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Immunity & Abnormal Responses Pathophysiology • Diseases to be discussed: • Tissue rejection » Includes Organ transplant rejection • Hypersensitivity reactions » These are hyperactive responses of the immune system » Called allergies • Autoimmune reactions » A misdirected immune response • Immunodeficiency » A deficient immune response Review of Immune System • Nonspecific immunity • • • • • Barriers Fluids Inflammatory reaction Phagocytosis Antimicrobial substances – See next slide • Specific immunity • Immune response – Humoral – Cellular • Acquired immunity • Natural – Active & passive • Artificial – Active & passive Non-specific Immunity System Molecules • Complement system – Group of inactive plasma proteins, part of non-specific immunity – Especially active against invading bacteria – When activated, system compliments action of antibodies by; – Destruction of target cell membranes – Attracts phagocytes (chemotaxis) – Stimulates & enhances phagocytosis – Stimulates inflammation – Activation occurs via: – Compliment binding to IgM or IgG antibody- antigen complex – Compliment attaching to foreign materials, e.g. bacterial cell wall • Interferon – Especially active against viruses – Small proteins released by lymphocytes & macrophages (primarily Tlymphocytes) when these cells activated by viral antigens – Interferons do 2 basic things – Bind to normal body cell with virus & via second messenger stimulate the production of antiviral proteins in cytoplasm which stop viral replication – Act as cytokines to stimulate production of more macrophages & lymphocytes Specific Immunity;The Immune Response • Step I – Macrophages alert lymphocytes • Step II – Humoral immune response • Step III – Cellular immune response Summary of Normal Specific Immune Response Normal specific immune response can be either Primary or Secondary Primary & Secondary Immune Responses • • Primary response = when person first exposed to antigen Secondary response = when repeat exposure to same antigen occurs – Deals primarily with memory cells (both B & T) • Memory B = antibodies • Memory T = T cells – Helper & Killer • Antibodies ---- Immunoglobulins – General structure = “Y”; 2 light chains & 2 heavy chains • Variable region--- binds to antigen • Constant region --- attaches to macrophage – 5 different types of “constant regions” » MADGE = all monomers, but M = pentamer & A = dimer – The constant regions have no effect on the specificity of the antibody • 5 types of immunoglobulins produced by plasma cells – IgM – – – – – First secreted after arrival of antigen In monomer form, can act as receptor on cell membrane Usually in pentamer form, thus large & can cause agglutination Activates compliment Present early in the course of infection & then falls as IgG levels rise – – – – – – Most numerous of circulating antibodies (75%) Called gamma globulin Effective against all pathogens & most toxins Can cross placenta Is key antibody in primary & secondary immune response Can activate compliment – IgG – IgA – In epithelium, thus in secretions (mucus, tears, saliva, colostrum, etc.) – Prevents attachment of viruses & bacteria to epithelial surfaces • 5 types of immunoglobulins produced by plasma cells – IgE – Attached to basophils & mast cells – When antigen attaches, these cells release histamine » Thus, they involved in allergic reactions (hypersensitivity rx) » Called “troublemaker antibody” since they cause allergic reactions when exposed to antigen – IgD – Always attached to B lymphocyte – Can activate B lymphocyte – May be important in causing B cell to become either plasma cell or memory cell • “Antigen presenting proteins” & the processing of the antigen – Those proteins made by the cell that are incorporated into the cell membrane & hold or present foreign antigenic material that has gotten into the cell – These are usually glycoproteins & everybody has different ones • Controlled by genes on chromosome 6 in region called MHC » MHC = major histocompatability complex • Antigen presenting proteins also called MHC proteins » Used to be called HLA (human leukocyte antigens) – In immune system key cell is macrophage --- it is an “antigen presenting cell” – 2 classes of MHC proteins – (1) MHC class I --- made continuously by all nucleated cells » For viral antigens & normal peptides made by cell – (2) MHC class II --- made only by macrophages & lymphocytes when cell is processing antigens » For antigenic fragments produced by lysosome • Activation of lymphocytes – Antigen presenting proteins + foreign antigen -------- fit into receptor proteins in cell membrane of cell that needs activation • Recognition proteins – Those in cell membrane that are unique to that individual, thus “name tags” – These are the same as MHC proteins Tissue & Organ Transplant Rejection • When the immune system of the individual responds to the HLAs in foreign tissue • Remember that HLAs = MHC proteins • Mechanism = – type IV cell-mediated hypersensitivity reaction – Humoral response (antibody production) • To decrease risk: – HLA match is excellent – Donor is living – Use of immunosuppressive drugs » Side effects --- opportunistic infections Hypersensitivity Reactions • Types – Type I hypersensitivity---- allergy • Mech = IgE bound to mast cell & release of histamine and chemical mediators – Person exposed to allergen causes B cells to make IgE antibodies – These IgE attach to mast cells & make them sensitized – Upon re-exposure get An + IgE & mast cell releases chemical mediators • Sx = depend on where the sensitized mast cells located – Hay fever (allergic rhinitis) – Food allergies – Atopic dermatitis(eczema) » Atopic means runs in families, thus genetic component – Asthma • Anaphylaxis = severe allergic reaction – Mech = large amounts of chemical mediators released from mast cells – Can get C-V collapse & severe bronco-constriction • Type I --- allergy • Type I --- anaphylaxis reaction • Type II hypersensitivity --- cytotoxic hypersensitivity – Mech • The antigen is on the cell membrane • Circulating IgG react with the antigen & get cell destruction – Examples: • ABO incompatibility • Rh incompatibility • Type III --- immune complex hypersensitivity – Mech • Antigen-antibody complex deposits in tissue • Tissue is frequently blood vessel walls • Complement is activated – Sx = inflammation & tissue destruction – Examples • Glomerulonephritis • Rheumatoid arthritis • Arthus reaction = localized inflammation & tissue necrosis – Seen in “valley fever”in humans • Type IV ---- Cell- mediated or delayed hypersensitivity – Mech • Antigen binds to T-lymphocyte – The sensitized T cell releases lymphokines – The sensitized T cell begins the immune response • The lymphokines release chemical mediators that destroy the antigen – Examples • Skin tests • Contact dermatitis – Poison ivy • Organ transplant rejection • Occurs after first exposure – Don’t need sensitization Step in Type I Autoimmune Disorders • Immune system forms antibodies to “self” antigens – Remember that these are MHC-proteins • Genetic factor involved in auto immune disease • Systemic(SLE) & localized diseases (Hashimoto’s disease) • Systemic Lupus Erythematosus • SLE – General • Primarily women; age 20-40 • Butterfly rash; face of wolf (lupo) • Course = remissions & exacerbations – Pathophys • Get circulating anti-DNA antibodies [anti-nuclear antibodies(ANA)] • Immune complexes deposited in connective tissue anywhere in body – Get inflammation & necrosis • Vasculitis gives ischemia – Sx • Initially; skin rash, joint inflammation(polyarthritis) • Pleuritis • Carditis • Raynauld’s phenomenon • Glomerulonephritis – Dx • LE prep • ANA SLE (Systemic Lupus Erythematosus) – General • Primarily women; age 20-40 • Butterfly rash; face of wolf (lupo) • Course = remissions & exacerbations – Pathophys • Get circulating anti-DNA antibodies [anti-nuclear antibodies(ANA)] • Immune complexes deposited in connective tissue anywhere in body – Type III hypersensitivity Rx – Get inflammation & necrosis – Bone marrow depression » Esp. thrombocytopenia • Vasculitis gives ischemia – Sx • Initially; skin rash, joint inflammation(polyarthritis) • Pleuritis • Carditis • Raynauld’s phenomenon • Glomerulonephritis – Dx • LE prep • ANA – Tx • Steroids • Avoid sun – Px • Was 5-10 years • Currently much better Immunodeficiency • Primary immunodeficiency disorders = congenital and/or genetic • Secondary immunodeficiency disorders = those acquired – Causes • Immunosuppressive therapy • Chemo & radiation cancer treatment • HIV infection • Use of corticosteroids • Effects • Opportunistic infections • Increase of certain cancers, especially non-Hodgkin’s lymphoma AIDS (Acquired Immunodeficiency Syndrome) • • • Etiology = HIV virus – Retrovirus (RNA) – Antibodies appear after initial infection • Avg time = 4-8 wks • May take as long as 6 months Transmission – Via blood & body fluids • Exception = saliva • Virus is fragile & cannot live outside body – Not by casual contact Tests – ELISA(enzyme-linked immunoassay) – Western blot – CD4 counts • Pathophys – Virus has predilection for: • Helper T lymphocytes • Macrophages • CNS cells • Course of HIV infection (see next slide) – Initial phase – like URI • May last longer than usual cold – Latent phase – up to 10 years – Active disease --- AIDS • Usually begins with generalized lymphadenopathy • G-I effects – esp diarrhea with cachexia • Opportunistic infections • HIV encephalopathy • Cancers Stages in development of AIDS AIDS (Acquired Immunodeficiency Syndrome) • Opportunistic infections – TB – PCP(pneumocystis carinii pneumonia) – fungus • Frequent cause of death in AIDS • – Toxoplasmosis – Candidiasis – Herpes – Varicella – Cytomegalovirus retinitis – Necrotizing periodontal disease Opportunistic cancers – Kaposi’s sarcoma – Non-Hodgkins lymphoma • • • HIV encephalopathy – Called AIDS dementia – Can end with seizures & coma Women with HIV – AZT & pregnancy Tx – Reverse transcriptase inhibitors – Protease inhibitors – Viral integrase inhibitors – Tx opportunistic infections