Diseases of the Immune System

Too little or Too much

The normal Immune response• Innate immunity• Epithelial barriers• Phagocytic cells (monocytes and neutrophils)• Dendritic cells (type 1 IF)• Natural killer cells • Plasma proteins ( including the complement system)• Adaptive Immunity• Humoral – extracellular microbes and their toxins• Cell-mediated - intracellular microbes•

Components of the Immune system

• Cells• Lymphocytes- heterogeneous and specialized• B lymphocytes – Antibody secretion• CD4+ helper T lymphocytes – activation of macrophages• inflammation• stimulation of B cells• DC8+ cytotoxic T lymphocytes – killing of infected cell

• Naïve effector or memory cells•

T Lymphocytes• Precursors in the thymus• 60-70% blood lymphocytes• T cell zones of the peripheral lymphoid organs• Recognizes a specific cell-bound antigen by means of an antigen-specific T

cell receptor (TCR)• Alpha and Beta polypeptide chains• Variable (antigen-binding) region and constant region• TCR recognizes peptide antigens that are displayed by MHC molecules on

the surfaces of antigen-presenting cells (MHC restriction)• Presence of rearranged TCR genes is a marker of T-lineage cells

(mediated by RAG)• Analysis of antigen receptor gene rearrangements is a valuable assay for

detecting lymphoid tumors

T Lymphocytes• Gamma –delta TCR recognize molecules (peptides, lipids, small

molecules) without MHC display, epithelial surfaces, function unknown

• NK-T cells recognize glycolipids displayed by CD1 ( MHC-like molecule) – function unknown

• CD4 – expressed on 60% lymphocytes, cytokine-secreting helper cells that help macrophages and B lymphocytes fight infections, bind to class I MHC

• CD8 - expressed on 30% lymphocytes, cytotoxic (killer) cells destrot host cells that are harboring microbes, bind to class II MHC

• T cells also recognize additional signals by antigen presenting cells

B Lymphocytes• Precursors in bone marrow• 10-20% circulating lymphocytes• Lymph nodes, spleen, mucosa-associated lymphoid tissue (MALT)• Recognize antigen via the antigen-binding component of the

receptor complex• IgM and IgD present on the surface of all mature naïve B cells• Each B cell receptor has a unique antigen specificity• Analysis of Ig gene rearrangements is ueful for identifying

monoclonal B cell tumors• After stimulation by antigen, B cells develop into plasma cells that

secrete antibodies• Express CR2 or CD21 = receptor for EBV

Dendritic Cells• Interdigitating dendritic cells – most important APCs in initiating T cell

responses against protein antigens, located under epithelia and in interstia, express many receptors to respond to microbes ( TLRs and mannose), in response to microbes are recruited to T cell zones of lymphoid tissue to present antigens to T Cells, express high levels of molecules needed to resent antigens to and ativate CD4+ cells

• Langerhan cells – immature dendritic cells in the epidermis

• Follicular dendritic cells – Found in germinal centers, Fc receptors for IgG and receptors for C3b, trap antigen bound to antibodies or complement proteins, present antigens to B cells and selecting B ells with highest affinity for the antigen, increasing the quality of the antibody produced

Macrophages

• Function as APCs in T cell activation (present peptide fragments from phagocytosed microbes and protein antigens to T cells)

• Key effector cells in cell-mediated immunity, t cells enhance their ability to kill ingested microbes (eliminate intracellular microbes)

• Participate in the effector phase of humoral immunioty by phagocytosing and destroying opsonized microbes

Natural Killer Cells• 10-15% of peripheral lymphocytes• Large granular lymphocytes• Ability to kill a variety of infected or tumor cells without prior exposure or

activation• Ability to lyse IgG-coated target cells – antibody–dependent cell-mediated

cytotoxicity (ADCC)• Functional activity regulated by a balance between signals from activating and

inhibitory receptors• NKG2D – activators• Inhibitor receptors recognize self-class I MHC present on all healthy cells• Secrete cytokines – interferon- gamma – activates macrophages• Activity regulated by cytokines – interleukins 2, 12, 15 (2 and 15 stimulate, 12

inhibits)

Tissues of the Immune system• Generative (primary or central) - T and B cells mature and become

competent, Thymus and bone marrow

• Peripheral (secondary) – Lymph nodes, spleen, mucosal and cutaneous lymphoid tissues; organized to concentrate antigens, APCs, and lymphocytes to optimize interactions and develop responses

• Paracortex in nodes or periarteriolar lymphoid sheaths in spleen– T cells

• Follicles – B cells ( germinal centers)• Lymphocytes constantly recirculate between tissues and home to

particular sites (T cells rome while plasma cells secrete antibodies that rome)

Major histocompatibility Complex (MHC) molecules

• Peptide display system of adaptive immunity• Discovered as products of genes that evoke rejection of

transplanted organs• Physiologic function is to display peptide fragments of proteins for

recognition by antigen-specific T cellls• Chromosome 6 – major histocompatibility complex or human

leukocyte antigen (HLA) complex• Three groups• Class I MHC molecules• Class II MHC molecules• Genes that encode complement components, TNF and

lymphotoxin

MHC Molecules• Class I• Expressed on all nucleated cells and platelets• HLA-A, HLA-B, HLAC• Display peptides that are derived from proteins, such as viral antigens, that are

located in the cytoplasm and usually produced in the cell, recognized by CD8+ cells• Class II• HLA-D : HLA-DP, HLA-DQ, HLA-DR• Present antigens that are internalized into vesicles, and are typically derived

from extracellular microbes and soluble proteins• HLA haplotype – combination of HLA alleles in each individual, polymorphism, no two

individuals except identical twins are likely to express the same MHC molecules, leading to graft rejection, associated with inflammatory diseases, autoimmune diseases, inherited errors of metabolism (e.g. ankylosing spondylitis and HLA-B27)

• Autoimmune diseases and DR locus; 21-hydroxylase HLA-BW47, Hereditary hemochromatosis HLA-A

Cytokines

• Messenger molecules of the immune system• Interleukins – mediate communications between

leukocytes• Cytokines of innate immunity – produced rapidly in

response to microbes and other stimuli; made by macrophages, dendritic cells, NK cells

• Cytokines of adaptive immunity – produced by CD4+ cells

• Colony-stimulating factors – cytokines that stimulate hematopoiesis

Overview of Lymphocyte Activation and Immune Responses• Display and recognition of antigens

• Clonal selection hypothesis:• Lymphocytes specific for a large number of antigens exist before exposure to the

antigen, and when an antigen enters, it selects the specific cells and activates them.• Cell-mediated Immunity: Activation of T cells and elimination of intracellular microbes• Some of the progeny of the expanded T cells differentiate into effector cells that can

secrete different sets of cytokines, and thus perform different functions• TH1 – Macrophage activation, stimulation of IgG, intracellular microbes,

role in chronic inflammatory diseases (IFN gamma)• TH2 – Mast cell and eosinophil activation, stimulation of IgE, parasites,

allergies (IL-4 and 5)• TH17 – Recruitment of neutrophils and monocytes, extracellular

bacteria, fungi, role in chronic inflammatory diseases• (IL-17)

Overview of Lymphocyte activation• Humoral immunity: Activation of B cells and elimination of

extracellular microbes• Activated B cells become plasma cells and secrete antibodies• Neutralization of microbes and toxins• Opsonization and phagocytosis• Antibody-dependent cytotoxicity• Lysis of microbes• Complement activation• Inflammation••

Hypersensitivity Disorders• General features• Both exogenous and endogenous antigens may elicit

hypersensitivity reactions• The development of hypersensitivity diseases ( both

allergic and autoimmune disorders) is often associated with the inheritance of particular susceptibility genes

• Hypersensitivity reflects an imbalance between the effector mechanisms of immune responses and the control mechanisms that serve to normally limit such responses

Hypersensitivity Disorders• Type I – immediate hypersensitivity, TH2 cells, IgE , mast cells, release

of mediators that act on vessels and smooth muscle and pro-inflammatory cytokines that recruit inflammatory cells

• Type II – antibody-mediated.,IgG and IgM participate directly in injury to cells by promoting their phagocytosis or lysis and injury to tissues by inducing inflammation, interfere with cellular functions

• Type III – immune complex-mediated, IgG and IgM bind antigens usually in the circulation, antibody-antigen complexes deposit in tissues and induce inflammation, leukocytes produce tissue damage by release of lysosomal enzymes and generation of free radicals

• Type IV – cellular-mediated, TH1 and TH17 and CTLs cause cellular and tissue injury

Type I Hypersensitivity• Rapid immunologic reaction occurring within minutes after the

combination of an antigen with antibody bound to mast cells in individuals previously sensitized to the antigen

• Often called allergy• Systemic or local• Two phases – • Immediate or initial - vasodilatation, vascular leakage, smooth

muscle spasm, glandular secretions, 5-30 minutes start, 60 minutes subsides

• Late-phase - starts 2-24 hours, last s up to several days, infiltration of tissues with eosinophils, neutrophils, basophils, monocytes, and CD4+ cells as well as tissue damage

Type I hypersensitivity• Mast Cells• Widely distributed in tissues, especially near blood vessels,

nerves, subepithelial tissues• Activated by cross-linking of high-affinity IgE Fc receptors• Also triggered by other stimuli -C5a and C3a – anaphylatoxins,

some chemokines,drugs such as morphine and codeine, adenosine, mellitin ( in bee venom), physical stimuli (heat, cold, sunlight)

• Basophils • Similar to mast cells, not normally present in tissues, not as

well understood•

Type I Hypersensitivity• Preformed mediators• Vasoactive amines – most important histamine• Enzymes – primary tissue damage or by generating kinins or activating complement• Proteoglycans – heparin and chondroitin sulfate – package and store amines in granules• Synthesized mediators –• Lipid mediators – Activation of phospholipase A arachidonic acid• Leukotrienes – C4 and D4 - most potent vasoactive and spasmogenic agents known

• Prostaglandin D2- intense bronchospasm and increased mucus secretion (most abudnant)• Platelet –activating factor – platelet aggregation, release of histamine,

bronchospasm,increased vascular permeability, vasodilation, chemotactic for neutrophils and eosinophils (not an arachidonic acid derivative)

• Cytokines – TNF, interleukins, chemokines••

Type I Hypersensitivity• The development of immediate hypersensitivity is dependent on the

coordinated actions of a variety of chemotactic, vasoactive, and spasmogenic compounds

• The recruited cells especially eosinophils amplify and sustain the inflammatory response without the additional exposure to the triggering antigen

• Susceptibility to immediate hypersensitivity is genetically determined

• Atopy

• Hygiene hypothesis

Type I hypersensitivity• Summary• Complex disorder resulting from IGE –mediated triggering of mast cells and

subsequent accumulation of inflammatory cells at sites of antigen deposition. These event are regulated mainly by the induction of TH 2 helper T cells that stimulate production of IgE ( which promotes mast cell activation), cause accumulation of inflammatory cells (particularly eosinophils), and trigger secretion of mucus. The clinical features result from release of mast cell mediators as well as eosinophil-rich inflammation.

• Systemic anaphylaxis • Itching, hives, skin erythema• Contraction of respiratory bronchioles and respiratory distress• Laryngeal edema, hoarseness, obstruction• Vomiting, abdominal cramps• Shock• Death

Type II hypersensitivity• Caused by antibodies that react with antigens present on

cell surfaces or in the extracellular matrix• Injury caused by:• Opsonization and phagocytosis – transfusion reactions,

hemolytic disease of the newborn, autoimmune hemolytic anemia. Agranulocytosis, thrombocytopenia, certain drug reactions

• Complement and Fc receptor mediated inflammation –glomerulonephritis, vascular rejection in tissue grafts

• Antibody-mediated cellular dysfunction – myasthenia gravis , Graves disease

Type III hypersensitivity• Antigen-antibody complexes produce tissue damage by eliciting inflammation at

the sites of deposition

• Systemic (e.g. acute serum sickness)• Formation of antigen-antibody complexes in the circulation• Deposition of the immune complexes in various tissues – particularly joints

and glomeruli (high pressure tissues)• Inflammatory reaction at the sites of deposition – fibrinoid necrosis,

granular lumpy deposits on immunofluorescence microscopy• Local ( Arthus Reaction)• Localized area of tissue necrosis resulting from acute immune complex

vasculitis usually in the skin• Acute Serum Sickness•

Type IV hypersensitivity• Delayed-type hypersensitivity and immune inflammation ( CD4+

cells, TH1, TH17)• The cellular events in T cell-mediated hypersensitivity

consists of a series of reactions in which cytokines play important roles (IFNgamma from Th1 and IL17 from Th17 activate macrophages and neutrophils as well as promoting more cytokine secretion)

• E.g. tuberculin reaction (PPD) -> may become granuloma, contact dermatitis

• T cell-mediated cytolysis ( CD8+ cells)• preformed mediators – perforins and granzymes• E.g. Type I DM, Graft rejection, viral infections

Autoimmune Diseases• General principles• Autoimmunity –immune reactions against self-antigens

• Organ-specific or systemic• Immune tolerance• Unresponsiveness to an antigen as a result of exposure of lymphocytes to that

antigen• Self-tolerance – lack of responsiveness to an individual’s own antigens

• Central tolerance – immature self-reactive t and B cells clones that reognize self antigens during their maturation in the thymus or bone marrow are killed or rendered harmless

• Thymus – AIRE gene, negative selection or deletion, change to regulatory T cells• BM – receptor editing•

Autoimmune Diseases

• Peripheral tolerance• Anergy – prolonged or functional

inactivation of lymphocytes, CTLA-4 or PD-1 genes• Suppression by regulatory T cells – CD25

Foxp3 gene, Il-2 receptor gene• Deletion by activation-induced cell death –

death by apoptosis (Bcl/Bim pro-apototic factor or FasL-Fas system)

• Immune-privileged sites – testis, eye, brain

Autoimmune Diseases• Autoimmunity arises from a combination of the inheritance of susceptible

genes, which may contribute to the break-down of self-tolerance, and environmental triggers, such as infections and tissue damage, which promote the activation of self-reactive lymphocytes

• Most autoimmune diseases are complex multigenic disorders (HLA/MHC )• PTPN-22 is said to be the gene from frequently implicated in autoimmunuty• Role of infections – induction of costimulators on APCs, molecular mimicry• but may protect against some autoimmune diseases (because incidence

of autoimmunie disease is higher in countries with fewer infections)• Amplification mechanisms exacerbate injury• Epitope spreading• Collagen vascular diseases – systemic autoimmune diseases that tend to

involve the blood vessels and connective tissue

Systemic Lupus Erythematosus (SLE)

• Prototype of a multisystem disease of autoimmune origin• Vast array of autoantibodies ( particularly antinuclear antobodies)• immunofluorescense test is sensitive but not specific• antibodes to dsDNA and SM antigen are diagnostic• Criteria for classification of SLE• Malar rash, discoid rash, photosensitivity, oral ulcers• Arthritis, serositis – pleuritis or pericarditis• Renal disorder – proteinuria or RBC casts• Neurological disorder – seizures or psychosis• Hematologic – Hemolytic anemia or cytopenias• Immunological disorder – positive antobodies other than ANA (antiphospholipid

antibodies to phospholipid B2 glycoprotein -> may give false positive in syphilis serology)• ANA• ( 4 or more of the above 11 criteria makes the diagnosis)•

SLE• Antinuclear antibodies• Antibodies to DNA• Antibodies to histone• Antibodies to nonhistone proteins bound to RNA• Antibodies to nucleolar antigens• Patterns of nuclear fluorescence• Homogeneous or diffuse nuclear staining – histone, chromatin,

double-stranded DNA• Rim or peripheral staining – double-stranded DNA• Speckled – least specific, non-DNA nuclear constituents: Sm,

RNP, SS-A ,SS-B• Nucleolar – RNA

SLE• ANA• Sensitive – Positive in virtually every patient with SLE• Not specific – Also positive in other auto-immune diseases and in 5-15% of

normal individuals• Antibodies to Smith antigen and ds-DnA are virtually diagnostic of SLE (HLA-DQ)• 40-50% have antiphospholipid antibodies – lupus anticoagulant, hypercoaguable

state• False positive RPR (syphilis serology)• Cause of SLE is unknown• Model for pathogenesis• UV irradiation and other environmental insults lead to apoptosis of cells Large

burden of nuclear antigens because not adequately cleared Self-reactive lymphocytes (because of defective tolerance) stimulated by these self nuclear antigens and antibodies are produced Cycle of antigen release and immune activation Production of high-affinity autoantibodies

sle• Mechanisms of tissue injury• Most of the visceral lesions are caused by immune complexes (Type III

hypersensitivity)• Autoantibodies specific for RBCs, WBCs, platelets opsonize these cells and promote their

phagocytosis and lysis• Clinical manifestations• Hematologic 100%• Arthritis, skin – 80-90%• Fever, fatigue, weight loss• Renal• Neuropsychiatric, peripheral neuropathy• Pleuritis, pericarditis• Myalgia• GI• Ocular• Raynaud phenomenon

SLe• Renal (granular deposits in all)• Class I Minimal mesangial (no glomerular capillary involvement)• Class II Mesangial proliferative (no glomerular capillary

involvement)• Class III Focal proliferative (<50% of all glomeruli; wire loop lesion)• Class IV Diffuse proliferative ( most severe) (entire glomerulus;

>50% of all glomeruli; wire loop lesion)• Class V Membranous (thickening of capillary wall and nephrotic

syndrome)• Libman-Sacks endocarditis – nonbacterial verrucous

• Most common causes of death – renal failure and intercurrent infections

Other forms of Lupus• Chronic Discoid LE• Skin manifestations without systemic usually• Positive ANA but usually not anti-ds-DNA antibodies• Subacute cutaneous LE• Skin lesions widespread, superficial and not scarring• mild systemic symptoms• anti- SS-A antibodies• HLA-DR3• Drug-induced LE ( e.g. hydralazine, procainamide)• Positive ANA• No renal or CNS involvement• anti-histone antibodies• HLA-DR4

Sjogren Syndrome• Dry eyes (keratoconjunctivitis sicca)• Dry mouth (xerostomia)• Destruction of lacrimal and salivary glands – lymphocytic infiltration and

fibrosis• Often associated with other autoimmune disorders RA, increased risk of B-

cell lymphoma• Anti–SS-A ( Ro) and anti-SS-B (La) antibodies• Diagnosis - biopsy of the lip (to examine minor salivary glands)• Clinical – blurring of vision, burning and itching, thick secretions; difficulty

swallowing dry foods, decreased taste, cracks and fissures in mouth, dryness of mucosa; parotid gland enlargement; dryness of nasal mucosa, epitaxis; bronchitis, pneumonitis; tubulointerstitial nephritis

• Mikulicz syndrome – lacrimal and salivary gland enlargement from any cause

Systemic Sclerosis (Scleroderma)• Chronic inflammation, widespread damage to small blood vessels,

progressive interstitial and perivascular fibrosis in the skin and multiple organs

• Diffuse vs limited scleroderma• CREST syndrome – calcinosis, Raynaud phemomenon, esopahgeal

dysmotility, sclerodactyly, telangiectasia• Anti-Scl 70 antibody (DNA topoisomerase I) -> pulmonary fibrosis• Anticentromere antibody -> CREST syndrome• Microvascular disease may be the initial lesion

• Mixed connective tissue disease – features of SLE, scleroderma, and polymyosits; antobodies to RNP (U1 )

Rejection of Tissue transplants

• Complex process in which both cell-mediated immunity and circulating antibodies play a role.

• T cells• Cellular rejection • Direct pathway – T cells recognize allogeneic MHC

molecules on the surface of APCs in the graft, major pathway in acute cellular rejection CD8 CTL and CD4

• Indirect pathway – T cells recognize MHC antigens after they are presented by the recipient’s APCs, more important in chronic rejection CD4 only

Rejection of tissue transplants• Antibody-mediated rejection• Hyperacute rejection• Preformed antidonor antibodies are present in the circulation• Currently screening by cross-matching has made this an insignificant clinical problem• Acute humoral rejection• Target the graft vasculature leading to rejection vasculitis• Antibodies to class I and class II MHC antigens from the donor graft• Acute cellular rejection• CD4+ and CD8+; causing endothelitis• Chronic Rejection• Fibrosis and sclerosis of arteries• Renal transplants• Rise in serum creatinine over 4-6 months signals chronic rejection• Hematopoietic transplants• Graft vs Host disease• Acute – immune system, skin, intestines, liver• Chronic – systemic sclerosis pitcture• Immunodeficiency••

Primary Immunodeficiency syndromes

• X-linked agammaglobulinemia (Bruton’s agammaglobulinemia)• Failure of B cell precursors to develop into mature B cells• Mutation in Bruton tyrosine kinase gene• X-linked • Becomes clinically apparent after 6 months of age when maternal immunoglobulins are

depleted• Recurrent bacterial infections of the respiratory tract: (H.flu, Strep pneumo, Staph aureus)• Enteroviruses, giardia• B cells are absent or marked decreased in the circulation• Serum levels of all immunoglobulins are depressed• Pre-B cells with B lineage marker CD19, but not membrane Ig, are found in normal

numbers in the bone marrow• Germinal centers of lymph nodes, Peyer’s patches, appendix and tonsils are

underdeveloped• Plasma cells are absent• T cell-mediated immunity is normal

Primary Immunodeficiency syndromes

• Common variable immunodeficiency• Near or near-normal B cell counts• Clinical manifestations similar to Bruton but onset later in childhood or

adolescence• Hyperplastic B cell areas – B cells can proliferate but not produce

antibodies so no feedback• Isolated IgA deficiency• Low levels of secretory IgA• Recurrent sinopulmonary infections and diarrhea• Severe reaction to blood transfusions containing IgA• Some also have deficiency of IGG2 and IgG4 subclasses• •

Primary Immunodeficiency Syndromes

• Hyper-IgM Syndrome• Make IgM antibodies but are deficient in their ability to

make IgG, IgA, and IgE• Recurrent pyogenic infections, some also get

pneumocystis• 70% x-linked, 30% AR• Defect affects the ability of helper T cells to deliver

activating signals to B cells and macrophages• Mutation in gene encoding CD40 or activation-induced

deaminase•

Primary Immunodeficiency Syndrome

• DiGeorge Syndrome• T cell deficiency resulting from failure of

development of the third and fourth pharyngeal pouches

• Hypocalcemia, CHD• 22q11 deletion syndrome• Abnormal facies• Fungal and viral infections

Primary Immunodeficiency Syndromes

• SCID• Both humoral and cell-mediated immune responses are

affected• Infants present with thrush, diarrhea, FTT, morbilliform rash

(GVH)• Susceptible to wide range of infections, die by one year of age

without bone marrow transplantation• X-linked 50-60% - mutation in the common gamma chain of

cytokine receptors• AR - most have deficiency of ADA• Gene therapy has been tried ( large % developed acute t cell

leukemia)

Primary Immunodeficiency Syndrome

• Wiskott-Aldrich syndrome• X-linked recessive• Thrombocytopenia, eczema, marked vulnerability to recurrent

infection• Mutation in WASP gene • Complement deficiencies• C2 – increased incidence of SLE• C3 – increased incidence of recurrent serious pyogenic

infections and imune- complex GN• C5-9 – increased incidence of Neisseria infections• C1 inhibitor – hereditary angioedema•

Acquired Immunodeficiency Syndrome (AIDS)

• Diseased caused by the retrovirus HIV• Profound immunosuppression leading to opportunistic infections, secondary neoplasms, and

neurologic manifestations• Epidemiology• Homosexual or bisexual men > 50%• IV drug abusers• Hemophiliacs• Recipients of blood transfusions• Heterosexual contacts of members of high-risk groups ( most rapidly growing group)• Unknown in 5%• Major routes of transmission• Sexual transmission• Parenteral transmission• Mother-to-infants••

AIDS• Two major targets of HIV infections• Immune system• CNS• Infection of and loss of CD4+ T cells

• Life cycle of HIV• Infection of cells• Integration of the provirus into the host genome• Activation of viral replication• Production and release of infectious virus

AIDS• Infection of cells• The initial step is the binding of the gp120envelope glycoprotein to CD4 molecules

conformational change new recognition site for coreceptors ( CCR5 and CXCR4)• Fusion of the virus with the host cell• Virus core containing the HIV genome enters the cytoplasm• Requires HIV binding to coreceptors – implications for resistance to infection• Infects memory and activated T cells, not naïve cells because of enzyme APOBEC3G

that causes mutation in the HIV genome• Viral replication• Reverse transcription Synthesis of ds-complementary DNA• Quiescent cells - cDNA remains in cytoplasm• Dividing cells - cDNA is incorporated into the host genome• After cell activation - cell lysis• HIV thrives when the host cells and macrophages are physiologically activated •

AIDS• Mechanism of T cell immunodeficiency in HIV infection• Loss of CD4+ T cells is mainly because of infection of the cells and the direct cytopathic effects of the

replicating virus•• Colonization of the lymphoid tissues by HIV leading to progressive destruction

• Chronic activation of uninfected cells leads to apoptosis ( activation-induced cell death)

• Loss of immature precursors

• Fusion of infected and uninfected cells ( synctia formation) cell death•• Apoptosis of uninfected cells by binding of the soluble gp120 to the CD4 molecule•• Qualitative defects in T cells even in asymptomatic persons

• Low –level chronic or latent infection of T cells

•

AIDs• Infection of non- T cells• Macrophages and dendritic cells• Important in the pathogenesis of HIV infection• Gatekeepers and potential reservoirs of infection• Mucosal dendritic cells are infected by the virus and transport it to regional

lymph nodes where the virus is transmitted to CD4+ cells• Despite the presence otfspontaneously activated B cells, patients with AIDS are

unable to mount antibody responses to newly encountered antigens• Pathogenesis of CNS involvement• Macrophages and microglia are the predominant cell types infected in the

brain• Neurologic deficits caused by viral products and soluable products from

infected microglia ?•

AIDS• Natural History of HIV infection: Primary infection• HIV disease begins with acute infection, partly controlled by the adaptive

immune response, advances to chronic progressive infection of the peripheral lymphoid tissues

• Early infection is characterized by infection of memory CD4+ T cells in mucosal lymphoid tissues and death of many infected cells

• Mucosal infection is followed by dissemination of the virus and development of host immune repsonses

• HIV-specific CD8+ T cells are detected in the blood at about the same time viral titers begin to fall and are most likely responsible for the initial containment of HIV infection

AIDs

• Acute retroviral syndrome• Self-limited acute illness• Non-specific symptoms – sore throat,

myalgias, fever, weight loss, fatigue• “Flu-like” picture• 3-6 weeks after infection• Resolves in 2-4 weeks• Extent of viremia after the acute infection is a

useful marker of HIV progression ( measured as HIV-1 RNA levels)

• For clinical measurements CD4+ counts are most important

•

AIDS• Chronic infection• Lymph nodes and spleen are sites of continuous HIV replication and

cell destruction• Phase of clinical latency• Asymptomatic or minor opportunistic infections• Progression to AIDS• Breakdown of host defenses• Dramatic increase in plasma virus• Severe, life threatening clinical disease – Serious opportunistic

infections, secondary neoplasms, clinical neurologic disease• Rapid progressors, long-term nonprogressors, elite controllers••

AIDS• Defining opportunistic infections and neoplasms• Cryptosporidiosis enteritis• Toxoplasmosis ( pneumonia or CNS)•• Pneumocystosis• Candidiasis ( esopahgeal, tracheal, or pulmonary)• Crytococcosis (CNS)• Coccidioidomycosis (disseminated)• Histoplasmosis (disseminated)

• MAC• Nocardiosis• Salmonella

• CMV• HSV• VZV• Progressive multifocal leukoencephalopathy

AIDS• Tumors• Kaposi sarcoma ( HHV8 virus)• AIDS –related lymphomas• Increased incidence of carcinoma of the cervix and anal cancer• CNS• Meningoencephalitis• Aseptic meningitis• Vacuolar myelopathy• Peripheral neuropathy• Progressive encephalopathy – AIDS-dementia complex••

AMyloidosis• Pathologic proteinaceous substance deposited in extra cellular spaces

in various tissues and organs in a wide variety of clinical settings• Continuous nonbranching fibrils • Most common• AL – immunoglobulin light chains (plasma cell tumors)• AA - 76 amino-aid residues ( chronic inflammatin – secondqry

amyloidosis)• Beta-amyloid - Alzheimer disease• Others• TTR ( transthyretin) – familial polyneuropathies, senile systemic• Beta 2-microglobulin – long-term hemodialysis• Prion proteins

Amyloidosis

• Primary Amyloidosis ( Immunoyte dyscrasias with amyloidosis)

• Bence Jones proteins• Reactive systemic • Hemodialysis-associated• Heredofamilial• Localized• Endocrine• Amyloid of aging – senile systemic