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Here is what Step 1 covers- did we get them all? • Production/function granulocyte, NK cells and macrophages/DC • Production/function of T cells, TCR, cytokines/chemokines • Production/function of B cells and PC, Ig structure, classes, molecular basis for specificity, receptors • Antigenicity/immunogenicity, host defenses(read Innate I), primary/secondary responses, passive transfer of immunity(all ways) • In vitro complement, other diagnostic tests and antigen antibody reactions • Mediators, complement, aa, histamine, NO and cytokines • MHC structure and function, RBC antigens. Transplantation • Vaccines, protective immunity, tumor immunity • Disease states like ID, HIV and pharmacological immunosuppression INNATE IMMUNITY • NOT ANTIGEN SPECIFIC • HAS NO MEMORY • MEDIATED BY – NEUTROPHILS – MACROPHAGES/MONOCYTES – NATURAL KILLER CELLS – EOSINOPHILS – BASOPHILS/MAST CELLS – MANNOSE BINDING PROTEIN AND COMPLEMENT – PROSTAGLANDIN & KININ SYSTEMS INDISCRIMINATE DESTRUCTION PRO-INFLAMMATORY CYTOKINES ADAPTIVE IMMUNITY • ANTIGEN SPECIFIC • CLONAL EXPANSION • AMPLIFIES AN IMMUNE RESPONSE AFTER A SPECIFIC RECEPTOR INTERACTION • INTEGRATES THE INNATE RESPONSE INTO THE REACTION • MEMORY OF THE ENCOUNTER KNOW THESE DIFFERENCES ANATOMY OF THE IMMUNE SYSTEM B-CELL DEVELOPMENT ANTIBODY STRUCTURE ANTIBODY FUNCTIONS ANTIBODY FUNCTIONS COMPLEMENT • FLUID PHASE AMPLIFIER OF INNATE AND ANTIBODY MEDIATED RESPONSES • THREE ARMS – ALTERNATE-BACTERIAL CELL WALLS – MANNOSE BINDING-BACTERIAL CELL WALLS and MBP – DIRECT(CLASSIC)-SPECIFIC Ag/Ab REACTIONS COMPLEMENT COMPLEMENT • ENZYME ACTIVATED CASCADE WITH GENERATION OF INFLAMMATORY AND REGULATORY FRAGMENTS • ACTIVATES INFLAMMATORY CELLS BY SPECIFIC RECEPTOR INTERACTIONS • HAS IMPORTANT IMMUNOREGULATORY AND IMMUNE COMPLEX DISPOSAL ROLES • Measured by serum C3 and C4, total hemolysis and individual components COMPLEMENT-RELATED DISEASES • Rare • C1esterase deficiency with angioneurotic edema• Deficiencies in the direct sequence associated with IC diseases like SLE • Homozygous C3 is lethal • Deficiencies in the alternate path very rare • Individual component deficiency after C5 associated with Neisserial bacteremia ANTIGEN PRESENTING CELLS MHC T-CELL DEVELOPMENT T-CELL FUNCTIONS QUESTIONS • • • • • • From stem cell to T cell why the thymus CD4 versus CD8 gamma delts versus alpha bets peripheral blood CDs to remember………. – 3,4,8,25,19,16,20, MORE CYTOKINES TO REMEMBER Il-12, INF- and IL-2 =TH1 response IL-4 =TH2 response & antibody formation IL-10, IL- 4 = suppression of Th1 INF- = suppression of TH2 IL-8 = neutrophils IL-5= eosinophils TGF- = healing IL-6 = fever and cachexia TNF- =inflammation (RA),sepsis and SIRS, monoclonals available to inhibit some syndromes MHC • • • • Co-dominant alleles Present on Chromosome 6 in humans A,B,C loci are Class I D loci are class II and control immune responses and rejection MLC TRANSPLANT TYPES • • • • Autograft Isograft Allograft (also known as Homograft) Xenograft TRANSPLANT REJECTION HERESY CLASSIC 1L-4 IL-4 DONOR DC 3 IL-4 Th1 Th1 4 IL-4 B CD8 3 B IL-2 Th2 HO ST DC 5 B CD8 B Th2 Th2 Th1 Th1 Th2 5 4 IL-2 CD8 CD8 INF- INF- 1 2 NK MAC C’ DONOR ORGAN 6 1 2 MAC NK IMMUNOSUPPRESSION • • • • • Corticosteroids-inhibit NFB Cyclosporine-inhibit T-cell activation Tacrolimus- inhibit T-cell activation Rapamycin- block IL-2 receptor activation Anti-cytokine/ligand monoclonals PREDICT THE TYPE OF INFECTION • Pure B cell…encapsulated bacteria and systemic spread of GI viruses..frequent after 6 mos of age • “pure” T cell….TB, fungi, pneumocystis since helper function is lost…occurs at birth. B cell infections will not occur until maternal antibody gone-approx 6 mos • B & T cell..at birth, severe and fatal if not transplanted • CGD –neutrophil inability to kill bacterial that produce catalase..esp staph • cytokine..IL-12, Interferon gamma, IL-4 DISEASES ASSOCIATED WITH TCELL DEFICIENCY • • • • • • • HIV/AIDS THYMIC APLASIA SENESCENCE BIRTH WISKOTT-ALDRICH ATAXIA-TELANGIECTASIA TREATMENT DISEASES ASSOCIATED WITH BCELL DEFICIENCY • X-LINKED AGAMMAGLOBULINEMIA • COMMON VARIABLE IMMUNODEFICIENCY • SELECTIVE IgA DEFICIENCY • CLL • HYPER IgM SYNDROME • TREATMENT DISEASES ASSOCIATED WITH T & B CELL DEFICIENCY • SCID • THERAPY: – STEM CELL TRANSPLANTS – BMT – GENE REPLACEMENT- recent problems with the retroviral vector insertion has led to leukemia TESTING IMMUNE FUNCTION • B-CELLS – SERUM IG LEVELS – ELECTROPHORECTIC DETECTION OF CLONALITY – ENUMERATION OF B-CELLS – DETECTION OF SPECIFIC ANTIBODIES – IMMUNOHISTOPATHOLOGIC Know your Flow! TESTING IMMUNE FUNCTION • T-CELLS – IN VIVO SKIN TESTING- will not be valid in patients with malnutrition, on steroids etc – ENUMERATION OF T-CELLS-can be misleading because doesn’t reflect tissue distribution – IMMUNOHISTOPATHOLOGIC – IN VITRO FUNCTIONS- rarely needed HYPERSENSITIVITY REACTIONS • TYPE I- Atopy, asthma & anaphylaxis • TYPE II-Antibody to cell structuresimmune thrombocytopenia, AIHA • TYPE III- Immune complex diseasesSLE is prototype • TYPE IV- Delayed hypersensitivitysarcoidosis AN ALLERGIC REACTION EARLY OR ACUTE VASOACT IVE MEDIATORS IL-5 MAST CELL IL-4 IgE EOS ALLERGEN B CELL IL-4 Th2 DENDRITIC CELL IL-5 MAST CELL LATE ALLERGY MEDIATORS ASTHMA Asthma • Limited early exposure to infections-socalled hygiene hypothesis • Obesity • Genes – Maternal 11 for IgE increase – T-bet gene abnormalitiesfor deficient INF- – IL-13 AUTOIMMUNE DISEASES AUTOIMMUNE DISEASES IMMUNE COMPLEX DISEASE-AKA SERUM SICKNESS AUTOANTOBODIES • SLE– ANA is a SCREENING TEST ONLY(HIGH SENSITIVITY, LOW SPECIFICITY) – double stranded(ds/native) DNA correlates loosely with renal disease, very specific – Sm very specific for SLE-low sensitivity – Histone- present in drug induced lupus but also SLE and other diseases – Ribonucleoprotein (RNP)- associated with mixed connective tissue disease AUTOANTOBODIES – ANCA • cANCA high specificity for Wegeners Granulomatosus • pANCA found in some glomerulonephritis, microscopic vasculitis and other vasculitis Polymyositis/Dermatomyositis……anti-JO-1 SS-A(Ro)/SS-B(La)- Sjogren syndrome, congenital heart block MORE AUTOANTIBODIES • Scleroderma – SCL-70( aka anti-topoisomerase) specific but very low sensitivity – Centromere-high sensitivity for CREST(limited scleroderma) and codes for presence of pulmonary hypertension Other Autoantibodies to remember • AntiAcR- myasthenia • Anti-endomysial- Sprue (anti gliadin) • Rheumatoid factor- not specific for RA Acute Phase reactants • C-reactive Protein• • • • Most accurate indicator of an inflammatory reaction Proxy for IL-6 May correlate independently of Lipids for CA High likelihood something about CRP will be on Boards!..especially as independent indicator of coronary artery disease Transferrin, ceruloplasmin, C3, haptoglobin increase with infection, albumin and hemoglobin decrease HLA ASSOCIATIONS WITH SPECIFIC DISEASES • • • • • • • • • • Ankylosing spondylitis-B27……………….90RR* Reactive Arthropathy-B27.………………...40 Rheumatoid Arthritis-DR4.………………...4 Behcet’s-B51.………………………………4 SLE-DR3.…………………………………..6 IDDM-DR3,4……………………………….6 Dermatitis Herpetiformis-DR3.…………….16 MS-DR2…………………………………….4 Goodpastures-DR2…………………………16 Birdshot Retinochoroidopathy-A29.……….109** – *…remember the caveats, ** …..for that extra point TERMS TO REMEMBER • • • • • • • ANTIGEN IMMUNOGEN EPITOPE HAPTEN ADJUVANT STEM CELLS PRIMARY AND SECONDARY IMMUNE RESPONSE TERMS TO REMEMBER • • • • • • • INNATE(AKA NATURAL) ADAPTIVE(SPECIFIC OR ACTIVE) CELL-MEDIATED IMMUNITY HUMORAL/ANTIBODY IMMUNITY PASSIVE IMMUNIZATION ACTIVE IMMUNIZATION ARTHUS REACTION TERMS TO REMEMBER • • • • • • • ISOTYPE IDIOTYPE MONOCLONAL SYNGENEIC ALLOGRAFT AUTOGRAFT ELISA & RIA Here is what Step 1 covers- did we get them all? • Production/function granulocyte, NK cells and macrophages/DC • Production/function of T cells, TCR, cytokines/chemokines • Production/function of B cells and PC, Ig structure, classes, molecular basis for specificity, receptors • Antigenicity/immunogenicity, host defenses(read Innate I), primary/secondary responses, passive transfer of immunity(all ways) • In vitro complement, other diagnostic tests and antigen antibody reactions • Mediators, complement, aa, histamine, NO and cytokines • MHC structure and function, RBC antigens. Transplantation • Vaccines, protective immunity, tumor immunity • Disease states like ID, HIV and pharmacological immunosuppression T-CELL FUNCTIONS Isotype switching