Immunopathology PDF

Immunopathology  OUTLINES: Immunopathology  Hypersensitivity reactions  Autoimmune disease  Immunology deficiency syndromes  Amyloidosis  Disorders of the immune system Divided in to four broad headings 1. Hypersensitivity reactions 2. Autoimmune disease: immune re...

Immunopathology  OUTLINES: Immunopathology  Hypersensitivity reactions  Autoimmune disease  Immunology deficiency syndromes  Amyloidosis  Disorders of the immune system Divided in to four broad headings 1. Hypersensitivity reactions 2. Autoimmune disease: immune reactions against self 3. Immunologic deficiency syndrome 4. Amyloidosis – a poorly understood disorder having immunologic association HYPERSENSITIVITY REACTIONS Hypersensitivity Reactions Outline Introduction Type I Hypersensitivity Type II Hypersensitivity Type III Hypersensitivity Type IV Hypersensitivity  Introduction Normal immune reactions do their job without hurting the host. Sometimes, immune reactions can be excessive, resulting in disease. People who mount normal immune responses are sensitized to that antigen. People who have excessive responses are hypersensitive.  Introduction What antigens initiate these “hypersensitivity reactions”?  Environmental antigens (exogenous) or Self antigens(endogenous)  Range from trival and annoying to fatal conditions  Imbalance between effector and control mechanisms  Associated with inheritance of susceptibility genes  Uncontrolled, misdirected or excessive responses  Introduction The immune response is triggered and maintained inappropriately. →imbalance between effector and control mechanisms Hard to eliminate stimulus! Hard to stop response once it starts! …so hypersensitivity diseases are often chronic, debilitating, hard to treat.  Introduction Four types of hypersensitivity reactions: Type I: allergy Type II: antibodies Type III: immune complex Type IV: T-cells  Type I Hypersensitivity ALLERGY “Immediate” hypersensitivity Antigen (allergen) binds to IgE antibodies on surface of mast cell Mast cell releases various mediators Injury by TH2, IgE, mast cells and leukocytes End result: vessels dilate, smooth muscle contracts, inflammation persists  Type I Hypersensitivity Sequence of events Allergen is inhaled/eaten/injected Allergen stimulates TH2 production TH2 cell secretes cytokines: IL-4 stimulates B cells to make IgE IL-5 recruits eosinophils IL-13 stimulates mucous secretion Mast cell binds IgE Allergen bridges IgE on mast cell on reexposure Mast cell degranulates  Type I Hypersensitivity What mediators does the mast cell release? Granule contents histamine some chemotactic factors Membrane phospholipid metabolites prostaglandin D2 leukotrienes Cytokines TNF interleukins IL-13  Type I Hypersensitivity What do these mediators do? Act on blood vessels, smooth muscle, and WBCs. Immediate response (minutes) vasodilation, vascular leakage, smooth muscle spasm granule contents, prostaglandin, leukotrienes Late phase reaction (2-24 hours) inflammation, tissue destruction (mucosal epithelial) cytokines  Type I Hypersensitivity What happens to the patient?  Systemic anaphylaxis: occur after administration of hormones ,drugs, and the like Itching, hives, erythema Constriction of bronchioles, wheezing Laryngeal edema, hoarseness Vomiting, cramps, diarrhea Laryngeal obstruction Shock DEATH  Local immediate reactions **Exemplified by so-called atopic allergy,10% of the population have allergy **Results from exposure to common allergen like pollen, house dusts, foods Skin: itching, hives GI: diarrhea Lung: bronchoconstriction  Type I Hypersensitivity Why do some people have allergies, while others don’t? “Atopy” – predisposition to react to allergens Atopic patients: higher IgE levels, more TH2 cells Candidate genes: 5q31 (bunch of cytokine genes here) 6p (close to HLA complex)  Type II Hypersensitivity ANTIBODIES “Antibody-mediated” hypersensitivity Antibodies bind to antigens on cell surface or extracellular matrix Macrophages eat up cells, complement gets activated, inflammation comes in End result: cells die, inflammation harms tissue  Type II Hypersensitivity What kinds of diseases involve type II hypersensitivity? Disease Antigen Symptoms Autoimmune RBC antigens, drugs Hemolysis hemolytic anemia Proteins between Pemphigus vulgaris Bullae epithelial cells Proteins in glomeruli and Nephritis, lung Goodpasture syndrome alveoli hemorrhage Myasthenia gravis Acetylcholine receptor Muscle weakness Graves disease TSH receptor Hyperthyroidism  Type II Hypersensitivity Sequence of events Antibodies bind to cell- surface antigens One of three things happens: Opsonization and Complement-dependent phagocytosis reactions Antibody-dependent cell- Inflammation mediated cytotoxicity (ADCC) Cellular dysfunction Antibody-mediated cellular dysfunction Opsonization and phagocytosis Complement and Fc receptor- mediated Inflammation  Antibody mediated Cellular dysfunction Graves disease Myasthenia gravis  Type III Hypersensitivity IMMUNE COMPLEXES “Immune complex-mediated” hypersensitivity Antibodies bind to antigens, forming complexes Complexes circulate, get stuck in vessels, stimulate inflammation End result: bad inflammation, necrotizing vasculitis  Type III Hypersensitivity What kinds of diseases involve type III hypersensitivity? Disease Antigen Symptoms Systemic lupus Nephritis, skin lesions, Nuclear antigens erythematosus arthritis… Post-streptococcal Streptococcal antigen Nephritis glomerulonephritis Polyarteritis nodosa Hepatitis B antigen Systemic vasculitis Arthritis, vasculitis, Serum sickness Foreign proteins nephritis Arthus reaction Foreign proteins Cutaneous vasculitis  Type III Hypersensitivity Two kinds of type III hypersensitivity reactions  Systemic immune complex disease eg. serum sickness Complexes formed in circulation Deposited in several organs and incites inflammation Favored sites of deposition includes, joints, glomeruli, heart, blood vessels Mechanism of tissue damage 1. Activation of complement cascades 2. Activation of neutrophils and macrophages through the Fc receptor  Local immune complex disease Complexes formed at site of antigen injection Precipitated at injection site Example: Arthus reaction  Type III Hypersensitivity How do the complexes cause inflammation? Immune complexes activate complement, which: Attracts and activates neutrophils and monocytes Makes vessels leaky Neutrophils and monocytes release chemicals (PG, tissue- dissolving enzymes, etc.) Immune complexes also activate clotting, causing microthrombi Outcomes: vasculitis, glomerulonephritis, arthritis, other -itises  Type III Hypersensitivity What are the important complement fractions to know? C3b: promotes phagocytosis of complexes C3a, C5a (anaphylatoxins): increase permeability C5a: chemotactic for neutrophils, monocytes C5-9: membrane damage or cytolysis  Type III Hypersensitivity Serum sickness In olden days: used horse serum for immunization Inject foreign protein (antigen) Antibodies are made; they form complexes with antigens Complexes lodge in kidney, joints, small vessels Inflammation causes fever, joint pain, proteinuria  Type III Hypersensitivity Arthus reaction “Arthus reaction” = localized area of skin necrosis resulting from immune complex vasculitis Inject antigen into skin of previously-immunized person Pre-existing antibodies form complexes with antigen Complexes precipitate at site of infection Inflammation causes edema, hemorrhage, ulceration  Type IV Hypersensitivity T CELLS “T-cell-mediated” hypersensitivity Activated T cells do one of two things: Release cytokines that activate macrophages, or Kill cells directly This process is normally useful against intracellular organisms (viruses, fungi, parasites) Here, it causes harmful responses: inflammation, cell destruction, granuloma formation  Type IV Hypersensitivity Two kinds of type IV hypersensitivity Delayed-type hypersensitivity (DTH) CD4+ T cells secrete cytokines Macrophages come and kill cells Direct cell cytotoxicity CD8+ T cells kill targeted cells  Type IV Hypersensitivity Delayed-type hypersensitivity (DTH) Patient exposed to antigen APC presents antigen to CD4+ T cell T cells differentiate into effector and memory T H1 cells Patient exposed to antigen again TH1 cells come to site of antigen exposure Release cytokines that activate macrophages, increase inflammation Results Macrophages eat antigen (good) Lots of inflammation and tissue damage (bad) Delayed-Type Hypersensitivity (DTH)  Type IV Hypersensitivity Delayed-type hypersensitivity (DTH) Good example of DTH: positive Mantoux test Patient previously exposed to TB Inject (inactive) TB antigen into skin See reddening, induration. Peaks in 1-3 days Prolonged DTH can lead to granulomatous inflammation  Type IV Hypersensitivity Delayed-type hypersensitivity (DTH) Perivascular CD4+ T cells replaced by macrophages Macrophages are activated, look “epithelioid” Macrophages sometimes fuse into “giant cells” Granuloma = collection of epithelioid macrophages Granuloma  Type IV Hypersensitivity DTH sounds a lot like cell-mediated immunity! Why, yes it does. The same mechanisms underlie both. Cell-mediated immunity is the major defense we have against intracellular microbes (like TB and fungi). Cell-mediated immunity (good) can coexist with DTH (bad)! Patients with AIDS: Lack CD4+ cells So have poor cell-mediated immune response! Macrophages sit there unactivated; can’t kill microbes.  Type IV Hypersensitivity T-cell-mediated cytotoxicity CD8+ T cell recognize antigens on the surface of cells T cells differentiate into cytotoxic T lymphocytes (CTLs) which kill antigen-bearing cells CTLs normally kill viruses and tumor cells In T-cell mediated cytotoxicity, CTLs kill other things: Transplanted organ cells Pancreatic islet cells (Type I diabetes) T-Cell-Mediated Cytotoxicity  Summary Type I Allergy TH2 cells, IgE on mast cells, nasty mediators Type II Antibodies Opsonization, complement activation, or cell dysfunction Type III Immune complexes Lodge, cause inflammation, tissue injury Type IV CD4+ or CD8+ T cells DTH or T-cell-mediated cytotoxicity Transplant immunology Transplant rejection Transplant= relocate, transfer Rejection= dismissal, elimination Organs transplanted currently are; – Heart, liver, kidney, skin…. Rejection is a complex phenomenon involving both cell- and antibody-mediated hypersensitivity reactions directed against histocompatibility molecules on the foreign graft. Rejection is a major barrier for transplantation from one individual to the other  Immune Recognition of Allografts : – Mechanisms by which the host immune system recognizes and responds to the MHC molecules on the graft – Direct recognition: Host T cells directly recognize the allogeneic (foreign) MHC molecules that are expressed on graft cells, CD4+ and CD8+ T-cells of host, and DC cells in graft  Indirect recognition Host CD4+ T cells recognize donor MHC molecules after these molecules are picked up, processed, and presented by the host's own APCs **production of antibodies against graft alloantigens  T-Cell-Mediated Rejection :CTL Antibody-Mediated Rejection (humoral rejection)  On the basis of mechanism, and resulting morphology the rejection process is classified to hyperacute, acute, chronic rejection 1. Hyperacute: occurs within minutes to a few hours after transplantation in a presensitized individual.cyanotic, mottled  The histology is characterized by widespread acute arteritis and arteriolitis, vessel thrombosis, and ischemic necrosis, all resulting from the binding of preformed antibodies to graft endothelium 2. Acute rejection: occurs within days to weeks Acute cellular: T cells destroy graft parenchyma by cytotoxicity and DTH reaction Acute humoral rejection. antibodies damage graft vasculature. There is necrotizing vasculitis and endothelial cell necrosis 3. Chronic rejection. Present late after transplantation(months to years).Dominated by arteriosclerosis, this type is probably caused by T- cell reaction and secretion of cytokines that induce proliferation of vascular smooth muscle cells, associated with parenchymal fibrosis  Graft versus host disease(GVHD)  It occurs when immunologically competent T cells (or their precursors) are transplanted into recipients who are immunologically compromised host generating DTH,CTL  Usually after bone marrow transplantation, and some other solid organs like the liver  Autoimmune Diseases Outline Autoimmune diseases Immunologic tolerance and autoimmunity Specific diseases  Immunologic Tolerance “Tolerance” = unresponsiveness to an antigen “Self-tolerance” = unresponsiveness to one’s own antigens In generating billions of B and T cells, some will react against self antigens! There are two ways of muzzling these cells: central tolerance and peripheral tolerance  Immunologic Tolerance Central tolerance Auto-reactive T and B cells deleted by apoptosis or in activated during maturation Occurs in thymus and bone marrow Process not perfect (some slip out!) Peripheral tolerance Auto-reactive cells muzzled in peripheral tissues  Some become “anergic” (inactive) in periphery  Some are suppressed by regulatory T cells  Some undergo apoptosis when activated  Antigen sequestration  Activation of Ag specific T cells requires; Recognition of peptide Ag in association with self MHCs Costimulatory signals(second) from APCs Anergy: prolonged or irreversible functional inactivation of lymphocytes, induced by encounter with antigens Why?? 1. Absence of costimulators (secondary signals from APCs) i.e. B7-1 and B7-2 2. Inhibitory signal from CTLA-4(receptor homologous to CD28)  Suppression by regulatory T-cells Mechanism:?? Secretion of immunosuppressive(TGF-beta,IL- 10) of by regulatory T-cells Express CTLA-4 – bind to B7 and inhibit activation of T cells through CD28  Clonal deletion by activation induced cell death CD4+ cells that recognize self antigens receive signals that induce apoptosis by; Mitochondrial pathway(expression of proapoptotic factor without antiapoptotic) Fas- FasL – Fas(CD95)- TNF receptor family – FasL(a protein which is structurally similar to TNF) Antigen sequestration  Some antigens are hidden, do not communicate with blood and lymph Eg. testis, eye, brain and they are called immune privileged site  Release of antigens from these sites results induction of immune response  Post-traumatic orchitis and uveitis  FAILURE OF TOLERANCE Failure of Activation-Induced Cell Death Breakdown of T-Cell Anergy Bypass of B-Cell Requirement for T-Cell Help Failure of T-Cell-Mediated Suppression Molecular Mimicry Polyclonal Lymphocyte Activation Release of Sequestered Antigens Exposure of Cryptic Self and Epitope Spreading  Autoimmunity “Autoimmunity” = immune reaction against self Self-tolerance breaks down, causing disease Two main reasons for breakdown: Inheritance of susceptibility genes(HLA- alleles, Fas genes) Environmental triggers(infection, tissue damage) Trigger a number of changes: Defective tolerance or regulation Abnormal display of self antigens Inflammation or an initial innate immune response  Autoimmunity Role of susceptibility Contribute for breakdown of self tolerance Role of infections (Environmental triggers) Up regulation of costimulators on APCs Mimic self antigens (antigen mimicry) – Streptococcal proteins vs myocardial proteins Polyclonal B cell activation – HIV, EBV Production of cytokines  General features of Autoimmune Diseases Tend to be chronic with relapses, remissions and progressive damage Clinical and pathologic manifestations depend on nature of immune response;  Autoantibodies caused diseases  Abnormal or excessive TH1 and TH 17 response  Psoriasis, Multiple sclerosis, IBD  CD8+ CTLs mediated cell killing  Combined autoantibodies and T cell mediated e.g. RA  Systemic Lupus erythematosus Multisystem disease (skin, kidneys, joints, heart) Immune complex and antibody mediated injury F:M is 9:1 in the age of 17-55 years Symptoms unpredictable (acute vs chronic relapsing/remitting) Antinuclear antibodies  Lupus Etiology Autoantibodies! Antinuclear Ab present in all patients with SLE... but found in other autoimmune diseases too Anti-RBC, -lymphocyte, -platelet, or –phospholipid antibodies may be present too Underlying cause unclear Genetic predisposition… Environmental factors (UV radiation, drugs)  Lupus What’s so bad about having these autoantibodies? They cause tissue injury! Form immune complexes Cause destruction, phagocytosis of cells Multisystem effects: Blood vessels Kidney (renal failure) Skin (“butterfly rash”) CNS (focal neurologic deficits) Joints (arthritis) Heart (pericarditis, endocarditis)  Lupus Morphology Blood vessels Acute necrotizing vasculitis Fibrous thickening Kidney (50% patients) Deposition of immune complexes in the mesangium, basement membrane , whole glomerulus Skin Vacuolar degeneration of basal layer Dermal perivascular inflammation and edema Libman sacks(valvular endocarditis)  Clinical manifestations ; relies on clinical, serological and morphologic changes Young woman with polyarthritis and a butterfly (or other) skin rash Sensitivity to sunlight Oral lesions: nonspecific, red-white, erosive Headaches, seizures, or psychiatric problems Pleuritic chest pain Unexplained fever  What’s the prognosis? Variable and unpredictable! Some have few symptoms, rare patients die within months. Most patients: relapses/remissions over many years. Some patients: indolent course. Acute flare-ups controlled with steroids 90% - 5 year and 80% -10-year survival Most common cause of death: renal failure  Rheumatoid Arthritis Is systemic inflammatory d/or of autoimmune origin affects many tissues and organ, mainly joint – Causes nonsuppurative proliferative and inflammatory synovitis Symmetric, mostly small-joint arthritis Systemic symptoms (skin, heart, vessels, lungs) Rheumatoid factor Cytokines (especially TNF) cause damage  Rheumatoid Arthritis Etiology Genetically predisposed patient Something (microbial? self-Ag?) activates T cells T cells release cytokines: activate macrophages (causing destruction) cause B cells to make antibodies against joint Most important of these cytokines: TNF, IFN 1, IL-1 and IL-17 Cytokines cause inflammation and tissue damage  Rheumatoid Arthritis Joint disease Mainly small joints (hands), but also knees, elbows, shoulders Symmetric; characteristic hand features Chronic synovitis with pannus formation which is mass of synovium and synovial stroma, and consists of synovial cell proliferation and hyperplasia inflammation, with follicle formation Increased vascularity due to angiogenesis increased osteoclastic activity Fibrous ankylosis and bony ankylosis  Rheumatoid Arthritis Systemic disease Weakness, malaise, fever Vasculitis(obliterating endarteritis, resulting in peripheral neuropathy, ulcer and gangrene Pleuritis, pericarditis Lung fibrosis Eye changes Rheumatoid nodules on forearms most common cutaneous lesions  Rheumatoid Arthritis Rheumatoid factor Circulating IgM antibody Directed against patient’s OWN IgG! Forms IgM-IgG immune complexes, which deposit in joints and cause badness Present in 80% of patients  Rheumatoid Arthritis Female patient with aching, stiff joints, especially in morning Symmetric joint swelling Fingers: ulnar deviation, swan-neck deformities, boutonniere deformities Rheumatoid nodules  Rheumatoid Arthritis What’s the prognosis? Variable! A few patients stabilize Most patients have chronic course with progressive joint destruction and disability Lifespan shortened by 10-15 years Treatment: steroids, anti-TNF agents  Sjögren Syndrome Chronic Inflammatory disease of salivary and lacrimal glands Dry eyes (keratoconjuctivitis sicca), dry mouth (xerostomia) Result from immunologically mediated destruction of lacrimal and salivary glands Isolated or in association with other disorders  Sjögren Syndrome Etiology CD4+ T cells attack self antigens in glands (why?!) Autoantibodies are present, but probably are not the primary cause of tissue injury ANAs RF Anti ribonucleic proteins Viral trigger? Genetic predisposition  Sjögren Syndrome Salivary and lacrimal glands (main targets) Enlarged Marked inflammation periductal and perivascular lymphocytic infiltration, follicle formation Hyperplasia of duct lining cells obstructing duct Atrophy and fibrosis of acini 5% will develop lymphoma! 25% of patients have Kidneys, lungs, skin, CNS  Sjögren Syndrome Extra glandular manifestations; Seen in one third of patients Synovitis Diffuse pulmonary fibrosis Peripheral neuropathy ~ 60% patients have accompanying auto immune disorders e.g. RA Systemic disease fatigue arthralgia/ myalgia vasculitis  Sjögren Syndrome Female between 50 and 60 years Enlarged salivary glands Keratoconjunctivitis sicca (dry eyes) Oral changes: Xerostomia (dry mouth) mucosal atrophy candidiasis mucosal ulceration dental caries taste dysfunction  Oral changes in Sjögren Syndrome atrophic papillae, missing teeth and angular cheilitis deeply fissured multiple caries epithelium  Sjögren Syndrome How do you treat it? Treatment is mostly supportive and symptom-based. Oral treatment: adequate hydration, scrupulous dental hygiene, cholinergic agents (stimulate saliva release), frequent dental exams Eye treatment: lubricating solutions, surgical procedures Systemic symptom treatment: steroids, other immunosuppressive drugs  Systemic Sclerosis (Scleroderma) A chronic disease of unknown etiology Characterized by  Chronic inflammation  Wide spread damage to blood vessels  Progressive interstitial and perivascular fibrousis Excessive accumulation of fibrous tissue throughout body Mainly skin…GI, kidneys, heart, muscles and lungs  Systemic Sclerosis (Scleroderma) Claw hands, mask-like face Microvascular disease also present Diffuse and limited types Diffuse –wide spread skin involvement at onset with rapid progression and early visceral involvement Limited- skin involvement confined to fingers , forearms and face  Visceral involvement occurs late  Systemic Sclerosis (Scleroderma) Etiology Unknown Likely causes are interrelated responses of; Autoimmune response Vascular damage Collagen deposition  Systemic Sclerosis (Scleroderma) Etiology CD4+ T cells accumulate for some reason T cells release cytokines that activate mast cells and macrophages, which release fibrogenic cytokines B cell activation also occurs; autoantibodies The cause of microvascular changes is unknown  Systemic Sclerosis (Scleroderma) Organs involved Skin: most commonly affected diffuse, sclerotic atrophy. Fingers first. GI: “rubber-hose” lower esophagus Musculoskeletal : inflammation- fibrosis Lungs: fibrosis, pulmonary hypertension Kidneys: narrowed vessels, hypertension Heart: myocardial fibrosis, pericarditis Systemic Sclerosis (Scleroderma) Limited type vs. diffuse type Limited Mild skin involvement (face, fingers) Involvement of viscera occurs later Also called CREST syndrome Calcinosis Raynaud phenomenon Esophageal dysmotility Sclerodactyly Telangiectasia Benign course Systemic Sclerosis (Scleroderma) Limited type vs. diffuse type Diffuse Initial widespread skin involvement Early visceral involvement Rapid course Systemic Sclerosis (Scleroderma) Female between 50-60 Raynaud phenomenon Stiff, clawlike fingers Mask-like face Difficulty swallowing Dyspnea, chronic cough Difficulty getting dentures in  Systemic Sclerosis (Scleroderma) Prognosis Steady, slow, downhill course over years Limited scleroderma may exist for decades without progressing Diffuse scleroderma is more common and has worse prognosis Overall 10-year survival = 35-70%  Immune Deficiencies: Basic Concepts Immune deficiencies Primary (inherited) Secondary (to infection, immunosuppression, etc.) Patients more susceptible to infections and cancer Type of infection varies: Ig, C’ or phagocytic cell defect: bacterial infection T cell defect: viral and fungal infections  Immune Deficiencies: Basic Concepts Primary immune deficiencies Rare! Genetic Can affect any part of immune system: Innate (C’, phagocytes, NK cells) Adaptive (humoral or cellular) Defects in lymphocyte maturation Defects in lymphocyte activation and function Typical patient: infant with recurrent infections Defects in Adaptive Immunity Severe Combined Immunodeficiency Group of syndromes with both humoral and cell- mediated immune defects Patients get all kinds of infections Lots of very different genetic defects Defects often reside in T cell compartment with secondary humoral immunity impairment Severe Combined Immunodeficiency Can be X linked or autosomal recessive – Common gamma chain subunit of cytokine receptors – Deficiency of enzyme ADA Mutations in RAG- (recombinase activating genes) Jak3 mutation Morphology Small thymus devoid of lymphoid cells Treatment: Stem Cell Transplantation  X-linked Agammaglobulinemia Failure of precursor B cells to differentiate into B cells Patients have no immunoglobulin Present with tyrosine kinase (BTK) Affects males Presents at 6 months of age (maternal Ig gone) Recurrent bacterial infections  X-linked Agammaglobulinemia Characteristics; B cells are absent or markedly decreased Germinal centers are underdeveloped Plasma cells are absent T cell mediated responses are normal  Autoimmune diseases(arthritis, dermatomyositis)- 35%  Treatment: intravenous pooled human Igs  DiGeorge Syndrome Developmental malformation affecting 3rd and 4th pharyngeal pouches Thymus doesn’t develop well Patients don’t have enough T cells Depleted T cell zones Infections: viral, fungal, intracellular pathogens Patients may also have parathyroid hypoplasia Treatment: thymus transplant! Common Variable Immunodeficiency Group of disorders characterized by defective antibody production Affects males and females equally Presents in teens or twenties Basis of Ig deficiency is variable (hence the name) and often unknown Patients more susceptible to infections, but also to autoimmune disorders and lymphoma!  Isolated IgA Deficiency Most common of all primary immune deficiencies Cause is unknown but can be familial or acquired Most patients asymptomatic Some patients get recurrent sinus/lung infections or diarrhea (IgA is the major Ig in mucosal secretions) Possible anaphylaxis following blood transfusion (patients have anti-IgA antibodies, and there is IgA in transfused blood!) Increased incidence of autoimmune disease  Hyper-IgM Syndrome Patients make normal (or even increased) amounts of IgM But can’t make IgG, IgA, or IgE! X-linked in most cases (70%) Patients also have a defect in cell-mediated immunity Patients have recurrent bacterial infections and infections with intracellular pathogens (Pneumocystis jiroveci) A good way to study immune deficiencies Disease Transmission Defect Clinical stuff No mature B cells; Infant with recurrent XLA X-linked no Ig bacterial infections Recurrent Sino Mature B cells pulmonary CVID Sporadic Vs. familial No Ig infections(teens and twenties) IgA deficiency Hyper-IgM DiGeorge SCID  ACQUIRED/ SECONDARY IMMUNODEFICIENCY Common than primary Can be caused by;  Defective lymphocyte maturation(marrow damage)  Defective Ig synthesis(malnutrition)  Lymphocytic depletion(drugs and severe infections) ACQUIRED IMMUNODEFICIENCY ACQUIRED IMMUNODEFICIENCY SYNDROME  Introduction AIDS is a retroviral disease caused by human immunodeficiency virus(HIV) Characterized by depletion of CD4+ cells lymphocytes, and by profound immunosuppression leading to opportunistic infections, secondary neoplasm, and neurologic manifestations  Epidemiology AIDS first recognized 1981 HIV RNA retrovirus discovered 1984 2nd leading cause of disease burden worldwide Leading cause of death in Africa Approximately 1 million people currently diagnosed in America  Estimated 34 million people living with HIV/AIDS in 2011, 30 million died 5 million new infections annually 3 million deaths per year 90% is in Africa and Asia Parts of Africa 25-40% of adults are infected In Eth around 730,000 people. 85% heterosexual transmission worldwide  Routes of Transmission of HIV Five population groups are at risk of infection by HIV 1. Sexual :the most common route of tranmission,75% of transmission Homosexual , heterosexual – The virus is present in semen and mononuclear inflammatory cells, and cervical and vaginal cells – STIs increase the risk of transmission 2. Parentral transmission IV drug users Recipients of infected blood and blood products (hemophiliacs) 3. Vertical transmission Mother to child transmission is the major cause of pediatric AIDS Transmission rates vary from 7 to 49% Three routes are involved I. In utero (transplacental) II. Intrapartum (during delivery) III. Postpartum(breast milk) Others methods of transmission Accidental exposure to infected needle and body fluids(blood) Risk of contracting infection after exposure to body fluid is dependent on  Viral load  Integrity of the exposed site  Type of body fluid  Volume of body fluid  Risk after a single exposure – >90% blood or blood products – 25% vertical – 0.5-1% injection drug use – 0.2-0.5% genital mucous membrane – 1 million Fall in CD4 count to 300-400 Recovery in 7-14 days Seroconversion 3-12 weeks, median 8 weeks Level of viral load post seroconversion correlates with risk of progression of disease Differential for this syndrome: EBV, CMV, Strep pharyngitis, toxoplasmosis, secondary syphilis The middle, chronic phase Can last for years Period of clinical latency (asymptomatic) or develop PGL Continuous viral replication in lymphoid tissues Patients can have minor opportunistic infections like herpes zoster, oral thrush Final phase(progression to AIDS) Usually 7-10 years after infection Break down of host defense Dramatic increase in plasma virus Patient present with :fever> 1 month, fatigue, weight loss, diarrhea Serious opportunistic infections Secondary neoplasm Natural history of HIV  Clinical feature Range from mild acute illness to severe disease The typical adult patient with AIDS presents with; Fever, weight loss, chronic diarrhea, generalized lymphadenopathy, multiple opportunistic infections, neurologic disease, and (in many cases) secondary neoplasms  Opportunistic Infections Account for majority of AIDS related deaths Mainly due to reactivation of latent infection P.jiroveci, candidia, CMV, atypical and typical mycobacteria, T.gondi, HSV Tumors 25-40% of untreated HIV infected Mainly due to oncogenic DNA viruses KS (HHV-8) Cervical Cancer (HPV) B cell lymphoma(EBV)  AIDS CD4