Alterations in Immunity and Inflammation (Including Hypersensitivities)

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Alterations in Immunity and Inflammation
(Including Hypersensitivities)

• Chapter 8

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Hypersensitivity

• Altered immunologic response to an antigen that
  results in disease or damage to the host
• Allergy
• Deleterious effects of hypersensitivity to
  environmental (exogenous) antigens
• Autoimmunity
• Disturbance in the 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 Hypersensitivity

• Manifestations
• Itching
• Urticaria
• Conjunctivitis
• Rhinitis
• Hypotension
• Bronchospasm
• Dysrhythmias
• GI cramps and malabsorption

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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 I Hypersensitivity
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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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Type II Hypersensitivity
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Type III Hypersensitivity

• Immune complex mediated
• Antigen-antibody complexes are formed in the
  circulation and are later deposited in vessel
  walls or extravascular tissues
• Not organ specific
• Immune complex clearance
• Largemacrophages
• Smallrenal clearance
• Intermediatedeposit in tissues

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Type III Hypersensitivity

• Immune complex disease
• Serum sickness
• Arthus reaction

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Type III Hypersensitivity
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Type IV Hypersensitivity

• Does not involve antibody
• Cytotoxic T lymphocytes or lymphokine producing
  Th1 cells
• Direct killing by Tc or recruitment of phagocytic
  cells by Th1 cells
• 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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Allergy

• Environmental antigens that cause atypical
  immunologic responses in genetically predisposed
  individuals
• Pollens, molds and fungi, foods, animals, etc.
• Allergen is 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
  receptor that react with self-antigens
• Ineffective peripheral tolerance
• Defects in regulatory cells
• Original insult
• Genetic factors

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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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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 rash (malar rash), discoid rash,
  photosensitivity, oral or nasopharyngeal ulcers,
  nonerosive arthritis, serositis, renal disorder,
  neurologic disorder, hematologic disorders,
  immunologic disorders, and presence of
  antinuclear antibodies (ANA)

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Graft Rejection

• Transplant rejection is classified according to
  time
• Hyperacute
• Immediate and rare
• Preexisting antibody to the antigens of the graft
• Acute
• Cell-mediated immune 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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Graft Rejection
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Transfusion Reactions

• Antibodies against blood group antigens
• ABO system
• Two major carbohydrate antigens
• A and B (co-dominant)
• 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 System
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Immune Deficiencies

• Failure of immune mechanisms of self-defense
• Primary (congenital) immunodeficiency
• Genetic anomaly
• Secondary (acquired) immunodeficiency
• Caused by another illness
• More common

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Immune Deficiencies

• 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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Primary Immune Deficiencies

• 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 immune deficiency

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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 deficiencies (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
• Psychological stress
• Dietary insufficiencies
• Malignancies
• Physical trauma
• Medical treatments
• Infections
• Acquired immunodeficiency syndrome (AIDS)

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Acquired Immunodeficiency Syndrome (AIDS)

• Syndrome caused by a viral disease
• Human immunodeficiency virus (HIV)
• Depletes the bodys Th cells
• Incidence
• Worldwide
• 5 million per year
• United States
• About 31,000 cases per year
• 400,000 currently living with AIDS

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Acquired Immunodeficiency Syndrome (AIDS)

• Effective antiviral therapies have made AIDS a
  chronic disease
• Epidemiology
• Blood-borne pathogen
• Increasing faster in women than men

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Acquired Immunodeficiency Syndrome (AIDS)

• Pathogenesis
• Retrovirus
• Genetic information is in the form of RNA
• Contains reverse transcriptase to convert RNA
  into double-stranded DNA
• Integrase

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Human Immunodeficiency Virus (HIV)
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Human Immunodeficiency Virus (HIV)

• Structure
• gp120 protein binds to the CD4 molecule found
  primarily on the surface of helper T cells
• CD4 Th cells
• Typically 800 to 1000 cells/mm3
• Reverses CD4/CD8 ratio
• Co-receptors
• CXCR4 and CCR5
• Strains can be selective for these receptors
  influences the tropism of the target cells

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Human Immunodeficiency Virus (HIV)
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Human Immunodeficiency Virus (HIV)
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Human Immunodeficiency Virus (HIV)

• Clinical manifestations
• Serologically negative, serologically positive
  but asymptomatic, early stages of HIV, or AIDS
• Window period
• Th cells lt200 cells/mm3
• Diagnosis of AIDS is made in association with
  various clinical conditions
• Atypical or opportunistic infections, and cancer

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Human Immunodeficiency Virus (HIV)
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Human Immunodeficiency Virus (HIV)

• Treatment and prevention
• Highly active antiretroviral therapy (HAART)
• Reverse transcriptase inhibitors
• Protease inhibitors
• New drugs
• Entrance inhibitors
• Integrase inhibitors
• Vaccine development

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Graft-vs.-Host Disease (GVHD)

• Immunocompromised individuals are at risk for
  graft-vs.-host 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