Immuno Immunodeficiency (17/18)

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mse263
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246019
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Immuno Immunodeficiency (17/18)
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2013-11-09 17:51:55
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Immunology
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Exam 4
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  1. If given a skin test (to TB protein, candidiasis etc.) & 48 hours later the site is red and inflamed, what does that show about the person?
    • that they have a NORMAL cell-mediated immune response, aka that their T cells are working normally (is delayed hypersensitivity)
    • before HIV was well described, in order to test people for it a pathogenic/foreign protein (such as Tetanus, which they had been previously exposed to & immunized against) was given
    • if the person did not present w/ inflammation/redness they were diagnosed w/ HIV; their T cells (cell-mediated immunity) weren't working properly
  2. Immunodeficiency disorders
    recurrent infections due to a breakdown in innate, humoral, or cell mediated immunity
  3. B cell Immunodeficiency
    • absent or reduced follicles (germinal centers) in lymphoid organs
    • reduced serum antibody levels - can't make antibodies
    • characterized by pyogenic bacterial infections --> give rise to pus formation*
  4. T cell Immunodeficiency
    • reduced T cell zones (diffuse areas) in lymphoid organs
    • no DTH reactions to common antigens
    • defective T cell proliferation in response to a mitogen (usually a protein that triggers mitosis) when tested in vitro
  5. Patients with defects of cell-mediated immunity (CMI) are susceptible to infections by which organisms?
    • viral-associated malignancies (EBV lymphoma, herpes, pox viruses)
    • pneumocystis (pneumonia)
    • mycobacteria (TB)
    • fungal infections (candidiasis)
    • parasites (toxoplasma)
  6. primary or (congenital) immunodeficiencies
    genetic defects that manifest early in childhood but are occasionally detected later in life
  7. Innate Immunodeficiency
    • is oftentimes a defect in polymorphonuclear leukocytes (PMN)
    • without neutrophils there is NO opsonization, early phagocytosis of a foreign particle, or killing of the foreign particle by joining phagosomes with bactericidal lysosomes (contain enzymes + superoxide anions)
    • these are important in the early stages of host defense against infectious agents
    • defects in number or function of neutrophils can give rise to severe/recurrent infections
  8. What two proteins are required for opsonization by neutrophils?
    • IgG & C3b
    • a deficiency in either of these two can also result in innate immunodeficiency
  9. Neutropenia
    • inadequate neutrophils
    • can occur especially in patients receiving chemotherapy - WBC counts drop
    • agranulocytosis = an almost complete absence of polymorphonuclear leukocytes (PMNs)
  10. Which is more common, acquired or congenital neutropenias?
    acquired neutropenias as a result of chemotherapy, malignancy, or aplastic anemia occur MUCH more frequently than congenital neutropenias
  11. Chronic Granulomatous Disease (CGD)
    • an X-linked condition characterized by defective intracellular killing of bacteria and viruses seen in young boys
    • neutrophils (PMNs) can phagocytose but CAN'T kill ingested pathogens because they have no superoxide anion (there's a mutated gene encoding a subunit of cytochrome b & NADPH oxidase)
    • this results in recurrent bacterial & fungal infections
    • granulomas are diagnostic of CGD
  12. What would a biopsied lymph node of a boy with Chronic Granulomatous Disease (CGD) look like & contain?
    • the lymph node would be swollen
    • it would contain neutrophils, granulomas (macrophages), & puss
  13. Leukocyte Adhesion Deficiency
    • a disease characterized by a mutated LFA-1, an adhesion molecule found on the surface of neutrophils & CD8+ T cells
    • without working LFA-1 PMNs are unable to adhere to endothelium and migrate through to sites of infection
    • CD8+ T cells have impaired binding to their target cells
    • the condition manifests as recurrent bacterial infection & impaired wound healing
    • *umbilical cord takes LONGER to fall off
  14. Chédiak–Higashi Syndrome
    • a defect in vesicle fusion that impairs the ability of endosomes (phagosomes) to fuse with lysosomes; neutrophils are unable to kill phagocytosed pathogens
    • people with the disease get persistent & recurrent bacterial infections
    • neutrophils look like they're carrying 'rocks' - they can't move well weighed down
    • the genetic basis for Chédiak–Higashi is unknown
  15. Humoral (B cell) Immunodeficiency
    • characterized by decreased or absent antibodies
    • the abnormality may be at different stages of B lymphocyte maturation, in the responses of mature B cells to antigenic stimulation, or abnormal helper T cell function
    • this results in recurrent pyogenic [pus-forming] bacterial infection (eg. streptococci, staphylococci, pneumococci)
  16. X-linked (Bruton) Agammablobulinemia
    • an X-linked disease a disease characterized by a mutated Btk, a protein tyrosine kinase that functions in the intracellular signaling pathway from the B cell receptor directing growth & differentiation of pre-B cells
    • this results in by antibody deficiency
  17. What is found in a person who has X-linked (Bruton's) Agammablobulinemia?
    • no B cells or plasma cells in blood
    • no germinal centers in the lymph nodes
    • small lymph nodes --> NO tonsils visible
    • a decrease in ALL immunoglobulin isotypes
    • *a normal number of pre-B cells in the bone marrow (in the pre-B cells of these patients, VDJ rearrangements and heavy chain (IgM & D) production are normal, but subsequent light chain gene rearrangements do NOT occur)
  18. Why are newborn infants with X-linked (Bruton) Agammablobulinemia usually normal?
    because protection is initially conferred by maternal antibody
  19. How are patients with X-linked (Bruton's) Agammablobulinemia treated?
    • treatment is with intravenous immunoglobulin (IVIG) every ~3 weeks - contains antibodies to diseases the average population sees
    • also given good access to a doctor & antibiotics that should be administered quickly
  20. IgA Deficiency
    • a more common disorder (1 in 700 individuals)
    • many patients have no symptoms
    • others [especially with IgG2 or IgG4 deficiency] have severe respiratory & gastrointestinal infections
    • IgA is usually made in the lamina propria & released into secretions from mucosal surfaces; it is important for neutralization of pathogens that come from the outside world (lung/GI tract)
  21. Why isn't intravenous gammaglobulin (IVIG) not usually helpful for people with IgA Deficiency?
    • patients with IgA deficiency may produce anti-IgA antibodies if given IgA in the form of a blood transfusion
    • anti-IgA antibodies are often of the IgE type, so that a patient with IgA deficiency given a blood transfusion for at least the second time could develop a serious anaphylactic reaction
  22. What is the most common immune deficiency disorder?
    IgA Deficiency
  23. What interaction between B & T cells is crucial for immunoglobulin isotype switching?
    • CD40L on a CD4+ T cell binding to CD40 on the B cell
    • cannot have Class Switch Recombination (CSR) without this interaction when dealing with a T cell dependent type of antigen
  24. T cell Dependent-Antigen B cell Activation
    • 1. BCR (B cell receptor = antibody) binds to antigen
    • 2. antibody/antigen complex is taken up by B cell 
    • 3. antigen is broken down in acid compartments to smaller peptides
    • 4. specific antigen peptides bind to MHC class II
    • 5. peptide-MHC class II complexes are trafficked to the cell surface
    • 6. here it interacts with a CD4+ T cell that has the matching TCR for the antigen peptide
    • 7. CD40L on the T cell binds to CD40 on the B cell --> B cell makes antibody & T cell is activated to proliferate cytokines
  25. Hyper IgM Syndrome
    • a mutation of the CD40 ligand gene results in a failure to switch between immunoglobulin isotypes
    • patients make only IgM and IgD; they cannot switch to IgG, IgA or IgE
    • results in recurrent infections
    • macrophage activation by T cells is also dependent on the interaction between CD40 ligand on the T cell with CD40 on the macrophage; Hyper IgM can also be characterized by defects in this interaction and therefore an IMPAIRED inflammatory response
    • patients are treated with IVIG
  26. Transient Hypogammaglobulinemia of Infancy (THI)
    • occurs when a child's humoral immunity (usually IgG) is developmentally delayed --> patients HAVE B CELLS but the delay still occurs
    • present with infections at 3-6 months of age because mom's antibody has DISAPPEARED and they haven't made enough of their own
    • (normal Ig levels are typically reached by 2-6 years of age in children with THI)
  27. Common Variable Immunodeficiency
    • a disease that usually appears in teenagers or adults and is characterized by LOW serum levels of all immunoglobulins, resulting to increased susceptibility to infections (hypogammaglobulinemia)
    • the exact defect is unknown but may be a problem with the maturation of B-cells into plasma cells
    • people are treated with IVIG & good access to antibiotics
    • *can potentially be CURED using allogeneic stem cell transplantation (ASCT)
  28. Primary Defects in T Lymphocytes
    • are manifested by increased susceptibility to infections caused by viruses, fungi, intracellular bacteria and protozoa - organisms that can survive & even replicate inside cells; T cell immunity is therefore crucial for their control
    • since some B cell function is T cell dependent defective T cell immunity can also result in deficient ANTIBODY production
    • combined B & T cell deficiency can present as forms of severe combined immunodeficiency (SCID)
  29. Besides susceptibility to infections caused by viruses, fungi, intracellular bacteria and protozoa, what features can be used to diagnose T cell immunodeficiencies?
    • 1.a reduced numbers of blood T cells
    • 2. no delayed hypersensitivity skin reactions
    • 3. reduced cytokine production (by what few T cells are present)
  30. The DiGeorge Syndrome (Thymic Hypoplasia)
    • there is defective development of third & fourth pharyngeal pouches caused by a micro-deletion on chromosome 22 (22q11) --> therefore hypoplasia of the thymus
    • immunologically patients get recurrent infections with intracellular bacteria, fungi, large viruses AND because of the lack of T cells B cells aren't activated and pyogenic infections can also occur
    • some thymic tissue may be present and T cells may appear as a patient ages
  31. What are some features of a person with DiGeorge Syndrome?
    • CATCH 22:
    • Cardiac Abnormality (especially tetralogy of Fallot)
    • Abnormal faces (widely spaced eyes, low slung ears)
    • Thymic aplasia
    • Cleft palate
    • Hypoparathyroidism & Hypocalcemia (absent parathyroid glands results in very low calcium levels…tetany = shaking from low Ca levels)
    • 22 is for the microdeletion on chromosome 22
  32. T Cell Activation Defects
    • Defective expression of CD3
    • Abnormal signal transduction by the TCR-CD3 complex
    • Defective cytokine production (eg. IL-2, IFNγ)
    • Defective expression of IL-2 receptors
  33. Severe Combined Immunodeficiency (SCID)
    • T cells are always abnormal but B cells may or may NOT be abnormal
    • there are numerous forms that can result from any one of several genetic defects
    • patients are susceptible to ALL infectious agents
    • treatment: reconstitution of the immune system w/ stem cell transplantation [BEWARE OF FOREIGN T CELLS GETTING IN THE TRANSPLANT --> GVH]
  34. What is the most common form of SCID?
    • X-linked severe combined immunodeficiency, in which there is a mutation of the common-chain of the IL-2 Receptor
    • 70% of SCID children have an abnormality in this IL-2R chain
  35. How else can SCID be caused?
    • adenosine deaminase (ADA) deficiency - biochem
    • bare lymphocyte syndrome - NO HLA
    • mutated CD3 molecule - no signal to proliferate
    • defective cytokine production
    • abnormal signal transduction:
    • 1) Mutations of protein kinases (JAK3 or ZAP 70) - no signal to proliferate
    • 2) Mutations of RAG1 & RAG2 - TCR doesn't work
  36. Wiskott-Aldrich Syndrome
    • an X-linked disease caused by a defect in a gene for WAS, a protein involved in cytoskeletal reorganization that occurs before T cells can deliver cytokines & signals to other cells they interact with
    • the T lymphocytes are smaller than normal and patients get recurrent infections
    • also characterized by thrombocytopenia & eczema
    • it can be successfully treated with bone marrow transplantation
  37. Ataxia Telangiectasia
    • occurs because of a defect in DNA repair mechanisms
    • is characterized by ataxia (trouble with motor movements), vascular malformations (telangiectasias: spider capillaries), & immunodeficiency
    • CANNOT be corrected by a bone marrow transplant
  38. secondary (acquired) immunodeficiencies
    • due to a secondary cause such as a viral or bacterial infection, malnutrition, or drug treatment
    • defective humoral immunity can be caused by things such as myeloma, burns, or lymphoma
    • defective cell mediated immunity can be caused by patients taking immunosuppressive drugs, malnutrition, viral infections (HIV, measles, CMV), or aging
  39. HIV
    • Viral gp120 binds to the CD4 on T cells' surface
    • Viral gp41 binds to CCR5 on T cells' surface, usually a chemokine receptor
    • CCR5 mutation = immune to HIV; virus can't enter the T cell
    • reversal of CD4:CD8 ratio; have more CD8 than CD4 as CD4 levels drop
  40. Immune Deficiency Associated with Aging
    • the aged immune system is less able to mount an effective immune response after challenges with infectious pathogens than the young because of complex changes collectively termed “immunosenescence”
    • this condition contributes to morbidity and mortality due to the greater incidence or reactivation of infectious diseases, as well as the possible enhanced susceptibility to autoimmune diseases and cancer
    • studies of the immune system in elderly humans have clearly demonstrated that both innate and adaptive immunity suffer severe deterioration with age
  41. Age Induced Defects of Innate Immunity
    • reduced neutrophil superoxide production, chemotaxis, & apoptosis
    • reduced TLR expression on APCs
    • reduced phagocytosis + cytokine production by APCs
    • reduced MHC expression leading to decreased antigen presentation
    • reduced dendritic cells
    • decreased cytotoxicity by NK cells
    • decreased response of NK cells to cytokines
    • decreased cytokine production by NK cells
  42. Age Induced Defects of Cell-Mediated Immunity
    • marked shift from naïve to memory cells --> an inability to mount a primary immune response
    • T cell dependent immune functions decline with age
    • decrease in CD4+ cells & an increase in CD8+ cells
    • an increase in the number of Treg cells (CD4+ CD25+)

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