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Topic 21 - Inherited Immunodeficiency & Testing for Immunodeficiency
Terms in this set (11)
Define the acronym SCID. List the currently known mutations that can lead to SCID, and the consequences of SCID in regards to infectious disease susceptibility (i.e. is SCID associated with bacterial infections, fungal infections, viral infections, or all of the above?)
SCID=Severe Combined Immune Deficiency and it is an absence of both T and B lymphocyte function. General susceptibility to all infectious agents, including fungal infections, systemic viral infections, recurrent bacterial infections, and normal flora.
Describe the basis of DiGeorge Syndrome and the immune cell population that is defective as a result. Explain why DiGeorge Syndrome can have variable levels of severity associated with it.
DiGeorge Syndrome causes variable decreases of T cells due to thymic aplasia (thymus doesn't form properly during neonatal development) resulting from a loss of a small portion of chromosome 22. Lack of T cell development in the thymus means CD4+ and CD8+ T cells are both missing to varying degrees. Variability in severity depends on how badly malformed the thymus is
Identify what two primary immune deficiencies lead to selective susceptibility to viral infections, and for each, whether the patient is susceptible to all virus infections or just certain types of viruses.
1. Bare Lymphocyte Syndrome - Loss of MHC-1 Susceptible to all viral infections
2.NK Cell Absence- leads to increased susceptibility to Herpes (viral)
Explain why Type II Bare Lymphocyte Syndrome causes infectious disease susceptibility similar to SCID.
Loss in transcription regulators of MHC 2 leads to an absence of CD4+ T cells due to lack of positive selection in the thymus. Resembles SCID b.c of lack of CD4+ T cell help
Compare and contrast X-linked agammaglobulinemia and X-linked Hyper-IgM syndrome, specifically listing whether B cells are present in circulation, and whether IgG, IgA, and IgM are absent or produced at reduced, normal or excessive levels, and the type of infection susceptibility associated with the diseases.
All cause susceptibility to pyogenic extracellular bacteria
x-linked agamma... is absence of B lymphocytes due to Btk deficiency (Pre-B cells die in BM). No IgM
x-linked hyper-IgM-due to lack of isotype switching because of of CD40L or CD40 deficiency, so basically can only make IgM.
lack all isotypes
Identify why complement deficiencies are associated with increased susceptibility to extracellular pyogenic bacterial infections (be sure to define pyogenic).
Pyogenic- pus production.
Since complement works with Ab, many complement deficiencies resemble Ab deficiency in their infection susceptibility. Deficiency of C3, Factor D, or Factor I increase susceptibility to extracellular encapsulated bacteria due to decreased opsinization. Deficiency of C5,6,7,8, or 9 leads to increased susceptibility to Neisseria infections; MAC complex proteins deficiencies prevent lysis
Identify whether deficiencies of early components of the classical complement pathway, the alternative complement pathway, or the lectin complement pathway can cause a risk for systemic lupus autoimmunity, and why this risk develops.
Complement deficiency prevents immune complex clearance. A deficiency of C1, C2, or C4 leads to immune complex disease. Anything in the early classical pathway that causes a lack of complement activation/coating of immune complexes leads to a build up of complement in fluids, which causes precipitation in the fluids, and leads to lupis and other immune diseases.
For the primary phagocyte deficiencies (CGD, Chediak-Higashi syndrome, G6PD or Myeloperoxidase deficiency, and LAD), identify the type of infectious disease susceptibility seen in patients, and whether the infections respond to antibiotic treatment or not, and why some do not respond to antibiotics.
Chronic granulomatous disease patients lack NADPH oxidase and can't activate granule proteases; granulomas common and cause pathology b/c phagocytes can't digest the pathogens. Respond well to antibiotics.
Chediak-Higashi syndrome patients can't fuse endosomes and lysosomes. Respond well to antibiotics.
G6PD or Myeloperoxidase deficiency leads to defective respiratory burst and impaired killing of phagocytosed bacteria and fungi. Respond well to antibiotics.
Leukocyte adhesion deficiency (LAD)-loss of CD18 component of CR3, CR4, LFA-1 leads to defective neutrophil and macrophage migration into inflamed tissues and the inability to phagocytize pathogens opsonized with iC3b. Respond poorly to antibiotics b/c migration of neutrophils and macrophages to inflamed tissues doesn't occur, the activation of innate responses doesn't occur, there is little to no tissue inflammation, so the antibiotics don't get carried to the site of infection.
Identify the infectious disease susceptibility that results from defects in the IL-12 or IFN-g receptors, and the immunological basis for this susceptibility.
Defects in IFN-gamma and IL-12 receptors lead to combined defects in innate and adaptive immune functions. NK cell cooperation with macrophages is blunted b/c IL-12 produced by macrophages can't activate NK cells to produce IFN-gamma, or IFN-gamma that is induced can't feed back to activate macrophage production of inflammatory cytokines. In other words, there is a positive feedback loop with NK and macrophages working together to cause inflammation for Th1 development responses that gets stopped. IL-12 is necessary for Th1 development and augments Tc production of IFN-gamma. While humans aren't normally susceptible, these defects lead to TB from M.avium and active infection with M. bovis vaccine
List 2 routine laboratory tests that can be performed using patient blood samples (serum or cells) which are useful in evaluating possible primary immune defects in humoral immunity.
CBC w/ complete WBC differential
Humoral immunity defect screen-B cell (CD19/20) counts by flow-cytometery (dual stained for IgA, D, G, M). IgG, M, A total Ab quantification. Serum protein electrophoresis to look for decrease or absence of gamma globulins.
Describe the steps of a Complement Activation Enzyme Immunoassay (specifically identifying what is coated onto the assay EIA plastic plate wells, the patient sample used, the detection reagent used, and how results are reported) and what pathway of complement is being assayed.
CAE immunoassay is EIA that detects C9 bound to IgM-coated microtiter wells. CH50 liposomal lysis assay replaces traditional hemolytic titration assay and measures the classical complement pathway ability to lyse Ab-sensitized membranes.
IgM causes activation of C1q binding, classical pathway activation all the way through MAC, detects C9 on the plate. Determines amount of compliment proteins available in circulation. CH50-complement hemolytic titration for 50% lysis. Coat sheep RBC with IgG and looked at ability for classical complement ability to lyse RBC's. sheep have short shelf life so use liposomes instead. Looking for decrease in activity in people suspect of defect.
THIS SET IS OFTEN IN FOLDERS WITH...
Topic 19 - Mucosal Immunity
Topic 20 - Non-classical Lymphocyte Subpopulations
Topic 22 - HIV/AIDS - Virus and Disease Mechanisms
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