Alterations in Immunity and Inflammation Including Hypersensitivities Chapter

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

Hypersensitivity o Altered immunologic response to an antigen that results in disease or damage to the host n Allergy o n Autoimmunity o n Deleterious effects of hypersensitivity to environmental (exogenous) antigens Disturbance in the immunologic tolerance of selfantigens Alloimmunity o Immune reaction to tissues of another individual 2 Mosby items and derived items © 2006 by Mosby, Inc.

Hypersensitivity o Characterized by the immune mechanism n Type I o n Type II o n Tissue-specific reactions Type III o n Ig. E mediated Immune complex mediated Type IV o Cell mediated 3 Mosby items and derived items © 2006 by Mosby, Inc.

Hypersensitivity o o o Immediate hypersensitivity reactions Anaphylaxis Delayed hypersensitivity reactions 4 Mosby items and derived items © 2006 by Mosby, Inc.

Type I Hypersensitivity o o Ig. E mediated Against environmental antigens (allergens) Ig. E binds to Fc receptors on surface of mast cells (cytotropic antibody) Histamine release n n H 1 and H 2 receptors Antihistamines 5 Mosby items and derived items © 2006 by Mosby, Inc.

Type I Hypersensitivity o Manifestations n n n n Itching Urticaria Conjunctivitis Rhinitis Hypotension Bronchospasm Dysrhythmias GI cramps and malabsorption 6 Mosby items and derived items © 2006 by Mosby, Inc.

Type I Hypersensitivity o o Genetic predisposition Tests n n n o Food challenges Skin tests Laboratory tests Desensitization n Ig. G-blocking antibodies 7 Mosby items and derived items © 2006 by Mosby, Inc.

Type I Hypersensitivity 8 Mosby items and derived items © 2006 by Mosby, Inc.

Type II Hypersensitivity o Tissue specific n o Specific cell or tissue (tissue-specific antigens) is the target of an immune response Five mechanisms n n n 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 9 Mosby items and derived items © 2006 by Mosby, Inc.

Type II Hypersensitivity 10 Mosby items and derived items © 2006 by Mosby, Inc.

Type III Hypersensitivity o o 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 n n n Large—macrophages Small—renal clearance Intermediate—deposit in tissues 11 Mosby items and derived items © 2006 by Mosby, Inc.

Type III Hypersensitivity o o o Immune complex disease Serum sickness Arthus reaction 12 Mosby items and derived items © 2006 by Mosby, Inc.

Type III Hypersensitivity 13 Mosby items and derived items © 2006 by Mosby, Inc.

Type IV Hypersensitivity o o Does not involve antibody Cytotoxic T lymphocytes or lymphokine producing Th 1 cells n o Direct killing by Tc or recruitment of phagocytic cells by Th 1 cells Examples n Acute graft rejection, skin test for TB, contact allergic reactions, and some autoimmune diseases 14 Mosby items and derived items © 2006 by Mosby, Inc.

Type IV Hypersensitivity 15 Mosby items and derived items © 2006 by Mosby, Inc.

Type IV Hypersensitivity 16 Mosby items and derived items © 2006 by Mosby, Inc.

Allergy o Environmental antigens that cause atypical immunologic responses in genetically predisposed individuals n o o 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 17 Mosby items and derived items © 2006 by Mosby, Inc.

Autoimmunity o Breakdown of tolerance n o Sequestered antigen n o Self-antigens not normally seen by the immune system Infectious disease n o Body recognizes self-antigens as foreign Molecular mimicry Neoantigen n Haptens become immunogenic when they bind to host proteins 18 Mosby items and derived items © 2006 by Mosby, Inc.

Autoimmunity o Forbidden clone n o Ineffective peripheral tolerance n o o During differentiation, lymphocytes produce receptor that react with self-antigens Defects in regulatory cells Original insult Genetic factors 19 Mosby items and derived items © 2006 by Mosby, Inc.

Alloimmunity o Immune system reacts with antigens on the tissue of other genetically dissimilar members of the same species n Transient neonatal alloimmunity o n Fetus expresses parental antigens not found in the mother Transplant rejection and transfusion reactions 20 Mosby items and derived items © 2006 by Mosby, Inc.

Autoimmune Examples o Systemic lupus erythematosus (SLE) n n Chronic multisystem inflammatory disease Autoantibodies against: o n n Nucleic acids, erythrocytes, coagulation proteins, phospholipids, lymphocytes, platelets, etc. Deposition of circulating immune complexes containing antibody against host DNA More common in females 21 Mosby items and derived items © 2006 by Mosby, Inc.

Systemic Lupus Erythematosus o Clinical manifestations n n n Arthralgias or arthritis (90% of individuals) Vasculitis and rash (70%-80%) Renal disease (40%-50%) Hematologic changes (50%) Cardiovascular disease (30%-50%) 22 Mosby items and derived items © 2006 by Mosby, Inc.

Systemic Lupus Erythematosus o o Eleven common findings Serial or simultaneous presence of at least four indicates SLE n 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) 23 Mosby items and derived items © 2006 by Mosby, Inc.

Graft Rejection o Transplant rejection is classified according to time n Hyperacute o o n Acute o n Immediate and rare Preexisting antibody to the antigens of the graft Cell-mediated immune response against unmatched HLA antigens Chronic o o Months or years Inflammatory damage to endothelial cells of vessels due to a weak cell-mediated reaction against minor HLA antigens 24 Mosby items and derived items © 2006 by Mosby, Inc.

Graft Rejection 25 Mosby items and derived items © 2006 by Mosby, Inc.

Transfusion Reactions o o Antibodies against blood group antigens ABO system n Two major carbohydrate antigens o o o 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 Ig. M class O blood type (universal donor) AB blood type (universal recipient) 26 Mosby items and derived items © 2006 by Mosby, Inc.

ABO System 27 Mosby items and derived items © 2006 by Mosby, Inc.

Immune Deficiencies o o Failure of immune mechanisms of selfdefense Primary (congenital) immunodeficiency n o Genetic anomaly Secondary (acquired) immunodeficiency n n Caused by another illness More common 28 Mosby items and derived items © 2006 by Mosby, Inc.

Immune Deficiencies o Clinical presentation n n Development of unusual or recurrent, severe infections T cell deficiencies o n B cell and phagocyte deficiencies o n Viral, fungal, yeast, and atypical microorganisms Microorganisms requiring opsonization Complement deficiencies 29 Mosby items and derived items © 2006 by Mosby, Inc.

Primary Immune Deficiencies o o Most are the result of a single gene defect Five groups n n n B lymphocyte deficiencies T lymphocyte deficiencies Combined T and B cell deficiencies Complement defects Phagocyte defects 30 Mosby items and derived items © 2006 by Mosby, Inc.

B Lymphocyte Deficiencies o Hypogammaglobulinemia or agammaglobulinemia n n n Bruton agammaglobulinemia Autosomal agammaglobulinemia X-linked hyper-Ig. M syndrome Ig. G subclass deficiency Selective Ig. A deficiency Common variable immune deficiency 31 Mosby items and derived items © 2006 by Mosby, Inc.

T Lymphocyte Deficiencies o Di. George syndrome n o Partial or complete absence of T cell immunity Chronic mucocutaneous candidiasis 32 Mosby items and derived items © 2006 by Mosby, Inc.

Combined T and B Cell Deficiencies o Severe combined immunodeficiency (SCID) n Reticular dysgenesis o n n n Most severe form Adenosine deaminase (ADA) deficiency X-linked SCID JAK 3 deficiency IL-7 receptor deficiency Purine nucleoside phosphorylase deficiency 33 Mosby items and derived items © 2006 by Mosby, Inc.

Combined T and B Cell Deficiencies o o o RAG-1 or RAG-2 deficiency Bare lymphocyte deficiency MHC class I and II deficiency Wiskott-Aldrich syndrome Ataxia-telangiectasia (AT) 34 Mosby items and derived items © 2006 by Mosby, Inc.

Complement Deficiencies o o o C 3 deficiency Mannose-binding lectin (MBL) deficiency Properdin deficiency Factor I and factor H deficiency C 9 deficiency 35 Mosby items and derived items © 2006 by Mosby, Inc.

Complement Deficiencies 36 Mosby items and derived items © 2006 by Mosby, Inc.

Phagocytic Deficiencies o Severe congenital neutropenia n o o Cyclic neutropenia Leukocyte adhesion deficiencies (LAD) C 3 receptor deficiency Chédiak-Higashi syndrome Myeloperoxidase deficiency n Chronic granulomatous disease 37 Mosby items and derived items © 2006 by Mosby, Inc.

Secondary Deficiencies o o Also referred to as acquired deficiencies Far more common than primary deficiencies 38 Mosby items and derived items © 2006 by Mosby, Inc.

Secondary Deficiencies o Causes n n n n Normal physiology conditions Psychological stress Dietary insufficiencies Malignancies Physical trauma Medical treatments Infections Acquired immunodeficiency syndrome (AIDS) 39 Mosby items and derived items © 2006 by Mosby, Inc.

Acquired Immunodeficiency Syndrome (AIDS) o Syndrome caused by a viral disease n n n Human immunodeficiency virus (HIV) Depletes the body’s Th cells Incidence o Worldwide n o 5 million per year United States n n About 31, 000 cases per year 400, 000 currently living with AIDS 40 Mosby items and derived items © 2006 by Mosby, Inc.

Acquired Immunodeficiency Syndrome (AIDS) o o Effective antiviral therapies have made AIDS a chronic disease Epidemiology n n Blood-borne pathogen Increasing faster in women than men 41 Mosby items and derived items © 2006 by Mosby, Inc.

Acquired Immunodeficiency Syndrome (AIDS) o Pathogenesis n Retrovirus o o o Genetic information is in the form of RNA Contains reverse transcriptase to convert RNA into double-stranded DNA Integrase 42 Mosby items and derived items © 2006 by Mosby, Inc.

Human Immunodeficiency Virus (HIV) 43 Mosby items and derived items © 2006 by Mosby, Inc.

Human Immunodeficiency Virus (HIV) o Structure n gp 120 protein binds to the CD 4 molecule found primarily on the surface of helper T cells o CD 4+ Th cells n n n Typically 800 to 1000 cells/mm 3 Reverses CD 4/CD 8 ratio Co-receptors o CXCR 4 and CCR 5 n Strains can be selective for these receptors; influences the tropism of the target cells 44 Mosby items and derived items © 2006 by Mosby, Inc.

Human Immunodeficiency Virus (HIV) 45 Mosby items and derived items © 2006 by Mosby, Inc.

Human Immunodeficiency Virus (HIV) 46 Mosby items and derived items © 2006 by Mosby, Inc.

Human Immunodeficiency Virus (HIV) o Clinical manifestations n n Serologically negative, serologically positive but asymptomatic, early stages of HIV, or AIDS Window period Th cells <200 cells/mm 3 Diagnosis of AIDS is made in association with various clinical conditions o Atypical or opportunistic infections, and cancer 47 Mosby items and derived items © 2006 by Mosby, Inc.

Human Immunodeficiency Virus (HIV) 48 Mosby items and derived items © 2006 by Mosby, Inc.

Human Immunodeficiency Virus (HIV) o Treatment and prevention n Highly active antiretroviral therapy (HAART) o o n New drugs o o n Reverse transcriptase inhibitors Protease inhibitors Entrance inhibitors Integrase inhibitors Vaccine development 49 Mosby items and derived items © 2006 by Mosby, Inc.

Graft-vs. -Host Disease (GVHD) o Immunocompromised individuals are at risk for graft-vs. -host disease n n T cells in the graft are mature and capable of cellmediated destruction tissues within the recipient Not a problem if patient is immunocompetent 50 Mosby items and derived items © 2006 by Mosby, Inc.

Evaluation of Immunity o Complete blood count (CBC) with a differential n o Quantitative determination of immunoglobulins n o o Subpopulations of lymphocytes Subpopulations of immunoglobulins Assay for total complement Skin tests 51 Mosby items and derived items © 2006 by Mosby, Inc.

Treatment for Immunodeficiencies o o Gamma-globulin therapy Transplantation or transfusion Treatment with soluble immune mediators Gene therapy 52 Mosby items and derived items © 2006 by Mosby, Inc.