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Cellular Biology

VIEWS: 8 PAGES: 48

									                             Chapter 8

Alterations in Immunity and
        Inflammation



Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.
                            Hypersensitivity
   Altered immunologic response to an antigen;
    results in disease/damage to host
       Allergy
         • Deleterious effects of hypersensitivity to environmental
           (exogenous) antigens
       Autoimmunity
         • Disturbance in immunologic tolerance of self-antigens
       Alloimmunity
         • Immune reaction to tissues of another individual



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                          Hypersensitivity
   Characterized by the immune mechanism
       Type I
         • IgE mediated
       Type II
         • Tissue-specific reactions
       Type III
         • Immune complex mediated
       Type IV
         • Cell mediated




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                        Hypersensitivity
   Immediate hypersensitivity reactions
   Anaphylaxis
   Delayed hypersensitivity reactions




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           Type I Hypersensitivity
   IgE mediated
   Against environmental antigens (allergens)
   IgE binds to Fc receptors on surface of mast
    cells (cytotropic antibody)
   Histamine release
       H1 and H2 receptors
       Antihistamines




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                                             Type I



Mast Cell




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           Type I Hypersensitivity
   Manifestations
       Itching
       Urticaria
       Conjunctivitis
       Rhinitis
       Hypotension
       Bronchospasm
       Dysrhythmias
       GI cramps and malabsorption



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Clinical Symptoms of IgE Type I
           Reactions




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                               Anaphylaxis
   Severity depends on level of sensitization
   Can be very small dose (ordinary skin testing)
   Within minutes after exposure:
     Itching
     Hives
     Skin erythema
     Contraction of respiratory bronchioles
     Laryngeal edema results in hoarseness
     Vomiting, abdominal cramps, diarrhea
     Laryngeal obstruction


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           Type I Hypersensitivity
   Genetic predisposition
   Tests
     Food challenges
     Skin tests
     Laboratory tests

   Desensitization
       IgG-blocking antibodies




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           Type II Hypersensitivity
   Tissue specific
       Specific cell or tissue (tissue-specific antigens) is
        the target of an immune response
   Five mechanisms
       Cell is destroyed by antibodies and complement
       Cell destruction through phagocytosis
       Soluble antigen may enter the circulation and
        deposit on tissues
       Antibody-dependent cell-mediated cytotoxicity
       Causes target cell malfunction


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                    Phagocytosis




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Neutrophil-Mediated Damage




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Antibody-Dependent Cell-Mediated
           Cytotoxicity




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Induced Cell Malfunction




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          Type III Hypersensitivity
   Immune complex mediated
   Antigen-antibody complexes formed in the
    circulation and later deposited in vessel walls
    or extravascular tissues
   Not organ specific
   Immune complex clearance
       Large—macrophages
       Small—renal clearance
       Intermediate—deposit in tissues

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Type III Hypersensitivity




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    Examples of Immune Complex–
      Mediated Diseases: Type III
   Systemic lupus erythematosus
   Vasculitis
   Poststreptococcal glomerulonephritis
   Acute glomerulonephritis
   Reactive arthritis




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            Type IV Hypersensitivity
   Mediated by T lymphocytes
       Destruction of the tissue usually caused by direct
        killing by toxins from Tc cells
       Th1 cells produce cytokines that recruit phagocytes,
        especially macrophages
   Examples
       Acute graft rejection, skin test for TB, contact allergic
        reactions, and some autoimmune diseases




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Type IV Hypersensitivity




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Type IV Hypersensitivity




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           Antigenic Targets of
         Hypersensitivity Reactions
   Allergy
        Environmental Ags
   Autoimmunity
        Self Ags, with damage to host tissues
   Alloimmunity
        Against foreign tissue Ags




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                                            Allergy
   Environmental antigens that cause atypical
    immunologic responses in genetically
    predisposed individuals
       Pollens, molds, fungi, foods, animals, etc.
   Allergen contained within a particle too large to
    be phagocytosed or is protected by a
    nonallergenic coat
   Original insult is apparent


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                               Autoimmunity
   Breakdown of tolerance
       Body recognizes self-antigens as foreign
   Sequestered antigen
       Self-antigens not normally seen by the immune
        system
   Infectious disease
       Molecular mimicry
   Neoantigen
       Haptens become immunogenic when they bind to
        host proteins

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                              Autoimmunity
   Forbidden clone
       During differentiation, lymphocytes produce
        receptors that react with self-antigens
   Ineffective peripheral tolerance
       Defects in regulatory cells
   Original insult
   Genetic factors




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           Autoimmune Examples
   Systemic lupus erythematosus (SLE)
       Chronic multisystem inflammatory disease
       Autoantibodies against:
         • Nucleic acids, erythrocytes, coagulation proteins,
           phospholipids, lymphocytes, platelets, etc.
       Deposition of circulating immune complexes
        containing antibody against host DNA
       More common in females




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    Systemic Lupus Erythematosus
   Clinical manifestations
       Arthralgias or arthritis (90% of individuals)
       Vasculitis and rash (70%–80%)
       Renal disease (40%–50%)
       Hematologic changes (50%)
       Cardiovascular disease (30%–50%)




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    Systemic Lupus Erythematosus
   Eleven common findings
   Serial or simultaneous presence of at least
    four indicates SLE
       Facial (malar) rash, discoid rash, photosensitivity,
        oral or nasopharyngeal ulcers, nonerosive
        arthritis, serositis, renal disorders, neurologic
        disorders, hematologic disorders, immunologic
        disorders, and presence of antinuclear antibodies
        (ANAs)



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                                Alloimmunity
   Immune system reacts with antigens on the
    tissue of other genetically dissimilar members
    of the same species
       Transient neonatal alloimmunity
         • Fetus expresses parental antigens not found in the
           mother
       Transplant rejection and transfusion reactions




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                             Graft Rejection
   Transplant rejection classified according to time
       Hyperacute
         • Immediate and rare
         • Preexisting antibody to the antigens of the graft
       Acute
         • Cell-mediated response against unmatched HLA antigens
       Chronic
         • Months or years
         • Inflammatory damage to endothelial cells of vessels due to
            a weak cell-mediated reaction against minor HLA antigens



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               Transfusion Reactions
   Antibodies against blood group antigens
   ABO system
       Two major carbohydrate antigens
         • A and B (codominant)
         • Individuals have naturally occurring antibodies to the A
              and B antigens they lack
         •    Anti-A and anti-B antibody production is induced by
              similar antigens on naturally occurring bacteria in the
              intestinal tract
         •    Antibodies are usually of the IgM class
         •    O blood type (universal donor)
         •    AB blood type (universal recipient)

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            ABO Incompatibility:
            Alloimmune Reaction
Blood                Ag                           Ab                         Incompatible with
type                                                                            blood type
   A                   A                        Anti-B                                       B, AB


   B                   B                        Anti-A                                       A, AB


   AB               A+B                         None                                          None
Universal
recipient

   O               None               Anti-A and Anti-B                                    A, B, AB
Universal
 donor

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                        Immunodeficiencies
   Result of impaired function of T cells, B cells,
    phagocytes and/or complement
       Primary (genetic)
       Secondary (acquired)
       Hallmark is recurrent infections often with
        opportunistic organisms
       Type of infection can lead to diagnosis of type of
        deficiency
         • Gonorrhea suggests complement deficiency
         • Viral infections suggest T cell deficiency


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                  Immunodeficiencies
   Clinical presentation
       Development of unusual or recurrent, severe
        infections
       T cell deficiencies
          • Viral, fungal, yeast, and atypical microorganisms
       B cell and phagocyte deficiencies
          • Microorganisms requiring opsonization
       Complement deficiencies




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                 Immunodeficiencies

   Primary (congenital) immunodeficiency
       Genetic anomaly
   Secondary (acquired) immunodeficiency
       Caused by another illness
       More common




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     Primary Immunodeficiencies
   Most are the result of a single gene defect
   Five groups
     B lymphocyte deficiencies
     T lymphocyte deficiencies
     Combined T and B cell deficiencies
     Complement defects
     Phagocyte defects




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        B Lymphocyte Deficiencies
   Hypogammaglobulinemia or
    agammaglobulinemia
     Bruton agammaglobulinemia
     Autosomal agammaglobulinemia
     X-linked hyper-IgM syndrome
     IgG subclass deficiency
     Selective IgA deficiency
     Common variable immunodeficiency




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        T Lymphocyte Deficiencies
   DiGeorge syndrome
       Partial or complete absence of T cell immunity
   Chronic mucocutaneous candidiasis




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           Combined T- and B-Cell
               Deficiencies
   Severe combined immunodeficiency (SCID)
     Reticular dysgenesis
        • Most severe form
     Adenosine deaminase (ADA) deficiency
     X-linked SCID
     JAK3 deficiency
     IL-7 receptor deficiency
     Purine nucleoside phosphorylase deficiency




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           Combined T and B Cell
               Deficiencies
   RAG-1 or RAG-2 deficiency
   Bare lymphocyte deficiency
   MHC class I and II deficiency
   Wiskott-Aldrich syndrome
   Ataxia-telangiectasia (AT)




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       Complement Deficiencies
   C3 deficiency
   Mannose-binding lectin (MBL) deficiency
   Properdin deficiency
   Factor I and factor H deficiency
   C9 deficiency




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Complement Deficiencies




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          Phagocytic Deficiencies
   Severe congenital neutropenia
       Cyclic neutropenia
   Leukocyte adhesion deficiency (LAD)
   C3 receptor deficiency
   Chédiak-Higashi syndrome
   Myeloperoxidase deficiency
       Chronic granulomatous disease




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        Secondary Deficiencies
   Also referred to as acquired deficiencies
   Far more common than primary deficiencies




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          Secondary Deficiencies
   Causes
     Normal physiology conditions
     Psychologic stress
     Dietary insufficiencies
     Malignancies
     Physical trauma
     Medical treatments
     Infections
     AIDS




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    Graft-Versus-Host (GVH) Disease

   Immunocompromised individuals are at risk for
    GVH disease
       T cells in the graft are mature and capable of cell-
        mediated destruction tissues within the recipient
       Not a problem if patient is immunocompetent




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           Evaluation of Immunity
   Complete blood count (CBC) with a differential
       Subpopulations of lymphocytes
   Quantitative determination of immunoglobulins
       Subpopulations of immunoglobulins
   Assay for total complement
   Skin tests




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                 Treatment for
               Immunodeficiencies
   Gamma-globulin therapy
   Transplantation or transfusion
   Treatment with soluble immune mediators
   Gene therapy




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