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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
Large—macrophages Small—renal clearance Intermediate—deposit 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 body’s 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 <200 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
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