1 Alterations in Immunity and Inflammation (Including Hypersensitivities) Chapter 8

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Alterations in Immunity and Inflammation (Including Hypersensitivities)

Chapter 8

Mosby items and derived items © 2006 by Mosby, Inc.

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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) 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) 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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1 Alterations in Immunity and Inflammation (Including Hypersensitivities) Chapter 8