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56 Cards in this Set
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Q: What are the different types of immunodeficiencies.
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-as one might expect form the different types of lymphocytes and numerous other mediators involved in the immune response, there are many hereditary Immunodeficiencies. There are immunodeficiencies of T cells, of B cells and of both T and B cells. In addition, there are deficiencies limited to only subsets of T or B cells and other, puzzling immunodeficiencies with bizarre patterns of expression.
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Q: What are the in vitro tests used to monitor T and B cells?
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-In vitro tests are used to monitor T and B cells. Lectins are proteins that bind to carbohydrates. The selectins of the endothelium (thatbind granulocytes) are lectins. Plant seeds also have lectins. A lectin from jack bens, phytohemagglutinin (PHA) selectively stimulates T cells to divide, while being without effect on B cells (or other cells). Another plant lectin, concanavalin A (ConA), also stimulates T cells to divide and is without effect on B cells. Another plant lectin, pokeweed mitogen, stimulates both Band T cells to divide and induces Ig production from the B cells. Epstein Barr Virus (EestBV) infects only B cells, transforms or immortalizes the B cells, and causes them to divide in an uncontrolled fashion.
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Q: What are the in vivo tests used to monitor T functions?
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-In vivo tests are also used to monitor T cell functions. Dinitrochlorobenzene (DNCB) is a hapten that chemically reacts to create an immunogens in the skin, by coupling to MHC II molecules to make the MHC IIs appear like "not-self' and thereby elicit DTH. For the DNCB test, one must allow time for "clonal expansion" of CD4+ immunogen-specific cells before one can challenge with antigen to test, after about 2 weeks is reasonable. Upos positive challenge, a DNCB response will resemble a positive TB skin test.
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Q: In what aspects are primary immunodeficiences presented?
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-Each primary immunodeficiency disease is presented in four aspects: its manifestations, treatment, genetics and our understanding of its causes.
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Q: Describe B cell immunodeficiencies.
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-These diseases produce deficiencies of serum immunoglobulins. Clinically, these diseases are associated with pyogenic tctions because opsonic and complement-fixing anti-bacterial antibodies are lacking.
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Q: Describe Bruton’s X-linked Agammaglobinemia.
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-is a hereditary B cell. Immunodeficiency that occurs in one case per 10^5 people. The patients have a gross deficiency of B cells.
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Q: How does Bruton’s agammaglobulinemia manifest?
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-The patients appear normal for the first 5-6 months of life until the passively acquired, maternal IgG has dropped to such low concentrations that the remaining IgG no longer affords protection. At this time, the infants present with recurring pyogenic infections of considerable severity. Bruton's patients will have infections of the middle ear, lungs, skin, and meninges (membranous covering of the brain and spinal cord)
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Q: What are the levels of the different Igs in patients with Bruton’s agammaglobulinemia?
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-Most of the Bruton's Agammaglobulinemia patients lack IgM, A, D or E in serum and have only 10% of normal serum IgG levels. A Bruton's patient will have a normal thymus, mature T cells, and normal T cell function.
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Q: Describe the treatment for Bruton’s.
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-The TREATMENT for Bruton's is the passive administration of gamma globulin either i.m. or i. v. at approx.l00 mg/kg per month. Treatment is successful. Affected individuals have an excellent prognosis. The treatment is an example of passive transfer of immunity. (Passive immunity is used to prevent disease after infection, e.g., anti-hepatitis virus A gamma globulin for prophylactic treatment).
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Q: Describe the genetics concerning Bruton’s.
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-Bruton’s disease is a rare, X-chromosome linked, recessive trait. it is associated with mutation of the gene btk, that encodes Bruton's tyrosine kinase, on the. X chromosome into a gene encoding a defective kinase.
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Q: Describe the defect involved in Bruton’s.
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-The Bruton's defect seems to be from pre-B to B maturation. The normal (wild type) “btk” kinase gets phosphorylated itself within seconds of cross linking surface Ig by antigen on normal B cells. The substrate that this kinase phosphorylated is STAT5A, a transcription factor of B cells. It is not known why the patients can make some IgG.
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Q: What are some conclusions that apply to normal individuals concerning Bruton’s?
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-Antibody is important in control of common pyogenic bacteria and parasites. In early neonatal life a child is truly protected by passively acquired, maternal IgG. As this IgG drops, normal, children start acquiring common ear, nose and throat infections and making their own immune responses. Note: Passively acquired antibodies clear antigens so rapidly that the antigens may not become immunogens. It is sometimes best to delay prophylactic immunizations until children are at least 6 months old. It does not directly harm a child to be vaccinated too early, but early vaccination may not result in immunization.
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Q: Describe common, variable, unclassifiable agammaglobulinemia (CVID).
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-results in low total immunoglobulins, occurs in patients of either sex, and often does not appear until the patients are 15-35 years old. It is the most common form of immunodeficiency in its clinical presentation and varies in phenotypes. Some patients have low IgG and IgA levels with hyper IgM, some have low IgG and IgM, and others have both IgG and IgM with variable antibody deficiency.
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Q: How does CVID manifest?
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-The manifestations are similar to Bruton's agammaglobulinemia but can appear at any age. The patients present with severe pyogenic infections. Surface Ig-positive B cells appear normal.
-Patients have recurrent pneumonia leading to chronic progressive bronchiectasis (dilation) as the most common presenting pattern. Also, the patients usually have symptoms of sprue (gluten enteropathy) which presents as diarrhea after eating wheat products |
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Q: What are the treatment optioins for CVID?
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-TREATMENT is similar to that for Bruton's agammaglobulinemia.
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Q: Describe the genetics concerning CVID.
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-There is a clear-cut genetic transmission for only one form of CVID. X-linked hyper IgM syndrome is associated with a mutation in the CD40 Ligand of T cells (which is signal 2 to B cells to respond to antigen and needed to trigger the isotype switch in B cells). There can be autosomal dominant and recessive forms of X-linked hyper IgM.
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Q: Describe the defect that applies to CVID.
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-The defect is different from Bruton's agammaglobulinemia. It is fair to state that the clinical manifestations arise from several different acquired or developmentally regulated disorders that can lead to the same syndrome.
-Lesions can be either: lack of T help, no B maturational division, or B cells failing to become plasma cells. |
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Q: What are some conclusions that apply to normal individuals concerning CVID?
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-similar to those for Bruton's--opsonic and complement-fixing immunoglobulins enable granulocytes to take care of common bacterial and yeast.
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Q: Describe selective IgA Deficiency.
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-This defect is the most common immunodeficiency, estimated to affect 1/600 to 1/800 people in the population.
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Q: How does IgA deficiency manifest?
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-Serum IgA is often barely present, less than 50 microg/ml in comparison to normal concentrations of ~3 mg IgA/mL. Only IgA is deficient in these people. The deficiency is in both secretory and serum IgA. B cells with membrane IgA are found, but not plasma cells secreting IgA. Individuals may be symptom-free or may be prone to allergies and sino-pulmonary infections.
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Q: Describe the treatment for IgA deficiency.
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-These patients should not be give passive immunoglobulins because they may see injected IgA as foreign and have life-threatening reactions. The patients are best left untreated for the disease and clinically managed with antibiotics to reduce and contain infections. The IgM found in secretions also protects the patients against many pathogens.
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Q: Describe the genetics concerning IgA deficiency.
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-Inheritance patterns vary and have not been clearly mapped.
-We do not understand the basis for this defect. Interleukin 5 promotes the switch to IgA, though. |
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Q: What are some conclusions that can be applied to normal individuals concerning IgA deficiency?
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-It would appear that in some of these patients, immunogens that are not trapped by secretory IgA may get through the mucosal membranes to immunize people for IgE responses. Another possibility is that without IgA antibodies higher concentrations of antigens get through the mucous membranes to react more vigorously with pre-existing IgE.
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Q: Describe DiGeorge Syndrome.
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-Thymic and Parathyroid Aplasia. is a lack of development of the thymus, almost always accompanied by a lack of the parathyroid. The congenital defect usually occurs as a result of a chromosomal deletion at chromosome 22q11. When the deletion is the cause, the defect can be hereditary. Similar problems can arise from developmental defects caused by fetal alcohol syndrome.
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Q: How does DiGeorge syndrome manifest?
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-The infants born with this syndrome are immediately recognizable as having severe problems. The complete syndrome includes abnormal facial features, hypoparathyroidisn congenital heart defects and T cell immunodeficiency. Their tetany is due to low serum calcium, a result of lack of parathyroid hormone, resulting from lack of parathyroid tissue.
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Q: What do the lab results of the thymus in DiGeorge patients show?
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-These patients also lack the "thymic" shadow on X-rays. Upon autopsy, the thymuses of these patients may be vestigial, mislocated, or totally absent, Laboratory finding confirm the malfunction of the thymic "environment" The peripheral blood lymphocyte counts will be low. DiGeorge patients have circulating Ig's, that may be produced by stimulation by T cell independent antigens produced by gut bacteria.
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Q: What are the different type of T cell independent antigens?
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-T cell independent "antigens" type 1 include bacterial endotoxins and lipopolysaccharides (LPS) that bypass normal Ig-receptor-mediated recognition of antigens and cause direct intracellular signaling of B cells. These B cells are Polyclonally activated and secrete nonspecific IgM. Type 2 T cell independent antigens include large repeating units of carbohydrates that are poorly immunogenic, such as the polymeric sugars of bacteria and yeast. Some T cell help (though less) is needed for these antigens. Usually only IgM specific responses are made to type 2 T cell independent antigens.
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Q: Is there any amounts of normal thymic tissue in DiGeorge patients?
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-In DiGeorge syndrome, there may also be variable amounts of normal thymic tissue, providing some T cells. The defect is in the development of the thymic epithelium, not in the entire thymus.
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Q: Do DiGeorge patients have problems with opportunistic infections?
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-The patients have major problems with opportunistic infections: a triad of clinical symptoms which include (1) oral and pharyngeal "thrush" of white colonies of Candida albicans (yeast) on the tongue, persistent vaginal candidiasis & also candidal skin infections
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Q: What is the treatment for DiGeorge syndrome?
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-Transplantation of a fetal thymus will restore immune function, provided that the transplanted thymus has not already been populated with pre-T cells. If the transplanted thymus is taken before ~14 weeks of fetal age, it will contain, no maturing T cells. Before about 14 weeks of fetal age, a thymus will lack pre-T cells. After about 14 weeks of fetal age, a transplanted thymus will already be populated with pre- T stem cells and have maturing T cells. The donor T cells leaving the thymic graft then react against and kill the cells of the DiGeorge child, causing graft vs. host (GVH) disease. GVH is characterized by "wasting" and leads to death. The T cells from the graft become T helper and T killer cells that recognize the host and kill host tissue. GVH will happen only if the donor is imrnunoincompetent.
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Q: What happens if the graft is taken from a fetus less than 14 weeks old?
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-If one takes the thymic graft from a fetus less than 14 weeks old, one is less likely to get GVH. However, even though the thymic graft may succeed, the cardiac and parathyroid problems of the DiGeorge syndrome are still with the patient.
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Q: Describe the genetics concerned with DiGeorge syndrome.
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-Usually, autosomal dominant. Monosomy at chromosome 22q11 will produce the syndrome. Similar clinical features can be caused by nonhereditary developmental defects, which may account for perhaps 10-15% of the cases.
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Q: Describe the defects concerned with DiGeorge syndrome.
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-Both the thymus and the parathyroid differentiate from the third and fourth pharyngeal pouches during embryonic development. A common insult results in defects of both organs and of cardiac blood vessels
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Q: What are some conclusions concerning normal individuals with DiGeorge syndrome?
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-DiGeorge immunodeficiency informs us of the difference between T and B cell roles in humans. The extreme importance of T cell killing to control viral infections is underscored by the fact that infections with common viruses usually kill these children. Also noteworthy is the presentation with recurring severe yeast infections. The role of T cells in controlling these infections is not understood.
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Q: What does the fact that we can treat DiGeorge syndrome with thymic grafts mean?
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-DiGeorge syndrome gives us information about the human thymic environment and the sources of cells in a normal thymus. The ability to treat the immunodeficiency component of the disease with thymic grafts indicates that there is no defect in the stem cells for thymocytes, only a defect in the thymic environment. The nature of the defect underscores the idea that endodermal and ectodermal tissues contribute to the thymic environment. In addition, a successful (at least immunologically) thymic graft indicates that the thymus does regulate recognition of self and tolerance of self in people as well as in mice. The transplanted graft provides the environment where "education" of self-nonself takes place. The grafted thymus tells the child's body that both the thymus and the child's cells are "self.” At the time of transplantation, thymic grafts older than 14 weeks (that give GVH) already contain matured T cells that can recognize the DiGeorge child's antigens as foreign.
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Q: Describe severe combined (T and B cell) immunodeficiencies (SCID).
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-are a group of rare hereditary immunodeficiencies. The patients lack both T and B cell functions. The genetics can be X-linked or autosomal recessive. The patients have severe lymphopenia and will die of viral infections unless they are the recipients of a successful transplant of bone marrow to provide normal lymphoid stem cells
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Q: How does SCID manifest?
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-These children appear- normal at birth. However, newborn SCID patients often have a skin rash symptomatic of graft vs. host disease due to maternal T cells as a "graft" trying to kill the baby. These children are protected by maternal IgG for humoral passive immunity but are extremely vulnerable to viral infections. The children have extreme lymphopenia.
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Q: What is the triad of immunological symptoms of SCID patients?
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-SCID patients have the same triad ofimmunological symptoms as the children with DiGeorge syndrome: 1) Oral thrush (and other monsiliasis, but not systemic candidiasis), 2) interstitial pneumonia usually due to Pneumocystis carina and 3) intractable diarrhea. SCID patients also are overwhelmingly susceptible to viral infections. Often herpes or cytomegalovirus (CMV) infections are fatal. Smallpox vaccinations have killed these patients.
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Q: What is the treatment for SCID?
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-Patients can be treated by grafts of bone marrow or fetal liver. The marrow transplant works best if mature T cells are removed from the bone marrow before grafting, otherwise one would get graft vs. host disease.
-Many of these bone marrow transplants are truly successful. Over 100 bone marrow transplants to treat SCID have been done at centers such as the National Institutes of Health. |
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Q: Describe the genetics concering SCID.
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-SCID occurs in X-linked and autosomal recessive forms. X-linked SCID is associated with defects in the common gamma chain of interleukin receptors, called IL-2R-gammae, a third chain of the IL-2 receptor which is involved in signal I transduction. This gamma chain is common to six different receptors that bind IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. There are some B cells in this type of SCID, but they are unable to respond without T cells. The autosomal recessive form of SCID is the so-called Swiss-type lymphopenic agammaglobulinemia. Defects in the genes RAG-1 and RAG-2, recombinase genes that encode proteins involved in V(-D)-J gene rearrangements, when inherited as autosomal recessives, can also produce SCID, Mutations in the encoding adenosine deaminase also will produce autosomal recessive SCID
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Q: What enzymes are involved in SCID?
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-Some forms of SCID are associated with hereditary deficiency of the enzyme adenosine deaminase (ADA). Lymphocytes do not divide upon challenge with, antigens--yet all other cells of the body appear to clivi adequately. It's still a mystery why ADA deficiency should affect only lymphocytes! (The genetics are autosomal recessive.) The patients have few T or B cells.
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Q: Describe the defects concerning SCID.
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-When X-linkd SCID is associated with loss of the common gamma chain that is a third chain of the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 receptors, signal transduction does not occur when the interleukins bind the receptors. IL- 7 is needed for thymic cell proliferation. Both Band T cells without the gamma receptor chain are unable to respond to the growth factors IL-2 and IL-4. The patients have few T cells or B cells. (The implication is clear that without IL signals, T cells do not persist and B cells do not function.)
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Q: What are some conclusions that apply to normal individuals concerning SCID?
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-The ability to transplant bone marrow stem cells or fetal liver blood stem cells indicates that, the stem cells are pluripotent. The success of the graft indicates that it is the thymic environment that eliminates T cells that recognize self. Thus pre- T stem cells from the donor can be conditioned in the host's thymus (with the host's MHCs) to accept two sets of MHC molecules as "self” - one set belonging to the host thymic cells and the other set displayed by the T cells themselves.
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Q: Describe ataxia-telangiectasia.
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-is a highly heterogenous autosomal recessive disease.
-It is characterized by a triad of symptoms: neurological ataxia, looped small blood vessels (seen in whites of eyes), and limited immune defects manifest in recurrent sinopulmonarfections. The patients have low serum Ig levels, particularly IgA which may be low or absent in 80% of the patients. |
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Q: What is the treatment for ataxia-telangiectasia?
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-None. Only management of infections.
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Q: What are the genetics assoacited with ataxia-telangiectasia?
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-Autosomal recessive in the ATM gene, which encodes a nuclear protein that may be involved in DNA repair.
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Q: Describe the defects associated with ataxias-telangiectasia.
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-The patients have numerous other clinical problems. Ataxia telangiectasia patients also have defects in DNA repair from ionizing radiation and are prone to skin cancers and, lymphoid tumors.
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Q: Describe Wiskcott-Aldrich Syndrome.
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-characterized by a triad of symptoms, thrombocytopenia, eczema, and recurrent infections. The patients have low IgM. Wiskott-Aldrich symptom is characterized by bleeding and multiple serious infections. The platelets (thrombocytes) are abnormally small.
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Q: How is Wiskott-Aldrich syndrome treated?
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-Antibiotics. Bone marrow transplantation is curative.
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Q: What are the genetics concerned with Wiskott-Aldrich syndrome?
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-X-linked recessive disorder with a mutation in the WASP gene that encodes the Wiskott-Aldrich syndrome protein that is involved in signal transduction.
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Q: What are the defects associated with Wiskott-Aldrich syndrome?
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-The patients have reduced glycophorin (CD43), an adhesion molecule found on both platelets and T cells. CD43 binds to ICAM-1, to enhance cellular signaling.
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Q: Describe chronic granulamtous disease (GCD).
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-Chronic Granulomatous Disease (CGD) causes defects in the oxidative burst and is either autosomal or X-linked. The patients present with pristent infections with pyogenic bacteria such as Staph. aureus, Serratia marcescens, and some coliforms (bacteria of the colon). The patients also have granulomatous lesions and abscesses in deep tissues. The diagnostic test for CGD is for failure of the NADPH oxidase to reduce the dye nitroblue tetrazolium (NBT). The oxidized dye is yellow and soluble. Neutrophils capable of transferring electrons to oxygen mediate the transfer electrons to NBT, which when reduced forms insoluble blue crystals offormazan.
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Q: What are the genetics assoacited with CGD?
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-GENETIC analyses of the familial inheritance and of the biochemical lesions of the granulocytes indicate that several different enzymes and other proteins are needed to keep the oxidative burst or respiratory pathway of granulocytes functional. For instance, failure of the NADPH oxidase, defects in the two protein chains of the cytochrome b558 which is part of the enzyme complex that mediates the respiratory burst (see the granulocyte handout), failure of the hexose monophosphate shunt to regenerate NADPH, and failure of the glutathione reductase path to support the hexose monophosphate shunt will all result in defective oxidative function.
-The problems of these patients suggest that the suboplal killing of bacteria and yeast is insufficient to control common potential pathogens. |
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Q: Describe hereditary myeloperoxidase deficiencies.
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-Hereditary Myeloperoxidase Deficiencies are quite common and usually asymptomatic. The deficiencies are detected by automated lab tests using the enzyme myeloperoxidase as a marker to help count granulocytes.
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Q: Describe Chediak-Higashi syndrome.
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-Chediak-Higashi Syndrome is characterized by abnormally large granules in many cells, including polymorphonuclear cells, hair (to result in partial albinism), etc. Chediak-Higashi granulocytes have a normal respiratory burst but low potential for intracellular killing. The neutrophil granules fail to fuse and form lymphocyts and low cytotoxic T killer cell activities but a normal respiratory burst. The killing times for bacteria are unusually slow. Patients have low resistance to bacterial infections and often die as children. Inheritance is autosomal recessive and caused by defects in the gene LYST that affects lysosomal and other granule fusion. The Chediak Higashi patients suggest that the nonoxidative lysosomal (primaary granule) system is critical for bacterial killing.
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Q: Give a perspective on acquired immunodeficiencies.
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-You are unlikely to see hereditary deficiencies in practice, except perhaps IgA deficiency.
-Surgical removal of the thymus in cardiac surgery is ill-advised, particularly in infants, and has been discontinued. -The most common immunodeficiency in the world is due to starvation in children. The immune system proliferates on demand. Cell growth requires protein. Impaired immunity as well as unsanitary conditions contributes to the diseases associated with poverty. -Neutropenia is an immunodeficiency that can be caused by anti-mitotic chemotherapy. |
