Immunodeficiency diseases. Prof. Mohamed Osman GadElRab. College of Medicine & KKUH.

Introduction. * A diverse spectrum of illnesses due to * A diverse spectrum of illnesses due to various abnormalities of the immune various abnormalities of the immune system. system. Prevalence (primary) 1 in 10,000 t I in Prevalence (primary) 1 in 10,000 t I in ( live births. ) ( live births. )

Overview of Immunodeficiency Disorders.

Clinical manifestations. Increased susceptibility to infections. I.D. Is considered when infections are : Frequent & severe. Resistant to therapy. Caused by opportunistic Infections.

It is critical to maintain an index of suspicion to diagnose I.D. Early diagnosis reduce morbidity.

Classification : Primary (congenital).Secondary (acquired). Genetic mutations. Genetic polymorphism. Monogenic or polygenic. malnutrition. viral bacterial infections. Immunosuppressive drugs. (cortico steroids). excessive protein loss, burns, nephrotic syndrome.

Primary or acquired. can affect. Natural immunity Acquired immunity. Phagocytic cells. Complement proteins. T-cells.B-cells.

T-cell. B-cell. Phagocytes.

JAK. STAT.

Gamma unit. IL- 2,4,7,9,& 15 All have same unit.

B-cell defects. Gammaglobulinaemias:

1. Diverse spectrum of diseases ranging from: Complete absence of B-cells, Plasma cells Complete absence of B-cells, Plasma cells and Immunoglobulins to selective absence and Immunoglobulins to selective absence of certain immunoglobulin classes. of certain immunoglobulin classes. 2. X- linked disease : Female carriers normal. Female carriers normal. Males manifest the disease. Males manifest the disease. 3. Severity of the disorder parallels the degree of the deficiency. of the deficiency. B-cell defects.

Early B-cell differentiation.

Patients with B-cell defects are subject to: * Recurrent bacterial infections. * Recurrent bacterial infections. but but * Display normal immunity to most * Display normal immunity to most viral & fungal infections. viral & fungal infections. because because T-cells are unaffected. T-cells are unaffected.

*The first I.D. recognized (1952). * The most common 80 to 90 percent. *Defect in Bruton tyrosine kinase (BTK). *The Defect involve a block in maturation of pre- B- cells to mature B- cells in B.M. - Reduced B-cell counts to 0.1 percent ( normally 5-15 percent.) - Absence of Immunoglobulins. - Small L.nodes, no germinal centers. 1. X-linked Bruton tyrosine no mature agammaglobulinaemia. Kinase (Btk) B-cells.

Affected children suffer from recurrent Affected children suffer from recurrent pyogenic bacterial infections of : pyogenic bacterial infections of : conjunctiva, throat, skin, ear, conjunctiva, throat, skin, ear, bronchi & lung. bronchi & lung. * Infecting microbes include : * Infecting microbes include : Pneumococci, H.influenzae Pneumococci, H.influenzae Streptococci. Streptococci. * Also susceptible to certain viruses (polio.) * Also susceptible to certain viruses (polio.) and intestinal parasites (giardia ). and intestinal parasites (giardia ). X-linked agammaglobulinaemia. (XLA).cont..

*Newborn infants are often normal, *Newborn infants are often normal, infectious complications are delayed infectious complications are delayed until months of age. until months of age. ( maternal IgG). ( maternal IgG). * Most intracellular microbes & fungi are handled normally (T- cells normal ). handled normally (T- cells normal ). 20 percent may develop autoimmune 20 percent may develop autoimmune diseases. diseases. X-linked agammaglobulinaemia. (XLA).cont..

2.X-linked hyper-IgM defective CD40 markedly Syndrome. Ligand. elevated IgM.

Characterized by : Characterized by : - Low IgG, IgA & IgE. - Low IgG, IgA & IgE. - Markedly elevated IgM. - Markedly elevated IgM. - High levels of autoantibodies - High levels of autoantibodies to neutrophils, platelets, red cells. to neutrophils, platelets, red cells. - Recurrent infections especially - Recurrent infections especially Pneumocystis carinii. Pneumocystis carinii. X- linked hyper-IgM Syndrome. (cont.).

Defect in the CD 40L in T- cells. * No co-stimulatory signal for B-cells. * No co-stimulatory signal for B-cells. * No response to TD antigens. * No response to TD antigens. * No class – switching. * No class – switching. * No memory cells. * No memory cells. * Marked lymphadenopathy. * Marked lymphadenopathy. X-linked hyper-IgM Syndrome. (cont.).

3. Common variable Immunodeficiency.(CVI). Heterogynous group that cause late - onset hypogammaglobulinaemia. hypogammaglobulinaemia. Recurrent infections between yrs. Characterized by : Characterized by : - Mature B- cells reduced. - Mature B- cells reduced. - B –cells normal but do not differentiate - B –cells normal but do not differentiate into Plasma cells. into Plasma cells. - Defective T- helper cells. - Defective T- helper cells. - Excess T –suppressor cells. - Excess T –suppressor cells.

Features: 1. Low IgG & IgA. 1. Low IgG & IgA. 2. Impaired antibody responses. 2. Impaired antibody responses. 3. Associated autoimmune diseases. 3. Associated autoimmune diseases. (seronegative arthritis,vasculitis.) (seronegative arthritis,vasculitis.) Common variable Immunodeficiency.(CVI).cont.

* Most are asymptomatic. ( but have * Most are asymptomatic. ( but have increased rate of (R.T.I.) increased rate of (R.T.I.) * Some have recurrent R.T.I. an * Some have recurrent R.T.I. an G.I.T. symptoms G.I.T. symptoms * Increased incidence of allergic * Increased incidence of allergic manifestations. manifestations. *anti- convlusant drugs (phenytoin) may cause deficiency. *anti- convlusant drugs (phenytoin) may cause deficiency. 4.Selective immunoglobulin deficiency. 1.IgA deficiency (1:700) 2.IgG subclass deficiency.

5. Transient hypogammaglobulinaemia of infancy: Characterized by: * Abnormally low IgG with recurrent Bacterial & viral infections mainly Bacterial & viral infections mainly R.T.I. R.T.I. * Resolve spontaneously by age 4.

6. Specific antibody deficiency with normal immunoglobulin (SANDI). *Recurrent respiratory bacterial infections. *Recurrent respiratory bacterial infections. *Impaired specific antibody responses, particularly against polysaccharide microbial antigens. *Impaired specific antibody responses, particularly against polysaccharide microbial antigens.

Ataxia telagiectasia defctive cell- low IgA, IgE. cycle kinase. A disease syndrome that include : Deficiency of IgA & some times IgE. Deficiency of IgA & some times IgE. Characterized by : Cerebellar ataxia, cutaneous telangectasia, Characterized by : Cerebellar ataxia, cutaneous telangectasia, and immunodeficiency. and immunodeficiency. Due to : Defective cell-cycle kinase. Due to : Defective cell-cycle kinase.

Management. *Periodic intravenous immunoglobulin (IVIG) reduces infectious complications.

T-cell defects.

Introduction : Introduction : Several genetic lesions selectively Several genetic lesions selectively impede cellular mechanisms involving: T-cells, NK-cells & Monocytes, T-cells, NK-cells & Monocytes, leaving antibody production intact. leaving antibody production intact. T-cell defects.

(congenital thymic aplasia ) (congenital thymic aplasia ) * First described in * First described in * Characterized by : * Characterized by : - Absence of the Thymus gland. - Absence of the Thymus gland. - Hyperparathyroidism. - Hyperparathyroidism. - Cardiovascular abnormalities. - Cardiovascular abnormalities. - Characteristic facial features. - Characteristic facial features. DiGeorge Syndrome. DiGeorge Thymic aplasia. Impaired T-cell Syndrome. development.

Failure of the third & fourth pharyngeal Failure of the third & fourth pharyngeal pouches to develop. pouches to develop. *Features : *Features : -Children may present with seizures -Children may present with seizures ( tetany) ( tetany) -Extreme susceptibility to viral, protozoal, -Extreme susceptibility to viral, protozoal, and fungal infections. and fungal infections. 1. profound depression of T-cell numbers. 1. profound depression of T-cell numbers. 2. absence of T-cell responses. 2. absence of T-cell responses. DiGeorge Syndrome.

In some cases B-cells are normal and In some cases B-cells are normal and produce effective humoral immunity produce effective humoral immunity to common bacterial infections. to common bacterial infections. (Partial Di George Syndrome.) (Partial Di George Syndrome.) ( thymic hypoplasia,Nezelof syndrome ). ( thymic hypoplasia,Nezelof syndrome ). * In some T-cell – dependant antibody production is absent. production is absent. DiGeorge Syndrome.

Management: Management: Fetal thymus tissue graft (14 week old) Fetal thymus tissue graft (14 week old) to prevent G.V.H. Reactions. to prevent G.V.H. Reactions. ( graft versus host ) ( graft versus host ) DiGeorge Syndrome.

Severe combined immunodeficiency. (SCID ).

Features: Features: 1. Increased susceptibility to viral, 1. Increased susceptibility to viral, fungal, bacterial & protozoal infection. fungal, bacterial & protozoal infection. ( start at 3 month of age.) ( start at 3 month of age.) 2. Failure to thrive. 2. Failure to thrive. 3. Reduced weight gain. 3. Reduced weight gain. 4. Prolonged diarrhea. 4. Prolonged diarrhea. 5. Moniliasis due to candida. 5. Moniliasis due to candida. Severe combined

Severe combined Autosomal recessive SCID. immunodeficiency : ( SCID ). - ADA deficiency. toxic metabolites in T & B-cells. - PNP deficiency.

A. Inherited enzyme deficiencies: A. Inherited enzyme deficiencies: 1. Adenosine deaminase (ADA). 1. Adenosine deaminase (ADA). 2. Purine nucleoside phophorylase(PNP). 2. Purine nucleoside phophorylase(PNP). Both result in the accumulation of Both result in the accumulation of dGTP & dATP which are toxic metabolites dGTP & dATP which are toxic metabolites to dividing cells. to dividing cells. * Result in defective T-cells & B-cells. * Result in defective T-cells & B-cells. Severe combined

A. Inherited enzyme deficiencies: A. Inherited enzyme deficiencies: 1. Adenosine deaminase (ADA). 1. Adenosine deaminase (ADA). 2. Purine nucleoside phophorylase(PNP). 2. Purine nucleoside phophorylase(PNP). Both result in the accumulation of Both result in the accumulation of dGTP & dATP which are toxic metabolites dGTP & dATP which are toxic metabolites to dividing cells. to dividing cells. * Result in defective T-cells & B-cells. * Result in defective T-cells & B-cells. Severe combined I.D.

B. JAK-3 deficiency B. JAK-3 deficiency & Defective IL-2R (gamma chain ). Defective IL-2R (gamma chain ). * The defect lie in the gamma chain * The defect lie in the gamma chain of the IL-2 receptor. Defect in this chain of the IL-2 receptor. Defect in this chain impede signaling through receptors for: impede signaling through receptors for: IL-2, IL-4, IL-7, IL-9, & IL-15. IL-2, IL-4, IL-7, IL-9, & IL-15. * Lymphocytes fail to develop. * Lymphocytes fail to develop. Markedly depressed T-cells & B-cells. Markedly depressed T-cells & B-cells. Severe combined I.D.

C. RAG-1 & RAG-2 deficiency : C. RAG-1 & RAG-2 deficiency : No TCR or Ig gene rearrangement. No TCR or Ig gene rearrangement.. D. ZAP-70 deficiency. Defective signal from TCR. Defective signal from TCR. Severe combined I.D.

3. Bare lymphocyte syndrome. Form a class of SCID individuals. Form a class of SCID individuals. Severe combined immunodeficiency Severe combined immunodeficiency Caused by a defect in the expression of the : MHC class11 gene promoter. Caused by a defect in the expression of the : MHC class11 gene promoter. A defect in the (TAP) transporters genes A defect in the (TAP) transporters genes is associated with defect in antigen processing by class 1 MHC molecules. is associated with defect in antigen processing by class 1 MHC molecules. (defective CD 8-mediated immunity.) (defective CD 8-mediated immunity.)

Bare lymphocyte syndrome.

Bare lymphocyte types : 1. Type 1 : defective MHC. Class1. 1. Type 1 : defective MHC. Class1. 2. Type2 : defective MHC. Class Type2 : defective MHC. Class Type 3 : defective MHC.Class1 & Type 3 : defective MHC.Class1 & 11. This results in impaired antigen This results in impaired antigen presentation. presentation. Children suffer recurrent bacterial & viral Children suffer recurrent bacterial & viral infections. infections. The condition is fatal. The condition is fatal.

1.Reticular dysgenesis : - Rare fatal congenital disease. - Rare fatal congenital disease. - Lymphoid & myeloid stem cells - Lymphoid & myeloid stem cells fail to differentiate. fail to differentiate. - Children lack T-cells, B-cells, - Children lack T-cells, B-cells, Monocytes & granulocytes. Monocytes & granulocytes.

Management of recessive (SCID.) 1. Infusion of purified enzymes. 1. Infusion of purified enzymes. 2. Gene therapy. 2. Gene therapy.

Defect in signalling pathways : X-linked. Consist of : Eczema, thrombocytopenia, & immunodeficiency. & immunodeficiency. Defect in : WAS protein (WASP), which connect T-cell signal pathway. connect T-cell signal pathway. Result in: defective T-cell help to B-cell in response to encapsulated bacteria. response to encapsulated bacteria. Wiskott-Aldrich defect in cytoskeletal defective T-cells & syndrome. protein (CD43). Platelets.

2. X-linked lymphoprolferative disorders. Pleomorphic disease. Defect in signal transducing protein. Defect in signal transducing protein. Inability to control B-cell growth. Inability to control B-cell growth. EBV - driven B – cell tumor & fatal I infectious mononucleosis. EBV - driven B – cell tumor & fatal I infectious mononucleosis. Pulmonary granulomatosis & lymphoma. Pulmonary granulomatosis & lymphoma.

Leukocyte defects. Quantitative. Qualitative.

1. Congenital agranulocytosis : 1. Congenital agranulocytosis : Kostmann syndrome. Kostmann syndrome. Defect in the gene inducing G-CSF (granulocyte colony stimulating factor). Defect in the gene inducing G-CSF (granulocyte colony stimulating factor). Features: pneumonia,otitis media, gingivostomatitis perineal abscesses. perineal abscesses. Management: Management: Respond to G-CSF therapy. Respond to G-CSF therapy. Quantitative.

Phagocyte defects.

2. Cyclic neutropenia : Deficiency of elastase lead to regular fluctuations in the level of neutrophils. fluctuations in the level of neutrophils. (every 21 days). (every 21 days). Features: Features: Fever, stomatitis, periodontitis Fever, stomatitis, periodontitis skin infections. skin infections.

1.Defect in response to chemotactic agents. 2.Defect in intracellular killing. A. Defect in chemotaxis: A. Defect in chemotaxis: Leukocyte adhesion deficiency (LAD.) Leukocyte adhesion deficiency (LAD.) 2 types. 2 types. *LAD type 1: defect in gene encoding CD18. (B integrin.) (B integrin.) Qualitative.

LAD type 1: 3.TYPES: 3.TYPES: *CD18+CD11a- leukocyte function *CD18+CD11a- leukocyte function associated molecule (LFA-1). associated molecule (LFA-1). CD18+CD11b- complement receptor (CR3). CD18+CD11b- complement receptor (CR3). CD18+CD11c- complement receptor (CR4). CD18+CD11c- complement receptor (CR4). LFA-1 mediate tight adhesion of leukocytes LFA-1 mediate tight adhesion of leukocytes to the endothelium. to the endothelium.

WITH DEFECT IN LFA-1: Leukocytes are trapped in the circulation. Leukocytes are trapped in the circulation. Leukocyte count can reach 100,000 cells per mm3. Leukocyte count can reach 100,000 cells per mm3. Abscesses do not suppurate. Abscesses do not suppurate.

LAD type 2: Defect in Sialyl lewis protein Defect in Sialyl lewis protein (ligand for E- selectin). (ligand for E- selectin). Leukocytes cannot attach to Leukocytes cannot attach to endothelium. endothelium. Defective chemotaxis. Defective chemotaxis.

B. Defect in intracellular killing: 1.Chronic granulomatous disease: X-LINKED. (75%) X-LINKED. (75%) AUTOSOMAL RECESSIVE.(25%). AUTOSOMAL RECESSIVE.(25%). DEFECT: in the oxidative complex. ( responsible for producing superoxide radicals.) ( responsible for producing superoxide radicals.) FEATURES: Extreme susceptibility to infections. Extreme susceptibility to infections. Granulomatous inflammation. Granulomatous inflammation. (chronic T-cell stimulation.) (chronic T-cell stimulation.)

2. Glucose -6- phosphate dehydrogenase deficiency. (G6-P-D). (no resp.burst.) 3. myeloperoxidase deficiency. (no resp. burst). (no resp. burst). 4. Chediak - Higashi syndrome: defect in formation of phagolysosome. Associated with: Associated with: abnormal platelet function. abnormal platelet function. partial albinism. partial albinism.

Complement deficiency.

Deficiency of all complement components Deficiency of all complement components have been described C1-C9. have been described C1-C9. 1. Deficiency of C1, C2 & C4. ( classical pathway ) ( classical pathway ) lead to immune-complex diseases which lead to immune-complex diseases which can cause significant pathology in can cause significant pathology in autoimmune diseases. autoimmune diseases.

Pathways of complement activation. CLASSICAL PATHWAY ALTERNATIVE PATHWAY activation of C5 LYTIC ATTACK PATHWAY antibody dependent LECTIN PATHWAY antibody independent Activation of C3 and generation of C5 convertase

4. Deficiency of membrane - attack complex. (MAC). ( C5 - C9 ) Lead to infection with N.meningitides Lead to infection with N.meningitides and N.gonorrhea. and N.gonorrhea. 5. Deficiency of C3. Lead to infections with pyogenic bacteria. Lead to infections with pyogenic bacteria. impaired clearance of immune-complexes.. impaired clearance of immune-complexes..

C1 - inhibitor deficiency: hereditary angioedema

2. Deficiency of mannose - binding lectin. (lectin pathway) *MBL, C2, & C4. *MBL, C2, & C4. Lead to bacterial infections mainly in Early childhood. Early childhood. 3. Deficiency of Factor D & Factor P. 3. Deficiency of Factor D & Factor P. (alternative pathway ). (alternative pathway ). Lead to infection with pyogenic bacteria. Lead to infection with pyogenic bacteria.

Diseases (other than I.D. ), caused by complement defects. 1.Loss of control proteins. 1.Loss of control proteins. (decay accelerating factor, DAF, & CD59.) (decay accelerating factor, DAF, & CD59.) Lead to destruction of R.B.C., which result Lead to destruction of R.B.C., which result in paroxysmal nocturnal hemoglobinuria. in paroxysmal nocturnal hemoglobinuria. 2.C1 esterase inhibitor deficiency (C1 inhibitor.) 2.C1 esterase inhibitor deficiency (C1 inhibitor.) result in excess of vasoactive mediators result in excess of vasoactive mediators (kinins). (kinins). Causes : Hereditary angioneurotic edema. Causes : Hereditary angioneurotic edema. *Recurrent attacks of subepithelial swellings *Recurrent attacks of subepithelial swellings involving the larynx & intestinal mucosa. involving the larynx & intestinal mucosa. ( may be fatal ) ( may be fatal )

Clinical approach to suspected immunodeficiency. 1.History. * Infections of unusual frequency, chronicity or severity. * Infections of unusual frequency, chronicity or severity. * Family history of infectious problems. * Family history of infectious problems. Consanguinity should be investigated Consanguinity should be investigated (inter-family marriages ). (inter-family marriages ).

2.Physical examination. * Absence of tonsils. * Absence of tonsils. * Partial albinism. * Partial albinism. * Telangiectasia. ( bleeding capillaries ). * Telangiectasia. ( bleeding capillaries ).

3.Radiologic evaluation. * Absence of thymic shadow. * Absence of thymic shadow. * Pneumatocele (hyper IgE syndrome) * Pneumatocele (hyper IgE syndrome)

4. Laboratory evaluation. 1. Complete blood count.(total & differential). 2. Evaluation of antibody responses.. A. determination of serum immunglobulins. B. measure specific antibody responses: B. measure specific antibody responses: -To polysaccharide antigens. -To polysaccharide antigens. ( measure isohemagglutinins. ) ( measure isohemagglutinins. ) - To protein antigens. - To protein antigens. ( measure antibodies to tetanus.) ( measure antibodies to tetanus.)

3. Determination of T & B cell counts. ( by flow cytometry ) 3. Determination of T & B cell counts. ( by flow cytometry ) 4. Determination of the complement 4. Determination of the complement components. C3, C4. components. C3, C4. - assess functional activity by CH50. - assess functional activity by CH Assess phagocyte function. 5. Assess phagocyte function. - phagocytosis & respiratory burst. - phagocytosis & respiratory burst. 6. Carrier detection & prenatal 6. Carrier detection & prenatal diagnosis. ( important for genetic diagnosis. ( important for genetic counseling.) counseling.)

Analysis of lymphocytes in umbilical cord blood during gestation * Help to diagnose immunodeficiency * Help to diagnose immunodeficiency In pregnancies at risk. In pregnancies at risk. * Bone marrow or stem cell transplantation may be applied before birth. may be applied before birth.

Therapy of immunodeficiency. 1. IVIG.( IV infusion of immunoglobulin.) 1. IVIG.( IV infusion of immunoglobulin.) For : a. agammaglbulinaemia. For : a. agammaglbulinaemia. b. CVI. c. WAS. b. CVI. c. WAS. 2. Periodic antibiotic treatment. 2. Periodic antibiotic treatment. 3. Bone marrow transplantation. 3. Bone marrow transplantation. For : a. SCID. b. WAS. For : a. SCID. b. WAS. 4. Enzyme replacement. 4. Enzyme replacement. For : a. ADA deficiency. For : a. ADA deficiency.

5. G-CSF.(colony stimulating factor ) For : neutropenia. 5. G-CSF.(colony stimulating factor ) For : neutropenia. 6. Thymus transplantation. 6. Thymus transplantation. For : DiGeorge syndrome. For : DiGeorge syndrome. 7. IFN – gamma. 7. IFN – gamma. For : CGD. For : CGD.

T-cell. HIV virus.

Practical points : Practical points : 1.Immunodiffusion plate. 1.Immunodiffusion plate. ( single radial immunodiffusion, SRID. ) ( single radial immunodiffusion, SRID. ) Antibody mixed in the agar medium. Antibody mixed in the agar medium. Antigen applied in the holes around. Antigen applied in the holes around. *antigen molecules will diffuse into the *antigen molecules will diffuse into the agar & precipitate with antibody forming agar & precipitate with antibody forming a ring. a ring. The diameter of the ring is proportional The diameter of the ring is proportional to the concentration of the antigen. to the concentration of the antigen.

SRID. Measure Diameter. 3-standards,conc. 10,25,50

Applications: 1.For measurement of immunoglobulins 1.For measurement of immunoglobulins in serum : IgG,IgA & IgM. in serum : IgG,IgA & IgM. 2.For measurement of complement 2.For measurement of complement proteins in serum. proteins in serum. NOTE: Immunoglobulins & complement NOTE: Immunoglobulins & complement can also be measured by can also be measured by nephlerometry (measures optical nephlerometry (measures optical density ) density )

2. Immunonephelometry : * A more accurate method for measurement of : a. immunoglobulins & b. Complement proteins. b. Complement proteins. - proteins form immune complexes with specific antibodies. A beam of light is passed through the sample. The intensity of the scattered light is proportional to the of the scattered light is proportional to the concentration. concentration.

2.Flow cytometry: 1.For enumeration of lymphocytes in the 1.For enumeration of lymphocytes in the peripheral blood.. peripheral blood.. ( laser – operated machine that utilize ( laser – operated machine that utilize monoclonal antibodies to CD markers). monoclonal antibodies to CD markers). 2.measures T-cells,B-cells, NK-cells. 2.measures T-cells,B-cells, NK-cells.

3.CH 50 test. Complement hemolytic assay. Complement hemolytic assay. * measures the functional activity of the * measures the functional activity of the complement system ( amount of complement system ( amount of complement that causes 50% lyses complement that causes 50% lyses of a fixed amount of cells. ) of a fixed amount of cells. )

Immunology quiz. (1)

A previously healthy 30 –years old man was admitted following a car accident.He is unconscious and had signs of brain damage. The patient has a tube inserted into his trachea, and a central venous line and urinary catheter are inserted.He is given high dose corticosteroids in an attempt to reduce cerebral edema. After a series of convulsions the anti – convulsant phenytoin is given intravenously. Two weeks later he developed pneumonia. In addition to physical stress this patient has poor nutrition. 1. What factors may impair the defense mechanisms in this patient ? 2. What type of immunodeficiency is affecting this patient ?

Immunology quiz.

Immunology quiz No.1 A 9-month old boy presented with history of recurrent episodes of serious bacterial infections. A 9-month old boy presented with history of recurrent episodes of serious bacterial infections. These included bacterial pneumonia, otitis media, These included bacterial pneumonia, otitis media, Sinusitis & septicemia. Repeated bacteriological cultures revealed Streptococcus pneumonae, H. Sinusitis & septicemia. Repeated bacteriological cultures revealed Streptococcus pneumonae, H. influenzae & Staphylococci. influenzae & Staphylococci. 1.List the relevant immunologic investigation in this case. case. 2.What immunologic processes are likely to be involved. involved.

3. What is the probable diagnosis ? 4.What are the appropriate lines of 4.What are the appropriate lines of management ? management ?.5.Why was the child normal up to 9-month of age and then started to develop infections? of age and then started to develop infections? 6.Can this disease affect female children ?

Immunosuppresion.

Strategies that diminish immune responses. specific Non-specific.

Immunosuppresion is required in : Allogeneic transplantation. Autoimmune diseases. Allergic diseases.

Mitotic inhibitors. Azathioprine ( Imuran ). Given just before & after Transplantation to diminish T-cell proliferation. Both T-cells & B-cells are Affected. Cyclophosphamide & methotrexate. Effective against rapidly dividing cells. Sometimes given at time of grafting. May affect other dividing Cells.

Corticosteroids.( glucocorticoids ). potent anti-inflammatory agents. Prednisone,prednisolone, dexamethasone etc. 1. Decrease size & lymphoid content of the spleen & lymph nodes. 2.Modify function of certain T –cells. 3. Inhibit inflammatory mediators including histamine prostaglandins & leukotriens. 4. Inhibit monocyte & neutrophil chemotaxis & activity. 5. Change leukocyte distribution causing lymphopenia. and neutrophilia. 6. Inhibit IL-1 production & expression of MHC11 by macrophages. decrease availability of IL Decrease IgG blood level.

Nonsteroidal anti-inflammatory agents.(NSAIDs). The most frequently used medications for treatment of Pain & inflammation. (also have antipyretic effect.) They inhibit the cyclooxygenase pathway that produce Prostaglandins & thrmboxanes from arachidonic acid. Reduction in prostaglandin production limits : Increase in vascular Permeability. Neutrophil chemotaxis. Reduce edema pain & fever.

Most NSAIDs inhibit both Cox1 & Cox2. Responsible for anti-inflammatory effect. Damage GIT tract, no significant anti- Inflammatory effect. This led to development of Cox2 –specific NSAIDs drugs.

Inhibition of thromboxanes production : Cause inhibition of platelet aggregation.

The main adverse effects of NSAIDs : Mild G.I.T. irritation G.I.T. bleeding Caused by ulcers. Decreased G.F.R. Acute renal failure &interstitial Nephritis.

Rheumatoid arthritis therapy. NSAIDs. Disease modifying anti-rheumatic drugs (DMARDS) Corticosteroids. Biologic agents. TNF inhibitor & IL-1. The most widely used is methotrexate. Alkylaing agents: cyclophosphamide. Purine analoques: azathioprine.

Certain fungal metabolites are immunosuppressants. - Cyclosporin –A. - FK506 (tacrolimus ). - Rapamycin (sirolimus ). Inhibit IL-2 gene transcription.

The profound immunosuppressive properties of these three agents have made them a mainstay of heart,liver, Kidney, and bone marrow transplantation Cyclosporin –A has been shown to prolong graft survival. but,the main side effect is acute nephrotoxicity. FK506 & rapamycin are times more potent than CsA as immunosuppressants, therefore have few side effects & can be given at lower doses.

Total lymphocyte irradiation eliminates lymphocytes. The typical protocol is daily x-irradiation treatments of 200 rads per day for several weeks until a total dose of 3400 has been administered. The bone marrow is not x-irradiated,lymphoid stem Cells proliferate and renew the population of lymphocytes.

Complement Deficiencies and Disease. Classical Pathway. Pathway Component DiseaseMechanism C1INH C1INHHereditaryAngioedema Overproduction of C2b (prokinin) C1, C2, C4 C1, C2, C4Predisposition to SLE Opsonization of immune complexes help keep them soluble, deficiency results in increased precipitation in tissues and inflammation

Complement Deficiencies and Disease. Alternative Pathway Pathway/ComponentDiseaseMechanism Factors B or D Susceptibility to pyogenic (pus- forming) bacterial infections Lack of sufficient opsonization of bacteria C3 Susceptibility to bacterial infections Lack of opsonization and inability to utilize the membrane attack pathway C5, C6, C7 C8, or C9 Susceptibility to Gram-negative infections Inability to attack the outer membrane of Gram-negative bacteria

Complement Deficiencies and Disease. Alternative Pathway cont. Pathway Component DiseaseMechanism Properdin (X-linked) Susceptibility meningococcal meningitis Lack of opsonization of bacteria Factors H or I C3 deficiency and susceptibility to bacterial infections Uncontrolled activation of C3 via alternative pathway resulting in depletion of C3

Specific immunosuppressive therapy. 1.anti-cytokine drugs: -TNF-alpha neutralizing monoclonal antibodies. - soluble recombinant TNF-alpha receptor & - IL-1 receptor blocking proteins. 2. Immunoadhesin molecules. Compete with cell-bound receptors.

Clinical case 1: Clinical case 1: A-52 year old woman presents with symptoms of joint pains presents with symptoms of joint pains and stiffness in hands,feet and knees for the past 6 months.In addition, the patient also noted a 10- pound weight loss and a low grade fever. She has been receiving: analgesic medications for 4 month and has not experienced much relief of her symptoms. analgesic medications for 4 month and has not experienced much relief of her symptoms.

What immunological process is likely to be involved in her problems ? What additional information would help you to confirm this ? What immunological process is likely to be involved in her problems ? What additional information would help you to confirm this ?

A. This patient most likely has rheumatoid arthritis. In addition to a complete history and physical examination, radiographic evidence of joint erosions and a positive In addition to a complete history and physical examination, radiographic evidence of joint erosions and a positive rheumatoid factor ( RF.) can confirm the diagnosis. rheumatoid factor ( RF.) can confirm the diagnosis. Because this patient has tried analgesics for 4-months without much Because this patient has tried analgesics for 4-months without much relief, DMARDs and / or TNF - alpha inhibitors should be considered. relief, DMARDs and / or TNF - alpha inhibitors should be considered.