Transcript Immunity & Abnormal Responses

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
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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
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Step I
– Macrophages alert
lymphocytes
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Step II
– Humoral immune response
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Step III
– Cellular immune response
Summary of Normal Specific Immune Response
Normal specific immune response can be either Primary or Secondary
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Primary response =w
first exposed to anti
• 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
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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
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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
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Type I --- allergy
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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)
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Systemic Lupus Erythematosus
• SLE
– General
• Primarily women; age 20-40
• Butterfly rash; face of wolf (lupo)
• Course =remissions & exacerbations
– Pathophys
• Get circulating anti
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Immune complexes deposited in connecti
Get inflammation & necrosis
• Vasculitis gives ischemia
– Sx
• Initially; skin rash, joint inflammation(p
• Pleuritis
• Carditis
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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)
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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
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Pathophys
– Virus has predilection for:
• Helper T lymphocytes
• Macrophages
• CNS cells
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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)
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Opportunistic infections
– TB
– PCP(pneumocystis carinii
pneumonia) – fungus
• Frequent cause of death in
AIDS
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– Toxoplasmosis
– Candidiasis
– Herpes
– Varicella
– Cytomegalovirus retinitis
– Necrotizing periodontal disease
Opportunistic cancers
– K
aposi’s sarcoma
– Non-Hodgkins lymphoma
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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