Immunodeficiency PDF

Immunodeficiency: failure to protect the host from disease-causing agents or malignant cells. Autoimmunity: loss of self-tolerance resulting in the attack of host cells and tissues. iiiiii Immunodeficiency & Autoimmunity sEnnsae tiii.io Immunodeficiency: o Primary: Defect present at birth (genetic...

Immunodeficiency: failure to protect the host from disease-causing agents or malignant cells. Autoimmunity: loss of self-tolerance resulting in the attack of host cells and tissues. iiiiii Immunodeficiency & Autoimmunity sEnnsae tiii.io Immunodeficiency: o Primary: Defect present at birth (genetic or developmental defects such as in the process of hematopoiesis due to stem-cell defect). Missing enzyme/cell, or non-functioning component. Accounts for 10% of cases. Manifest early in life. giiIaerinn www o Secondary/acquired: Defect due to exposure to various agents (e.g. HIV infection, immunosuppressant agents). Malnutrition. Lymphoid malignancy. Accounts for 90% of cases. Manifest at any age. ice go.ae i.ae Lymphoid immunodeficiencies: B-cell immunodeficiency disorders Examples of lymphoid immunodeficiencies (affective the adaptive immunity): Severe combined immunodeficiency (SCID) man Complete absence of mature recirculating B-cells. Selective absence of specific Ig class. Increased susceptibility to extracellular bacterial infections (encapsulated bacteria; staphylococci, streptococci, and pneumococci). Display normal immunity to viral and fungal infections. Genetic defects in the development of lymphoid cells (T-cells or both T/B-cells). T-cell immunodeficiency disorders Characterized by impaired thymus development and very low circulating lymphocytes (normal circulating RBC number). More serious forms, and often result in early death. o Defect in purine nucleotide phosphorylase (PNP) enzyme (similar mechanism to the ADA defect). e.am Affect BOTH cellular and humoral immunity. t.napercaaun Consequences are severe. Reduce delayed-type hypersensitivity reactions and cell-mediated cytotoxicity. Increased susceptibility to viral, protozoan, and fungal infections (Candida albicans, Pneumocytis carinii, Mycobacteria, cytomegalovirus). Combined T- and B-cell immunodeficiency disorders o Defect in the adenosine deaminase (ADA) enzyme (ADA catalyze the conversion of adenosine to inosine, defect results in adenosine accumulation which interfere with purine metabolism and BNA synthesis affecting the rapidly dividing T- and B-cells). o a new guanidine Usually fatal, result in severe recurrent infections (fungi, viruses). SCID infants usually suffer from chronic diarrhea, sore throat, pneumonia, and skin/mouth lesions. 0 Even live attenuated vaccines can cause infections. nobit.ca a Bubble kids d Wiskott-Aldrich syndrome (WAS) eititfemaesIniii www.ea.EE Caused by mutation in the gene encoding Wiskott-Aldrich syndrome protein (WASP) located at xp11.23. X-linked disorder. WASP in involved in cell migration and signal transduction. Severity increase with age and result in fatal infection (bacteria) or malignancy. anaemia Manifested by defective response to bacterial polysaccharides leading to bacterial infections, thrombocytopenia, bloody diarrhea, and eczema. low IgM levels. Normal IgG levels. Increased IgA and IgE levels. Initially T- and B-cells present at normal numbers but decrease with age. was X-linked inheritance Carried mother Affected father if i P moral X-linked agammaglobulinemia or Bruton`s hypoglobulinemia Disease don’t appear until 6 months of age. of Defect in B-cell signal transduction due to defect in a transduction molecule called Bruton`s tyrosine kinase (Btk). No peripheral mature B-cells (only secrete Ig with H-chains, while L-chains remain in the germ-line configuration. Extremely low IgG levels and absence of other Igs. Recurrent bacterial infections, normal response to viruses. Ein na 9Legion Antigen encounter 9995 Mature B-cell Plasma cell Without functional Btk: B-cells struggle to receive important signals. They can’t activate their full powers to fight infections. Because of the Btk defect, B-cells don’t grow up properly. They remain immature and can’t become strong fighters. Can still fight viruses pretty well! But when it comes to bacteria, they struggle. So, kids with X-linked agammaglobulinemia might get sick more often from bacterial infections. I S b lymphoid X-linked hyper-IgM syndrome mnemin.uaanonmapc Most common type of specific Ig deficiencies. fat at Igf gi itncnonn gag g Class switch and formation of memory B-cells require contact with Th cell through CD40-CD40L interaction. Elevated IgM levels (normal B-cells expressing membrane bound IgM/d). if IgA deficiency Due to defect in the gene encoding the CD40 ligand and fail to express it on the membrane of Th cells. B-cell response to T-cell-independent antigens is unaffected. h ai Deficiency in IgG, IgA, and IgE levels (lack B-cells expressing membrane bound IgG/A/E). that diamer I t.iiiiiiiiii.it Asymptomatic in most (85-90%) affected individuals. Symptomatic in minority (recurrent respiratory or genitourinary infections, intestinal malabsorption, and increased risk of allergic/autoimmune diseases). Failure of germinal center formation. Recurrent infections (specially respiratory). c c coao centnot activated B Beens that areindependentonin except lymphoid i DiGeorge syndrome Examples of myeloid immunodeficiencies (affecting the innate immunity): Due to deletion in the embryo of a region on chromosome 22 causing complete absence of the thymus along with characteristic facial abnormalities, hypoparathyroidism, and congenital heart disease. Neutropenia or agranulocytosis iiiiii Significant decrease in T-cell number and absence of T-cell response. Normal B-cell number but do not produce antibodies in response to antigens. anana.ami.a n.ann Congenital defects: due to genetic defects affecting the myeloid progenitor stem cell leading to reduced production of neutrophil during hematopoiesis (reduced G-CSF synthesis). Acquired: radiation, chemotherapeutic drugs, in association with other disease conditions (SLE, Sjogren`s syndrome). Transient neutropenia may develop after viral/bacterial infections but return to normal levels when the infection is cleared. ff Lead to frequent bacterial infections, oral ulcers with thick pus of bacteria or fungi (often Candida species), chills, and fever. ieiI ses.naron orpneensideettea pregnancy during is iiiiiiiiiiii y Chronic granulomatous disease (CGD) Genetic disease with two forms; X-linked (70%), and autosomal recessive (30%) leading to defect in cytochrome or proteins (phagocyte oxidase; phox) that stabilize the cytochrome. on Lead to defect in the oxidative pathway and reduced generation of ROS during phagocytosis. Increased susceptibility to bacterial and fungal infections, gingivitis, swollen lymph nodes, non-malignant granulomas, osteomyelitis, and pneumonia. ii propnox femalesmales a innonoxidativearmorneutrophils Chediak-Higashi syndrome problem Leukocyte adhesion deficiency (LAD) Autosomal recessive disease causing mutation in a LYST protein involved in regulating the intracellular trafficking in endosomes and pigmentation. Type I: www.msn.com Recurrent bacterial infections, partial oculo-cutaneous albinism (lack of skin and eye pigment), and Of neuropathy. The integrins: LFA-1 (CD11a), Mac-1 (CD11b), and gp150/95 (CD11c) have a common beta-2 integrin chain (CD18). Mutation in CD18 Type II: Absence of neutrophil sialyl-LewisX, a ligand of P- and E-selectin on vascular endothelium. Type III: Mutations in the FERMT3 gene leading to an activation defect of all beta-integrins. Lead to impaired leukocyte rolling (Type II), adhesion to vascular endothelium (Types II/III), and subsequent recruitment to the site of inflammation/infection. Increased bacterial and fungal infections, many of patients die within few years. Autoimmune disorders Organ-specific, or systemic. B-cell mediated: autoimmune hemolytic anemia and Hashimoto`s thyroiditis. T-cell-mediated: DM, RA, and MS. Hashimoto`s thyroiditis Most frequently seen in middle-aged women. Generation of auto-antibodies and sensitized Th1 cells specific for thyroid antigens (thyroglobulin and thyroid peroxidase). DTH characterized by intense infiltration of lymphocytes, macrophages and plasma cells attacking the thyroid gland. Goiter, hypothyroidism, weight gain, and muscle weakness. Autoimmune anemia Pernicious anemia: caused by autoantibodies formation targeting the intrinsic factor. Autoimmune hemolytic anemia: caused by autoantibodies formation targeting RBC antigens (e.g. Rh) leading to complement-mediated lysis or antibody-mediated opsonization and phagocytosis of RBCs. Normal Hashimoto`s Insulin-dependent DM CTLs infiltration to islets of Langerhans, macrophage activation and cytokine secretion (IL-1, TNFα, IFNγ), followed by cell-mediated DTH response. Autoantibodies against the beta cells in the islets of Langerhans (insulin producing cells) leading to complement-mediated lysis or ADCC. This lead to destruction of beta cells, decreased insulin production and increased blood glucose levels. Drug-induced anemia: the drug (e.g. penicillin and methyldopa) interact with RBC making it antigenic, leading to complement mediated RBC lysis. Grave`s disease Autoantibodies that bind to the receptor of thyroid stimulating hormone (TSH) receptor and mimic its action. Goodpasture's syndrome This lead to enhanced thyroid hormone production and hyperthyroidism. Autoantibodies targeting certain basement membrane antigens (glomerular basement membrane; GMB) of the kidney glomeruli and the lung alveoli. Goiter, bulging eyes, hear intolerance, anxiety, tremors, and tachycardia. Tissue-mediated destruction through complement activation. Glomerulonephritis and pulmonary hemorrhage leading to death soon after diagnosis. Myasthenia gravis Systemic lupus erythematosus (SLE) Autoantibodies that bind to acetylcholine receptors on the motor-end plates of muscle causing blocking of the normal binding of Ach and inducing complement mediated lysis of the cells. Systemic disorder. Lead to progressive weakness (problems with movement) of the skeletal muscle, drooping eyelids (blurred vision), and inability to retract the corners of the mouth (problems with eating and talking) giving the appearance of snarling. so Typically appear in young women (20-40 years), female to male ration is 10:1. Autoantibodies against various tissue antigens such as DNA, histones, RBCs, platelet, leukocytes, and clotting factors leading to complement mediated lysis resulting in hemolytic anemia, thrombocytopenia, vasculitis, and glomerulonephritis. Characterized by fever, weakness, arthritis, skin rashes, pleurisy, and kidney dysfunction. Multiple sclerosis (MS) Rheumatoid arthritis (RA) Production of auto-reactive T-cells that participate in the formation of inflammatory response along the myelin sheath of the nerve fibers leading to demyelination of the nerves and neurological dysfunction. Autoantibodies (called rheumatoid factors, IgM) that are reactive with determinants in the Fc region of IgG. Symptoms may be mild like numbness in the limbs or severe like loss of vision and paralysis. These IgM autoantibodies bind with circulating IgG forming IgM-IgG complexes that deposit in the joints leading to complement activation and chronic inflammation.