Grig D.

Misiona, MD PLM-College of Medicine

General Properties of Immune Responses Immune system - cells and molecules responsible for immunity Immune response - cells and molecules and their collective and coordinated response to the introduction of foreign substances Physiologic function of the immune system is defense against infectious microbes - reaction to foreign substances (microbes) and macromolecules (proteins and polysaccharides) regardless of the physiologic or pathologic consequence of such a reaction

Innate and Adaptive Immunity

Defense against microbes is mediated by the early reactions of innate immunity and the later responses of adaptive immunity 1. Innate (natural or native) immunity - cellular and biochemical defense mechanisms that are in place even before infection and poised to respond rapidly to infections - react only to microbes and not to noninfectious substances - respond in essentially the same way to repeated infections - specific for structures common to groups of related microbes & may not distinguish fine differences between foreign substances - provides the early lines of defense against microbes

Principal components of innate immunity 1. physical and chemical barriers (epithelia and antimicrobial substances produced at epithelial surfaces 2. phagocytic cells (neutrophils, macrophages) and NK (natural killer) cells 3. blood proteins - complement system and other mediators of inflammation 4. cytokines - regulate and coordinate many of the activities of the cells of innate immunity

Characteristics
Specificity Diversity Memory Nonreactivity to self Components Physical & chemical barriers Blood proteins Cells

Innate
For structures shared by groups of related microbes Limited; germline-encoded None Yes

Skin, mucosal epithelia; antimicrobial chemicals Complement Phagocytes (macrophages, neutrophils), natural killer cells

2. Adaptive (specific) immunity - exquisite specificity for distinct molecules - ability to "remember" and respond more vigorously to repeated exposures to the same microbe - able to recognize and react to a large number of microbial and non - microbial substances - extraordinary capacity to distinguish among different, even closely related, microbes and molecules

- also called acquired immunity, to emphasize that potent protective responses are "acquired" by experience - components: lymphocytes and their products

Antigens - foreign substances that induce specific immune responses

Characteristics Adaptive
Specificity Diversity For antigens of microbes and for nonmicrobial antigens Very large; receptors are produced by somatic recombination of gene segments Yes Yes Lymphocytes in epithelia; antibodies secreted at epithelial surfaces Antibodies Lymphocytes

Memory Nonreactivity to self Components Physical & chemical barriers Blood proteins Cells

Innate and adaptive immune responses are components of an integrated system of host defense. 1. Innate immune response to microbes stimulates adaptive immune responses and influences the nature of the adaptive responses 2. Adaptive immune responses use many of the effector mechanisms of innate immunity to eliminate microbes, and they often function by enhancing the antimicrobial activities of the defense mechanisms of innate immunity

Two Types of Adaptive Immune Responses

1. Humoral immunity 2. Cell-mediated immunity - mediated by different components of the immune system and function to eliminate different types of microbes

Humoral immunity - mediated by antibodies in the blood and mucosal secretions produced by B lymphocytes - principal defense mechanism against extracellular microbes and their toxins because secreted antibodies can bind to these microbes and toxins and assist in their elimination

Cell-mediated (cellular) immunity - mediated by T lymphocytes - defense against intracellular microbes (viruses and some bacteria) that survive and proliferate inside phagocytes and other host cells, where they are inaccessible to circulating antibodies

Protective (active) immunity - may be induced by the host's response to the microbe or by the transfer of antibodies or lymphocytes specific for the microbe Naive - individuals (person) and lymphocytes that have not encountered a particular antigen Immune - individuals who have responded to a microbial antigen and are protected from subsequent exposures to that microbe Passive (adoptive) immunity - immunity conferred on an individual by transferring serum or lymphocytes from a specifically immunized individual - useful method for conferring resistance rapidly, without having to wait for an active immune response to develop

Cardinal Features of Adaptive Immune Responses

Feature
Specificity Diversity Memory Specialization Self-limitation Non- reactivity to self

Functional significance
Ensures that distinct antigens elicit specific responses Enables immune system to respond to a large variety of antigens Leads to enhanced responses to repeated exposures to the same antigens Generates responses that are optimal for defense against different types of microbes Allows immune system to respond to newly encountered antigens Prevents injury to the host during responses to foreign antigens

Hypersensitivity Diseases

A. Type I (immediate) hypersensitivity - IgE antibody-mediated activation of mast cells (effector cells) produces an inflammatory reaction 1. IgE antibody production (sensitization) - Allergens (pollen, drugs) are first processed by APCs (macrophages or dendritic cells) - APCs interact with CD4 TH2 cells, causing interleukins (ILs) to stimulate B-cell maturation - IL-4 causes plasma cells to switch from IgM to IgE synthesis - IL-5 stimulates the production and activation of eosinophils

2. Mast cell activation (re - exposure) - Allergen-specific IgE antibodies are bound to mast cells - Allergens cross-link IgE antibodies specific for the allergen on mast cell membranes - IgE triggering causes mast cell release of preformed mediators a. Early phase reaction with release of histamine, chemotactic factors for eosinophils, proteases = produces tissue swelling and bronchoconstriction b. Late-phase reaction - mast cells synthesize and release prostaglandins and leukotrienes = enhances and prolongs acute inflammatory reaction

B. Type II (cytotoxic) hypersensitivity = Antibody- dependent cytotoxic reactions = Complement - dependent reactions Lysis Antibody (IgG or IgM) directed against antigen on the cell membrane activates the complement system, leading to lysis by the membrane attack complex Phagocytosis Fixed macrophages (in spleen) phagocytose hematopoietic cells (RBCs) coated by IgG antibodies and/or complement (C3b).

= Complement-independent reactions Antibody (IgG, IgE)-dependent cell-mediated cytotoxicity Leukocytes with receptors for IgG or IgE lyse but do not phagocytose cells coated by antibodies. IgG autoantibodies directed against cell surface receptors

C. Type III (immunocomplex) hypersensitivity - Activation of the complement system by circulating antigen-antibody complexes (DNA-anti-DNA complexes) 1. First exposure to antigen Synthesis of antibodies 2. Second exposure to antigen Deposition of antigen-antibody complexes Complement activation, producing C5a, which attracts neutrophils that damage tissue 3. Arthus reaction Localized immunocomplex reaction Example - farmer's lung from exposure to thermophilic actinomycetes, or antigens, in air

D. Type IV hypersensitivity - Antibody-independent T cell-mediated reactions (cellular immunity) - Delayed reaction hypersensitivity CD4 cells interact with macrophages (APCs with MHC class II antigens), resulting in cytokine injury to tissue - Cell-mediated cytotoxicity CD8 T cells interact with altered MHC class I antigens on neoplastic, virus-infected, or donor graft cells, causing cell lysis

Transplantation

Transplantation - the process of taking cells, tissues, or organs, called a graft, from one individual and placing them into a (usually) different individual - the individual who provides the graft is a donor - the individual who receives the graft is either the recipient or the host orthotopic transplantation - graft is placed into its normal anatomic location heterotopic transplantation - if the graft is placed in a different site Transfusion - transplantation of circulating blood cells or plasma from one individual to another

TERMS: 1. autologous graft (autograft) - a graft transplanted from one individual to the same individual 2. syngeneic graft - a graft transplanted between two genetically identical or syngeneic 3. allogeneic graft (allograft) - a graft transplanted between two genetically different individuals of the same species 4. xenogeneic graft (xenograft) - a graft transplanted between individuals of different species 5. alloantigens / xenoantigens - molecules that are recognized as foreign on allografts on xenografts 6. alloreactive or xenoreactive - lymphocytes and antibodies that react with alloantigens or xenoantigens

Basic rules of transplantation immunology: 1. Cells or organs transplanted between individuals of the same inbred strain of a species are never rejected. 2. Cells or organs transplanted between individuals of different inbred strains of a species are almost always rejected. 3. The offspring of a mating between two different inbred strains will typically not reject grafts from either parent. - an (A B)F1 animal will not reject grafts from an A or B strain animal 4. Graft derived from the offspring of a mating between two different inbred strains will almost always be rejected by either parent. - graft from an (A B)F1 animal will be rejected by either an A or a B strain animal.

Types of rejection 1. Hyperacute rejection Irreversible reaction occurs within minutes. Pathogenesis ABO incompatibility or action of preformed anti-HLA antibodies in the recipient directed against donor antigens in vascular endothelium Type II hypersensitivity reaction Pathologic finding Vessel thrombosis Example: blood group A person receives a blood group B

2. Acute rejection (most common transplant rejection) - Reversible reaction that occurs within days to weeks - Type IV cell-mediated hypersensitivity - CD4 T cells release cytokines, resulting in activation of host macrophages, proliferation of CD8 T cells, and destruction of donor graft cells = Extensive interstitial round cell lymphocytic infiltrate in the graft, edema, and endothelial cell injury - Antibody-mediated type II hypersensitivity reaction - Cytokines from CD4 T cells promote B-cell differentiation into plasma cells, producing anti-HLA antibodies that attack vessels in the donor graft = Vasculitis with intravascular thrombosis in recent grafts Intimal thickening with obliteration of vessel lumens in older grafts

3. Chronic rejection Irreversible reaction that occurs over months to years Pathogenesis Not well characterized Involves continued vascular injury with ischemia to tissue Blood vessel damage with intimal thickening and fibrosis

Autoimmune Diseases

Autoimmune dysfunction is associated with a loss of selftolerance, resulting in immune reactions directed against host tissue

Mechanisms of autoimmunity: 1. Release of normally sequestered antigens 2. Sharing of antigens between host and pathogen 3. Defects in functions of helper or suppressor T cells 4. Persistence of autoreactive T and B cells 5. Presence of specific autoantibodies

1. Systemic lupus erythematosus (SLE) - Occurs predominantly in women of childbearing age - Pathogenesis : Polyclonal B-cell activation, sustained estrogen activity, environmental triggers (sun, procainamide) - Clinical findings 1. Hematologic : Autoimmune hemolytic anemia, thrombocytopenia, leukopenia 2. Lymphatic : Generalized painful lymphadenopathy , Splenomegaly 3. Musculoskeletal : Small-joint inflammation (hands) with absence of joint deformity 4. Skin: Immunocomplex deposition along basement membrane Produces liquefactive degeneration Malar butterfly rash 5. Renal : Diffuse proliferative glomerulonephritis (most common glomerulonephritis)

6. Cardiovascular Fibrinous pericarditis with or without effusion Libman-Sacks endocarditis (sterile vegetations on mitral valve) 7. Respiratory Interstitial fibrosis of lungs Pleural effusion with friction rub 8. Pregnancy-related Complete heart block in newborns Caused by IgG anti-SS-A (Ro) antibodies crossing the placenta Recurrent spontaneous abortions Caused by antiphospholipid antibodies

Drug-induced lupus erythematosus Associated drugs Procainamide, hydralazine Features that distinguish drug-induced lupus from SLE Antihistone antibodies Low incidence of renal and central nervous system (CNS) involvement Disappearance of symptoms when the drug is discontinued

Laboratory findings in SLE Positive serum antinuclear antibody (ANA) (almost all cases) Anti-double-stranded DNA antibodies and anti-Sm antibodies Used to confirm the diagnosis of SLE, because they are highly specific for the disease (i.e., few false-positive results) Anti-Ro antibodies are positive in 25% to 50% of cases. Antiphospholipid antibodies Lupus anticoagulant and anticardiolipin antibodies Damage vessel endothelium, producing vessel thrombosis Increased incidence of strokes and recurrent spontaneous abortions Lupus erythematosus cell Neutrophil containing phagocytosed altered DNA Not specific for SLE Decreased serum complement Used up with activation of complement system Immunocomplexes at the dermal-epidermal junction in skin biopsies Immunofluorescent studies identify complexes in a band-like distribution along the dermal-epidermal junction

2. Systemic sclerosis (scleroderma) - Occurs predominantly in women of childbearing age - Pathogenesis : Small-vessel endothelial cell damage produces blood vessel fibrosis and ischemic injury T-cell release of cytokines results in excessive collagen synthesis - Clinical findings: a. Raynaud's phenomenon Sequential color changes (normal to blue to red) caused by digital vessel vasculitis and fibrosis Digital infarcts b. Skin Skin atrophy and tissue swelling beginning in the fingers and extending proximally Parchment-like appearance Extensive dystrophic calcification in subcutaneous tissue Tightened facial features (radial furrowing around the lips)

c. Gastrointestinal Dysphagia for solids and liquids No peristalsis in the lower two thirds of the esophagus (smooth muscle replaced by collagen) Lower esophageal sphincter relaxation with reflux Small bowel Loss of villi (malabsorption) Wide-mouthed diverticula (bacterial overgrowth) d. Respiratory Interstitial fibrosis of lungs Respiratory failure (most common cause of death) e. Renal Vasculitis involving arterioles (hyperplastic arteriolosclerosis) and glomeruli Infarctions, malignant hypertension

Laboratory findings in systemic sclerosis Serum ANA is positive in 70% to 90% of cases. Antitopoisomerase antibody is positive in 15% to 40% of cases. CREST syndrome Limited sclerosis Clinical findings C-calcification, centromere antibody R-Raynaud's phenomenon E-Esophageal dysmotility S-sclerodactyly (i.e., tapered, claw-like fingers) T-telangiectasis (i.e., multiple punctate blood vessel dilations) Laboratory findings Anticentromere antibodies in 30% of case

3. Dermatomyositis (DM; with skin involvement) and Polymyositis (PM; no skin involvement) - Occurs predominantly in women 40 to 60 years of age - Associated with risk of malignant neoplasms (15-20% of cases) particularly lung cancer - Pathogenesis DM is associated with antibody-mediated damage PM is associated with T cell-mediated damage - Clinical findings Muscle pain and atrophy - shoulders are commonly involved Heliotrope eyelids or "raccoon eyes" (purple-red eyelid discoloration) Laboratory findings Serum ANA is positive in fewer than 30% of cases Increased serum creatine kinase Muscle biopsy shows a lymphocytic infiltrate

4. Mixed connective tissue disease (MCTD) Signs and symptoms similar to SLE, systemic sclerosis, and PM Renal disease is uncommon Antiribonucleoprotein antibodies are positive in almost 100% of cases

Immunodeficiency Disorders

Feature Diagnosis Serum Ig levels DTH reactions to common antigens

B cell deficiency Reduced Normal

T cell deficiency Normal or reduced Reduced

Features of Immunodeficiencies or reduced Morphology of lymphoid AbsentAffecting T or B Lymphocytes Usually normal follicles, tissues follicles and germinal may be reduced centers (B cell zones) parafollicular cortical regions (T cell zones) Susceptibility to infectionPyogenic bacteria (otitis, Pneumocystis carinii, pneumonia, meningitis, many viruses, atypical osteomyelitis), enteric mycobacteria, fungi bacteria and viruses, some parasites

Defects of Lymphocyte Maturation Presumed mechanism Disease Functional deficiencies of defect Severe combined immunodeficiency X-linked Markedly decreased T cells, Cytokine receptor common normal or increased B cells, chain gene mutations, reduced serum Ig defective T cell maturation from lack of IL-7 signals ADA, PNP deficiency Progressive decrease in T ADA or PNP deficiency (autosomal recessive) and B cells (mostly T); leading to accumulation of reduced serum Ig in ADA toxic metabolites in deficiency, normal B cells lymphocytes and serum Ig in PNP deficiency Other autosomal recessive Decreased T and B cells, Defective maturation of T reduced serum Ig and B cells; mutations in RAG, Artemis, CD45, CD3 genes

Defects of Lymphocyte Maturation Disease B cell immunodeficiencies X-linked agammaglobulinemia Presumed mechanism Functional deficiencies of defect Decrease in all serum Ig isotypes, reduced B cell numbers Block in maturation beyond pre-B cells because of mutation in B cell tyrosine kinase IgG1, IgG2, or IgG4 Chromosomal deletion at absent; sometimes 14q32 (Ig heavy chain associated with absent IgA locus) or IgE Decreased T cells, normal Anomalous development of B cells, normal or 3rd and 4th branchial decreased serum Ig pouches leading to thymic hypoplasia

Ig heavy chain deletions

T cell immunodeficiencies DiGeorge syndrome

Defect i
Di ease Selective Ig isotype deficiencies

cyte ctiv ti
Mechanisms f defect Defect in B cell differentiation or T cell help; rare cases of homozygous deletions/mutations of Ig constant region genes

Hyper-IgM syndromes

Fu cti al deficiencies Reduced or no production of selective isotypes or subtypes of Ig (IgA deficiency most common isotype deficiency, IgG3 deficiency most common subtype deficiency); susceptibility to bacterial infections or no clinical problems Defects in helper T celldependent B cell and macrophage activation

Mutation in CD40 ligand (Xlinked), CD40 or AID

Defects in ymphocyte ctivation

Mechanisms of defect Defect in B cell activation, usually caused by intrinsic B cell abnormality (nature unknown) T cell receptor complex Decreased T cells or Rare cases caused by expression or signaling abnormal ratios of CD4+ and mutations or deletions in defects CD8+ subsets; decreased genes encoding CD3 cell-mediated immunity proteins, ZAP-70 X-linked lympho-proliferative Uncontrolled B cell Mutation in the gene syndrome proliferation in the setting of encoding the SAP adapter Epstein-Barr virus infection protein, which is normally leading to B cell lymphomas required for inhibiting and signaling by the SLAM hypogammaglobulinemia molecule Disease Common variable immunodeficiency Functional deficiencies Variable reductions in multiple Ig isotypes; normal or decreasd B cells

Defects in Lymphocyte Acti ation

Disease Selective Ig isotype deficiencies Functional deficiencies Reduced or no production of selective isotypes or subtypes of Ig (IgA deficiency most common isotype deficiency, IgG3 deficiency most common subtype deficiency); susceptibility to bacterial infections or no clinical problems Mechanisms of defect Defect in B cell differentiation or T cell help; rare cases of homozygous deletions/mutations of Ig constant region genes

Defects in ymphocyte ctivation

Disease TAP deficiency Functional deficiencies Lack of class I MHC molecule expression, decreased number of CD8+ T cells; susceptibility to bacterial infections Mechanisms of defect Mutation in the TAP genes preventing peptide loading of class I MHC molecules

Defects in B cells, T cells, complement, or phagocytic cells I. Congenital Immunodeficiency Disorders B-Cell Disorders 1. Bruton's agammaglobulinemia (X-linked recessive disorder) - Failure of pre-B cells to become mature B cells - Mutated tyrosine kinase - Sinopulmonary infections - Maternal antibodies protective from birth to age 6 months - Decrease immunoglobulins

2. IgA deficiency - Failure of IgA B cells to mature into plasma cells - Sinopulmonary infections, giardiasis - Anaphylaxis if exposed to blood products that contain IgA - Decrease IgA and secretory IgA 3. Common variable immunodeficiency - Defect in B-cell maturation to plasma cells - Adult immunodeficiency disorder - Sinopulmonary infections, GI infections (Giardia), pneumonia, autoimmune disease - Decrease immunoglobulins

T-Cell Disorder 1. DiGeorge syndrome - Failure of third and fourth pharyngeal pouches to develop - Thymus and parathyroids fail to develop

Combined B- and T-Cell Disorders 1. Severe combined immunodeficiency (SCID) - Autosomal recessive disorder - Adenosine deaminase deficiency (adenine toxic to B and T cells) - Decrease deoxynucleoside triphosphate precursors for DNA synthesis - Defective CMI - Decrease immunoglobulins - Treatment: gene therapy, bone marrow transplant (patients with SCID do not reject allografts)

2. Wiskott-Aldrich syndrome (X-linked recessive disorder) - Progressive deletion of B and T cells - Symptom triad: eczema, thrombocytopenia, sinopulmonary infections - Associated risk of malignant lymphoma - Defective CMI - Decrease IgM, normal IgG, Increase IgA & IgE 3. Ataxia-telangiectasia (Autosomal recessive disorder) - Mutation in DNA repair enzymes - Thymic hypoplasia - Cerebellar ataxia, telangiectasias of eyes and skin - Risk of lymphoma and/or leukemia - Increase serum -fetoprotein

II. HIV / AIDS

Modes of transmission Sexual transmission (>75% of cases) Homosexual transmission (anal intercourse between men) is the most common cause in western countries Heterosexual transmission is the most common cause in developing countries Virus enters blood vessels or dendritic cells in areas of mucosal injury Intravenous drug abuse Rate of HIV infection is markedly increasing in female sex partners of male intravenous drug abusers

Other modes of transmission Vertical transmission Transplacental route, blood contamination during delivery, breast-feeding Most pediatric cases of AIDS is due to transmission of virus from mother to child Accidental needlestick Risk per accident is 0.3%. Most common mode of infection in health care workers Blood products Risk per unit of blood is 1 per 2 million units of blood transfused Body fluids containing HIV Blood, semen, breast milk Virus cannot enter intact skin or mucosa

Etiology RNA retrovirus HIV-1 is the most common cause in the United States HIV-2 is the most common cause in developing countries

Pathogenesis 1. HIV envelope protein (gp120) attaches to the CD4 molecule of T cells. 2. HIV infects CD4 T cells causing direct cytotoxicity. 3. Infection of non-T cells - Can infect monocytes and macrophages in tissue (lung, brain) - Can infect dendritic cells in mucosal tissue = Dendritic cells transfer virus to B-cell germinal follicles - Macrophages and dendritic cells are reservoirs for virus = Loss of cell-mediated immunity 4. Reverse transcriptase - Converts viral RNA into proviral double-stranded DNA - DNA is integrated into the host DNA

Clinical findings Acute phase Mononucleosis-like syndrome 3 to 6 weeks after infection Latent (chronic) phase Asymptomatic period 2 to 10 years after infection CD4 T-cell count greater than 500 cells/ L Viral replication occurs in dendritic cells (reservoir cells) in germinal follicles of lymph nodes. Early symptomatic phase CD4 T-cell count 200 to 500 cells/ L Generalized lymphadenopathy Non-AIDS-defining infections, including hairy leukoplakia, or Epstein-Barr virus (EBV)-caused glossitis, oral candidiasis Fever, weight loss, diarrhea

AIDS Criteria HIV-positive with CD4 T-cell count of 200 cells/ L or less or an AIDS-defining condition Most common AIDS-defining infections Pneumocystis jiroveci pneumonia, systemic candidiasis AIDS-defining malignancies Kaposi's sarcoma , Burkitt's lymphoma (EBV), primary CNS lymphoma (EBV) Causes of death Disseminated infections (cytomegalovirus, Mycobacterium avium complex)

Immunologic abnormalities Lymphopenia (low CD4 T-cell count) Cutaneous anergy (defect in cell-mediated immunity) Hypergammaglobulinemia (due to polyclonal B-cell stimulation by EBV) CD4:CD8 ratio <1 CD4 count and risk for certain diseases 700 to 1500: normal 200 to 500: oral thrush, herpes zoster (shingles), hairy leukoplakia 100 to 200: Pneumocystis jiroveci pneumonia, dementia Below 100: toxoplasmosis, cryptococcosis, cryptosporidiosis Below 50: CMV retinitis, Mycobacterium avium complex, progressive multifocal leukoencephalopathy, primary central nervous system lymphoma

Amyloidosis

Amyloid
- Fibrillar protein that forms deposits in interstitial tissue resulting in organ dysfunction - Pathogenesis : Abnormal folding of normal or mutant proteins - Characteristics Linear, nonbranching filaments in a -pleated sheet Apple green-colored birefringence in polarized light with Congo red stain of tissue Eosinophilic staining with H &E stain Derived from various proteins

Major types of amyloid proteins Amyloid light chain (AL) Derived from light chains (Bence Jones protein) Amyloid-associated (AA) Derived from serum associated amyloid (SAA), an acute phase reactant -Amyloid (A ) Derived from amyloid precursor protein (protein product of chromosome 21)

Types of amyloidosis 1. Systemic - similar tissue involvement in both primary and secondary types a. Primary amyloidosis AL amyloid disposition Associated with multiple myeloma (30% of cases) b. Secondary (reactive) AA amyloid Associated with chronic inflammation (RA, tuberculosis) 2. Localized a. Confined to a single organ (brain) Alzheimer's disease (A ) - most common cause of dementia 3. Hereditary Autosomal recessive disorder involving AA amyloid (familial Mediterranean fever)

Techniques used to diagnose amyloidosis 1. Immunoelectrophoresis (to detect light chains) in primary amyloidosis 2. Tissue biopsy (kidney)