Flashcards in Autoimmune Insulin-dependent Diabetes Deck (16):
What is Type 1 insulin-dependent diabetes mellitus?
autoimmune destruction of the insulin-secreting islets of Langerhans in the pancreas
When does IDDM occur?
up to early adult live
What is IDDM characterized by?
islet cell infiltration by lymphocytes, T cell reactivity to islet proteins, and autoantibody response
Progressive destruction of beta cells in IDDM is mediated by
CD4 and CD8 T cells
Progressive destruction of beta cells in IDDM leads to
gradual loss of insulin secretion and insulin dependence
IDDM occurs more frequently in people with which alleles?
What is the pathogenesis of IDDM?
direct beta cell cytotoxicity induced by antigen-specific (or proinsulin-specific) cytotoxic T cells that escape negative selection become activated due to high concentration of antigen in draining lymph nodes of pancreatic islets (some insulin may be altered to look different than insulin previously presented in the thymus thus triggering the response) recognized by presentation by APCs (DCs) migrating from islets to LNs; T cells migrate from LN via bloodstream to islet where Ag is concentrated; damage is induced by activated CD4 T cells and inflammatory cytokine producing macrophages; recognition of beta cells results in damage by CD8 T cells via perforins and granzyme B
What are potential mechanisms of control (or cure) of IDDM?
reducing inflammation; enancing Treg production to induce tolerance; prevention of antigen-specific effector T cells; boosting beta cell mass
What antibodies are implicated in Type I IDDM?
insulin autoantibodies; glutamic acid decarboxylase (GAD); zinc transporter 8 (ZnT8); IA-2 (tyrosine phosphatase)
What are the clinical signs & symptoms of type 1 IDDM?
polydipsia (thirst, drinking); polyuria (passing too much urine); weight loss; ketoacidosis; eventual insulin requirement; autoantibodies
Which cell is primarily responsible for beta cell destruction?
cytotoxic CD8 T cells; via cytotoxic granules in the cytoplasm containing perforin and granzyme B
How do CD8 cytotoxic T cells cause destruction if islet beta cells?
cytotoxic granules in the cytoplasm containing perforin and granzyme B (both mediate apoptosis)
What genetic syndromes are associated with type 1 IDDM?
18%: autoimmune polyglandular syndrome I (APS-I) due to deficiency of AIRE gene involved in central tolerance via thymus; immune dysfunction, polyendocrinopathy, enteropathy, X-linked (IPEX) mutation of FoxP3 gene that controls Tregs - 80% develop IDDM Type 1
T cells in IDDM type I primarily recognize what region of insulin?
c-peptide region (in precursor to insulin), not the metabolically active regions (A & B chains) in the context of HLA-DQ8
What are suggested environmental triggers for autoimmunity?
UV; diet; drugs; hygiene (early interaction with microbiota is important); tissue specific ie iodine (thyroid); infection (trigger or protection)