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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
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Immunodeficiency disorders
recurrent infections due to a breakdown in innate, humoral, or cell mediated immunity
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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*
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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
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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)
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primary or (congenital) immunodeficiencies
genetic defects that manifest early in childhood but are occasionally detected later in life
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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
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What two proteins are required for opsonization by neutrophils?
- IgG & C3b
- a deficiency in either of these two can also result in innate immunodeficiency
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Neutropenia
- inadequate neutrophils
- can occur especially in patients receiving chemotherapy - WBC counts drop
- agranulocytosis = an almost complete absence of polymorphonuclear leukocytes (PMNs)
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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
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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
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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
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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
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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
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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)
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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
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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)
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Why are newborn infants with X-linked (Bruton) Agammablobulinemia usually normal?
because protection is initially conferred by maternal antibody
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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
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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)
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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
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What is the most common immune deficiency disorder?
IgA Deficiency
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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
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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
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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
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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)
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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)
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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)
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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)
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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
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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
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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
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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]
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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
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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
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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
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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
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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
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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
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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
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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
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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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