)Immune deficiency disease(

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1 )Immune deficiency disease( ((( Last lecture ))), First of all as we all know our lovely doctor, refuse to give us the slides due to our behavior, anyway I try my best to write all notes and extra info, which is already mentioned in last lecture. And I also resorted to info from previous years. Study well focus well... Then u gonna do in ur exam very well. Slide 2: ** Primary Congenital & - Genetic ** Secondary acquired - Infections, particularly viruses - Malnutrition or malabsorption - Medications It may develop in response to infection, for example by HIV, which is the most important immunosuppressive virus present. In fact, all viruses can cause immunodeficiency because they may infect lymphocytes. Malnutrition is the most common cause of immunodeficiency. No cause, whether primary or secondary, can match malnutrition as a cause of immunodeficiency because famine affects the majority of the world. The respiratory tract is the preferred route for most viruses and bacteria because of frequent exposure with the environment in the form of inhaled

2 particles loaded or contaminated with microorganisms. Other systems like the GI tract, CNS and urogenital tract may be involved. ENT clinics most frequently encounter patients affected with infections associated with immunodeficiency. Slide 3: Primary immunodeficiency occurs when one or more of the components of the immune system are defective. Immunodeficiency can arise as a defect in cell-mediated immunity, antibody-derived immunity, antigen processing, complement or phagocytic function. When both T- lymphocytes and B-lymphocytes are involved, combined immunodeficiency manifests. Slide 4: Without such disorders, we would not be able to appreciate the role of the immune system. We now know that antibodies are important because people who lack antibodies suffer from severe infections. Moreover, we know that T-lymphocytes are central for the regulation of the immune system because those who lack T-lymphocytes can not regulate their immune system. The recognition that ZAP-70 is very important was derived from studies on individuals who lack ZAP-70. The same applies to the CD40/CD 40 ligand interaction and its main role in the generation of the immune response. Furthermore, studies on individuals lacking enzymes for the activation of B and T-lymphocytes have illustrated the molecular basis of the immune responses. Slides 5 and 6: Undue meaning infection that takes place at times when an individual is not expected to develop infection. One of the characteristics of autoimmunity is immunosuppression; something central is lost in the regulation of the immune system and that leads to immunosuppression in autoimmune diseases. Allergy is common as well.

3 Individuals with primary immunodeficiency are more likely to develop malignancies involving their immune systems. Because primary immunodeficiency is inherited as an X-linked disorder, boys die early in life and the ratio of preponderance reverses in adulthood. Slide 8: Antibodies mediate immunity to organisms causing pyogenic infections. These organisms include Staphylococci, Streptococci, Streptococcus pneumoniae and Haemophilus influenzae. They usually cause infections on the skin and respiratory tract. Otitis media, conjunctivitis, paranasal sinusitis, bronchitis and pneumonia (collectively called sinopulmonary infections) are common in individuals who lack antibodies. Usually, B-cell maturation is arrested at the pre B-cell level. They do not develop into mature IgD and IgM expressing B-lymphocytes. There may be a defect in the interaction with T-lymphocytes and the response to antigenic stimulation is consequently lost. Normally, B-cell activity starts after the decay of maternal antibodies, and this happens after the first 6 months of life. Maternal antibodies are important because the newborn can not process its own antibodies efficiently during the first six months of its life. However, after that, the decay of these antibodies is critical for the survival of the newborn because they may interfere with the normal function of its B-cells. Maternal antibodies may influence the ability of the newborn to produce its own antibodies because they may saturate antigens and impede antigen processing. They may also interfere with vaccination. Sometimes, this antibody production may be delayed until the first 18 months of the newborn; this is known as physiologic immunodeficiency. It is very important to differentiate between physiologic immunodeficiency and true B-cell deficiency. Slides 9 and 10: In Burton's agammaglobulinemia, B-cell maturation is arrested at the pre B-cell level. IgM expressing immature B-cells are not present in the circulation of individuals with XLA.

4 The autosomal variant results from mutations in the heavy chain and as a result, B-cell maturation is arrested at the pro B-cell level. This is rare, however. Onset is the same as physiologic immunodeficiency and that's why they must be differentiated from each other. The germinal centers where B- cells reside are usually atrophic in tonsils and other lymph tissue. Patients are given immunoglobulins for the rest of their lives to protect them from infections. Slides 11 and 12: In the majority of the cases, the defect is in the T-cells (CD 40 ligand). However, some individuals have normal CD40 ligand, but they fail to switch to IgA and IgG-producing cells. In these rare cases, it is truly a B- cell defect which is reflected as a defect in CD40 itself. Normal B-cell number in the circulation distinguishes immunodeficiency with hyper IgM from Burton's agammaglobulinemia. Plasmapheresis removes excess IgM because it causes hyperviscosity when it exceeds a certain concentration. Patients can undergo bone marrow transplantation to replace their defective T-lymphocytes with ones capable of interacting with B-cells normally. Slide 17 Drug induced (reversible), like those associated with penicillamine, sulfasalazine, which are used for treatment of rheumatoid arthritis, captopril, which is a hypertensive drug, phenytoin for epilepsy, thyroxine, valproic acid also for epilepsy, and dilantin. Slide 18 Although most patients are asymptomatic, they may develop sinopulmonary and parasitic infections such as Giardia. One study linked IgA deficiency with atopy with the production of IgE antibodies against IgA, and it has been associated with anaphylaxis during blood transfusion (1/3 of patients have anti-iga). Those individuals who receive blood transfusion mount an anaphylactic response because of the presence of IgE which can bind to mast cells.

5 Once blood is transfused, IgA present in the transfused blood can mount the anaphylactic response. Slide 19 Treatment is with immunoglobulins to reduce the risk of infection; however, we should make sure of the inflammatory response. Total absence of IgA might lead to anaphylaxis, that s why this treatment is performed with care. Slide 22 One or more subclass may be defective, IgG2 is most commonly affected (although it is the least important among IgG subclasses) and most important are those involving IgG1 or IgG3, which can predispose for recurrent infections. Slide 23 Affected individuals are apparently healthy until they experience infectious mononucleosis. Infections take place early in life, usually in the first 3 years, which is when manifestations start to appear. Slide protein electrophoresis This method demonstrates the presence of low concentration of antibodies in the case of B cell deficiency. 2. Quantitation of IgG,IgA, IgM and IgD This is done by radial immunodiffusion or ELISA tests. 3. Isohemagglutinin Screening is best achieved by the measurement of isohemagglutinins. Measuring IgM antibodies produced against RBC antigens is the most effective way to evaluate B cell deficiency. It is a very simple test where a titer less than 4 ml in an individual above one year of age indicates B cell deficiency. 4. Specific antibody response This test is done in response to specific antigen stimulation. Failure to mount a response indicates B cell deficiency or lack in T cells help.

6 5. B cell quantitation The number of B cells can be measured. The best is to use either flow cytometry or direct immunofluorescence techniques. 6. B cell markers (CD19) Antibody special marker B 19 is specific for B lymphocytes. Slide 28 T Cell Deficiency * DiGeorge Syndrome (a congenital disease that appears in the form of T cell deficiency) * Defect in CD3/TCR (necessary for antigen recognition and T cell activation) * Defect in signaling, Defect in ZAP-70 (essential for signal transduction after the activation of T lymphocytes) * Defect in Cytokine production as IL-2 and IFN gamma * Defect in Cytokine response Slide 29 DiGeorge Syndrome - Either complete or partial absence of thymus. May occur in both males and females. - T cell defects à fungul infections develop. - Aortic arch, heart à great vessel defects. - facial features and parathyroid glands are affected. - Micro deletion of the long arm of chromosome 22 ( q22), which is known as the DiGeorge s coding region have been shown in these patients. - The most common manifestation is tetany due tohypoparathyroidism. - The infant might develop tetany because ofhypocalcemia in the first 24 hours and this is the time the infant start to develop the immunodeficiency state. Slide 31 : picture - The abnormal facial appearance of the patient are : hypertolerism ( large distance between the eyes ) short philtrum low set ears anti- Mongolians slant eyes

7 slide 32 - The syndrome is mostly sporadic, but 3 cases of autosomal dominant inheritance have been reported. - Another deletion on short arm of chromosome 10 ( p10 )has been identified. - Treatment is by thymic transplantation. The transplanted thymus should be from a fetus aged 14 weeks or less <WHY?> <To prevent the mounting of an immune response> - In partial DiGeorge syndrome patients, spontaneous improvement indicate the presence of extrathymic tissue or ectopic thymic tissue or ectopic parathyroid. Slide 33 : Evaluation of T cell immunity 1- Total lymphocyte count. 2- DTH ( delayed-type hypersensitivity ) skin test à BEST TEST! Skin test assist the afferent arm of immune response;processing + presenting antigens + mounting an immune response by T lymphocytes ( cytokines, neutrophils, trafficking and homing etc) kol el immunology elia5athna byetla3 fil skin test ;p 3- Lymphocyte transformation assay. à measure the response of T lymphocytes, by culturing them and test their response. 4- Total T cell count using Anti-CD3. 5- CD4 & CD8 subset count. 6- Cytokine production. #slide 34: SCID : - SCID is the second most common syndrome in primary immune deficiency. - Two types : Autosomal & X- linked. - Extreme wasting develop after infections and diarrhea. - Here, those can cause defects in T, B, and sometimes NK (natural killer) cells. slide 35 - defects in T, B, and NK cells could be due to gamma chain mutation à No Jak-3 activation à No signal transduction by IL-2,4,7,9 and 15 receptors. - X-linked severe combined immunodeficiency patients in pediatric emergency die unless they receive bone marrow transplantation; so there should be immediately proper bone marrow transplantation with HLA identical orhaploidentical donor and the survival is more than 95%. Slide 36 : - Gamma chain is present in all IL-2,4,7,9,15 receptors. - If gamma chain is defected the cell cannot be activated. Slide 37: Has all the manifistations of B + T cells deficiency. Slide 38 :

8 A child showing SCID symptoms. Slide 39: Autosomal Recessive (AR) type of SCID - 3 enzyme deficiencies that can be due to SCID : à ADA, Jak-3, and RAG 1+2 deficincies. Slide 40 : ADA : - Affects primarily T cells due to accumulation of toxic purine metabolites. - Distinguishing features in ADA deficiency include rib cage and multiple skeletal abnormalities. - They develop lymphopenia ( deficiency in lymphocytes ), which is more profound in ADA than in other SCID types, BUT NK cells function is NORMAL. Slide 41 : - The gene encoding ADA was mapped to long arm on chromosome 20 (20q). - Gene mutation à Accumulation of Adinosine + deoxyadenosine (toxic purine) à Suicide inactivators of SAH (S- adinosylhomocysteine hydrolase) enzyme à May lead to Death! - Treatment of ADA is Bone marrow transplantation. Slide 42 : - this picture shows few types of deficiencies, ADA and PNP deficiencies. - Adenine should be converted to inosine, but with lack ofada it accumulates, and are then converted to deoxyatpby the enzyme KINASE, which exert a toxic effect on lymphocytes especially T cells. - The same happens with Guanosine. Lack of PNP leads to accumulation of guanosine which will be converted todeoxygtp by KINASE enzyme. The accumulateddeoxygtp exert a toxic effect on T lymphocytes in particular. - So, mainly T cells toxicity develop in such type on SCID. Slide 43 : Jak-3 Deficiency à High level of B cells Vs Very low level of T & NK cells. RAG 1 & 2 à they are very essential for T & B lymphocytes by being involved in gene rearrangement and genetic recombination to form the antigen receptor. - Thus deficiency in RAG 1+2 enzymes lead to low expression of receptors on T & B cells. Slide 44: CIM: - All the previous combined immunedeficincies were SEVERE, but this is Combined Immunodeficincy NOT SEVERE. - LOW T cell function. - Neutropenia & eosinophilia are found in CIM.

9 Slide 45 : PNP Deficiency: - PNP encoding gene is on chromosome 14 ( 14q ). - Not as severe as ADA deficiency. - 2/3 of the patients have neurological abnormalities. - Profound lymphopenia. - T cell deficiency (not absence) & increased NK cells count and function. Slide 46 : Cartilage Hair hypoplasia: - AR disorder; The defective gene maps to chromosome 9 (9q). - Short-limbed dwarfism; fine sparse light hair & eyebrows. - Frequent & severe infections. - Increased NK cells number & function. - 3 patterns of immune dysfunction: 1- defective Antibody-mediated immunity. 2- defective cellular immunity. 3- severe combined immune deficiency (SCID). Slide 47: Wiskott Aldrich Syndrome. - Another type of CIM, that is X-linked Recessive. - Mutated gene was mapped to X chromosome. Slide 48 : Ataxia Telangiectasia with immunodeficincy: the dr only read the slide - Many abnormalities. - Selective IgA deficiency may develop (in 50-80% of patients). Slide 49 : - Defective DNA and chromosomal abnormalities in the form of breakages involve the genes that encode T cell and B cell receptors. - AR disorder; the mutated gene is mapped to chromosome 11 (11q). Slide 50 : Defective Express of MHC Antigens. - In MHC class 1, MHC1 antigens are not detected on any cells in the body. - Mutation in gene encoding for transporters 1+2 proteins( TAP1+2 ). Slide 51 - MHC class 2, also called Bare Lymphocyte Syndrome, can be affected too. - AR disorder. - Very low CD No response to IFN-gamma; No HLA-DP, DR, DQ expression on antigen presenting cells.

10 - Transcription Factor RFX5 OR C2TA is affected. Slid 52 : Phagocytic Dysfunction: - EXTRINSIC: No chemotaxis, abnormal opsonization(cd 3, IgG), immunosuppression. à can suppress phagocytosis. - INTRINSIC: low neutrophil count, CGD, MPD, G6PD deficiency. - GCD à NADPH inactivation. - could be X-linked (65%) OR recessive (35%). Slide 53 : Components of NADPH oxidase - The normal ( 4 up ) and defective ( 4 down ) enzyme components. # A picture showing the mechanism of NADPH oxidase activation. NADPH oxidase converts NADPH to NADP + H à (2Hs + O2) form hydrogen peroxidase à Catalase converts hydrogen peroxidase to water and O2. Generation of toxic metabolites like hypochloride and hydroxyl radical are important in intracellular killing by macrophages and more importantly neutrophils. # A picture showing clinical presentation: - Cervical lymph node. Gingivitis ( inflammation of the gum ) - abcesses. Slide 54 : Clinical presentation of CGD: - Usually patients die before the age of 20 years due to severe infections. - G6PD deficiency is X-linked disorder. - Deficiency in H2O2 OR failure to oxidize via shunt. Slide 55 : MPO (Myeloperoxidase) deficiency: - failure to utilize H2O2 à defective fungal killing. -MOST COMMON Neutrophil disorder. _ worsen with diabetes mellitus. The last of phagocytic dysfunction is : Tuftsin Deficiency. - Tuft is a tetrapeptide that normally promotes phagocytosis. - It was discovered at tuft university in Boston by a Lebanese scientist who discovered this substance. - Splenectomized patients ( individuals that had their spleen removed ) usually develop this disorder, so they must be immunized against streptococcus bacteria to prevent infections. #Hyper IgE ( Job s Syndrome ): - Skin & lower respiratory tract infections & anti-staph.ige is specific for Job s. - Differential diagnosis for elevated IgE is important, we have to rule out allergy, diseases, infections, malignancies(b-cell malignancy, or multiple myeloma) in order to confirm the diagnosis of Job s syndrome.

11 Slide 56 : Leukocyte Adhesion Deficiency (LAD) - LAD 1 due to mutation in gene encoding for CD18 on chromosome 21q. - Beta chain defective à Alfa chain will not be expressed on LFA-1, CR3, & P Immune cell interaction and recognition is impaired. - Molecules for trafficking, homing, and cell contact are no longer expressed; LFA-1, CR3, & P150,95. Slide 57: - LAD-2 à Absence of neutrophil Sialyl Lewis X (ligand of E-selectin). -Chediak Higashi Syndrome: - AR disorder on chromosome 1q. - Abnormal lysosomal granule function (fused large granules)à complete absence of cytotoxic T cells & NK cells activity. - They don t respond to chemotaxis. - FUSED LARGE CELLS/GRANULES present. Slide 58 : Complement Defects ( CD ): - Caused by recurrent systemic bacterial infection. - Best screen : Total hemolytic complement. - Pneumonia à common with early defects in classical & alternative pathway. - Collagen vascular disease + lupus à Early CD - Recuurent Neisseria bacteremia + meningitis à Late CD ( C 5 9 ). - C3 and C4 can be defective as well. Slide 59 : the complement & infection. - Classical Autoimmunity (occasional infections). C1 - Alternative pyogenic/ pulmonary infections. C3b - Early components collagen vascular disease + lupus. - Late components recurrent Neisserial infections ( C5,6,7,8,9 ). - C3 Is the KEY player involved in the complement activation. ((So sorry for any mistakes as this is my first sheet, and a very big thank you for Bailasan HimmoJ<3, Best wishes dear colleaguesj God bless you all brothers & sisters.)) Noor Alm. " Don t ever frustrated from how mush study you have. Just be very grateful About how much science u collect, from this looooong year. look directly forward and Just fight for your dream ". ( Ayham Deghaim ) Done by : Ayham deghaim Noor Alm