KICK THE BOARDS USMLE STEP 1

IMMUNOLOGY Prepared by Dr. Irfan Mir

KICK THE BOARDS. USMLE STEP 1 “IMMUNOLOGY”

Prepared by Dr. IRFAN MIR

IMMUNOLOGY * Lymphokines Function : IL 1 --- produce by macrophages& monocytes --- Activate & proliferate Ag specific T cells. it produce IL2, fever & is GF for hepatic syn of acute phase protein IL 2 --- Produce by Th - 1 Helper CD4 T Cells --- Activate and growth of Helper CD4 and Cytotoxic CD8 T Cells. IL 3 --- Stimulates bone marrow IL 4 --- Produce by Th - 2 Helper T CD4 cells --- B cell Growth Factor, Increase Isotype switching and IgE, increases Helper T Cells. IL 5 --- Produce by Th - 2 Helper T CD4 cells --- promote end stage maturation of B cell into plasma cell. Increase IgA and Eosinophils. IL 6 --- produce by T cells & monocytes --- promote maturation of B cells and T cells. IL 10 --- produce by T helper cells --- inhibit development of cytotoxic CD8 T cells. inhibit interferon  production. IL 12 --- produce by macrophages --- promote development of cytotoxic CD8 T cells. promote interferon  production. Remember IL1 and IL12 is produce by macrophages where as other IL produce by helper CD4 T cells. Alpha Interferon ------ is a glycoprotein release from leukocytes due to viral infection, it is Growth inhibitor & has antiviral activity. Beta Interferon ------- is a glycoprotein produce by fibroblast and has antiviral activity. Gamma Interferon --- is a glycoprotein produce by Th - 1 CD4 helper T cells. It activates macrophages phagocytic activity, NK cells and Neutrophils, it also enhance the syn of Class I & II MHC proteins. Remember only gamma  interferon is produce by helper CD4 T cells. TNF  (Cachectin) --- produce by macrophages --- Activates T cell, neutrophil. TNF  (lymphokines) produced by activated T lymphocytes -- It cause similar effect as TNF . Macrokines & Monokines --- produce by macrophages --- Inflammatory mediator Nitric Oxide --- Produce by Macrophages & Endothelial cells --- It cause vasodilation, hypotension and shock. * 4 imp Biologic effects of TNF are (At low conc) 1.  syn of adhesion molecules by endothelial cells with resultant Neutrophil adhesion. 2.  Lymphokine syn by Helper CD4 T Cells. (At high conc) 1. Mediator of endotoxin and produce toxic shock. 2. Inhibit lipoprotein lipase which results in  fatty acid which lead to cachacxia. 3. Death and necrosis of certain Tumor cells. * Antibodies and Cell mediated immunity are the major protective function of human body. Ab mediated immunity is associated with B cells whereas Cell mediated immunity is associated with T cells (helper T cells & Cytotoxic T cells). * CD4 T cells are also called Helper T cells where as CD8 T cells are also called Cytotoxic T cells. * Major function of Ab and cell mediated immunity. ---------------------------------------------------------------------------------------------------------------------------------------------------------------------Antibodies mediated immunity (humoral immunity) vs. Cell mediated immunity ---------------------------------------------------------------------------------------------------------------------------------------------------------------------Neutralize toxin and viruses Kills fungi, parasites and certain IC bacteria’s Opsonised bacteria and phagocytes Killing of virus infected cells and tumor cells Allergy and autoimmunity Allergy, graft and tumor rejection. ---------------------------------------------------------------------------------------------------------------------------------------------------------------------* Cells contribute to cell mediated immunity are macrophages, CD4 T Cells and CD8 T Cells. * Process of host defense contain 3 steps 1. Recognization 2. Activation 3. Response.

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KICK THE BOARDS. USMLE STEP 1 “IMMUNOLOGY”

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* Ab response -- after phagocytization of the opsonin by macrophages, fragment of the Ag appear on the surface of macrophages in association of class II MHC protein (Ag) which is than bind to CD4 T cells which respond by releasing IL (lymphokines). IL 3, IL 4 activate B cells proliferation & differentiation into Ab producing Plasma cell. (note: It is plasma cell which produce immunoglobins or Ab). * Cell mediated response --- M tuberclosum first phagocytized by macrophages and broken into fragments (Ag and Epitopes) later those fragments appear on the surface of macrophages in association with Class II MHC protein (Ag) which reacts with receptors on Helper CD4 T cells which in turn produce IL 2 which results into delayed hypersensitivity reaction against M tuberclosum.  Influenza virus enter the cell, later viral envelope glycoprotein appear on the cell surface in association with Class I MHC protein(Ag) & react with cytotoxic CD8 T cell which produce IL 2 (which further Proliferate CD8 T cells) & perforin (which kills the virus infected cells). * Natural immunity is non specific and include host defense such as skin, mucous mem, natural killer cells, certain proteins (like complement, Interferon, c - reactive protein, mannose binding protein), phagocytosis & inflammation. vs. * Acquired immunity is specific occur after exposure to an Ag. It is mediated by Ab & T lymphocytes. It can be passive or active. * Difference b/w Active and Passive immunity :Active immunity is resistant induced after contact with foreign Ag like infection, immunization, toxins. Active immune response consist of Ab and T lymphocytes. Major advantage is long-term resistance and disadvantage is slow onset of action specially in primary response. vs. Passive immunity is based on antibodies perform in other host ( Ab against rabies etc). major advantage is prompt availability of large no of Ab where as disadvantage is short life span of Ab and hypersensitivity reaction. * Epitope is small chemical group on antigen (Ag) that can elicit immune response and react with Ab. (antigenic determinants). Mostly Ag have many epitopes. * Hapten is a molecule that is not immunogenic by its self but can react with specific Ab eg. Penicillin, catechol in plant oil, poison oak, poison ivy. ( hapten binds with carrier protein than hapten - carrier - protein is internalized and later appear on Class II MHC protein cause Ab reaction ). * Adjuvant are chemically unrelated to immunogen but enhance immune response for eg aluminum hydroxide and lipids used in certain vaccines. Because weak or simple Ag do not elicit cell mediated hypersensitivity alone. * Main attribute that make subs a good Ag are Foreignness, molecular size, chemical structure complexity, epitopes, Dosage, route, timing of Ag administration and adjuvant. * Ag and Ab binds with weak forces such as hydrogen bond, vander waal forces. (but not with covalent bond which is strong bond) * Humoral immunity in new born is differ from that in the elderly. In new born Ab are provided primarily by transfer of maternal IgG across the placenta. Colostrum also contain Ab specially IgA. Fetus can mount IgM response to certain Ag where as Ig G, IgA begin to made shortly after birth. In elderly immunity generally declines reduced IgG, fewer T cells, reduced delayed hypersensitivity response. Frequency of autoimmune dis is also high in elderly. * CD 4 T cells comprise of 65 % of total T cells where as CD 8 T cells are 35 %. T cell to B cell ratio is 3:1. * Process of stem cell differentiation : Stem cell which initially express neither CD4 nor CD8 cells ( Double negative ). First differentiate to express both CD4 & CD8 ( double positive ) in the cortex of the thymus. Here Thymic education begins. Which is that CD4 and CD8 positive cells bearing Ag receptors for self protein are killed ( clonal deletion ) by the process of program cell death apoptosis, this result in tolerance to our (self) own protein (prevent autoimmune dis). CD4 and CD8 positive cells that do not react with self MHC protein are also killed which results into positive selection of T cells that react well self MHC protein. Than CD4 and CD8 positive cells are send to the medulla from where they migrated out side the thymus.

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KICK THE BOARDS. USMLE STEP 1 “IMMUNOLOGY”

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* Function of helper CD4 T cells is regulatory which means it produce IL (activate CD4 & CD8 T cells) and  IF (activate macrophages). vs. Function of cytotoxic CD8 T cells are effector, which means it kills virus infected cells, tumor cells & allograft by perforin which destroy cell mem. Remember CD4 T cells has regulatory function where as CD8 T cells has effector function. * Helper T Cells CD4 are two types Th-1 cells and Th-2 cells. * To activate T cells 2 molecules must be recognized on the Ag presenting cells that is Ag & Class I or II MHC protein. * Ab mediated immunity (Humoral Immunity) -- Ab production by B Cells usually requires participation of helper CD4 T cells called T Cell Dependent Response but some time Ab are produced with out helper CD4 T cells participation called T Cell Independent Response. B cell surface Ab (only IgM, IgD) bind with Ag after internalization some fragments return to surface with association of Class II MHC protein which further react with helper CD4 T Cells which in turn produce IL2, IL4 and IL5 which stimulates B cells proliferation and differentiation into plasma cells. (produce Ab. IgG, IgM, IgA, IgD, IgE) Protein CD 40 on the surface of B Cell stimulate the differentiation of B Cell into Ab producing Plasma cells. (IL5 also play role) * Cell mediated immune response -- Ag processed by macrophages and fragments in conjunction with Class II MHC protein appear on the cell surface which further interact with helper T Cell (CD4) receptors and stimulate Helper T Cells to produce IL which results into growth of CD4 and CD8 T cells. * B cell surface bear a receptor either IgM or IgD. It recognize peptides, polysaccharides, nucleic acid, small chemicals. * T cell surface receptor CD3 recognize only peptides Ag. (CD3 Receptor for Ag consist of 2 peptides  and  unit). * Macrophages have 3 main function 1. Phagocytosis. 2. Ag presentation 3. Cytokines production * Cytokines produced Macrophages are IL1, TNF, macrokines, monokines. * Natural killer cells kills virus infected cells and tumor cells by perforin. Ab enhance their activity. NK cells do not have memory and are not specific for any virus. Monoclonal Ab : Ab that arise from single clone of cells eg. Plasma cell tumor (Myeloma). They are homogenous (monoclonal). Monoclonal Ab can be made in the lab by fusing myeloma cell in Ab producing cell. Such as Hybridomas produce unlimited quantity of monoclonal cells that used in diagnostic tests. Polyclonal Ab : When Ab produced by several different classes of plasma cells. Antibodies classification . IgG -- contain 2 light chain and Heavy chain linked by Disulfide bond. It is divalent because IgG have two identical Ag binding sites. IgM -- is pentamer, composed of 5, H2 and L2 plus one molecule of J (joining) has 10 Ag binding site. It is most efficient and has highest Avidity (binding strength) of the Ig. IgA -- consist of 2, H2 and L2 unit plus one molecule of J chain (joining) chain and secretory component. In serum IgA exist as a monomeric H2 L2. It present in Colostrum, saliva, mucous mem, tears, respiratory, Intestinal and genital tracts. * The variable region are the Ag binding sites on the Fab fragmant of Ab where as Complement binds to the constant region of Fab and Fc fragment. Constant region is also responsible for various biologic activities eg. Binding to cell surface receptors. * Light and heavy chains are subdivided into variable and constant region. These regions are composed of three dimensionally, folded, repeating segment called Domain. * Light chain consist of 1 variable and 1 constant domain.

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KICK THE BOARDS. USMLE STEP 1 “IMMUNOLOGY”

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* Most heavy chains consist of 1 variable & three constant Domain where as IgM and IgE have 4 constant domain on H chain. Remember variable portion bind Ag and constant portion bears biologic activity like binding the cell receptor & complement.

* Hypervariable are 3 extremely variable amino acid sequence at amino acid terminal end of L and H chain form Ag binding site. * Isotype -- are antigenic differences of immunoglobulin in their constant region eg. IgG and IgM have different isotypes. * Allotype -- Additional Antigenic features that are variable among individuals because of gene code. * Idiotype -- Antigen determinant form by specific amino acid in hyper variable region is unique for Ig produced by specific clone Immunologlobin (Ig) : IgG ------------------- make 75% of Ig in adult serum. Remember GAMDE IgG ------------------- is the Ig in new born because IgG is the only Ig that can cross placenta (because Fc bind to it). IgG ------------------- opsonized bacteria directly IgG and IgM --------- can activate complement to yield C3b (which interact with receptor on phagocytes). IgM ------------------- has  avidity IgM ------------------- opsonized bacteria indirectly IgM and IgE ---------- only Ig that have 4 constant Domain on H chain. IgM and IgA ---------- only Ig that contain J chain. IgA -------------------- secret on mucosal surface IgE -------------------- triggers anaphylaxis IgE -------------------- only Ig on mast cell surface Reason of Ab specificities by small no of gene : * For each type of immunoglobulin chain, there is a separate pool of gene segment locate on different chromosomes. Each pool contain a set of different V gene segment widely separated from D (diversity, seen on H chain), J (joining) and C segment. * The V region of each light chain is encoded by 2 gene segments (V & J). The V region of the each Heavy chain is encoded by 3 segments (V, D and J). these various segments are united into one functional V gene by DNA rearrangement. Each of these assembled V gene is transcribed with the appropriate C gene & splice to produce mRNA which encode complete peptide chain. * The Light chains are Kappa and lambda chains where as Heavy chains are Mu, Gamma, Delta, alpha & epsilon. * The gene for L and L and 5 other H chains are on Ch 2, 22, and 14 respectively. * In response to Ag first Ig that release is IgM later gene rearrangement permit the elaboration of the Ab of the same Antigenic specificity but of different Ig class. Antigenic specificity remains the same for the life time of B cell and Plasma cell. In class switching the same assembled VH gene can sequentially associated with different CH gene so that the Ig produced later (IgG, IgA, IgE) are specific for same antigen as the original IgM but have different biologic characterstics. HUMORAL IMMUNITY (Ab mediated immunity) : * Humoral immunity is Ab dependant which is produce by B cell & Plasma Cell. It provide imp defense against Bacteria & viruses. * Time for Ab to appear in primary response is 7 - 10 days where as Ab appear in secondary response is 3 - 5 days. * In primary response 1st IgM & than IgG produced in almost equal amount (IgM = IgG) vs. In secondary response much larger quantity of IgG is produced (IgG > IgM). * Ab persist less longer in primary response where as in secondary response Ab last longer.

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KICK THE BOARDS. USMLE STEP 1 “IMMUNOLOGY”

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* Two important function of Ab are Opsonization and Neutralization. Opsonization -- Fc portion of IgG interact with the receptor on the phagocyte surface to facilitate ingestion. IgG & IgM activatE compliment to yeild C3b which interact with receptor on phagocytes. Neutralization -- Ab Actively or Passively neutralize toxins by attaching with them eg. Diptheria, tetnas, botulism. Cell Mediated Immunity : * Cell mediated immunity depands upon macrophages, Helper T cell, Cytotoxic T cell and NK cells. It provide imp defense against Fungi, parasite, tumor cells, and Graft. * Macrophages are Ag presenting cells, than Helper T cells recognize Ag and Regulate function. At last Cytotoxic T cells kills the infected cell. Remember there is no Ab involve in that. * NK cells killes pathogens independently. * One can evaluate Pts cell mediated immunity and function by skin test. Major Histocompatibility Complex (MHC) : * The gene for HLA proteins clustered in the MHC complex located on the short arm of ch 6. Three of these genes HLA A., HLA B, & HLA C code for Class I MHC protein. Several HLA D loci DP, DQ and DR code for Class II MHC protein. Fig :

* Each person has 2 haplotypes ie. 2 set of genes one on paternal and one on maternal ch 6, that’s why each person can make 12 HLA proteins. 3 at Class I loci & 3 at Class II (= 6). 6 from paternal and 6 from maternal (= 12). * Class I MHC protein are produce by all nucleated cells. Where as Class II MHC protein are only produced by Macrophages, B cells, Dendritic cell of spleen. Langerhan cells of skin. * Class I MHC protein can be detect by Lymphocytes with the battery of specific Ab and complement. Where as Class II MHC protein can be detected by mixed leukocytes reaction. * Class I MHC protein have heavy chain which possess constant region which binds with CD8 T cells vs. Class II MHC Protein have 2 chain which have constant region which binds CD4 Helper T cells. * Autograft -- transfer of an individual’s own tissue. * Synergic graft -- Transfer of tissue b/w genetically identical individual e.g. Identical twin. * Allograft -- Transfer of tissue b/w genetically different mem of the same species. * Xenograft -- Transfer of tissue b/w different species ( always rejected ). Allograft Rejection : * Acute Allograft reaction -- Graft is initially normal than in 11 - 14 days marked reduction in circulation and mononuclear cell infiltration and than eventually necrosis occur. It is also called primary or First set reaction. * Accelerated reaction -- occur in 2nd allograft from the same donor, it is rejected into 5 - 6 days primarily due to Presensitized CD8 Cytotoxic T cells. It is also called Second set reaction. * 5 yrs survival rate of 2 haplotype match kidney transplant from the related donor is near 95 %. * One haplotype match kidney transplant was near 80%. * Transplant kidney from Cadaver donor was near 60%. * Heart transplant survival rate for 5 years is 50 - 60 %. * Liver transplant survival rate for 5 yrs is lower. * Corneas are easily grafted because they are avascular. Graft versus Host reaction : Well matched transplant of bone marrow may establish themselves initially in 85% of recipients but subsequently graft versus host reaction develop in about 2/3 of them. This reaction occur because grafts immunocompetent T cells proliferate in the irradiated immunocompromised

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KICK THE BOARDS. USMLE STEP 1 “IMMUNOLOGY”

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host & reject cells with Class II protein resulting in severe organ dysfunction. It characterized by maculopapular rash, jaundice, hepatosplenomegaly, diarrhea, overwhelming infection, and death. GVH reaction can be reduced by treating the donar tissue with Antithymocyte globulin, or monoclonal Ab before grafting this process eliminate T Cells from graft. Graft can also be treated with immunotoxins eg Recin. Complement : Complement synthesize mainly by liver. * 3 major biologic effect of complement are 1. Lysis -- destroy bacteria, allograft, tumor cells. 2. Generate mediators -- inflammation, attract phagocytes. 3. Opsonization -- Enhance phagocytosis. * Classic and Alternative pathway of complement activation. * Classic pathway starts with Ag-Ab complex (only IgG, IgM) activates C1 to form a protease to initiate pathway. * Alternative pathway initiates when Microbial surface polysaccharide eg. Endotoxins, viral envelop, fungal cell wall, bind to C3 (H2O) and factor B to initiate complement pathway. * C5 serve as a common entry point to continues the pathway. Complement pathway fig :

* C3 convertase: cleaves C3 mole into C3a & C3b which further in pathway produce C5b,6,7,8,9 (mem attack comp) * C3b facilitate Opsonization ---------- Better phagocytization. * C5a, C5,6,7 is Chemotactic --------- attract neutrophil cause adhesion. * C3a C5a Facilitate Anaphylaxis ---- Degranulation from mast cell. * C5b C6,7,8,9 is cytotoxic --- Lysis of mem. (mem attack complex lyses the cell mem  water enters into cell  cell death) Complement Deficiencies : C1 inhibitor deficiency ----------------- Hereditary Angioedema (Laryngeal edema can be fatal). C1, C3,or C5 Deficiency ------- -------- Susceptibility to bacterial infection. C2 Deficiency ( most common ) ----- Disease resembles Autoimmune diseases. C4 Deficiency ------------------------------ Diseases resemble Autoimmune diseases. C3 Deficiency ------------------------------ Sepsis, pyogenic infection ( S Aureus ) C6,7,8 Deficiency ------------------------- Gonnococcal, meningococcal Bacteremia Lab Reactions : * Agglutination -- In this test the Ag is perticulate and Ab cross linked the antigenically multivalent particles and form a lattice work and clumping (agglutination) can be seen. * Precipitation -- In this test the Ag is in solution to which Ab cross-link in variable proportion & produce aggregate (precipitates). It shows 1.Zone of equivalence -- In which optimal proportion of AgAb combine results into max precipitation. No excess of Ag Ab. 2. Zone of Ab excess -- results into  precipitation 3. Zone of Ag excess -- results into too small precipitation.

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* RIA -- is used to quantize Ag, heptans or hormones that can be radioactively labeled in pts serum. It is based on the competition for specific Ab b/w the labeled (known) and unlabeled (unknown) conc of material. (RIA assay hormones & drug in the serum). * Elisa -- is used to quantize either Ag or Ab in pts Specimens. It is based on covalently linking of enz to a known Ag or Ab, reacting with pts specimen and than assay for enz activity by adding the substrate of the enz. (It is used to measure Ab and Ag). * Fluorescent Ab Assay : Flourescent Dye (Flourescin and auramine) can be covalently attached to Ab molecules and made Ab visible by UV light in fluorescence microscope. Direct Flourescent - Ab assay -- is when known (labeled) Ab is used to interact directly with unknown Ag. Indiect Flourescent - Ab assay -- is a 2 Stage process. First the known Ag is attached to a slide, a pts serum (unlabeled) is added and preparation is washed. If the pts serum is contained the Ab against the Ag it will remain fixed to it on the slide and can be detected on addition of flourescent dye labeled Ab to Human IgG and can be examinated by UV microscopy. * Complement Fixation test: is used to identify Ag-Ab complex if one of them is known (Ag or Ab). It consist of 2 steps. * First Ag and Ab one known and other unknown (e.g. Use a known Ag and determine wheather pts serum contain Ab or not) are mixed and measured amount of complement is added. If the Ag Ab match they will combine and take up (fix) the complement. * Secondly, An indicator system consisting of sensitized RBC (ie. RBC and anti RBC Ab) is added. If the Ab match the Ag in step 1, complement was fixed and less is available to attached to the sensitized RBC. The RBC remain unhemolyzed and said to be +ve test, because pts serum has Ab to that Ag. If the Ab did not match the Ag in first step, complement is free to attach to the sensitized RBC and they are lyzed and said to be -ve test. * In many hemolytic anemia’s for example Hemolytic dis of new born (Rh compatibility) and Drug related hemolytic anemia, Ab are bound to RBC but are undetected these Ig can be detected by Direct Coombs test. * Coombs Test : * Direct Coombs Test -- In which antiserum against human immunoglobulin is use to agglutinate the pts RBCs. * Indirect CoombsTest -- In which pts serum is mixed with normal RBCs and antiserum to human Ig is added. If Ab are present in pts serum agglutination will occur. * Human RBC contain Alloantigen which determine ABO groups. ---------------------------------------------------------------------------------------------------------------------------------------------------------------------Groups Ag on RBC Ab in plasma -----------------------------------------------------------------------------------------------------------------------------------A A Anti B B B Anti A AB A&B No Ab in Plasma. O No Ag (no A or B) Anti A and Anti B -----------------------------------------------------------------------------------------------------------------------------------* If blood group is transfused in a person who contain Ab for that group than the recipient RBC Ab complex will activate complement which results in shock. C3a and C5a (anaphylatoxin) caused shock and C5b,6,7,8,9 cause hemolysis. * 85% humans are Rh positive. * When Rh D -ve person is transfused with Rh D +ve or when Rh D -ve women has Rh D +ve fetus (D gene from father), the Rh D Ag will stimulate the Devlopement of Ab. This occur most often when Rh D +ve RBC of the fetus leak into maternal circulation during delivery of first Rh D +ve child. Subsequent Rh D +ve pregnancies are likely to be effected by the mother who now contain anti Rh D Ab, Hemolytic dis of the new born results called Erythroblastosis Fetalis. (maternal IgG anti Rh D is involved). Direct Coomb test is typically +ve. It can be prevented by administration of high titer Rh D immunoglobulin (RhGam) at time of delivery.

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KICK THE BOARDS. USMLE STEP 1 “IMMUNOLOGY”

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HYPERSENSITIVITY REACTIONS : * Type I Hypersensitivity -- IgE Ab is induced by allergen and bind to mast cells and basophill. When a person exposed to the allergen again the bound IgE induced degranulation and release histamine, SRS - A, Serotonin which  the permeability of the capillaries and smooth muscle contraction and resultant shock. * Atopic Disorder are immediate hypersensitivity reaction that exhibit strong Familial predisposition and are associated with elevated IgE level. Common antigen are Pollen, dust, shell fish, nuts (peanut), animal dander etc. it results into asthma, eczema, urticaria. Hay fever. * Desensitization can mitigate or prevent Type I Hypersensitivity reaction. Acute Desensitization -- involve the administration of very small amount of Ag at 15 minute interval. Small Ag-IgE complex are not good enough to provoke reaction. This permits drugs or foreign protein to the hypersensitive person, but hypersensitivity restored days or weak later. Chronic Desensitization -- Involves long term administration at weakly interval of Ag to which person is hypersensitive, which stimulates the IgG Ab in the serum which prevent subsequent Ag from reaching to IgE on mast cells thus prevent reaction. * Anaphylactoid Reaction -- Is similar to anaphylactic one but IgE is not involved. In Anaphylactoid reaction inciting agent like Iodinated contrast media or drugs directly induced the mast cell & basophill to release their mediator with out involvement of IgE. * Type II Hypersensitivity -- Ag on cell surface combine with Ab IgM or IgG and lead to complement mediated lysis. For eg. Transfusion or Rh reaction, drugs. * Serum Sickness can follow after the injection of foreign serum (nowadays drug like penicillin cause that) because of slow elimination of Ag and Ab production against the Offending agent which results into Typical serum sickness (fever), Urticaria, arthralgia, lymphadenopathy, splenomegaly, and eosinophilia. (serum sickness occur in few days to 2 weak after injection) * Post streptococcal Glomerulonephritis occur several weeks after the skin infection by pathogen Group A  hemolytic streptococcus and nephritogenic serotype of Streptococcus Pyogenes. Complement level is typically low suggesting AgAb reaction. Lumpy deposits of Ig and C3 are seen along glomerulus’s basement mem by immunoflourescence. (Similar lesion with lumpy deposite occur in infective endocarditis, serum sickness, certain viral infction e.g. Hepatitis B, Dengue HF & some autoimmune dis). * Type III (Immune Complex) Hypersensitivity -- It occur when Ag Ab complex induce an inflammatory response in tissue for eg. infection or autoimmune disorder. * Arthus Reaction -- is occur when Ag given to a person who has previously Ab to that Ag shows intense edema, hemorrhage reaching at peak in 3 - 6 hrs. Clinical example is Hypersensitivity pneumonitis associated with inhalation of Thermophillic actinomycetes (Farmers Lung). It is Type III hypersensitivity reaction. * Type IV Delayed (Cell mediated) hypersensitivity -- it starts hours or days after contact with Ag and Often last few days. It consist mainly mononuclear cell infiltration & tissue induration (macrophages & CD4 Helper T cells). eg. TB Some plants material like poison ivy, poison oak, acts as hapten, which enter the skin attached to the body protein and become Complete Ag. Sensitized person develop asthma, itching, vesicle, eczema or necrosis of skin with in 12 - 48 hrs, called contact Hypersensitivity. This is also type IV delayed (cell mediated) hypersensitivity reaction. * Tuberculin (PPD) when injected intradermally cause little reaction in first few hour shows induration, redness and reach at peak in 48 - 72 hrs. It does not does not confirm the presense of current dis. An infected person does not always have a positive skin test.

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IMMUNODEFICIENCY : * Bruton Agammaglobinemia ( X-linked Agammaglobulinemia )-- is caused failure pre B cells to differentciate into B cell due to mutant gene encoding for Tyrosine Kinase with resultant hypogammaglobulinemia (very low level of IgG, IgA, IgM, IgE, IgD). The disorder results into recurrent pyogenic infection form the age of 6 month. The Tx is gamma globulin. * Selective IgA deficiency -- it s more common than IgG and IgM deficiency. It is csused by failure of heavy chain gene switching. Since pts IgG and IgM level is normal there is no systemic infection but pt usually suffer from sinus and recurrent lung infection. The subject should not be TX with gamma globulin because of cross reaction with pts Ab. If pt receives blood transfusion which contain IgA can results into severe reaction or shock. * Thymic Aplasia ( Digeorge $ ) -- occur due to developmental failure of thyroid and parathyroid due to defect in 3rd and 4th pharyngeal pouch which results into absence of T cells. It is characterized by severe viral, fungal and protozoal infection early in life, also tetany due to hypoparathyroidism. TX is Thymus transplantation from less than 14 week old donor because it prevent graft vs. host dis. (remember it is not a genetic dis rather a developmental failure) * Severe Combined immunodeficiency disease (SCID) -- occur due to defective or absence of both B cell and T cell. It is characterized by recurrent infection due to bacteria, viruses, protozoa and fungi. There are 2 types 1. SCID X linked Type -- Occur due to defect in IL-2 receptor on T cells (Note: IL-2 activates CD4, CD8 & B cells) . 2. SCID Autosomal Type -- Occur due to mutation in gene ZAP-70 encoding for tyrosine Kinase. TX is bone marrow transplant. 3. Another form of dis is caused by absence of Class II MHC protein as a result of a failure to transcription of HLA-\ DR gene. 4. Another form is Adenosine deaminase and nucleoside phosphorylase deficiency. Tx is Bone marrow transplantation. * Chronic Glomerulonephritis Dis of childhood -- This is X linked dis commonly appear at the age of 2 yrs, but in some pt dis is Autososmal and show defect intracellular microbial activity of neutrophil due to lack of NADPH Oxidase activity with resultant no Oxidative burst, no peroxide, no super oxide hence no bacterial killing. Pt is susceptible to opportunistic infection with certain bacteria and fungi e.g S aureus, G - ve Rods, Aspargillus Fumigatus. Remember viral and protozoal infection are not major concern. * AIDS -- HIV destroys host defense specifically CD4 Helper T cells which results into Opportunistic infection by certain bacteria, viruses, fungi, protozoa. e.g Mycobacterium avium, herpes virus, CMV (Kaposi sarcoma), Candida Albican, Pneumocystic carinii.

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