• Hypersensitivity

  •  Excessive response ® significant tissue damage

• Autoimmunity

  • Immunoreactivity against "self" antigens

• Immunodeficiency

  •  Diminished reactivity

• Hypersensitivity

  • Classification:  determined by time required for expression of clinical symptoms following antigen exposure: Immediate, Delayed

• Immediate Hypersensitivity

  • Immediate Hypersensitivity: antibody mediated; symptoms occurring within minutes to a few hours following antigen exposure. Three Categories:

  • Type I:

    • Characteristics type I:

      • Antigen cross-linking of membrane-bound IgE on blood basophils or tissue mast cells

    • Consequences type I:

      • Cellular Degranulation: releasing histamine, leukotrienes, and other mediators)

      • These mediators may induce:

        • Asthma

        • Hives

        • Hayfever

  • Type II:

    • Characteristics:  type II:

      • Antigen-antibody complex formation between foreign antigen +IgM or IgG immunoglobulins

      • Examples:

        • Hashimoto's thyroiditis-slide A

        • Hashimoto's thyroiditis-slide B

    • Occurrence:  type II:

      •  Blood transfusion reactions

      •  Newborn: hemolytic disease

        • Mechanism:

          • antibodies formed «foreign erythrocyte membrane antigens

      •  Drug Induced

    • Consequences-type II:

      • Complement cascade activation

      •  Generation of membrane attack complex ® destroys red blood cells

    • Newborn hemolytic disease:

      •  anti-Rh IgG antibodies (produced by an Rh negative mother):

        1. Cross the placenta

        2. Bind to erythrocytes of Rh-positive fetus;damage fetal erythrocytes

      • Prevention:

        • Administration of anti-Rh antibodies to the mother; 24-48 hours after delivery of the first Rh+ child

    • Drug Induced: Examples --

      •  Penicillin administration to allergic patients

        • Mechanism: penicillin binds to erythrocytes or other host tissue ® neoantigen production of antibodies ® induction complement-mediated cell lysis

        • Repeat administration may cause ® systemic anaphylaxis

  • Type III:

    • Characteristics-type III:

      • Presence of increased antigen-antibody complex concentrations ® tissue damage

      • Example: polyarteritis

      • Complexes activate complement producing components with:

        • Anaphylatoxic / chemotactic actions (C5a, C3a, C4a) which:

          1.  Increase vascular permeability

          2.  Attract neutrophils to the site of complex deposition

             • Complex deposition; neutrophil-release of lytic enzymes may cause:

               1. Skin rash

               2. Glomerulonephritis

               3. Arthritis

Delayed Hypersensitivity

• Cell-mediated;

• Responses: 2-3 days after sensitizing antigen exposure

• Tissue Characteristics:

  •  Local inflammatory response

  •  Significant damage associated with influx of antigen-nonspecific inflammatory cells especially neutrophils and macrophages

• Macrophage/Neutrophil Recruitment-Mediation:

  • TH1-produced cytokines cause:

    1. Extravasation and chemotaxis of neutrophils and circulating monocytes

    2. Induction of myelopoiesis

    3. Macrophage activation causing enhanced:

       • Phagocytic

       • Microbicidal activity

       • Antigen-presenting functions

       • Digestive enzyme release, contributing to extensive tissue damage

•  Delayed-type hypersensitivity however are very effective in combating/eliminating infections caused by intracellular pathogens:

  • M. tuberculosis

  • Leishmania

Autoimmunity

• Introduction

  • Failure to distinguish "self" tissues and cells from foreign ("nonself") antigens

  • Caused by activation of self-reactive T and B lymphocytes which induce:

    • Cell-mediated responses against self antigens

    • Humoral immune responses against self antigens

• Clinical Pathologic Consequences, Autoimmune Disease:  Examples

  • Rheumatoid arthritis

    • IgM antibodies (rheumatoid factors) react with Fc IgG component to form immune complexes.

      • Immune complexes ® split complement components ® joint and kidney inflammation

  • Systemic lupus erythematosus

    • Antibodies produced against:

      • Self DNA

      • Red blood cells

      • Platelets

      • Histones

  • Insulin-dependent diabetes mellitus

    • Cell-mediated autoimmune attack destroys:

      • Insulin-producing pancreatic B cells

      • Activated CD4+ T_DTH :

        • Infiltrate islets of Langerhans

        • Recognize self islet B-cell peptides

• Possible Explanations for Autoimmune Disease:

  • Self-reactive T cell exposure to previously unseen antigens (e.g. myelin basic protein, lens protein)

  • Molecular mimicry in which immune responses are directed against pathogenic antigenic determinants sharing identical or very similar epitopes with normal host tissue.  Example:

    •  Rheumatic fever following Streptococcus pyrogenes infection-- heart muscle damage secondary to host-immune responses against streptococcal antigenic determinants shared with myocardial tissue.

    •  In the case of viral etiology:  Cell-mediated and humoral immune responses are directed against viral epitopes mimicking sequestered self antigens.

  • Inappropriate class II MHC molecular expression on cell membranes that should not and normally do not expressed class II MHC (pancreatic islet B cells).

    • B cells then present "self" peptides to helper T cells ® induce CTL, T_DTH, and B lymphocyte cells ® react against self antigens.

Primary Source: Barbuto, J.A.M, Akporiaye, E.T. and Hersh, E.M. Immunopharmacology, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 916-940

Haynes, B. F., Fauci, A.S. Disorders of the Immune System, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 1753-1776.

Carpenter, C. B. The Major Histocompatibility Gene Complex, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 1777-1782.

Cooper,M.D, and Lawton III, A. R. Primary Immune Deficiency Diseases, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 1783-1791.