Active passive immunity - Through
  immunizations

• Active natural immunity - Through having
  the disease

• Present for a life-time

                                             150
Passive Adaptive Immunity




                            151
    Passive Adaptive Immunity
• Transferred from another source (in utero,
  breast milk, antibodies)

• Short-term
  – It is only around as long as we are given the
    substances




                                                    152
Characteristics of the Adaptive
     Immune Response




                              153
Characteristics of the Adaptive Immune
               Response
• Self tolerance: Discrimination of self and non-self
• Self-regulation: the immune system can initiate,
  maintain, and down-regulate without help of the
  nervous system (NS) or other systems
   – This is one of the only body systems that can do this
• Specificity: Targets very specific antigens
• Diversity: Can invoke specific immune response to
  an indefinite number of different antigens
• Memory: Makes memory cells (only IS and CNS
  have memory)
                                                             154
Major Functional Cells of the
Adaptive Immune Response




                                155
    Major Functional Cells of the
    Adaptive Immune Response
B-Cell Lymphocytes including:
• Plasma B Cells
• Memory B Cells

T-Cell Lymphocytes including:
• T-Helper Cells
• Cytotoxic T Cells

                                    156
Antigens




           157
                              Antigens
Antigens: Initiators of Immune response and
  Adaptive Immunity

Antigens (aka immunogens) are:
• Substances foreign to the host which stimulate an immune response
• Antigens are ligands that are recognized by receptors on immune
  cells and by antibodies (immunoglobulin's; Igs)
• Often proteins or polysaccharides and less often lipids or nucleic
  acids.
   – Your DNA can actually act as an antigen in some instances, but it is not as
     common



                                                                                   158
Locations of Antigens




                        159
       Locations of Antigens
Antigens are found on:
• Bacteria, fungi, protozoa, parasites or non-
  microbial agents such as pollens, plant
  resin, insect venom, transplanted organ.




                                            160
Antigens
Diagram




           161
Antigens
Diagram




           162
Immunity Antigens




                    163
                  Immunity Antigens
• Many antigens are large molecules.
   – The antigen may be recognized by multiple antibodies at a number
     of locations
• Small fragments, often single sites, can be immunologically
  active. These sites are called epitopes.
• Antigens or epitopes are what is recognized by a specific Ig
  receptor
• Often a single antigen can have several antigenic sites. A
  distinct lymphocyte clonal population will recognize each
  distinct site
• Certain small molecules are unable to stimulate an immune
  response (Haptens) .
   – Too small to stimulate a response
   – These molecules can become immunologically active when bound to a carrier
      protein (e.g., penicillin hypersensitivity)
        • The body is now able to recognize the body as foreign and can
          recognize the antigen as foreign

                                                                                 164
Major Histocompatibility
       Complex




                           165
          Major Histocompatibility
                 Complex
• Cell surface molecules which provide a mechanism to
  differentiate “self” from “non-self”
     – The portion of your DNA that encodes for your MHC molecules is
       what makes you unique
         • This becomes important when we want to transplant organs because one
           person’s MHC may not match the other person’s MHC

• Region of genetic information that makes each individual of
  one and the same species different:
•   aka Human Leukocyte Antigens (HLA) since these were first identified
    on white blood cells.
•   Cytotoxic T cells and helper T cells both recognize MHC complexed
    with antigen
•   Because these molecules (MHC) play a big role in transplant rejection,
    they are also termed antigens in this instance.


                                                                                  166
MHC-II Complex




                 167
                 MHC-II Molecules
• Found primarily on antigen-presenting cells (APC’s) such as
  macrophages, dendritic cells, and B lymphocytes.

• MHC-II molecule contains a groove in them that contains a
  recognition site which binds a peptide fragment of an antigen from
  pathogens engulfed/digested during phagocytosis.

• The APC comes into contact with a virus, recognizes an antigen on
  the virus, activates complement, opsonizes the virus, which
  increases the phagocytic action, the phagocytic cell ingests the
  virus, takes the foreign antigen and then presents it on itself
    – Holds the antigens out to a T helper cell and the T cell agrees that it is
      foreign
    – The T cell then calls in other players to become immune to it and calls
      cytokines to destroy the cell

• Helper T cells (Th) recognize these complexes on APC’s and they
  become activated.
                                                                               168
MHC-II Molecules




                   169
MHC-I Molecules




                  170
                       MHC-I Molecules
•   Found on cell surface glycoproteins on most nucleated cells of body.
•   They Interact with antigen receptor and CD8 molecule on cytotoxic T
    lymphocytes (Tc)
     – Tc cells are responsible for direct cell killing

•   The virus enters a cell and the cell presents the virus on the outside
     – Indicates that the cell has been infected with the virus

•   Cytotoxic T-cells (Tc) become activated only when they are presented with
    an antigen associated with a Class I MHC.
•   MHC has the ability to present antigens on our body cells
     – Distinguishes self from non-self

•   Antigen peptides associate with MHC-I in cells that are infected with
    intracellular pathogen
     – E.g., as virus multiplies, small degraded peptides associate with MHC-I and are
       transported to the membrane.
     – This antigen-MHC complex communicates with the Tc cell and the host cell is
       destroyed.

                                                                                    171
                  MHC-I Molecules
                     Diagram




Virus particles




                                    172
Comparison of MHC-II and
        MHC-I




                           173
174
Humoral vs. Cell-Mediated
       Immunity




                            175
       Humoral vs. Cell-Mediated
              Immunity
• Lymphocyte stem cells are located in the
  bone marrow

  1. Lymphocytes which migrate through lymphoid
     tissue  B cells (make antibodies)

  2.   Lymphocytes which migrate through the thymus 
       T lymphocytes (cell-mediators)



                                                    176
 Development of B
Lymphocytes and T
   Lymphocytes



                    177
Development of B Lymphocytes
     and T Lymphocytes
• If the bone marrow lymph cell matures in the thymus, it
  is called a T cell
   – T cells can become memory, cytotoxic, or helper T cells
   – Cell mediated immune response

• If the cell leaves the bone marrow and goes to the
  bursal equivalent tissue (lymphoid tissue), it becomes
  a B cell
   – Can become a memory cell or antibodies (plasma cell)
   – Produce cells that make antibodies
      • A part of the humoral immune system




                                                               178
 Development of B
Lymphocytes and T
   Lymphocytes
     Diagram



                    179
180
B Lymphocytes




                181
                     B Lymphocytes
Responsible for antibody production (humoral immunity)

Function
• Identified by the presence of surface immunoglobulin (antibody)
  bound to them permanently that functions as an antigen receptor,
  particular CD proteins and complement receptors
• Plasma cells are antibody factories
• Manufactures specific antibodies that target bacteria, neutralize
  bacterial toxins, prevent viral infection, and produce immediate
  allergic response
• Formed from bone marrow stem cells
  --Pre-maturation in the bone marrow to immature precursor cells
  --Genetic rearrangement results in a unique receptor and type of effector
   antibody (IgM or IgD)
         - shown an antigen by a presenting cell
                  - the plasma cell recognizes the cell with the antigen and
                  inside the cell itself, a genetic rearrangement is made so that 182
                  the antibody will only ever recognize the specific antigen
Differentiation of B
   Lymphocytes




                       183
              Differentiation of B
                 Lymphocytes
•Mature B Lymphocytes leave the bone marrow, enter the
blood and travel to peripheral tissues

• B lymphocytes bind antigens with help of Th and then
differentiate into

1. Plasma cells (large # of cells: which are responsible for antibody
   secretion)
2. Memory cells (small # of cells: pre-programmed to become
   plasma cells from that clonal line)




                                                                    184
B Lymphocytes
   Diagram




                185
186
B Lymphocytes
  Description




                187
                 B Lymphocytes
                   Description
• Helper T cell can present cell to B cell and the B cell
  can recognize the antigen from then on
   – Later, if the B cell recognizes the antigen it can do
     something about it

• A mature B cell produces a memory B cell and a
  plasma cell

• A memory just remembers what antigen it should
  recognize and then goes dormant

• Plasma cells are not dormant like memory cells
   – Produce antibodies
   – Look for the foreign antigen                            188
Activation of B Lymphocytes




                              189
190
        Antibodies
Primary Immune Response




                          191
                    Antibodies
            Primary Immune Response
• Sensitization
   – Antigen is first introduced into the body
   – Antigen is processed by Antigen Presenting Cells (APCs)
• Activation
   – MHC complexed Antigen is recognized by Th cells
• Differentiation
   – Activated Th cells release cytokines and trigger B
     lymphocytes to proliferate into a clonal line of plasma cells
     and memory cells
   – Plasma cells release antibody
• This time course has a significant lag time.

                                                                192
        Antibodies
Secondary Immune Response




                        193
               Antibodies
       Secondary Immune Response

• Once re-challenged with antigen at a later
  time, the memory cells recognize antigen
  and respond quickly to the antigen.

• Immunization boosters (e.g., tetanus) take
  advantage of this response.



                                           194
  Primary and Secondary B
Lymphocyte Immune Response
           Diagram




                             195
Primary and Secondary B Lymphocyte Immune Response
                     Diagram




                                                196
  Primary and Secondary B
Lymphocyte Immune Response
         Description




                             197
    Primary and Secondary B Lymphocyte
             Immune Response
                 Description
• A B cell that has never been exposed to an antigen but is
  mature is naïve
   – A naïve B cell does not know what it wants to be yet

• The first time that a B cell sees the antigen, the antigen has to
  be injected, complement binds to it, presented to helper T
  cells, B cell is sensitizes and becomes a memory B cell or a
  plasma cell
   – Takes about two weeks
   – Creates a bunch of memory B cells that remember the antigen
     and can mount a quicker response

• The second exposure is very quick because the memory B
  cell is present
   – Secondary immune response
                                                                   198
  Antibody Types
(Immunoglobulins)




                    199
            Antibody Types
          (Immunoglobulins)
•   IgA
•   IgM
•   IgD
•   IgE
•   IgG




                              200
IgA Antibodies




                 201
            IgA Antibodies
•Secretory (saliva, colostrum, bronchial,
 pancreatic, GI,prostatic, vaginal).

•Prevents viral and bacterial binding to
 epithelial tissues.

•IgA is first line of defense in mucosal
 tissues
  –Secretions can bind the pathogen so that it
   does not enter the vasculature

                                                 202
IgM Antibodies




                 203
            IgM Antibodies
•Large macromolecular Ig complex.

•First Ig made in response to an antigen.

•First antibody type made by a newborn
  –During fetal development, the fetus is
   receiving Igs passively




                                            204
IgD Antibodies




                 205
            IgD Antibodies
• Found primarily on cell membranes of B
  Lymphocytes.

• Acts as antigen receptor.




                                           206
IgE Antibodies




                 207
            IgE Antibodies
• Involved in inflammation, allergic
  responses and combating parasitic
  infections.

• Antigen binding to IgE on mast cells or
  basophils causes histamine release

• Important in inflammation and allergies.
                                             208
IgG Antibodies




                 209
             IgG Antibodies
• Most abundant circulating antibody in blood

• Only Ab that can cross the placenta.

• Ig in fetus/newborn is passed from mother
  until new Ig’s are formed by newborn.

• Targets bacteria, virus and toxins.

• Can activate complement.
                                                210
Maternal vs. Fetal/newborn
    IgG Contributions




                             211
Maternal vs. Fetal/newborn IgG
          Contributions




                                 212
T Lymphocytes




                213
                         T Lymphocytes
              Responsible for cell mediated immunity
• Formed from bone marrow stem cells which migrate to the
  thymus (T) for maturation. Mature T-cells then migrate to
  peripheral lymphoid organs
      •   Genetic modification to form a unique T-cell antigen
          receptor (clonal selection)
          •      Produce a specific receptor (T cell receptor) which
                 recognizes the antigen
      •       TCR: two polypeptide grooves that recognize
              processed antigen-peptide MHC complexes.
      •       -TCR is associated with CD3 cell surface molecules,
              which is a protein
          •      The TCR is bound to the CD3 protein
      •       Subpopulations of CD proteins offer further cell
              specificity:
          •      1. CD4+: T-helper cells (have CD3 and CD4)
          •      2. CD8+: T-cytotoxic (have CD3 and CD8)
                                                                       214
Types of T Lymphocytes




                         215
     Types of T Lymphocytes
• CD4 cells: T helper cells

• CD8 cells: Cytotoxic T cells




                                 216
Helper T Cell




                217
                  Helper T Cell
• Helper T cell (Th or CD4+ cell): Regulatory cells

Master switch of immune system
• Do not do direct cell killing
• Recognizes Ag-MHC-II complex
• Once activated by APC, they release cytokines that
  affect most other cells of immune system
   – Orchestrate the immune response by telling the B cells
     what to become and by secreting cytokines
• Activated Th cell can differentiate into
  distinct sub-populations based on cytokines secreted
  by the APC.


                                                              218
Cytotoxic T Cell




                   219
                  Cytotoxic T Cell
Cytotoxic T cell (Tc or CD8+ cell): Effector
• Get activated by Th cells
• Recognize Ag-MHC-I complex on infected cells
• Destroy infected cells by releasing cytolytic enzymes,
  toxic cytokines, Perforins
• Important in controlling intracellular pathogens (bacteria
  and viruses)
• Do a lot of self vs. nonself checking
• Natural killer cells do not check the MHC, like the
  cytotoxic cells do
   – Tc cells are much more selective


                                                           220
Types of T Lymphocytes
       Diagram




                         221
222
Cell-mediated Immunity




                         223
        Cell-mediated Immunity
• Provide protection from viruses, bacteria, cancer cells

• T lymphocytes and macrophages predominate

• APC cells present MHCII-Ag to Th cells
   – Th cells become activated by antigen recognition and by
     interleukin-2.

   – Th cells then produce IL-2 and IL-4 to drive clonal expansion of
     Th cells and Interferon-gamma which activate Tc cells (cytotoxic
     T cells).

• Tc cells and macrophages form the basis of the cell-
  mediated cell destruction in the immune response, while
  Th cells modulate the process.                        224
Cell-mediated and Humoral
        Immunity
         Diagram



                            225
226
Cell-mediated and Humoral
        Immunity
       Description



                            227
 Cell-mediated and Humoral Immunity
             Description
• T helper cell recognizes the antigen that becomes
  activated, releases cytokines, sensitizes B cell, helper
  T cell recruits Tc cell, Tc cell can kill cells that
  recognize the MHC-1 antigen

• When B cells are sensitized, they either make memory
  cells or plasma cells

• T helper cells orchestrate virtually the entire process

• Both the memory cells and the other cells all have
  specific genetic memory for the certain antigen
                                                            228
Natural Killer Cells




                       229
              Natural Killer Cells
   Natural Killer Cells: an effector cell important in innate immunity.
• Small % of lymphocytes
• Can bind with antibody coated target cell  Antibody
  dependent cell-mediated cytotoxicity (ADCC)
• Can attack virus-infected cells or cancer cells without help or
  activation first
• Can recognize antigen without MHC restrictions
   – Difference between NK and T cells
• NO MEMORY
• Activity is regulated by cytokines, prostaglandins and
  thromboxane locally
• Release NK perforins, enzymes, and toxic cytokines to
  destroy target cells
   – They do not phagocytize

                                                                          230
Cytotoxic C vs. Natural Killer
           Cells




                                 231
   Cytotoxic C vs. Natural Killer
              Cells
Cytotoxic T Cells    Natural Killer Cells
• T lymphocyte       • Small percentage of
                       lymphocytes
• Do phagocytize     • Do not phagocytize
• Do have memory        – Release NK perforins,
                          enzymes, and toxic
• Do require MHC-1        cytokines to destroy target
                          cells
  restrictions       • Do not have memory
                     • Do not require MHC
                       restrictions
                     • Activity is regulated by
                       cytokines, prostaglandins
                       and thromboxane locally

                                                    232
Secondary Lymphoid Organs




                            233
  Secondary Lymphoid Organs
• Connected by blood and lymphatic vessels

• The secondary lymphoid organs provide an
  environment for lymphocytes to circulate, meet and
  fight antigens, spread antigens, encounter
  information

• Lymphocytes circulate constantly between blood 
  tissuelymphatic ducts  lymph nodes  thoracic
  duct –bloodstream
   – This is a good place for immunosurveillance

                                                   234
Lymph Nodes




              235
              Lymph Nodes
• Localize and prevent the spread of infection

• Contain both B and T cells

• Discrete locations of concentration of the
  lymphatic system

• Good place to aggregate and look for
  antigens
                                                 236
Spleen




         237
                Spleen
• Filters and processes antigens from blood
• Contains both B and T cells
• Functions as a reservoir for blood (red
  pulp)
• RBC “graveyard”  Hb released
• Macrophages and other phagocytic cells in
  white pulp
• Some parts innervated by sympathetic NS

                                         238
MALT




       239
                       MALT
   MALT (Mucosa –Associated Lymphoid Tissue):
• Major portion of secondary lymphoid tissues
• Non-encapsulates areas of lymphoid tissue
• Around mucosal membranes of respiratory,
  digestive, and urogenital tract.
   – Located at the interface of the environment and your
     body
• Contains T and B lymphocytes.
• E.g. tonsils, Peyer’s Patches (intestine),
  appendix
                                                        240
Secondary Lymphoid Organs
         Diagram




                            241
242
Immunodeficiency




                   243
            Immunodeficiency
• Abnormality in one or more branches of the Immune
  System (IS)

          1. Antibody-mediated (aka Humoral)
          2. Cell mediated
          3. Complement
          4. Phagocytosis

   – Increased vulnerability to opportunistic disease
     (infections and malignancies)
   – Diseases may cross or more of these branches

                                                        244
Normal Immunity in Infancy




                             245
Normal Immunity in Infancy
• After 6 months, maternal
  Igs 

• Between 1-2 years adult
  levels of all Igs are
  reached

• First Ig to be produced by
  maturing plasma cells is
  IgM

• IgM can transform into
  other Igs after antigenic
                               246
  stimulus
Primary Immunodeficiency




                           247
    Primary Immunodeficiency
• Transient hypogammaglobulinemia

• Defective congenital or inherited genes
  are rare and include
  – X linked agammaglobulinemia – Bruton’s=

  – DiGeorge Syndrome – lack of thymus
    development


  – Severe combined immunodeficiency
    syndrome (SCID)                           248
      Transient
Hypogammaglobulinemia




                        249
              Transient
        Hypogammaglobulinemia
Transient Hypogammaglobulinemia of
Infancy (B cell) involves:
•   The transient lack of antibodies in infancy
•   Delay in maturation process of B cells
•   Prolonged deficiency in IgG levels
•   Fewer B cells = fewer Antibodies
    •   More prone to opportunistic infections
        –   Increased amount of upper respiratory and middle ear
            infections
• Resolves at ± 2-4 yrs old
    •   Many children are not specifically tested for this
        because it resolves
                                                                   250
X-Linked Agammaglobulinemia
          Bruton’s




                          251
X-Linked Agammaglobulinemia
          Bruton’s
• Impaired ability of B lymphocytes to
  produce antibodies

• More common in males

• Have much less or no humoral immunity




                                          252
DiGeorge Syndrome




                    253
        DiGeorge Syndrome
• Affects T cells
  – Problems with the development of the thymus

• Impaired ability of T-helper lymphocytes
  (Th cells) to orchestrate an immune
  response or Cytotoxic T- lymphocytes (Tc
  cells) to mount a cytotoxic response



                                             254
    Severe Combined
Immunodeficiency Syndrome
         (SCID)



                            255
    Severe Combined Immunodeficiency
             Syndrome (SCID)
• No T or B cells !!!

• Tends to be in the stem cell lineage of
  these cells

• Need a bone marrow transplant




                                            256
Secondary Immunodeficiency




                             257
     Secondary Immunodeficiency
Acquired later in life due to:
• Selective loss of Igs through GI and/or GU tracts
    - e.g. Nephrotic Syndrome
            - the kidney is not able to obtain protein, so it passes into the urine
                      - loss of the protein leads to a loss of antibodies
• Chronic or recurrent infections with:
      –   AIDS
      –   Viruses, Fungi, Intracellular bacteria (TB)
      –   Burden the immune system
• Neoplasia (e.g. Lymphoma)
      – Lead to an inability to produce cells in the bone marrow
•    Iatrogenic causes (e.g. immunosuppressive therapy with
     cyclosporine)
      – You are treating one issue by suppressing the immune system but are creating
        another problem
• Stress and aging
• Drug abuse and maternal alcoholism
      – Due to alterations in the nervous system and the liver’s ability to            258
        produce proteins
Hypersensitivity Disorders




                             259
      Hypersensitivity Disorders
•Exaggerated immune responses to allergens (Ags)
   –Ex. pollen


•Leads to inflammation and tissue injury caused by
inhalation (depends on the amount of antigen and how we
come into contact with the antigen), ingestion, skin contact,
or injection

•Sensitization depends on:
   –Allergen
   –Exposure
   –Person’s genetic make-up


                                                           260
Types of Hypersensitivity
       Disorders




                            261
Hypersensitivity Disorders
• Four Types
 Type I: IgE-mediated hypersensitivity

 Type II: Antibody-mediated hypersensitivity

 Type III: Immune Complex Allergic Disease

 Type IV: T-cell mediated Hypersensitivity




                                               262
Type I Hypersensitivity
    IgE Mediated




                          263
          Type I Hypersensitivity
              IgE Mediated
• Appears within few minutes; fades within few hours

• Minor symptoms : localized, pruritic (itchy), skin wheal

• Severe symptoms: vasodilation and
  bronchoconstriction (=anaphylactic shock)

• Triggered by the binding of an antigen (allergen) to mast cell
  or basophil with attached IgE, leading to degranulation:
   – The antigen-antibody complex binds to a mast cell or basophil and
     that cell degranulates
       • Release a lot of histamine


• Ex. pollen allergy in the spring

                                                                     264
Type I Hypersensitivity
  Primary Response




                          265
    Type I Hypersensitivity
      Primary Response
Primary Phase: Fast-acting or primary
 mediators:
  • Histamine
  • Complement
  • Acetylcholine causes bronchoconstriction
    and vasodilation of small vessels
  • Eosinophil chemotactic factor (ECF)
    causes chemotaxis
  • Kinins: Prepared from inactive form
  • Can result in a significant, localized event

                                                   266
Type I Hypersensitivity
Secondary Response




                          267
    Type I Hypersensitivity
    Secondary Response
Secondary Phase: Slow-reacting or
 secondary substances of anaphylaxis:
  • Leukotrienes: lipid based; cause
    vasodilation, chemotaxis,
    bronchioconstriction
  • Cytokines: ( Interleukins and Tumor
    Necrosis Factor)
  • Platelet activating factor (PAF)
  • Prostaglandins (PGs) : lipid based



                                          268
Type I Hypersensitivity
       Diagram




                          269
270
 Types of IgE-mediated
Hypersensitivity Disorders




                             271
     Types of IgE-mediated
    Hypersensitivity Disorders
• Atopic

• Non-atopic




                                 272
 Types of IgE-mediated
Hypersensitivity Disorders
    Atopic Disorders



                             273
     Types of IgE-mediated
    Hypersensitivity Disorders
        Atopic Disorders
• Atopic = Local Anaphylaxis:
 • Local reaction to common allergens
     – Ex. allergic rhinnitus
     – Organ specific
     – High IgE serum levels and high basophil and
       mast cell numbers
     – Allergic rhinitis, allergic asthma, atopic
       dermatitis (eczema), certain food allergies,
       certain aspects of latex allergy
     – Diagnosis needs careful history, identification
       of nasal eosinophilia and skin testing.
                                                     274
 Types of IgE-mediated
Hypersensitivity Disorders
  Non-atopic Disorders



                             275
    Types of IgE-mediated
   Hypersensitivity Disorders
     Non-atopic Disorders
• Non-atopic = Systemic Anaphylaxis:
    – Not organ specific
    – Can be lethal (anaphylactic shock)
    – Common allergens are : Nuts, shellfish,
      penicillin, insect stings, etc.
    – Urticaria (hives) , pruritis (itching) ,
      bronchospasm (asthma), angioedema,
      contraction of GI and uterine muscles,
      laryngeal edema  asphyxiation and
      erythema                                   276
Antihistamines (H1 blockers)




                               277
  Antihistamines (H1 blockers)
• Two types of histamine receptors – H1
  and H2
  – H1 receptor blockers block the effects of
    histamine that are responsible for allergy
    symptoms (Type 1 hypersensitivity)
  – H2 blockers block the secretion of stomach
    acid (to be covered in a later lecture)



                                                 278
H1 Blockers




              279
                 H1 Blockers
• See Table 66-1 in Lehne
• Most first generation H1 blockers also
  block muscarinic receptors and have
  sedating properties
• Second generation H1 blockers (non-
  sedating antihistamines) do not cross the
  BBB very well.
  – Also do not block muscarinic receptors very
    well.
     • More tolerated with fewer side effects     280
H1 Blockers Block Histamine
        Receptors




                              281
  H1 Blockers Block Histamine
          Receptors
• Block symptoms of allergies that are due
  to histamine
  – Remember, histamine is only one of the
    mediators of Type 1 hypersensitivity
• Symptoms of a cold are caused by viral
  infection, not Type 1 hypersensitivity
  – H1 blockers are probably not useful for cold
    symptoms.
  – However, in many combination cold pills, you
    will find an antihistamine.                  282
Type II Hypersensitivity
  Antibody-Mediated




                           283
              Type II Hypersensitivity
                Antibody-Mediated
• Have preformed reactions to an antigen and then when
  you come into contact with the antigen, you have a
  reaction

Types of Type II Antibody-mediated Disorders:
• ABO antigens in blood transfusion reactions
• Rh Antigens of fetus (erythroblastosis fetalis)
• Drug Reactions (e.g., penicillin)
   – Binds to a carrier in the body and then is recognized
• Autoimmune hemolytic anemia: Antibodies against own
  RBCs
• Graft rejections, parasites (lysis without phagocytosis)
   – Mount a hypersensitivity reaction to the antigens in the
     graft
                                                           284
Type II Hypersensitivity
 Antibody Cytotoxicity




                           285
       Type II Hypersensitivity
        Antibody Cytotoxicity
• IgG and IgM antibodies interact with antigens on
  cell surfaces. This activates complement and/or
  Antibody-dependent cell-mediated cytotoxicity:
  e.g., the activation of Natural Killer Cells (NK)
   – Involves antigens on RBCs, neutrophils,
     platelets, basement membranes
   – Involves stimulation or inhibition of cellular
     function




                                                 286
Type II Hypersensitivity
        Injuries




                           287
       Type II Hypersensitivity
               Injuries
• Complement fixation  inflammation,
  opsonization with phagocytosis, or cell lysis
   – Antibody-dependent cell-mediated
     cytotoxicity: Null or NK cells recognize
     antibodies and release toxins causing cell
     lysis




                                                  288
 Type III Hypersensitivity
Complex Allergic Disease
  Triggers and Injuries



                             289
           Type III Hypersensitivity
          Complex Allergic Disease
            Triggers and Injuries
Triggered by:
• Formation of insoluble Antigen-antibody
  complexes in blood circulation or extravascular
  sites, leading to:
    - Precipitate formation
    - Complement activation

• Injuries due to:
   – Change in blood flow
   – Vascular permeability
   – Inflammatory response
                                                    290
  Type III Hypersensitivity
Antigen-Antibody Complexes




                              291
    Type III Hypersensitivity
  Antigen-Antibody Complexes
• Antigen-Antibody complexes are formed and
  – Get deposited in the blood vessels, which activates
    complement, which in turn causes vasculitis
    (inflammation of the vessels), and leads to vessel wall
    damage.

• Antigens bound to antibodies bind with one
  another and become insoluble complexes, settle
  down toward the endothelium, activate
  complement, the MAC complex goes into the
  endothelium and kills the endothelium
  – Leads to a vasculitis secondary to lack of blood flow

                                                            292
Type III Hypersensitivity
        Diagram




                            293
294
Immune Complex Disorders
       Localized




                           295
     Immune Complex Disorders
            Localized
•    At site of injection, localized tissue
    necrosis due to blockage by Ag-Ab
    complexes that precipitate

•    Onset within 4-10 hrs




                                              296
Results of Immune Complex
         Disorders




                            297
Results of Immune Complex
         Disorders
Vasculitis:
- If Blood vessel bursts  hemorrhage into surrounding tissue
- If Blood vessel becomes occluded  ischemia  necrosis


Immune complex pneumonitis (Allergic
        Pneumonitis):
-       Probably involves Type IV hypersensitivity as well
-       E.g., Miner’s, farmer’s, pigeon breeder’s, mushroom lung
-       Individuals inhale the antigen that results in vasculitis in the
        respiratory tract
    -       Cough, malaise, fever, dyspnea, radiographic densities


                                                                       298
Immune Complex Disorders
       Systemic




                           299
   Immune Complex Disorders
          Systemic
• Systemic response
• Urticaria (hives), edema, rash, fever
• Antigen-antibody complexes precipitate in blood
  vessels, joints, heart, kidneys. This leads to pain
  and edema in these areas (rheumatoid arthritis)
• Usually temporary; symptoms go away when the
  antigen is taken away
• Penicillin, foods, drugs, insect venoms can initiate
  the response.
• Need preformed antibodies to drive this response

                                                     300
Type IV Hypersensitivity
    T-cell Mediated




                           301
         Type IV Hypersensitivity
             T-cell Mediated
• Delayed: 24-72 hours after exposure
• Triggered by specifically sensitized T lymphocytes
  (CD4 memory cells) and Not antibodies
• The T cell system is presensitized to the antigen
   – When the antigen is present, there is an exaggerated
     response
• T cell and Antigen combine and release
  lymphokines which attracts macrophages.
  Macrophages then release monokines which leads
  to inflammation.
• Direct attack by Tc cells can also occur
• Not tissue specific
   – Depends on where the antigen is and the route of the
     administration

                                                            302
Type IV Hypersensitivity
    T-cell Mediated
       Diagram



                           303
304
Types of T-cell Mediated
       Immunity




                           305
     Types of T-cell Mediated
            Immunity
Contact dermatitis:
– e.g. poison ivy  erythema, papules, vesicles, warm, swollen,
  exudation, crusting
     • Not immediate, have been sensitized where it came into contact with skin
     • Takes a while to react because the T cells must be activated
– Latex allergy


 Response to the Tuberculin test:
 - Erythema and induration within 8-12 hours at site of injection


 Granulomatous inflammation with large,
insoluble Antigens:
- e.g. splinter, silica, tuberculosis bacteria
                                                                                  306
Which type of hypersensitivity
 disorder is related to ABO
 antigen blood transfusion
         reactions?



                                 307
   Which type of hypersensitivity
 disorder is related to ABO antigen
    blood transfusion reactions?
                                    25% 25% 25% 25%
1. Antibody
   mediated
2. IgE-mediated
3. Immune Complex
   Allergic Disease
4. T-cell mediated




                                                                            d
                                                    d
                                      d




                                                               ...



                                                                         te
                                                 te
                                   te




                                                            lle



                                                                         ia
                                              ia
                                ia




                                                        A



                                                                       ed
                                              ed
                               ed




                                                       ex



                                                                     lm
                                             m
                              m




                                                     pl
                                          E-
                            y




                                                                   l
                                                   om



                                                                ce
                          od



                                     Ig




                                                              T-
                         ib




                                                   C
                      nt




                                               e
                      A




                                             un
                                            m
                                          Im
Host vs. Graft Disease




                         309
Host vs. Graft Disease

•       Recipient attacks donor cells: e.g. you receive
        liver and your body rejects it

•       Cell-mediated responses: Th  Tc (Type IV
        Hypersensitivity)
    –     Tc and Th severely respond to the graft




                                                      310
Results of Host vs. Graft
        Disease




                            311
      Results of Host vs. Graft
              Disease
•   Th cells activate the production of antibodies
    through B cells which circulate and target graft
    vasculature. This causes:
    1. Complement-mediated toxicity (Type II
       reaction)
    2. Antigen-antibody complexes (Type III
       reaction)
    3. Antibody-mediated cytolysis (Type II
       reaction)

                                                  312
Autoimmunity




               313
                          Autoimmunity
•   Breakdown of immune system  cannot differentiate between self and
    non-self
     –   Breakdown in the immunosurveillance

•   Can lead to localized or systemic injury depending on what you have an
    autoimmune reaction to

•   Response may be T cell-mediated or involve Ag-Ab complexes that
    precipitate Type III or even anaphylactic response depending on the
    severity and type of reaction

•   More common in females and elderly

•   May be tissue specific: e.g. Graves’ disease (thyroid), myasthenia
    gravis (neuromuscular junction)

•   May be system specific: e.g. systemic lupus erythematosis (SLE),
    rheumatoid arthritis

•   Causes unclear:
     – Possibly due to an inheritance in the alterations of MHC Genes.    314
     – However, individuals may still need a trigger event
Rheumatoid Arthritis (RA)




                            315
Rheumatoid Arthritis (RA)
• Systemic, inflammatory disease

• Affects ± 0.3 – 1.5% of population

•   Affects all races
• Women 2-3 times more than men

• Prevalence  with age:
     – Peak for women: 40-60 YOA
     – Peak for men: 30-50 YOA

• Etiology of RA
     – Not sure, but:
        • Many patients (not all) have specific genes (although some people have
           these genes and do not develop RA)
        • Environment: virus, bacteria
                                                                                   316
Rheumatoid Arthritis (RA)
      Diagram




                            317
318
Pathogenesis of Rheumatoid
       Arthritis (RA)




                             319
         Pathogenesis of Rheumatoid Arthritis (RA)
•   70-80% of patients have Rheumatoid Factor (RF): RF is an Antigen against
    IgG that is found in blood, synovial fluid and synovial membrane
     –   Antigen against protein in own body that is highly enriched in the synovial fluid and
         membrane, it makes sense that you would get joint problems
           •   Problems could also happen in similar membranes around the heart and lung



•   RF + IgG form immune complexes which leads to synovitis and the
    development of PANNUS (granulation tissue)  swollen and puffy joint
     –   Complex activates complement, settles in joints, recruits immune cells, inflammation, MAC


•   Cartilage and subchondral bone get destroyed

•   Surrounding muscles, ligaments and tendons weaken, and cannot function
    well.

•   Reduced joint motion and possibly ankylosis (fusion of joint) due to
    calcification and inflammation

•   Pannus differentiates RA from other arthritis (granulation tissue)
     –   This is what separates RA from OA


                                                                                                     320
 Signs and Symptoms of
Rheumatoid Arthritis (RA)




                            321
     Signs and Symptoms of
    Rheumatoid Arthritis (RA)
•   Mild: May last only few months or 1-2 yrs

•   Moderate: Flares and remissions

•   Severe: Active most of time for many yrs;
    causes serious joint damage and disability




                                                 322
Extra-articular Manifestations
             in RA
          Systemic




                                 323
Extra-articular Manifestations in RA
                     Systemic
•   Fatigue
•   Anorexia
•   Weight loss
•   Aching of muscles and joints
•   Stiffness
•    ESR due to significant burden
•   Anemia
•   Rheumatoid nodules: Bumps under skin close to
    joints. There are Granulomatous lesions that develop
    around small BVs ± ¼ of patients
•   Vasculitis, pleuritis, pericarditis


                                                      324
Emotional and Mental
  Symptoms of RA




                       325
      Emotional and Mental
        Symptoms of RA
•   Depression

•   Anxiety

•   Feelings of helplessness

•   Can’t perform ADL or work (arthritis
    self-management programs help
    patients cope)

                                           326
Diagnosis of RA




                  327
           Diagnosis of RA
1. Morning stiffness for > 1 hour
2. Swelling of >3 joints for >6 weeks
3. Symmetric joint swelling
  - because this is systemically based, it is
  present bilaterally
4. Rheumatoid nodules present (around
  small blood vessels)
5. Presence of serum rheumatoid factor
  (RF) antibody

                                                328
Evaluation of RA




                   329
            Evaluation of RA
• History

• Physical exam

• Radiographs are NOT diagnostic

• Lab tests (RF is NOT diagnostic)

• Check for Cloudy synovial fluid
                                     330
Goals of RA Treatment




                        331
      Goals of RA Treatment
• Relieve pain

• Reduce inflammation (anti-inflammatories)

• Slow down or stop joint damage

• Improve a patient’s sense of well-being
  and ability to function (Educate patient!)

                                               332
Treatment of RA
    Lifestyle




                  333
         Treatment of RA
             Lifestyle
•   Rest and exercise
•   Joint care
•   Stress reduction
•   Balanced diet




                           334
Treatment of RA
  Medications




                  335
           Treatment of RA
             Medications
•   NSAIDs
•   DMARDs (Disease Modifying Anti-Rheumatic
    Drugs) reduce joint destruction and retard
    disease progression
      • Reduced number of immune cells (methotrexate)
      • Block cytokines (anti-TNF (anti-cytokine); Etanercept)
        decreases inflammation
•   Immunosuppressants
•   Corticosteroids
•   New approach: Combination therapy

                                                                 336
Treatment of RA
    Surgery




                  337
       Treatment of RA
           Surgery
• Joint replacement

• Tendon reconstruction and
  synovectomy

• Arthrodesis (joint fusion)

                               338
Osteoarthritis




                 339
               Osteoarthritis
• Degenerative Joint Disease; Osteoarthrosis
• Most common form of arthritis
• Second to CV disease for chronic disability in
  US
• 1/3 of all adults in US show OA on X-rays
• Only affects articular cartilage and
  subchondral bone of diarthrotic joints
  – Shows reduction of bone and calcification, not
    pannus
                                                     340
Influences on Osteoarthritis




                               341
   Influences on Osteoarthritis
• In age: Men affected at younger age
  than women, but rate for affected
  women exceeds that of men by
  middle age

• Occupation

• Obesity

• Heredity (e.g. hand OA)
                                        342
Causes of Osteoarthritis




                           343
      Causes of Osteoarthritis
• Primary OA: Idiopathic; no identified risk factors

• Secondary OA: Associated with risk factors:
   • Joint stress (obesity, sports injuries)
   • Congenital abnormalities
   • Joint instability leads to chronic stress of
     a joint over time
   • Trauma


                                                   344
Pathogenesis of OA




                     345
           Pathogenesis of OA
•Joint cannot absorb mechanical stress.
  – This leads chondrocytes to release cytokines which
  causes release of enzymes and more joint damage.
  –Articular cartilage breaks down and wears away.
  –Bone wears on bone  Pain, swelling, loss of motion.

•Other results:
  –Osteophytes
  –Fragments
  –Microfractures
  –Loss of capability to secrete synovial fluid
  –Joint immobility  lubrication  more cartilage atrophy


                                                             346
Signs of Symptoms of OA




                          347
    Signs of Symptoms of OA
•Sudden or insidious

•Mild synovitis

•Mostly hips, knees, lumbar and cervical
regions, proximal and distal joints of hand, first
CMC joint and first MTP joint

•Joint enlargement

•Joint feels hard
                                                 348
Process of OA
   Diagram




                349
350
Warning Signs of OA




                      351
        Warning Signs of OA
• Steady or intermittent pain in a joint
• Stiffness > bed
• Joint swelling or tenderness in 1 or > joints
• Crepitus (a grinding sound in the joint)
• Hot, red, or tender?? No….. probably not
  OA, maybe RA
• Not always pain



                                             352
Diagnosis of OA




                  353
            Diagnosis of OA
• No single test

• History

• X-rays

• Lab tests (usually normal)


                               354
Treatment Goals of OA




                        355
      Treatment Goals of OA
• Control pain

• Improve joint care

• Maintain acceptable body weight

• Achieve healthy life style


                                    356
Joint with OA
  Diagram




                357
358
Differences between RA and
             OA




                             359
    Differences between RA and
                 OA
OA is different because...
•   No or very little synovitis
•   No systemic signs and symptoms
•   Normal synovial fluid (no pannus)
•   Affects cartilage and subchondral bone only
•   Not always symmetric
•   Not always polyarticular
•   Hardness around joint
                                                  360
Differences between RA and
             OA
          Diagram



                             361
:




    362
Congenital Immunodeficiency




                              363
    Congenital Immunodeficiency
•       Congenital (primary)
    –     Lymphocyte development disrupted in fetus or embryo (rare)
          •   T cell
          •   B cells




                                                                   364
Acquired (Secondary)
 Immunodeficiency




                       365
          Acquired (Secondary)
           Immunodeficiency
1. Immune /inflammatory deficiency after birth.
2. Not related to genetic defects:
•   Nutritional
    •     Need folate in order to help properly dividing cells develop healthily
•       Iatrogenic Deficiencies
•       Medical treatment
         - chemotherapy
         - immunosuppression
•       Trauma:
         - Burn victims
•       Stress
         - sympathetic lymphoid innervation
         - cortisol
•       Acquired Immunodeficiency Syndrome (AIDS)


                                                                               366
Human Immunodeficiency
     Virus (HIV)




                         367
    Human Immunodeficiency Virus
              (HIV)
A retrovirus unknown until early 1980s:
•   Contains only RNA; no DNA
•   Most infections caused by HIV-1 variant of the virus
•   Cannot replicate outside of living host cells

Infection leads to relentless destruction of immune system  AIDS:
   One of leading causes of death in US and in other countries

Patients infected with HIV are at risk for illness and death from:
•   Opportunistic infections
•   Neoplastic complications

Mainly present in blood, genital secretions, breast milk

Presence in saliva, tears, urine, sweat is not important or a high risk for
   transmission
                                                                        368
Transmission of HIV




                      369
                Transmission of HIV
• Sex: Semen, vaginal secretions, cervical secretions, and rectal secretions

• Blood: Open wound, injection with contaminated needle, blood transfusion
     (<1985)

•    Perinatally:
1.   In utero
2.   Inoculation during birth and delivery due to the mixing of blood
3.   Breast-feeding

•    NOT TRANSMITTED BY:
1. Casual contact
2. Mosquitoes or other insects


• Occupational transmission is very rare

                                                                           370
HIV Structure




                371
 HIV Structure
• Viral genome: Two short strands of RNA with
  three major genes that encode enzymes:
   – Reverse transcriptase (Makes mistakes 
     mutations  HIV variants)
   – Protease: breaks down proteins
   – Integrase: incorporates viral DNA into host
     genome to make more virus



• Outer lipid envelope with surface projections
  containing gp120 antigen which binds to CD4
  proteins of Th
   – CD4 are part of the T cell receptor in T helper cells
   – When the HIV virus gets into the body, it seeks out
     cells with the CD4 receptor, and the virus
     incorporates into contents into the host’s cell, lying
     dormant and waiting for more virus to be made

                                                              372
Mechanism of HIV Infection
      Description




                             373
      Mechanism of HIV Infection
            Description
•   Gp 120 antigen binds to CD4 cell
•   Fusion of HIV virus with cell membrane
•   RNA is incorporated
•   Reverse transcriptase makes DNA
•   Protease breaks down proteins
•   Integrase integrates proteins into host’s viral genome

• Cell lies dormant
• Cell at some time decides to make all of the proteins for HIV,
  virus buds out of the host cell, killing the host cell (CD4) in the
  process, the virus incorporates some of the host’s cell
  markers with it, helping it to further evade detection
    • Kills T helper cells, which orchestrate the immune system,
      release cytokines

                                                                   374
Mechanism of HIV Infection
        Diagram




                             375
376
Mechanism of Infection
 Detailed Description




                         377
          Mechanism of Infection
           Detailed Description
•   gp120 of virus binds to CD4 molecule
     - virus and host membranes fuse
     - virus enters host and sheds protein coat
•   Viral RNA is converted to viral DNA with reverse transcriptase
•   After integration of proviral DNA, virus may remain latent for
    some time
•   Eventually, productive virus synthesis occurs  virions released
    (protease)  T cell dies
•   Virions invade other CD4 cells  fast amplification  first few
    years, destruction of millions of T cells  release of millions of
    virions, but all T cells still get replaced
•   After several years, however, T cell numbers begin to crash to
    very low levels.

                                                                         378
Clinical Course of HIV
       Infection




                         379
Clinical Course of HIV Infection

• Latest classification based on CD4 cell count rather than
  signs and symptoms

• Primary or Initial Infection:
  -Window Phase: Between time of exposure to time Abs are detectable

• Latent period 8-10 years
  -Acute Phase
  -Latent Phase
   -Clinically Apparent Disease with Constitutional Symptoms


• Full-blown AIDS

                                                                  380
Primary Infection with HIV




                             381
 Primary Infection with HIV
• Immune response  HIV Abs (2 weeks to 6 months after infection) 
  Patient will test positive for HIV Ab (seropositive)

• Acute phase that may go unnoticed or produce mild disease:
   –   Acute mononucleosis-like syndrome (acute retroviral syndrome)
   –   Fever, myalgia, sore throat, nausea, lethargy, lymphadenopathy, rash, headache
   –   Symptoms  after 1-2 months
   –   Burst of viral replication (viremia)  CD4 count  (as low as 200), but then immune
       system tries to control viral replication  viremia   CD4 cells rebound, but not to
       pre-infection levels
        •   The individual is then asymptomatic because the CD4 cells increase



• Both humoral and cell mediated responses play role in the primary
  infection phase

• Sometimes mistaken for flu or cold
                                                                                          382
Viral Load in the Blood
       (Viremia)




                          383
Viral Load in the Blood (Viremia)




                                    384
Clinical Latency of HIV




                          385
Clinical Latency of HIV

• May last 10 years

• Disease concentrates in lymph nodes
   – Lymph nodes are areas where T cell congregate


• Asymptomatic and little detectable virus in blood
   – There will not be an active viremia


• Gradual fall in CD4 count as more virus occurs

• Patient still tests seropositive for antibodies against HIV
                                                            386
Clinically Apparent HIV
        Disease




                          387
Clinically Apparent HIV Disease
• Persistent generalized lymphadenopathy (PGL)
  (>3mos.) : Lymph nodes swell; not life threatening

• Fatigue, weight loss, night sweats, diarrhea, fungal
  infections of mouth and nails
   – These occur because immunosurveillance is decreased


• CD4 count < 500 cells/l (normal 800-1000)




                                                           388
Full-Blown or Clinical AIDS




                              389
    Full-Blown or Clinical AIDS
• CD4 count < 200 cells/l

• Confirmed by a variety of lab tests

• Opportunistic infections (risk correlated with CD4
  count)




                                                  390
Full-Blown or Clinical AIDS
          Lungs




                              391
   Full-Blown or Clinical AIDS
             Lungs
• PCP: Pneumocystis carinii pneumoni:
 Fever, chest pain, sputum,
 tachypnea


• TB: Mycobacterium tuberculosis



                                    392
Full-Blown or Clinical AIDS
         GI Tract




                              393
   Full-Blown or Clinical AIDS
            GI Tract
• Esophageal candidiasis, thrush: painful
  swallowing; retrosternal pain

• Diarrhea or gastroenteritis




                                            394
Full-Blown or Clinical AIDS
      Nervous System




                              395
   Full-Blown or Clinical AIDS
         Nervous System
• Toxoplasmosis: Toxoplasma gondii
  (parasite): affects CNS; fever, altered
 mental status, seizures, motor deficits


• AIDS Dementia: Ataxia, tremor,
 spasticity, paraplegia

• Cerebral atrophy
                                            396
Full-Blown or Clinical AIDS
 Neoplastic Malignancies




                              397
  Full-Blown or Clinical AIDS
   Neoplastic Malignancies
• Kaposi’s sarcoma
 - Neoplasm of endothelium
 - Opportunistic cancer
 - Small discolored elevated tumors of skin
 that invade viscera


• Lymphoma
                                          398
Full-Blown or Clinical AIDS
    Wasting Syndrome




                              399
    Full-Blown or Clinical AIDS
        Wasting Syndrome
Wasting syndrome (Cachexia):
  – Emaciation, severe diarrhea, chronic weakness, fever, fatigue,
    lethargy, severe negative nitrogen balance




                                                                     400
Patients with HIV disease are
   most likely to die from:




                                401
Patients with HIV disease are most
         likely to die from:
1. Neoplastic
                                               33% 33% 33%
   complications
2. Opportunistic
   infections
3. Neurological disease
4. Wasting

All of the above




                                                              ..
                                               .




                                                                               ...
                                             ..




                                                           tio




                                                                             at
                                          at




                                                            c
                                          ic




                                                                             ic
                                                         fe
                                        pl




                                                                          pl
                                                      in
                                       m




                                                                         m
                                                     ic




                                                                       co
                                     co




                                                   st
                                 tic




                                                                     ic
                                                 ni




                                                                   st
                                               tu
                                 s




                                                                   a
                              la




                                             or




                                                                pl
                             p




                                           pp




                                                           eo
                          eo




                                          O
                          N




                                                          N
Diagnosis of HIV Infection




                             403
    Diagnosis of HIV Infection
• HIV antibody test (ELISA: enzyme-linked
  immunosorbent assay):
   – Detects Abs produced in response to HIV
     infection
• Western Blot (done if ELISA is positive):
   – Identifies Abs specific to viral Ags
• CD4 count
• Based on symptoms

                                               404
Treatment of AIDS




                    405
Treatment of AIDS
• No cure; no vaccine

• Treat opportunistic infections with drugs

• Therapeutic management:
   –   Inhibit reverse transcriptase
   –   Inhibit protease
   –   Inhibit integrase
   –   Prevent transcription from host DNA into viral RNA
   –   Vaccine??



                                                            406
Treatment of HIV
    Diagram




                   407
1.Fusion inhibitor

2.RT inhibitor

3.Protease inhibitor

4.Under development

5. Integrase inhibitor




                         408

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:32
posted:9/19/2012
language:English
pages:408