Immunity & Abnormal ResponsesImmunity & Abnormal Responses

PathophysiologyPathophysiology

• 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 SystemReview 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 T-lymphocytes) 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 ResponseSpecific Immunity;The Immune Response

• Step I– Macrophages alert

lymphocytes

• Step II– Humoral immune response

• Step III– Cellular immune response

Summary of Normal Specific Immune ResponseNormal specific immune response can be either Primary or Secondary

PrimaryPrimary & & SecondarySecondary Immune Responses Immune Responses

• 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

• Primary response = when person first exposed to antigen

• 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

– IgG

– 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

– 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 RejectionTissue & 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 ReactionsHypersensitivity 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 DisordersAutoimmune 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 SLE (Systemic Lupus Erythematosus)(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

ImmunodeficiencyImmunodeficiency

• 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

• 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

AIDS (Acquired Immunodeficiency Syndrome)

Stages in development of AIDS

• 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

AIDS (Acquired Immunodeficiency Syndrome)