General Features of the Immune System Deficiency infections, tumor Hyperactive fatal disease Autoimmunity immune reaction vs own

tissues and cells Mechanisms of immunity: 1. Innate immunity - inherent 2. Adaptive immunity Only IgG passes placenta passive immunity Innate natural, native immunity -defense mechanism -1st line of defense Epithelial barriers (intact skin, mucous mem), phago cells, dendritic cells, NK, plasma proteins no need for previous exposure Lymphocyte one nucleus, dense, chromatin basophilic and faint ring of bluish cytoplasm Vs Natural killer more cytoplasm, + granules in cytoplasm 2 most impt cellular rxns 1. Inflammation phago cells (neutron, then monocytes) 2. Anti-viral defense dendritic and NK cells - Dendritic: Langerhan cells immature cells in epithelium with dendrites (endings have projections which pick up viruses) Adaptive Acquired, specific Mechanisms that are stimulated by microbes and capable of recognizing non microbial substances (Ag) Ag char large molecules; have specific complex configuration Develop later after exposure to microbes More powerful immune response Consists of lymphocytes and their products like Aby + cytokines a. Cell mediated or cellular vs IC and EC microbes, parasites, abnormal cells - Mediated by T cells (passes through thymus where genes are assembled and where it possesses receptors by

which it recognizes Ag; immature to immunocompetent); thymic dependent lymphocyte - i.e. TB with lipid covering resistant - virus-infected cells, tumors b. Humoral vs EC microbes and toxins (diffused in the tissue) - Mediated by B cells and Aby - Birds: cloaca has lymphoid follicles called Bursa of Fabricius equivalent to B cells in humans which mature in bone marrow (gene rearrangement in bm progenitor B cells possess receptors) transform to plasma cells after stimulation plenty of RER which synthesize proteins (gamma globulins) called antibodies Components of the Immune system Lymphocytes - CD4+ (T4) and CD8+ (T8) - Nave lymphocytes/ progenitors immunologically inexperienced - Effector cells eliminates microbes - First exposure clone first (mitosis) one population produces cytokines, the others become memory cells (with heightened awareness because they have previous exposure) - Memory cells: basis of vaccination Homing: lymph node Cortex and medulla T cells go to the paracortical/ parafollicular area B cells go to the germinal center T cells from bm stem cells Mature in thymus Found in blood 60-70% and tcell zones = paracortical TCR recognizes peptides presented by MHC of APC needed before activation of Tcells Don t recognize Ag by themselves Macrophages engulf bacteria digest protein mac has MHC or HLA (human lymphocyte antigen) through the MHC, give Ag to T cell which has TCR

B cells from bm precursors Found in blood 10-20% and lymphoid follicles (GC) Recognize Ag by Bcell Ag rec complex (IgM) that can recognize Ag (bacteria, not processed peptide) directly Stimulation by Ag and other signals Develop into plasma cells eccentric nucleus, chromatin condensed at periphery, many ER (SER, RER) Aby gamma globulins Electrophoretic tracing: Albumin, alpha, beta, gamma (increases during immune response) Antibody H chain L chain Fab key-lock interaction, specific i.e. staphyloccus has M protein, heart muscle has M protein so anti-streptococcal antibody reacts with the heart (cross-reaction autoimmune disease) Fc complement Monomer D, E, G Dimer A; in mucous membranes; secretory Ig - In the intestines, dimer form is resistant to digestion Pentamer M; 10 binding sites; first Aby produced; immune response later on changes to IgG DC interdigitating - Most important APC (first to encounter because present in muc mem, skin; under the epithelium) - Located under epithelia and interstitial - Dendritic langerhans cells Follicular DC - Found in GC - Has Fc rec for IgG and rec for C3b Macrophages -APC in T cell activation Key effectors in CMI Involved in effector phase humoral immunity

(because T helper cells activate B cells) NK cells 10-15% of blood lymphocytes Large granular lymphocytes Ability to kill infected and tumor cells without prior exposure or activation to the Ag Part of innate immune sys CD16 , Cd56 aby-dependent cell mediated cytotoxicity (ag must first react with aby) They have inh rec which are inh from reacting against self-antigens Fxns balanced by activating and inhibtory rec Secretes cytokines like ifn gamma (antiviral protein) Cytokines messenger molecules of immune system Tissues of the Immune System Generative lymphoid organs thymus and bm Peripheral lymphoid organs - Ln, spleen, mucosal and cutaneous lymphoid tissues, mucosal associated lymphoid tissue (MALT) - B cell in white pulp, t cell around splenic arterioles - MALT: tonsils, peyer s patches, in appendix Lymphocyte recirculation More on T cells B cells stay, Aby circulates T cell t cell zone ag from APC activation circulation tissues, microbes MHC mol -

Impt in Ag recognition by T cells Assoc with many autoimmune dse Products of genes that evoke rejection of transplanted organs Display peptide fragments of proteins for recog by Ag-specific T cells Chromosome 6 Mhc complex or HLA complex

Class I Expressed on all nucleated cells and platelets Encoded by HLA-A, B, C Bind peptides derived from proteins like viral Ag in the cytoplasm recognized by CD8 T cells Class II CD4 T cells Encoded by HLA-D Mhc locus also has genes that encode complement component, tnf, endotoxin? HLA and Dse assoc 1. Inflame dse hla-B27 asso with ankylosing spondylitis 2. Inherited errors of metab Hla bw47 21 hydroxylase def Hla a hereditary hemochromatosis 3. Autoimmune DR locus Cytokines produced by T cells Messenger mol of IS Short acting soluble mediators IL Mediate innate immunity TNF, il1, 12, type 1 ifn, ifn-y, chemokines Adaptive responses il 2, 4, 5, 17, ifn y Stimulate hemtopoiesis CSFs Hypersensitivity Reactions Altered reaction Exogenous and endogenous ag may trigger hypersensitivity rxns Often assoc with inheritance of susc genes Imbalance bet effector mech of immune responses and control mechanisms 1. 2. 3. 4. Immediate hypersensitivity Aby-mediated affects cells Immune complex mediated Cell mediated delayed type because i.e. tuberculin test if sensitized to TB, after 48 hours, reaction occurs 1-3 are humoral involved 4 are CMI

Immediate -rapid immunologic rxn within iminutes after combi of Ag (allergen with Ab IgE bound to mast cells (in tissues) of previously sensitized individuals -allergy - IgE: very minimal in the blood (measured in nanograms) in allergic rxn, increase Basophilic cells in tissue mast cells Most mediated by TH2, IgE Aby, mast cells Release of mediators and proinflammatory cytokines A. Systemic usu. Fallows injection of Ag -may be in state of shock within mins (anaphylactic shock) B. Local 1. Immediate or initial phase 2. Late phase Mast cells bm derived - Near bv, n, subepith - Have cytoplasmic membrane bound basophilic granules with mediators - Have igE Fc receptors - Sensitizing dose (1st exposure) Allergen -> APC -> TH cells -> cytokines (IL4) -> B cells -> Ig E mast cells release granules which are mediators (i.e. histamine) --IL3, IL 5 GMCSF eosinophilic recruitment (figure: initial response, late-phase) More than 2 hrs to 8 hrs. Basophils similar to mast cells; found in circulation; recruited to inflam sites TH2 ini and propag - IL4 B cells switch to IgE and THw production (autocrine) -promotes inflammation Preformed mediators (w/in mast cells) 1. Vasoactive amines hista 2. Enzymes 3. Proteoglycans

Lipid mediators synth in mast cell mem - Activates PLA2 - LT, PG D2 LT C4 and D4 most potent vasoactive and spasmogenic agents - B4 chemotactic for neutrophils, eosinophils, monocytes PG D2 most abundant mediator from COX pathway - Bronchospasm - Increased mucus secretion PAF PL aggregation -histamine release - bronchospasm Inc vasc perm Cytokines tnf , il-1,4, chemokines; many from mast cells Eosinophils -recruited by chemokines -il5 most potent eosinophil activating cytokine -liberate proteolytic enzymes, MBP, eosinophilic cationic proteins Type 1 hypersensitivity -susc genetically determined Basis not clear Chr 5q31 and 69 Atopy predisposition to develop localized immediate hypersensitivity Non-atopic allergy triggered byt T extremes and exercise; no TH2 cells nor IgE involved Systemic anaphylaxis vascular shock (vasodilation, pooling of blood, cold extremities); edema; DOB - May go into shock - i.e. penicillin, food allergens, insect toxins local immediate hypersens -allergic rxns -atopic allergy -dses: urticaria, angioedema, allergic rhinitis, bronchial asthma Aby mediated hypersens (type ii) cytotoxic type

mediated by aby directed toward ag on cell surfaces or ECM - 3 mech o Opsoni and phago o Complement and Fc mediated inflame o Aby-mediated cellular dysfunction I. Opsonization - Cells opsonized by IgG aby are recognized by phagocyte Fc rec - Phago and destruction of opsonized cell follows - C3b is an opsonin; c3a is anaphylatoxic and chemotactic - Act of complement also occurs - Formation of MAC c5b-c9 cell lysis - MAC acts like an enzyme phospholipase destroy cell mem Complement pathway - Transfusion reactions (type A patient transfused with type b blood) - Erythroblastosis fetalis (HDN) RhAg of baby plus anti-Rh (from previous exposure) of mother who is Rh - Autoimmune hemolytic anemia, agranulocytosis, thrombocytopenia - Drug reactions i.e. malarial drugs which combine with RBC ag ADCC Cell lysis without phagocytosis Nk cells reproduce perforin which perforate CM

Complement and Fcrec mediated inflammation -abs deposit into fixed tissues, injuries due to inflame Complement activated c3a, c5a (chemotactic to neutrophils) Fc rec involvement -GN, vascular rejection Aby mediated cellular dysfunction -impariment; no injury no inflammation (?) - MG, pemphigus vulgaris, Grave s disease

- thyroid has TSH rec bind TSH from pituitary hyperplasia, produce T3, T4 negative feedback - abN: autoimmune Aby vs receptor thyroid is stimulated without hormone excess T3, T4 because no negative feedback Type 3 Tissue damage by inflame at the site of deposition of the immune complex (IC) Mostly Ag-aby within circulation

a. Presence of immune reaction specific for self-ag or self-tissue b. Reaction is not secondary to tissue damage c. Absence of another well defined cause of dse. Types: organ specific or generalized/systemic Tolerance lack of rxn to self ag Autoimmune dse loss of self tolerance Immunological tolerance: phenomenon of unresponsiveness to an ag as a result to exposure of lymphocytes to that Ag Self tolerance Central tolerance death of slef reactive t and b cells clones cduring maturation ___ - In thymus, immature t cells with tcrs enocutner ag and die by apopotosis (negative selection or deletion) - Autoimmune regulatore AIRE stimulates expression of some peripheral ____________ - In bm, b cell receptor editing renders b cell not specific for self aG; apoptosis occurs if editing doesn t occur - _____ Peripheral tolerance mech that silence self reactive cells inperipheral tissues a. Prolonged or irreversible functional inactivation of lymphocytes b. Suppression by regulatory T cells regulatory t cells dvelop in thymus or ______ CD 25 c. Deletion by activation induced cell death mutation in Foxp3 causes sever AI _________ - Cd4 T cells undergo apoptosis Ag sequestration some Ag are hidden from the immune system - Testis, eye, brain (immune privileged sites) - Sympathetic ophthalmia (Ag released from damaged eye have

Formation, deposition, inflammation (fibrinoid necrosis) 2 types: 1. Generalized 2. arthus reaction Table 6-5 Immunofluor microscopy Granular fluor exogenous Linear fluor endogenous (i.e. glomerular basement membrane) Type 4 -initiated by Ag activated t cells 1. delayed - CD4 2. Direct cell toxicity CD8 Delayed Granulomatous disease (mycobacteria, fungi) Tuberculin skin test Transplant rejection Contact dermatitis Macrophage epitheliod giant cells CTL mediated Neoplastic cell lysis Transplant rejection Virus infected cells (hepatitis) Type1 diabetes -produce perforin and introduce granzyme Autoimmune diseases - Immune rxns against self-ag 3 requirements

aby that attack ag in the other eye which was initially inflamed) Combi of inheritance of susc genes and environmental triggers - Inheritance of susc genes o Contribute to breakdown of self-tolernace__________ - Environmental o Promote activation of selfreactive lympho o i.e. infections, tissue damage o mechanisms ______ general features: single organ RA, hashimoto s 2-3 sjogren Multi-system sle, scleroderma, mixed CT dse RA Arthrtiogenic Ag loss of self-tolerance CD4 T cell activation release cytokines and inflame mediators >> Pannus reaction of T4 with Ag in joint Sjogren Chronic dse characterized by dry eyes, dry mouth Immunologic destruction of ____ 2 forms: primary, secondary Sicca syndrome 3rd and 4th branchial pouch thymus, parathyroid