Immunity

: Introduction :The immune system is Defense body mechanism an interacting set of specialized cells and proteins designed to identify and destroy foreign invader The immune system must be able to: differentiate between material that is a normal component of the body (self) and material that is not native to the body nonself A highly specialized receptors are present for discriminating between self and nonself body components The discrimination between self and non-self and the subsequent destruction and removal of foreign material is accomplished by the two arms of the immune system The innate (natural or nonspecific) immune system (1 The adaptive (acquired or specific) immune system (2 These two systems perform many of their functions by* cooperative interactions

: Innate Immunity Component Innate Immune system

First line Mechanical barriers Chemical & biochemical inhibito Normal flora B- Soluble C- Inflammatory barriers First line Mechanical barriers (1 Intact skin Mucous coat Second line A- cells (1 1- Natural killer (2 2- Phagocytes (3 factors

Mucous secretion Blinking reflex and tears The hair at the nares Coughing and sneezing reflex Chemical & biochemical inhibitors (2 Sweet and sebaceous secretion Hydrolytic enzymes in saliva HCl of the stomach Proteolytic enzyme in small intestine Lysozyme in tears Acidic pH in the adult vagina Normal bacterial flora (3 Competition for essential nutrients Production of inhibitory substances :Second line A) cells (Natural killer (NK -1 Definition: Large granular lymphocytes Innate cytotoxic lymphocytes Source : Bon marrow precursors Location : 10% or 15% of lymphocytes in peripheral blood or 2% of lymphocytes in spleen 1% Tumor cells Function : Cytotoxic for Viral infected cells Bacterial, fungal, parasitic infection Responsible for mediated (cytotoxicity (ADCC Phagocytes -2 Specialized cells for capture, Ingestion and destruction of invading microorganisms Polymorphonuclear leucocytes, mainly * :neutrophils granulocytes circulate in blood (Mononuclear cells (macrophages * antibody dependent cell

Monocytes in blood Histocytes in connective tissues Fixed reticuloendothelial cells in liver spleen, lymph nodes, bone marrow B- Soluble factors Acute phase protein (Plasma protein, CRP=C, -1 (.reactive protein, Fibrin (Complement (proteins in serum, body fluids -2 (Interferons (Proteins against viral infections -3 (Properdin (Complement activation -4 (Beta lysine (Antibacterial protein from Platelets -4 (Lactoferrrin,Transferrin (Iron binding protein -5 (Lactoperoxidase (Saliva & Milk -6 (Lysozyme (Hydrolyze cell wall -7 :Interferons Proteins usually produced by virally infected cells :Types of interferons * Alpha interferon Secreted by Macrophages -1 Beta interferon Secreted by Fibroblasts -2 Gamma interferon T- lymphocytes -3 :Protective action of interferons Activate T-cells (1 Activate macrophages (2 Activate NK (3 :Phagocytosis The engulfment, digestion, and subsequent processing of microorganisms by macrophages and neutrophils :Chemotaxis & attachment (1 a- Attraction by chemotactic substances ((microbes, damaged tissues b- Attachment by receptors on surfaces of phagocytes :Ingestion (2 Phagocyte pseudopodia surround organism * forming phagosom Opsinins and co-factors enhance phagocytosis *

Fusion with phagocyte granules and release * digestive, toxic contents (Killing (two microbicidal routes -3 a- Oxygen dependent system (powerful microbicidal (agents Oxygen converted to superoxide, anion, hydrogen peroxide, activated oxygen and .hydroxyl radicals b- Oxygen-independent system (anaerobic (conditions Digestion and killing by lysozyme. Lactoferrin, low pH, cationic proteins and hydrolytic and proteolytic enzymes C) Inflammatory Barriers Tissue damage by a wound or by invading pathogen * :Inflammatory response * Tissue damage Release of chemical mediators from Leukocytes Histamine, fibrin, kinins, cytokines) Invading) microbe Redness of tissue Tissue Vasodilatation of capillaries Influx of fluids Influx of phagocytes into tissues temperature Capillary permeability

:Acquired (Adaptive) Immunity

: Defensive mechanisms include (Innate immunity (Natural or Non specific (1 (Acquired immunity (Adaptive or Specific (2 Cell-mediated immunity Humoral immunity :Aquired (specific) immunity The acquired immune response is more specialized than * innate immune response The acquired immune response involves a combination * : of two mechanisms Humoral immune response (1 cell mediated immune response (2 They interact with one another to destroy foreign body * ((microorganisms, infected cells, tumor cells Two mechanisms :Humoral immune response (1 Antibodies are produced by B-lymphocytes These can recognize and bind antigen that induced their formation (The cell mediated immune response (CMI (2 It is mediated by certain types of T-lymphocytes T-lymphocytes recognize foreign material by means of surface receptors T-lymphocytes attack and destroy foreign material directly or through release of soluble mediators i.e. cytokines :Characters Of Acquired Immune Response Highly specific for the invading organism (1 Discrimination between self and non self molecules (2 The response only occurs to non self molecules : Diversity (3 It can respond to millions of different antigens Lymphoctes population consists of many different (clones (one cell and its progny Each clone express an antigen receptor and responds only to one antigenic epitope :Mechanism Of Acquired Immune Response :Acquired immune response is initiated by

Recognition of the antigen by specific lymphocytes * Activation of these specific lymphocytes * ;Proliferation and differentiation into effector cells * The effector cells eliminate the antigenReturn of homeostasis and development of memory cellsMemory cells evoke a more rapid and long response on * re-exposure to same antigen :Acquired Or Adaptive Immunity Passive acquired immunity.1 : a- Naturally passive acquired immunity to the fetus . Antibodies are passed through placenta b- Artificially passive acquired immunity such as gamma globulin The injection of alredy ,prepared antibodies short-term immunization :Mechanism of Humoral immunity :Antibodies induce resistance through * Antitoxin neutralize bacterial toxins (1 ((diphtheria,tetanus :Antitoxin are developed actively as a result of a- Previous infection b- Artificial immunization c- Transferred passively as antiserum Neutralization of toxin with antitoxin prevents a * combination with tissue cells Antibodies attach to the surface of bacteria and (2 a- act as opsonins and enhance phagocytosis b- prevent the adherence of microorganisms to their target cells, e.g. IgA in the gut c- Activate the complement and lead to bacterial lysis d- Clump bacteria (agglutination) leading to phagocytosis

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: Cells Of Immune Response :Cells involved in specific immune mechanisms are I) Hematopoitic leucocytes Lymphoid -1 :T-lymphocytes * Antigen specific cells carrying CD3 complex, CD4, CD8 (Dominant blood lymphocytes (70% Produce cytokines (Activation of other cells (Th CD4 (Suppressors for others (Ts CD8 :B-lymphocytes * Antigen specific cells with surface receptor (Less common lymphocytes (20% Responsible for antibody production :NK, K cells * Not antigen specific Carry Fc receptors , NK-target cell receptor Monocytic myeloid -2 :a- Monocyte-tissue macrophages Non specific . Carry Fc receptors . Phagocytic . Antigen processing and presenting cells . Produce cytokines . :b- Neutrophils Non specific . Carrying Fc, complement molecules .

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Lm o yp i hd s re e s i

B-l m oy s T y p ct h e

:c- Eosinophils Non specific . Carrying Fc receptor . Produce allergic mediators . :d- Basophils and Mast cells Non specifc . Carrying Fc receptors . Produce allergic mediators . :-Non hematopoietic cells Dentritic cells Astrocytes and Endothelial cells Function : antigen presentation : Antibodies or Immunoglobulins :Definition * Glycoprotein in serum and tissue fluid :Produced by * B-lymphocytes in response to exposure to antigen React specifically with antigen * :Five classes of Antibodies * IgG , IgM , IgA , IgD , IgE

:Antibody Structure Immunoglobulins are glycoproteins made up of :(Four polypeptid chains (IgG a- Two light (L) polypeptide chains b- Two heavy (H) polypeptide chains

The four chains are linked by disulfide bonds H-chains are distinct for each of the five immunoglobulins Terminal portion of L-chain& H-chain participate in antigen binding site The other (Carboxyl) terminal portion forms Fc fragment An antibody molecule is composed of two identical Ig heavy chains (H) and two identical light chains (L), each .(with a variable region (V) & constant region (C

:Variable(V) and Constant (C) Regions Each H-chain and each L-chain has V-region and C- region V-region lies in terminal portion of molecule V-region shows wide variation in amino a. sequences Hypervariable region form region complementary to Ag determinant It is responsible for antigen binding C-region lies in carboxyl or terminal portion of molecule C-region shows an unvarying amino acid sequence It is responsible for biologic functions :Antibody Fragments Fab fragment: antigen binding site :(Fc (crystallizable fragment (Complement fixation (IgM and IgG (Opsonization (IgG (C- Placental attachment (IgG (Mucosal attachment (IgA (Binding to mast cells (IgE

: IgG :Properties Major serum Ig.1 Major Ig in extravascular spaces.2 The only Placental transfer Ig.3 Fixes complement.4 Phagocytes opsonization.5 :IgM :Properties First Ig made by fetus and B cells.1 Present in colostrum and mother milk to protect.2 .newly born Fixes complement.3 :IgA :Found in serum and body secretionTears, saliva, gastric and pulmonary secretions Major secretory Ig on Mucous surfaces give Local.1 Immunity by coating bacteria or viruses preventing their adherence to mucosal cells (Does not fix complement (unless aggregated.2 Present in colostrum and mother milk to protect.3 .newly born :IgE Least common serum Ig.1 Binds to basophils and mast cells (Does not (require Ag binding Allergic and hypersensitivity reactions.2 (Parasitic infections (Helminths.3 Binds to Fc receptor on eosinophils

Does not fix complement.4 :IgD Present in very small amount in serum.1 B cell surface Ig.2 Does not bind complement.3

Antibody Production :Clonal selection theory B-cells have immunoglobulin molecules on surfaces* Immunoglobulin serve as receptors for specific antigen* The antigen binds to immunoglobulin receptor of B-cells* B-cells is stimulated to divide and form a clone* B-cells become plasma cells and secrete antibodies* Some stimulated B-cells revert to small lymphocyte* ((memory cells Memory cells proliferate on re-exposure to same* antigen

Property

:Activation of B-cells :Two mechanisms** :T-dependent antigen (1 Most antigen require T-helper cells to activate B-cells . Antigen is phagocytosed by macrophages or B-cells . Macrophages or B process present Ag to T-cells . These activate T-cells to produce lymphokines .

Heavy chain symbol

lymphokines (IL-2,IL-4,IL,5) stimulate B-cells to . divide and differentiate into plasma cells specific antibody Plasma cells form or . differentiate into memory cells All classes of antibody (IgG,IgM,IgA,IgD,IgE) are T-cell . dependant

:T-independent antigens (2 Activation of B-cells directly without help of T-cells . (e.g. bacterial capsular polysaccharides) IgM antibody is primarily produced . :Antibody Diversity (Immunoglobulins are protein (antigenic* : Immunoglobulins subdivided into* a- Isotypes: Antigenic difference in C-region five immunogl. classes are different isotypes .b- Idiotypes: Ag difference in V-region of immunogl c- Allotypes: Antigenic feature of immunogl. that vary among individual under genetic controlAg difference in Cregion of H and L chain

:B and T LYMPHOCYTES

:The Life Of The B Cell B lymphocytes are formed within the bone marrow and undergo their development there :They have the following functions To interact with antigenic epitopes, using their immunoglobulin receptors To subsequently develop into plasma cells, secreting ,large amounts of specific antibody or To circulate as memory cells To present antigenic peptides to T cells

:B-lymphocytes in bon marrow The lymphoid stem cells differentiate into B cells * B-cells precursors mature, differentiate into * immunocomptent B-cells with a single antigen specificity Immature B-cells that express high affinity receptors * for self antigens, die or fail to mature i.e negative selection or clonal deletion This process induces central self tolerance and * reduces autoimmune diseases Immature B cells express IgM receptors on the surface * Mature B cells express IgM, IgD molecules on surfaces * IgM and IgD molecules serve as receptors for * antigens Memory B-cells express IgG or IgA or IgE on the * surface B-cells bear receptors for Fc portion of IgG and a * receptor for C3 component of the complement They express an array of molecules on their surfaces * that are important in B-cells interactions with other cells such as MHC II, B7 and CD40 B cells become plasma cells, which produce * antibodies when a foreign antigen triggers the immune response

:T-Lmphocytes T-lmphocytes migrate from bon marrow to enter thymus :In the outer cortex of thymus (1 (T-lymphocytes acquire specific receptors (TCRs This receptor commit lymphocyte to a single antigen specificty They differentiate to express CD3, both CD4 and CD8 (coreceptors (double positive cells :In the medulla of thymus (2 TCRs recognize MHC molecules, loaded with normal (self-peptides (p-MHC TCRs capable of binding with low affinity to p-MHC will receive positive selection signals to divide and establish clones TCRs that bind too strongly to p-MHC undergo ((negative selection This selection process will eliminate the potentially (most harmful self reactive T-cells (central self tolerance Immature T-cells express both CD4 and CD8 As they(3 mature T-cell with TCRs that have affinity to bind to MHC * class II will become helper T-cells with CD4 molecule only T-cell with TCRs that have affinity to bind with MHC * class I will become cytotoxic T-cells with CD8 molecule only Mature positively selected T-cells are MHC restricted (4 CD4 T-cells are MHC II restricted and only recognize * specific foreign peptide only when they are presented in association with specific MHC II molecules CD8 T-cells are MHC I restricted and recognize specific * foreign peptidees only when they are presented in association with specific MHC I molecules :T-cell surface markers These are molecules that by witch we can identifyT-cells and divide them to subsets

They are required to for interactions between T-cells andAPC and for antigen recognition These are TCRs, CD3, CD4, CD8, CD2, CD28,and CD40 onactivated T-cells :T-cell subpopulation (CD4 T helper lymphocytes (TH (1 TH lymphocytes recognize antigen on the surface of APC in association with class II MHC molecules They are activated and secrete several cytokines (There are two main subsets of TH cells (THI and TH2 The two subsets are differentiated on basis of the cytokine they produce :CD4 T helper lymphocytes Subsets (1 : Th1 produce mainly Cytokines of CMI and inflammation e.g. IFN-, TNF- , IL-3 and IL-2 :TH2 produce mainly Cytokines that stimulate B-cells Suppressor cytokines e.g. Il-4, IL-5, IL-6 and IL-10 : (CD8 Cytotoxic T-lymphocytes (CTLs (2 They constitute 35% of peripheral T-cells * CTLs recognize antigen on suurface of target cells (APC) * in association with MHC-I They are activated and kill the virus infected cell or * tumour cell : Activation of helper T cells

: Activation of cytotoxic T cells

: Professional APCs Dendritic cells, macrophages, and B-lymphocytes*** :Dendritic cells* They are the most efficient APCs They are the main inducers of primary immune response Presenting antigen to and activating native T-cells in the recognition phase They express class I and class II MHC molecules Dendritic cells are primarly located under skin and mucosa of most organs They capture foreign antigens and transport them to local lymph nods They present antigen to native helper T-cells :Macrophages* Derived from myeloid stem cells in bon marrow * They exist as free cells in blood e.g. monocytes and fixed * cells in tissues e.g. Kupffer cells of liver They are important link between innate and aquired * immune responses They are activated and attracted to the site of foreign * material by action of different cytokines e.g IFN- , C5a :Functions of Macrophages Pagocytosis (1 Opsonization (2 APCs: they ingest foreign material, process it, and (3 fragments of antigen are presented on its surface (in association with MHC molecules) for interaction with Tcells Macrophages may kill antibody coated infected cells or (4 tumour cells through release of lytic enzymes

They produce IL-1, IL-6, IL-12, IL-15, TNF-alpha (5 They secret prostaglandins and synthesize complement (6 components :Natural killer (NK) Cells Large granular lymphocytes which lack most surface * markers of B and T-cells They comprise 5-10% of the peripheral lymphocytes * They function mainly in innate immunity * They have spontaneous non-specific cytotoxic activity on * virus infected cells, tumour cells and graft cells They are not MHC restricted and MHC I inhibits their * killing functions The mechanism of NK mediated cytolysis is as that of * CTLs :NK cells differ from CTLs in They are non-specific(1 They act spontaneously without prior recognition or(2 activation They do not require antigen presentation by MHC(3 They destroy cells coated with antibodies, a mechanism(4 called antibody dependant cellular cytotoxicity ((ADDCC Antibodies produced by B-cells of the immune system recognize foreign antigens and mark them for destruction

: Cell Mediated Immunity Host defenses against extracellular infection are * mediated by: - Antibody Complement Macrophages Intracellular infections are mediates by CMI * :CMI are responsible for Resistance to * intracellular pathogens fungal and protozoal infectionstumors :CMI may play a role in some harmful conditions *

Hypersensitivity reactions type IV (contact (dermatitis Graft rejection Autoimmune diseases :Cell mediated cytotoxicity mediated by * T-cytotoxic cells cells Natural killer cells Activated macrophages :Characters Of CMI Macrophages present antigen via their surface MHC to T- * cells T-cells recognize antigen through their specific receptors * ((TCR A specific T-cell clone becomes activated and begins to * proliferate Activated TH lymphocytes becomes effectors cells that * secrete cytokines Cytokines stimulate other effectors cells of CMI and :humoral immune response and mediate the following Attract monocytes, macrophages and lymphocytes to the site Activate macrophages to kill intracellular microbes Promote activity of CD8 CTLs which directly kill virus infected cells, tumour cells, and graft rejection They activate NK cells increasing their cytotoxic functions Stimulate B-cells to differentiate into plasma cells that secret antibodies :Phases Of CMI Antigen processing and presentation (1 Protein antigens processed and converted to peptides then bind to MHC molecules on Antigen Presenting Cell (APCs ) to be presented to T-cells a- Extracellular proteins are internalized into vesicular (compartment of APCs (Dentritic, macrophages,B-cells They are degraded to generate peptides These peptides bind into class II MHC molecules Peptide-MHC II complex is transported to surface of (APCs to be presented to CD4 TH cells (T Helper cell

:Outcome Secretion of cytokines by TH cells b- Endogenously synthesized proteins are degraded to (peptides (all nucleated cells e.g virus infected cells They bind to class I MHC in endoplasmic reticulum Peptide-MHC I complex is expressed on surface of nucleotide cells to be represented to CD8 cytotoxic cells :Outcome Killing of presenting cells by CTLs :Activation of T-cells (2 Mature CD4 and CD8 cells are activated by two ** :signals First signal is recognition of antigenic peptide-MHC complex on surface of APC by TCR-CD3 complex CD4 and CD8 molecules are co-receptors that stabilize the interaction of TH cells and TC-cells respectively with APCs CD3,CD4, and CD8 act as signal transduction molecules :Second co-stimulatory signal is interaction of CD28 on T-cells with CD7 on APCs TH-cells express IL-2 receptors and secrete cytokines * including IL-2 IL-2 auto activate TH-cells * APC release IL-I which acts on both APC and TH cell to * promote their activation All mentioned interactions lead to activation of mature * TH-cells Mature TH-cells proliferate and differentiate into * effectors antigen specific TH-cells releasing cytokines Some of them become memory cells which provide * secondary immune response Cytokine released from activated TH-cells activate * macrophages, NK and B-cells Activation of Macrophages and Delayed Type (3 :(Hypersensitivity (DTH

Activated TH cells (TH1) secrete IFN- which activates * macrophages and increase their ability to kill ingested intracellular pathogens The process of activation of macrophages, NK cell and * cytotoxic T-cells, infiltration and proliferation of inflammatory cells, stimulated by cytokines released from TH-cells (TH1) is important protective mechanism against intracellular pathogen Activated CD8 TC-cells proliferate and differentiate into a * clone of effectors cells CTLs Effectors CTLs kill target cells * i.e. nucleated cells (expressing MHC-I) infected with viruses, tumor cells or graft cells Activated macrophages can also kill abnormal host cells * ((abnormal or tumor cells Its ctotoxicity is non specific and done by TNF, nitric * oxid, enzymes and oxygen metabolites If infection is not fully resolved, activated macrophages * cause tissue injury and fibrosis i.e. DTH reaction :Cytokines Low molecular weight soluble proteins (polypeptides) produced in response to microbes and other antigens They act via cell surface receptors to mediate and regulate the amplitude and duration of the immuneinflammatory responses, through activation of macrophages, controlling growth and differentiation of T and B cells :General Properties Of Cytokines (Cytokine secretion is a self limited event (transient * They are potent in minute amounts * (One cytokine can act on different cells (pleiotropic * Multiple cytokines may have the same functional effects * ((reduntant Cytokines often influence synthesis and action of other * cytokines Two cytokines may antagonize each others action * (produce additive or synergetic effects) Action of cytokine may be local or systemic * Cytokine act close to the site of production (autocrine * (.act

(Cytokine act on a nearby cell (paracrine action * Large amount secretion may enter circulation and act * (at a distance from site of production (endocrine action Their action is not antigen specific * It is initiated by binding to specific cytokine receptors on the membrane of target cells They act as intracellular messengers * :The response to cytokine is * a- Expression of new functions b- proliferation of target cells :Functional Categories of Cytokines Cytokines classified according to their biologic actions into :three groups Mediators and regulators of innate immunity (1 Produced by activated microphages and NK cells in response to microbial infection they act mainly on endothelial cells and leukocytes to stimulate the early inflammatory response to microbes Mediators and regulators of acquired immunity (2 Produced mainly by T lymphocytes in response to specific recognition of foreign antigens They include IL-2, IL-4, IL-5,, IL-13, IFN, Transforming (growth factor- (TGF-) and lymphotoxin (TNF- Stimulators of haematopoiesis (3 Produced by bon marrow, stormal cells, leukocytes Stimulate growth and differentiation of leukocytes Stem cell factor, IL-3, IL-7, GM-CSF :(Interferons (IFNs Interferons (IFNs): are proteins secreted in response to * viral infections or other stimuli :They include * INF- produced by leucocytes induced by virus infected cells INF- produced by fibroblasts INF- produced by NK cells,TH1 cells, CD8 T-cells : Action of INF- and IFN- Prevent viral replication -

Increase MHC-I expression on viral infected cells helping their recognition by CD8 T-cells Increase cytotoxic action of Nk cells Inhibit cell proliferation and tumor growth : Action of IFN- Activate Macrophages Increase expression of MHC-I and II on APCs Enhance cytotoxic actions of Nk cells Promote production of TH1 and inhibits proliferation of TH2 :Therapeutic Uses of Cytokines Interferon in treatment of viral diseases, cancer (1 Several cytokines are used to enhance T-cell activation (2 in immunofideficincy diseases, e.g. IL-2, IFN- ,TNF- IL-2 and lymphokine activating killer cells (LAK) in (3 treatment of cancer :GM-CSF induces increase in white cell count, it is used (4 a- To restore leukocytic count after cytotoxic chemotherapy induced neutropenia b- After bon marrow transplantation C- To correct AIDS-associated leukopenia Anti-cytokines antibodies in management of (5 :autoimmune diseases and transplant rejection a- Anti-TNF in treatment rheumatoid arthritis b- Anti-IL2R to reduce graft rejection Anti-TNF antibodies in treating septic shock (6 Anti-IL-2R in treating adult T-cell leukemia (7 Anti-IL-4 is under trial for treatment of allergies (8 :Complement Definition : series of heat-labile serum protein Site : serum and all tissue fluids except urine and CSF Synthesis : in liver appear in fetal circulation during 1st 13 W Function : Responsible for certain aspects of immune response and inflammatory response Activation : antigen-antibody complex or endotoxin, sequentially capsule, series of proteins activated

(Inactivation : inhibitors in plasma (short lived Biological effects : either beneficial or harmful to host :Complement pathway :A) Classical pathway Complement is activated by antigen antibody complex ((IgM or IgG Fc portion of the antibody form a binding site for C1q The numerical sequence of the complement factors in :the classic pathway is C1q,r,s , C4, C2, C3, C5, C6, C7, C8, C9 :The reaction sequence divided into three stages :Recognition stage (1 C1q act as the recognition element It binds to Fc portion of IgM or IgG .The activated C1 molecule can cleave many C4 molec :Activation stage (2 ,The complement components C4, C2, C3, C5, C6, C7 C8, C9 participate in that order :Membrane attack stage (3 Complement components C5, C6, C7, C8, C9 participate where cell membrane damage and cell lysis occur :B) Alternative pathway :This pathway is initiated by * Bacterial endotoxin, polysaccharide capsule, aggregates of IgE and properdin It starts at C3 then C5, C6, C7, C8, C9 * The complement components C1, C4, C2 are by-passed * Antibodies are not required to initiate activation of this * pathway This pathway provides a means of non-specific * resistance :Classic And Alterenative pathways : Biological Effects of Complement :Beneficial effects :Cytolysis (1

activated complement proteins polymerize on cell surfaces of bacteria or erythrocyte to form pores in its (membrane (killing by osmotic lysis :Opsonization (2 binding of complement proteins opsonin (C3b) to surfaces of foreign organisms or particles Phagocytic cells express specific receptors for opsonins, so promote phagocytosis : Inflammatory response (3 Small fragments released during complement :activation have several inflammatory actions a) C5a is chemotactic and attract neutrophiles and macrophages b) C5a activate phagocytes and neutrophils C) C3,C4 and C5 are anaphylatoxin Cause degranulation of mast cells and release of histamine and other inflammatory mediators :Immune complex clearance (4 C3b facilitate binding of immune complex to several surfaces (erythrocytes) and enhance removal by liver and spleen binds erythrocytes to blood vessels , make them as easy prey for phagocytosis C3 deficiency associated with Immunocomplex disease and susceptibility to recurrent infections :Enhancement of antibody production-5 Binding of C3b to its receptors on activated B cells (CR2) greatly enhances antibody production Patient who are deficient in C3b produce much less antibody than normal individuals and more susceptible to pyogenic infection :Harmful effects If complement is activated systematically on a large scale (Gm ve bacilli) it will activate an autoimmune response to host cells :(Major Histocompatibility Complex (MHC The MHC is a closely linked complex of genes that govern production of the major histocompatibility In humans, MHC resides on the short arm of chromosome 6

Three genes (HLA-A, HLA-B, HLA-C) code for the class I MHC proteins Several HLA-D loci determine the class II MHC proteins i.e. DP, DQ and DR (HLA genes are very diverse (polymorphic i.e. there are many alleles of the class I and II genes Between the class I and class II gene loci, there is a third * (locus (Class III This locus contains genes encoding tumor necrosis * factor, lymphotoxin and two complement components (C2 (and C4 Class III antigens do not participate in MHC restriction or * graft rejection :MHC Class I Antigens Class I MHC antigens are : HLA-A, HLA-B and HLA-C * These antigens are glycoproteins found on surfaces of all * nucleated human cells and on platelets Class I MHC antigens are involved of MHC restriction of * (cell mediated cytotoxicity (CD8 T cell :MHC Class II Antigens Class II antigens are: HLA-DP, HLA-DQ, HLA-DR antigens These antigens are glycoproteins found on the surface of macrophages, B-cells, Dentritic cells, langerhans cells of skin and activated T cells Helper T-cells recognize antigens on antigen-presenting * cells only when the antigens are presented on the surface of cells in association with class II MHC Class II antigens react with the CD4 molecule on the * helper T-cells which secrete cytokines : Transplantatio and Graft Rejection :Types of grafts : Autografts (1 The transfer of an individuals own tissues from place to place (e.g. Skin grafts (regularly accepted : Isografts (2 Transfer of tissues between genetically identical persons (e.g. Identical twins ( accepted permanently :(Allografts (homograft (3

Transfer of a graft between genetically different members of same species e.g from one human to another Rejection occur if donor and recipient are not matched :(Xenograft (heterograft (4 Transfer of tissues between different species Always rejected :Mechanism Of Graft Rejection Both TH and TC are activated TC cells destroy graft cells by direct contact TH cells secrete cytokines that attract and activate macrophages, NK cells and polymorphs leading to cellular (infiltration and destruction of graft (Type IV B cells recognize foreign antigens on the graft and produce antibodies which bind to graft cells and Activate complement causing cell lysis . (Enhance phagocytosis, i.e. opsonization (Type II . Lead to ADCC by macrophages, NK,PML . Immune complex deposition on the vessel walls induce platelets aggregation and microthrombi leading to (ischemia and necrosis of graft (Type II : Types Of Graft Rejection :Hyperacute rejection (1 It occurs hours after transplantation In individual with preformed antibodies either due to - blood groups incompatibility or previous sensitization by blood transfusion, previous transplantation :Acute Rejection (2 It occurs 10 to 30 days after transplantation It is mainly T-cell mediated :Chronic or late rejection (3 It occurs over a period of months or years It may be cell mediated, antibody mediated or both :Graft Versus Host (GVH) Reaction An immunologically competent graft is transplanted into * (an immunologically suppressed recipient (host The grafted cells survive and react against the host cells * i.e instead of reaction of host against the graft, the reverse occurs

GVH reaction is characterized by fever, pancytopenia, * weight loss, rash , diarrhea, hepatsplenomegaly and death

: Immunogens Or Antigens ,A foreign substance, when introduced into human body * stimulate formation of specific antibodies or sensitized lymphocytes Antigens have the ability to combine specifically with * antibodies produced or sensitized T-lymphocytes induced :Haptens Low molecular weight substances These substances not immunogenic by itself If couple to a larger carrier molecule (albumin, globulins), they become immunogenic : Examples :simple chemicals and drugs penicillin, sulphonamid, aspirin, cosmetic, tranquillizers, neomycin skin ointment :Epitopes or Antigenic determinants Sites on or within antigen with which antibodies react * Antibodies are specific for epitopes * :Types of Antigens Exogenous Antigens :Bacterial antigens -1 a- Antigens related to bacterial cells Somatic antigen (O): part of cell wall gm ve bacteria Capsular antigen: usually polysaccharide Flagellar Ag (H) : a protein made of flagellin Fimbrial Ag: surface antigens in fimbriated bacilli :b- Antigen secreted by bacteria Exotoxins Enzymes :Viral antigens -2 a- protein coat viral antigens b- Soluble antigens (soluble nucleoproteins as in (influenza

: Endogenous antigens Endogenous antigens :Human tissue antigens :a- Blood group antigens A, B and Rh antigens :b- Histocompatibility antigens :Glycoprotein molecules on all nucleated cells (Major histocompatibility complex antigens (MHC (Human leucocyte antigen (HLA :(Superantigens (SAgs They activate multiple clones of T-lymphocytes * :Bacterial toxins * Staph. aureus toxic shock syndrome toxin (TSST) and enterotoxins Strpt. pyogenes pyrogenic toxin A They have the ability to bind both class II MHC molecules * and TCR chain They act as a clamp between the two, providing a signal * for T-cell activation They are active at very low concentration causing * release of large amounts of cytokines The massive T-cell activation and release of large * amounts of cytokines cause systemic toxicity This method of stimulation is not specific for the * pathogen It does not lead to acquired immunity i.e no memory * :Factors influencing Immunogenicty : Foreigness-1 Foreign substances are immunogenic :Molecular size -2 High molecular weight increase immunogenicty :Chemical structure complexity -3 High complexity increase immunogenicty :Route of administration -4 Parenteral routes are more immunogenic to oral route :Method of administration -5 :a- Antigen dose Appropriate dose optimum antigenicty Low dose low- zone tolerance High dose high-zone tolerance

:b- Adjuvant Substance when injected with an antigen enhance immunogenicity :Antigen Binding And Recognition Molecules :Antigens are recognized by and bind to : (B-cell receptors (BCR (1 These are membrane-bound immunoglobulins (IgM (and IgD on B-cells BCRs can be secreted in plasma as antibodies (T-cell receptors (TCR (2 and chains anchored to T-cells There is a groove which binds small peptides presented by MHC on surface of APCs MHC molecules (3 They are essential for presentation of peptides so that they can be recognized and bind to TCRs :Hypersensivity Reactions

A sm St i y en
Hypersensitivity reactions (Allergies)= over reaction of the immune system to harmless environmental antigens :Immunopathology Exaggerated immune response may lead to different forms of tissue damage :An overactive immune response (1 produce more damage than it prevents e.g. hypersensitivity reactions and graft rejection :Failure of appropriate recognition (2

I m oup mu spr n e

as in autoimmune diseases :Hypersensitivity Reaction Hypersensitivity or allergy An immune response results in exaggerated reactions * harmful to the host :There are four types of hypersensitivity reactions * Type I, Type II, Type III, Type IV Types I, II and III are antibody mediated * Type IV is cell mediated * :Type I : Immediate hypersensitivity (An antigen reacts with cell fixed antibody (Ig E * leading to release of soluble molecules (An antigen (allergen(soluble molecules (mediators Soluble molecules cause the manifestation of disease * Systemic life threatening; anaphylactic shock * Local atopic allergies; bronchial asthma, hay fever and * food allergies :Pathogenic mechanisms First exposure to allergen * (Allergen stimulates formation of antibody (Ig E type Ig E fixes, by its Fc portion to mast cells and basophiles Second exposure to the same allergen * It bridges between Ig E molecules fixed to mast cells leading to activation and degranulation of mast cells and release of mediators

:Pathogenic mechanisms :Three classes of mediators derived from mast cells histamine, leukotrienes, prostaglandins, platelets activating factor TNF, IL3, IL-4, IL-5 IL-13, chemokines ,These mediators cause: smooth muscle contraction * ,mucous secretion and bronchial spasm, vasodilatation vascular permeability and edema :Anaphylaxis Systemic form of Type I hypersensitivity * Exposure to allergen to which a person is previously * sensitized :Allergens * Drugs: penicillinSerum injection : anti-diphtheritic or ant-tetanic serumanesthesia or insect venom :Clinical picture * Shock due to sudden decrease of blood pressure, respiratory distress due to bronhospasm, cyanosis, edema, urticaria :Treatment corticosteroids injection, epinephrine, antihistamines :Atopy Local form of type I hypersensitivity * Exposure to certain allergens that induce production of * specific Ig E : Allergens *

Inhalants:dust mite faeces, tree or pollens, mould.spores Ingestants: milk, egg, fish, choclateContactants: wool, nylon, animal furDrugs: penicillin, salicylates, anesthesia, insect venomThere is a strong familial predisposition to atopic allergy * The predisposition is genetically determined * :Methods of diagnosis History taking for determining the allergen involved (1 :Skin tests (2 Intradermal injection of different allergens A wheal and flare (erythema) develop at the site of allergen to which the person is allergic Determination of total serum Ig E level (3 Determination of specific Ig E levels to the different (4 allergens : Management Avoidance of specific allergen responsible for condition (1 :Hyposensitization (2 Injection gradually increasing doses of extract of allergen production of Ig G blocking antibody which binds allergen and prevent combination with Ig E It may induce T cell tolerance :Drug Therapy (3 corticosteroids injection, epinephrine, antihistamines :Type II: Cytotoxic or Cytolytic Reactions An antibody (Ig G or Ig M) reacts with antigen on the cell * surface This antigen may be part of cell membrane or * circulating antigen (or hapten) that attaches to cell membrane :Mechanism of Cytolysis : Cell lysis results due to * Complement fixation to antigen antibody complex on (1 cell surface The activated complement will lead to cell lysis

Phagocytosis is enhanced by the antibody or (2 complement (opsinin) bound to cell antigen leading to opsonization of the target cell :(Antibody depended cellular cytotoxicity (ADCC (3 Antibody coated cells e.g. tumour cells, graft cells or infected cells can be killed by cells possess Fc receptors The process different from phagocytosis and independent of complement :Cells most active in ADCC are NK, macrophages, neutrophils and eosinophils :Clinical Conditions Transfusion reaction due to ABO incompatibility (1 (Rh-incompatability (Haemolytic disease of the newborn (2 Autoimmune diseases (3 The mechanism of tissue damage is cytotoxic reactions e.g. SLE, autoimmune haemolytic anaemia, idiopathic thrombocytopenic purpura, myasthenia gravis, nephrotoxic nephritis, Hashimotos thyroiditis A non-cytotoxic Type II hypersensitivity is Gravess (4 disease It is a form of thyroditits in which antibodies are .produced against TSH surface receptor This lead to mimic the effect of TSH and stimulate cells to over- produce thyroid hormones :Graft rejection cytotoxic reactions -5 In hyperacute rejection the recipient already has performed antibody against the graft :Drug reaction -6 Penicillin may attach as haptens to RBCs and induce antibodies which are cytotoxic for the cell-drug complex leading to haemolysis Quinine may attach to platelets and the antibodies cause platelets destruction and thrombocytopenic purpura ::Laboratory diagnosis measurement of complement activity demonstration of the activation of PMN, monocytes/macrophages

: Type III: Immune Complex Mediated Reaction When antibodies (Ig G or Ig M) and antigen coexist* immune complexes are formed Immune complexes are removed by reticuloendoth.* .syst Some immune complexes escape phagocytosis* Immune complexes deposited in tissues on the* basement membrane of blood vessels and cause tissue injury :Mechanism Of Tissue Injury :Immune complexes trigger inflammatory processes activate release Immune complexes the complement (1 anaphylatoxins ;C3a, C5a stimulate release degranulation of basophiles and mast cells histamine Histamine vascular permeability and help deposition of immune complexes Neutrophils are attracted to the site by immune (2 complexes and release lysosomal enzymes which damage tissues and intensify the inflammation Platelets are aggregated with two consequences (3 a- release of histamine b- form of microthrombi which lead to ischemia :Clinical conditions of Type III Hypersensitivity Diseases produced by immune complexes are those in :which antigens persists without being eliminated as a- Repeated exposure to extrinsic antigen b- injection of large amounts of antigens c- Persistent infections d- Autoimmunity to self components :Arthus Reaction -1 This is a local immune complex deposition * phenomenon e.g. diabetic patients receiving insulin subcutaneously

edema Local reactions in the form of necrosis deposited Immune complexes vasculitis leading to vascular occlusion necrosis

erythema * in small blood * vessels formation

microthrombi

:Serum Sickness -2 A systemic immune complex phenomenon * Injection of large doses of foreign serum * Antigen is slowly cleared from circulation * Immune complexes are deposited in various sites * fever urticaria days after injection arthralgia 10 * lymphadenopathy splenomegaly glomerulonephritis antidiphtheritic serum e.g. treatment with sulphonamides penicillin

Post-streptococcal glomerulonephritis -3 glomerulitis associated with infective endocarditis (Hypersensitive pneumonitis (farmer lung -4 immune complexes depositition in lung after repeated inhalation of dust , mould spores Endogenous antigen antibody complexes involved in -5 autoimmune diseases e.g. SLE, rheumatoid arthritis :Laboratory diagnosis Measurement of IC level in serum Measurement of complement factor activity in serum Histology: microscopic IC verification

Type IV Hypersensitivity Clinical Conditions : Tuberculin Type Hypersensitivity (1 When PPD is injected intradermally in sensitized * person (Local indurated area appears injection site (48-72 hs * :Indurations due to accumulation Of * macrophages and lymphocytes Similar reactions observed in diseases * e.g. brucellosis, lepromin test in leprosy, Freis test in lymphogranuloma venereum :Granulomatous lesions (2 In chronic diseases : T.B., Leprosy, schistosomiases * Intracellular organisms resist destruction by * macrophages Persistent antigen in tissues stimulate local DTH * reaction Continuous release of cytokines leads to accumulation * of macrophages which give rise to epitheloidal and giant cell granuloma :Contact Dermatitis (3 Contact of skin with chemical substances or drugs * e.g. poison, hair dyes, cosmetics, soaps, neomycin These substances enter skin in small molecules * They are haptens that attached to body proteins, form * immunogenic substances :DTH reaction to these immunogenic subst. lead to * eczyma inflammtory reaction of skin in rash vesicular eruption Auto immune diseases and graft rejection are due to (4 in part to delayed hypersensitivity reactions Insulin dependant diabetes mellitus (5 T-cells invade the pancreatic islets and specifically destroy insulin secreting beta cells :Laboratory diagnosis (Histology (mononuclear cell infiltration

Lymphoblast transformation induced by the antigen Measurement of cytokine production :Tolerance And Autoimmune Diseases

As i B Se n ym t
: Tolerence It is a specific immunologic unresponsiveness * i.e. the absence of specific immunoresponses to a particular antigen in a fully immunocomptent person Unresponsiveness to self antigens is known as auto- * tolerance Both B-cells and T-cells participate in tolerence * But T-cells play the primary role * :Central Tolerance :Clonaldeletion The process by which T-cells acquire the ability to * distinguish self from non self, in fetal thymus This involves the killing of T-cells that react against * antigens present in the fetus at that time :Peripheral Tolerance :(T-cell tolerance (clonal anergy * Some self-reactive T cells are not killed in thymus * Functional inactivation of surviving self-reactive T cells * :Tolerance :B-cells become tolerant to self by two mechanisms * Clonal deletion (1 Probably while B-cell precursors are in bon marrow Clonal anergy (2 B cells in the periphery Tolerance in B-cells is less complete than in T-cells * The most autoimmune diseases are mediated by * antibodies

I mo p e i m n u rs usp s

A r d st n t le r i a e t e es c o I f c uD a n to i e e ei s s s a N ps n el i d oaa

:Factors Influencing The Induction Tolerance :Immunologic maturity of the host (1 Neonates are immunologically immature and well accept allograft that would be rejected by mature host :Structure and dose of antigen (2 a- Simple molecules induce tolerance more readily than complex ones b- Very high and very low doses of antigen may result in tolerance T-cells become tolerant more readily and remain (3 tolerant longer than B-cells The continuous presence of antigen helps to (4 maintain tolerance Administration of immunosuppressive drugs (5 enhances tolerance as in transplantation :Clinical Importance of Tolerance :Organ transplantation (1 Introduction of tolerance may help in prevention of rejection :Tumor development (2 Tolerance to tumor antigen results in growth of the tumor without being detected by the immune mechanisms :Autoimmune disorders (3 Disturbance of self-tolerance results in autoimmune disease : Autoimmune Diseases Autoimmune diseases occur due to breakdown of the * mechanisms that maintain auto tolerance Auto-antibodies and self reactive T-cells are produced, * resulting in tissue damage by several mechanisms :Etiology Of Autoimmune Diseases :Genetic predisposition (1 Familial incidence of autoimmune diseases Most of them appear to be associated with certain MHC genes, specially MHC II genes e.g. Rheumatoid arthritis is associated with DR4 Thyroditis with DR5

Multiple sclerosis with DR2 SLE with DR2/DR3 Type I diabetes with DR3/DR4 Ankylosing spondylitis with B27 Exposure to infectious antigens that cross react (2 with self antigens An immune response to these antigen will result in immune attack against self antigens e.g. Antibodies against M protein of Streptococcus pyogens may react with heart valves and cause Rheumatic fever Alteration of self antigens or the appearance of new (3 antigens under the effect of drugs, chemicals, or viral infections Hormonal influences play a role e.g. SLE affects (4 women 10 times more than men

: Mechanisms Of Disease Production The disease may be organ specific * e.g Hashimoto thyroditis The disease may be systemic * e.g. SLE or rheumatoid arthritis Binding of an autoantibody to host cells result in (1 complement fixation and tissue destruction (e.g. Haemolytic anemia (Type II hypersensitivity Formation of immune complexes and their (2 deposition in tissues, joints, kidney and skin The immune complexes fix complement resulting in tissue damage e.g. SLE and rheumatoid arthritis (Type III (hypersensitivity

DTH reactions (Type IV hypersensitivity) due to auto (3 reactive T-cells e.g. Ulcerative colitis, multiple sclerosis and type I diabetes :Examples of Autoimmune Diseases :Nervous System .1 Multiple sclerosis Myasthenia gravis (acetylcholine receptor (autoantibodies Autoimmune neuropathies such as Guillain-Barr Autoimmune uveitis :Gastrointestinal System .2 Crohn's Disease Ulcerative colitis Primary biliary cirrhosis Autoimmune hepatitis :Blood .3 Autoimmune hemolytic anemia Pernicious anemia Autoimmune thrombocytopenia Antiphospholipid antibody :Skin.4 Psoriasis Dermatitis herpetiformis Pemphigus vulgaris Vitiligo :Endocrine .5 DM Hashimoto thyroiditis Graves diseases Addison disease Type I (insulin -dependent) diabetes -(pancreatic beta(cell autoreactive T cells and autoantibodies : Graves Disease Graves Disease is an autoimmune condition that strikes more women than men at a rate of 7:1. It affects the

functioning of the thyroid and causes hyperthyroidism, .but it can also affect the tissue surrounding the eyes :Rheumatology .6 SLE RA Systemic Scelerosis Dermatomyocytis Ankylosing spondylitis Progressive systemic sclerosis is an example of an autoimmune disorder in which skin .cells show extensive dermal fibrosis SLE is the most commonly known autoimmune .disorder This characteristic butterfly rash is made worse by .exposure to sunlight Lupus is a potentially fatal autoimmune disease that strikes 1 in 2,000 Americans and 10 times as many .women as men :Rheumatoid arthritis Ankylosing spondylitis (Bechterew's Disease), a joint inflammation mainly affecting the spine, occurs only in individuals carrying a certain variant of MHC molecule (HLA-B27). Much evidence suggests that molecules derived from microorganisms interact with the B27 molecule in causing the destructive immune reactions :Laboratory Diagnosis There is elevated serum immunoglobulins -1 Complement levels may be decreased -2 Immune complexe detected in serum or organ biopsy -3 Auto antibodies can be detected in serum -4 e.g. anti-nuclear, anti-smooth muscles, Rh factor and anti-mitochondrial Ab ,Testing for antibodies specific to particular Ag -5 (involved in organ specific diseases (anti-thyroid Ab

: Tumor immunology

A sm Sei B y t n
Pathological cell masses derived by abnormal and * uncontrollable clonal expansion of single cell :Transformation of normal cells to malignant cells by * a- Spontaneous mutation during daily cell division chemical b- It may be induced by viruses Cells become antigenically different from normal cells *

carcinogens u e I mo pr s m ns p s u physical carcinogens

They are recognized and destroyed by immune * system :Etiology Of Tumor : Inherited (1 Expression of inherited oncogene e.g. viral gene incorporated into host gene :Viral (2 (Human papilloma, herpes type 2, HBV, EBV (DNA (Human T-cell leuckemia virus (RNA :Chemical (3 Poly cyclic hydrocarbons cause sarcomas Aromatic amines cause mammary carcinoma Alkyl nitroso amines cause hepatoma Radiological: Ultraviolet & ionizing irradiation (4 Spontaneous: failure in the cellular growth control (5 :Tumor Associated Antigens : Viral Antigen (! a- Viral proteins and glycoproteins b- New antigens produced by virally infected host cells under control of viral nucleic acid : Tumor specific antigens (2 Tumor cells develop new antigen specific to their carcinogens : Tumor specific transplantation antigens (3 Tumor cells express new MHC antigens due to alteration of normally present MHC antigens :Oncofetal antigens (4 (a- Carcino-embryonic antigens (CEA Normally expressed during fetal life on fetal gut :Reappearance in adult life GIT, pancreas, biliary system and cancer breast :b- Alpha fetoprotein Normally expressed in fetal life Reappearance in adult life; hepatoma :Immune Surveillance System During neoplastic transformation, new antigen develop * The host recognize them as nonself antigens * Cell mediated immune reactions attack these nonself * tumor cells

Immune response act as surveillance system to detect * and eliminate newly arising neoplastic cells : This system include Natural killer (NK) cells (1 They kill directly tumor cells,helped by interferon, IL2 Cytotoxic T-cells (2 They also kill directly tumor cells (Cell mediated T-cells (effector T-cells (3 : They produce and release a variety of lymphokines a-Macrophage activation factor that activate macrophag b-Gamma interferon and interleukin-2 that activate NK (c-Tumor necrosis factor (cachectine :Tumor Escape :Mechanisms by which tumor escape immune defenses Reduced levels or absence of MHCI molecule on (1 tumor so that they can not be recognized by CTLs Some tumors stop expressing the antigens (2 These tumors are called antigen loss variants Production of immunosuppressive factors by tumor (3 (e.g. transforming growth factor (TGF- Tumor antigens may induce specific immunologic (4 tolerance Tumor cells have an inherent defect in antigen (5 processing and presentation Blocking of receptors on T-cells by specific antigen (6 antibodies complex (after shedding of tumor Ag) prevents them from recognizing and attacking tumor cells Antigens on the surface of tumors may be masked by (7 sialic acid-containing mucopolysaccharides Immune suppression of the host as in transplant (8 patients who show a higher incidence of malignancy : Tumor markers * Tumor antigens They are either or *

Tumor products ((enzymes and hormones Tumor products are released in the serum of patients * They are used to confirm diagnosis and follow up the * response to therapy :Tumor Antigens Alpha fetoprotein antigen (AFP) in cases of hepatoma (1 Carcinoembryoinic antigen (CEA) in gastrointestinal (2 tumors, tumors of biliary system and cancer breast Cancer antigen 125 (CA 125) in ovarian carcinoma (3 Cancer antigen 15-3 (CA15-3) in breast cancer (4 Cancer antigen 19-9 in colon and pancreatic tumor (5 Prostatic specific antigen (PSA) in prostatic tumors (6 :Tumor Products : a) Hormones Human chorionic gonadotrophins (HCG) are secreted in cases of choriocarcinoma Thyroxin (T3 & T4) is secreted in cases of cancer of thyroid gland : b) Enzymes Acid phosphatase enzymes in cases of cancer prostae Alkaline phosphatese, lipase and amylase enzymes in cases of cancer pancreas

: Immunodefeciency Diseases ?What is Immunodeficiency A failing of one or more of the bodys defensive .mechanisms resulting in morbidity or mortality Any part of the immune system can be deficient cells, .proteins, signalling mechanisms The body is susceptible to infection by organisms that .meet with little or no resistance Or, in certain cases, other homeostatic systems in the .body will be disrupted by the defect

.Severity is variable .Immunodeficiency may be Primary or Secondary :Classification of Immunodeficiencies Antibody deficiencies Cellular deficiencies Phagocytic disorders Complement deficiencies :Clinical features associated with immunodeficiency Feature frequency present and highly* :suspicious Chronic infection (Recurrent infection (more than expected Unusual microbial agents Incomplete clearing of infection Incomplete response to treatment Feature moderately suspicious (Diarrhea (chronic Growth failure Recurrent abscesses Recurrent osteomyelitis Feature associated with specific immunodeficiency disorder Telangiectasia Partial albinism :Secondary Immunodeficiency Infection Renal failure, or protein losing enteropathy Leukaemia or Lymphoma Myeloma Extremes of age Certain Drug Therapies

: (Evaluation of antibody (B cell Protein electrophoresis.1 Quantitative of IgG ,IgA, IgM and IgD.2 Isohemagglutinin.3 Specific antibody response.4 B cell quantitation.5 (B cell markers (CD19.6 : Primary Immunodeficiency Antibody (B cell) mmunodeficiency Antibody (B cell) ID X- linked agammaglobulinemia.1 Selective IgA deficiency.2 IgG Subclasses deficiency.3 Hyper IgM.4 CVID.5

B n Mr o o e ar w

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Ig M

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?What is XLA ( X- linked agammaglobulinemia ) .First immunodeficiency described .Defect on the X chromosome affecting the Btk gene Results in an absence or severe reduction in B lymphocytes and .hence immunoglobulin of all types :The Btk gene .Located on the X chromosome Gene consists of 19 exons over a length of DNA of 37 .kilobases Function of the Btk gene product is related to BCR .signalling Without Btk pre-B cells fail to develop into mature B .cells : (Intravenous Immunoglobulin (IVIG :Clinical Findings !LITTLE BOYS WITH BIG INFECTIONS Symptoms appear at 6-9 months of age (after loss of . (maternal Ig Sites of infection: mucous membranes, ear (otitis media), lungs (bronchitis/pneumonia), blood (sepsis), .gut (Giardia, or enterovirus), skin, eyes, meningitis Also seen: joint problems kidney problems, neutropenia, malignancy in .older patients

P tie tsw a n it e tra e la x c llu

Ssetb ucp i i l
: Selective IgA Deficiency Selective IgA deficiency is the most common ID .disorder. The prevalence is about 1:700

H m p ilu e oh

Su i s n

Pathogenesis : block in B cell differentiation is due to intrinsic B cell defect or abnormal T cell help such as production of cytokine (TGF-B,IL-5) or in B cell .responses to these cytokines

:IgA Deficiency Clinical feature: Recurrent sinopulmounary infection, Gastrointestinal disorders, Allergy, Cancer and .Autoimmune disease IgA Deficiency and genetic factors: association with .HLA-A2, B8 and DW3 or A1 and B8 .IgA Deficiency and drug Serum IgA<5mg/dl but normal IgM and IgG Immunopathogenesis :arrest in the B cell .differentiation :Selective IgG subclass deficiency Total serum IgG levels are normal .One or more subclasses are below normal .IgG3 deficiency is the most common subclass in adults IgG2 deficiency associated with IgA deficiency in .children .Pathogenesis: abnormal B cell differentiation .Some individual have recurrent bacterial infection Common Variable CVID Immunodeficiency CVID is characterized by hypogammaglobulinemia CVID has a tendency to autoantibody formation

:CVID abnormalities CVID is a heterogenous group of disorders with intrinsic B-cell defect or a B-cell dysfunction related to abnormal .T-cell B-cell interaction Lack of inducible costimulator (ICOS) expression by activated T cell which associated with lack of T cell help for B cell differentiation, class switching and .memory B-cell generation In 10-20% of families another member may have .selective IgA def Pathogenesis: defect in differentiation into Ig . secreting plasma cells Reduction class switching .Defect in somatic hypermutation Reduction production of cytokines .Increased apoptosis in B and T cells Defect in CD27 and CD134 ligand, important in promoting into plasma cells : Hyper IgM syndrome

: T cell deficiency :Evaluation of cell- mediated immunity Total lymphocyte count DTH Lymphocyte response Total T cell using Anti-CD3 CD4 and CD8 subset Cytokine production :Cell mediated ( T cell) Immunodeficiency Defect in CD3/TCR -1 Defect in signaling, Defect in ZAP-70 -2 Defect in Cytokine production as IL-2 and IFN -3 gamma Defect in Cytokine response -4 DiGeorge Syndrome -5 :DiGeorge Syndrome

Defective development in thymus and parathyroid that develop from third and fourth Pharyngeal pouch Thymic hypoplasia leading to variable :immunodeficiency. Other features Characteristic faces Abnormal calcium homeostasis : Combined Immunodeficiencies (Severe combined immunodeficiency (SCID Omenn syndrome (ADA (Adenosine Deaminase Deficiency (Ataxia-Telangiectasia syndrome (AT (Wiskott -Aldrich syndrome (WAS Common Features of Severe Combined : (Immunodeficiency (SCID Failure to thrive Onset of infections in the neonatal period Opportunistic infections Chronic or recurrent thrush Chronic rashes Chronic or recurrent diarrhea Paucity of lymphoid tissue :Types of SCID X-linked ID with absent T, NK and Ig synthesis Autosomal Recessive SCID

:WISKOTT-ALDRICH Syndrome X-linked Eczema ,thrombocytopenia ,bacterial infection ((polysaccharide antigen Defective gene encode a cytoplasmic protein Cell surface glycoproteins reduced ;CD43 or sialophorin) normally on Lymphocytes,) neutrophils, Macrophages and Platelets These alterations interfere with migration of Leukocytes .to inflammation sites :ATAXIA-TELANGIECTASIA Autosomal recessive (Abnormal gait (ataxia Vascular malformations (telangiectasia), neurologic defects, tumors and ID ID may affect T&B cells .IgA and IgG2 deficiency .T cell function is variably depressed Gene responsible on chromosome 11 Gene product may play a role in DNA repair

Defective Class II MHC Expression Bare lymphocyte :syndrome Autosomal recessive Fail to express HLA DP,DQ,DR on APC and in response to IFN-gamma Mutation in genes encoding proteins regulate class II MHC transcription May result in defective positive selection of T cell in +thymus and reduction of T CD4 Affected individual are deficient in DTH response and in .antibody response to T dependent antigens

:Phagocyte Deficiencies (Chronic granulomatous disease (CGD (Leukocyte adhesion deficiency (LAD I Chediak- Higashi syndrome IL-12 / IFN pathway deficiencies Chronic or cyclic neutropenia CGD patient with skin infectionsdue to Serratia marcescens