IMMUNODEFICIENCY DISORDERS CHAPTER 21
PRIMARY IMMUNODEFICIENCY DISORDERS 2 CONGENITAL. INHERITED.
SECONDARY (ACQUIRED) IMMUNODEFICIENCY DISORDERS 3 MALNUTRITION. INFECTION (HIV). FROM: NEOPLASIA (LYMPHOMA, LEUKEMIA). IMMUNOSUPRESSIVE THERAPY (CHEMO, CORTICOSTEROIDS).
HUMORAL IMMUNODEFICINCY 4 B-Cells, Antibodies (immunoglobulins). Risk for pyogenic infections: Strep. pneumonia, Haemophilus influenza, Staph., Pseudomonas. Not a problem for: intracellular bacteria (chlamydia), protozoa, and fungi. Viruses, except enteroviruses, are handled by cellular (T-Cell) immunity.
HUMORAL IMMUNODEFICINCY 5 PRIMARY: Transient hypogammaglobulinemia of infancy. X-linked hypogammaglobulinemia. Common variable immunodeficiency. Selective deficiency of IgG, IgA, IgM. SECONDARY: Increased loss of immunoglobulins, such is w/ the proteinuria of nephrotic syndrome,
CELL-MEDIATED IMMUNODEFICIENCY 6 THE T-CELLS: T-Cells are immunologically diverse, protect against: fungi, protozoa, viruses, and intracellular bacteria, and control (sort of) malignant cell proliferation. As such, T-Cell-mediated immunodeficiency results in infections or other problems that are more severe than w/ humoral immunodeficiency. Examples: see text.
COMBINED T-CELL T AND B-B CELL IMMUNODEFICIENCY 7 Called Combined Immunodeficiency = CIDS, and Severe Combined Immunodeficiency = SCIDS. Results from a mutation in one of several genes that regulate lymphocyte development or response: lymphocyte receptors, cytokines, or HLA antigens. Range from mild to severe to fatal.
DISORDERS OF THE COMPLEMENT SYSTEM 8 Review- complement involved in innate immunity; promotes chemotaxis, phagocytosis, and opsonization of pathogens; also involved in anaphylactic reactions. Lead to: susceptibility to infection and immune-mediated diseases- collagen vascular diseases, hemolytic anemia, etc.
DISORDERS OF THE COMPLEMENT SYSTEM 9 PRIMARY- inherited. SECONDARY- acquired; develops as a result of another disease.
PRIMARY DISORDERS OF THE COMPLEMENT SYSTEM 10 RESULT IN: susceptibility to infection, or the development of auto-immune diseaseslupus, vasculitis, etc. No treatment; supportive care only; vaccinations against Strep pneumonia, Hemophilus influenza, Neisseria meningitidis.
PRIMARY DISORDERS OF THE COMPLEMENT SYSTEM 11 HEREDITARY ANGIONEUROTIC EDEMA Missing a functional C1 inhibitor activation of the complement system is uncontrolled breakdown of C2 and C4 release of C-kinin, a potent vasodilator. Episodic attacks of swelling of the face, neck, joints, abdomen, lasting from 1-4 days.
PRIMARY DISORDERS OF THE COMPLEMENE SYSTEM 12 HEREDITARY ANGIONEUROTIC EDEMA Can be fatal if swelling involves the trachea.
SECONDARY DISORDERS OF THE COMPLEMENT SYSTEM 13 DUE TO: 1) INCREASED TURNOVER OF COMPLEMENT. 2) DECREASED PRODUCTION OF COMPLEMENT.
PRIMARY DISORDERS OF PHAGOCYTOSIS 14 susceptibility to infections w/ : fungi, Candida, bacteria. Most well-known is Chronic Granulomatous Disease = a spectrum of diseases associated with impaired ability to kill ingested micro-organisms due to impaired ability of phagocytes to generate toxic metabolites of oxygen ie superoxide anion and hydrogen peroxide.
CHRONIC GRANULOMATOUS DISEASE 15 RESULTS IN: Acute and chronic infections of the skin, liver, lung, and other soft tissues, such as w/ Staph. aureus, E. coli, Candida albicans, and Aspergillus. Bone marrow transplant the only cure.
HYPERSENSITIVITY DISORDERS 16 HYPERSENSITIVITY = excessive or inappropriate activation of the immune system. Once exposed to an antigen, these patients are exquisitely sensitive to subsequent exposure. Usually protective, hypersensitivity disorders can be destructive.
HYPERSENSITIVITY DISORDERS 17 4 EXCITING FLAVORS: 1) TYPE I, IMMEDIATE HYPERSENSITIVITY DISORDERS. 2) TYPE II, ANTIBODY-MEDIATED DISORDERS. 3) TYPE III, IMMUNE COMPLEX-MEDIATED DISORDERS. 4) TYPE IV, T-CELL-MEDIATED DISORDERS.
TYPE I, IMMEDIATE HYPERSENSITIVITY DISORDERS 18 IgE-mediated. This is yer allergic reaction. The antigen here is referred to as an allergen. Can result in: 1) An atopic reaction (seasonal allergies). 2) A debilitating reaction (allergies). 3) A life-threatening reaction (anaphylaxis).
TYPE I, IMMEDIATE HYPERSENSITIVITY DISORDERS 19 2 TYPES OF CELLS INVOLVED: 1) MAST CELLS OR BASOPHILS 2) T-HELPER CELLS, SUB-TYPE 2 (TH2) 2 PHASES: 1) THE PRIMARY / INITIAL PHASE 2) THE SECONDARY OR LATE PHASE
TYPE I, IMMEDIATE HYPERSENSITIVITY DISORDERS 20 THE MAST CELL OR BASOPHIL Kick in first. Release: histamine, acetylcholine, chemotactic mediators, and enzymes. HISTAMINE vasodilatation, increased capillary permeability. ACETYLCHOLINE bronchoconstriction, vasodilatation.
TYPE I, IMMEDIATE HYPERSENSITIVITY DISORDERS T-HELPER CELLS, SUB-TYPE 2 (TH2) These are types of CD4 Cells, the other type being TH1. TH1 diff. of B-Cells into Plasma Cells IgG, IgM. TH2 Release cytokines differentiation of B-Cells into IgE-producing Plasma Cells, growth factors for Mast Cells, recruit and activate eosinophils. 21
TYPE I, IMMEDIATE HYPERSENSITIVITY DISORDERS See Fig. 21-4 for the full picture. 22 Take home lesson: this type of hypersensitivity leads to allergies when mild, and anaphylaxis when severe.
TYPE II, ANTIBODY-MEDIATED DISORDERS 23 Mediated by IgG and IgM. Elicited by: endogenous or exogenous antigens attached to cell membranes. EXAMPLES: transfusion reactions, Rh disease, drug reactions. Drugs bind to surface of red or white cells antibody response cell lysis.
TYPE III, IMMUNE COMPLEX- MEDIATED DISORDERS 24 Antigen-Antibody Complex deposits in vessels or tissue activation of complement chemotactic and vasoactive mediators inflammatory response by recruiting neutrophils, etc. tissue damage. Deposit in: lining of vessels, glomeruli, skin venules, lung, joint synovia. Damage caused not by Ag-Ab complex but by the inflammatory response that follows from activation of complement.
TYPE III, IMMUNE COMPLEX- MEDIATED DISORDERS 25 EXAMPLES: vasculitis seen in autoimmune diseases (lupus), glomerulonephritis Read about: serum sickness, Arthus Reaction.
TYPE IV, T-CELLT CELL-MEDIATED HYPERSENSITIVITY DISORDERS 26 T-Cells- 1) Fight against a variety of microorganisms: viruses, TB, fungi, protozoa, parasites. 2) Respond to chemical antigens & organic substances. 3) Respond to self-antigens = autoimmune diseases. 2 FLAVORS: 1) DIRECT CELL-MEDIATED CYTOTOXICITY. 2) DELAYED-TYPE HYPERSENSITIVITY.
DIRECT CELL-MEDIATED CYTOTOXICITY 27 Involves the CD8 Cells = Cytotoxic T Lymphocytes = CTL s. Kill the antigen-presenting target cells. Some viruses cause cell lysis (cytopathic), others do not (non-cytopathic). CD8 s don t care destroy all virus-infected cells. Damage in hepatitis is largely from CTL response not completely from the virus itself.
DELAYED-TYPE HYPERSENSITIVITY 28 DTH. Involves the T-Helper Cells ( = TH1 s = CD4 s) production of immuno-regulatory and proinflammatory cytokines differentiation and activation of macrophages function as phagocytic and antigen-presenting cells (APC s). TUBERCULIN SKIN TEST: the prototypical DTH reaction.
ALLERGIC RHINITIS, FOOD ALLERGIES 29 Atopic reactions: a Type I, Immediate Hypersensitivity Disorder. Atopy: genetically-determined hypersensitivity to environmental allergens. Mediated by an IgE-Mast Cell reaction.
30 CONTACT DERMATITIS A Type IV, T-Cell-Mediated Hypersensitivity Disorder, Delayed Type (DTH). Initiated by re-exposure to an allergen to which the skin has previously become sensitized. Examples: poison ivy, nickel allergy. Exact mechanism not known. Lasts days to weeks, lesions that are erythematous, vesicular, papular, weeping, pruritic.
HYPERSENSITIVITY PNEUMONITIS 31 A Type IV, T-Cell-Mediated Hypersensitivity Disorder, Delayed Type (DTH). Response to inhaled organic dusts, other occupational antigens. Activation of pulmonary T-Cells release of inflammatory cytokines. Farmer s Lung, exposure to moldy hay. Labored breathing, dry cough, fever, chills headache. Subsides within hours.
32 LATEX ALLERGY Latex = the sap from Heva brasiliensis + additives including corn starch. Allergy to either the sap or the additives. Can be caused by: 1) Type IV, Delayed-Type Hypersensitivity, OR 2) Type I, IgE-mediated Immediate Hypersensitivity Reaction.
33 LATEX ALLERGY Most are Type IV, DTH. A contact dermatitis. Remains local, topical. The Type I, IgE-mediated reaction can be more severe, resulting in not only local urticaria but asthma and anaphylaxis. Type I reactions cross-reaction to bananas, kiwi, avocado, tomatoes, chestnuts; contain proteins similar to those in latex.
TRANSPLANTATION IMMUNOPATHOLOGY 34 Triggered by HLA = Human Leukocyte Antigen, aka MHC = Major Histocompatibility Complex molecules. The closer the match, the less the problem 2 EXCITING FLAVORS: 1) HOST-VERSUS-GRAFT DISEASE. 2) GRAFT-VERSUS HOST DISEASE.
35 HOST-VERSUS VERSUS-GRAFT DISEASE Seen in organ transplantation. Immune cells of the recipient attack the cells of the transplanted organ. Involves both Cellular and Humoral Immunity, but the T-Cells are absolutely required. HLA activation of CD4 (Helper T-Cells) and CD8 (cytotoxic T-Cells) lymphocytes. CD4 s B-Cell-mediated Ab production. CD8 s direct cytotoxicity.
36 GRAFT-VERSUS HOST DISEASE Seen in Bone Marrow Transplants, occasionally in Liver Transplants. Immunologically-competent cells are transplanted into an immunocompromised host. 3 Elements Required: 1) Immunocompetent cells from the donor. 2) Cells in the recipient w/ foreign antigens. 3) Immunity in the recipient compromised can not destroy the transplanted cells.
37 GRAFT-VERSUS HOST DISEASE Transplanted / donor immune cells recognize recipient / host cells as foreign CD4 and CD8 Cells Type IV, Cell-Mediated and CTL Hypersensitivity Reaction.
38 AUTOIMMUNE DISEASE Results from a breakdown in the ability of the immune system to recognize self from non-self antigens. This ability is called Self-Tolerance. Self is determined by the HLA Antigens encoded by the MHC genes.
39 AUTOIMMUNE DISEASE TOLERANCE- THE SKINNY Normal immune response depends on presenting of an antigen by an APC to CD4 and CD8 cells. Chemical messengers and costimulatory signals required for activation of the immune response, and preservation of selftolerance. Tolerance occurs by eliminating the T-Cells and B-Cells that respond to self, so-called Self- Reactive or Autoreactive cells.
40 AUTOIMMUNE DISEASE Elimination of self-reactive cells occurs via: 1) CENTRAL TOLERANCE: elimination in the bone marrow (B-Cells) and Thymus (T-Cells). 2) PERIPHERAL TOLERANCE: elimination of those that escaped central tolerance. ANERGY = IMMUNOLOGIC TOLERANCE TO SPECIFIC ANTIGENS
41 AUTOIMMUNE DISEASE Pg 422. KEY FEATURES OF AUTOIMMUNITY 1) LOSS OF SELF-TOLERANCE. 2) FORMATION OF AUTO-ANTIBODIES 3) FAILURE TO RECOGNIZE HOST ANTIGENS AS SELF.
MECHANISMS OF AUTOIMMUNE DISEASE 42 FAILURE OF SELF-TOLERANCE 1) Failure of T-Cell-mediated suppression. 2) Breakdown in T-Cell anergy. 3) Disorders of reaction of the MHC-Antigen complex w/ the T-Cell receptor (TCR). 4) Release of sequestered antigens. 5) Molecular mimicry. 6) Superantigens.
MECHANISMS OF AUTOIMMUNE DISEASE 43 BREAKDOWN IN T-CELL ANERGY ANERGY: the inactivation of T-Cells; Activation of antigen-specific CD4 Cells requires: 1) Recognition of Ag-MHC II on the surface of APC s, and 2) Production of a set of costimulatory signals by the APC. If the co-stimulatory signal is not produced, the T-Cell becomes anergic. Most tissues do not express the co-stimulatory molecules and are thus protected.
MECHANISMS OF AUTOIMMUNE DISEASE 44 BREAKDOWN IN T-CELL ANERGY Protection is broken if cells are induced to express the co-stimulatory molecules. Up-regulation of co-stimulator molecule B7-1 seen in: Multiple Sclerosis, Rheumatoid Arthritis, and Psoriasis.
MECHANISMS OF AUTOIMMUNE DISEASE 45 MOLECULAR MIMICRY Foreign antigens closely resemble self antigens. Antibodies produced against foreign antigens also react w/ self. Seen in: rheumatic fever, acute poststreptococcal glomerulonephritis antigens on Group A beta-hemolytic strep. are similar to Ag s (in some patients) to Ags in the heart & kidney.
MECHANISMS OF AUTOIMMUNE DISEASE 46 MOLECULAR MIMICRY Drugs: certain drugs bound to host proteins form a complex to which a humoral response is directed with cross-reactivity to the host protein. EXAMPLE: Aldomet (alpha-methyl-dopa) binds to proteins on red cells Abs hemolytic anemia.
MECHANISMS OF AUTOIMMUNE DISEASE 47 SUPER ANTIGENS Bypass the step where the Ags are presented by APC s normally required to induce a T-Cell response. Property of Staph. and Strep. and their toxins. Superantigens directly link MHC II Complex Molecules to the TCR release of cytokines. Seen in: Toxic Shock Syndrome.
48 AUTOIMMUNE DISEASES SYSTEMIC Mixed connective tissue disease. Polymyositis, dermatomyositis. Rheumatoid Arthritis. Scleroderma. Sjogren s Syndrome. Systemic Lupus Erythematosus (SLE).
49 AUTOIMMUNE DISEASES BLOOD Autoimmune hemolytic anemia. Autoimmune neutropenia & lymphopenia. Idiopathic thrombocytopenic purpura aka I.T.P. aka Immune thrombocytopenic pupura, aka A.I.T.P. = Autoimmune thrombocytopenic purpura.
50 AUTOIMMUNE DISEASES OTHER ORGANS Atrophic gastritis / pernicious anemia. Goodpasture s Syndrome. Hashimoto s disease / thyroiditis. Type 1 diabetes. Myasthenia gravis. Premature ovarian failure. Primary biliary cirrhosis. Temporal arteritis.
51 AUTOIMMUNE DISEASES Thyrotoxicosis. Crohn s Disease. Ulcerative Colitis. OTHER ORGANS
CRITERIA FOR DETERMINING AN AUTOIMMUNE ETIOLOGY 52 1) EVIDENCE OF AN AUTOIMMUNE REACTION. 2) IMMUNOLOGIC FINDINGS NOT DUE TO ANOTHER CONDITION. 3) LACK OF ANOTHER CAUSE FOR THE DISORDER.