Flashcards in Immuno Deck (14):
Describe the role of environmental factors in Type 1 DM (6)
-Breast feeding leads to a decreased risk in type 1 DM. Early exposure to cows milk-->T1DM due to immune tolerance to insulin.
-Risk of T1D higher with GSE
-Vit D is an immune modulator and suppressant
-Chemicals (Nitroso)-->descrtruction of B cells
-Streptozocin & bafilomycin A1 are cytotoxic for B cells
-Viruses may act as direct cytotoxicity & autoimmunity by molecular mimicry
Explain susceptibility factors (genetics) in the development of Type 1 DM (4)
HLA (chr 6)-->pres of insulin Ags to CD8 T cells
Insulin gene IDDM2 (chr 11)-->Ag for autoimmune response
AIRE-->Regulation of insulin gene expression in thymus
CTLA-4 gene (Chr 2)-->Regulation of autoimmune response
List auto-Ags and auto-Abs found in patients with Type 1 DM and explain their role in disease diagnostic pathogenesis
-Islet cell autoantibodies (ICA):
-Appears in advance and confirms dx
-2 or more highly predictive (5 yr risk=28-66%)
-W/ HLA, useful for predicting dz in gen pop
Explain the role of T-cells in the pathogenic mechanisms of Type 1 DM
T1DM is a Th1-mediated dz (cytotoxic T lymphocytes)
T cells activated in LN (pancreas)-->
Islet specific T cells traffic to the pancreas where they proliferate and accumulate (inflammation)-->
Local APCs w/ MHC II secrete ____-->
APCs activate Ag-specific CD4 T cells-->
Inhibits Th2 cytokine production (IL-4, IL-5, IL- 10) and enhance IL-1β, TNF-α, and free radical production by Mφ which all are toxic to islet beta cells.
How is central tolerance to insulin established normally?
￼￼￼￼In the thymus insulin-Ags are presented within Class II MHC-->negative selection!
Which HLA alleles put individuals at high risk for T1DM?
DR3/DR4 (children <5)
MHC II lacking Asp57 of B chain
Which HLA class II-->protection?
The insulin gene is mapped to a region with variable number of tandem repeats (VNTR) in the promoter region of the insulin gene. The susceptible class I alleles of the insulin VTNR are assoc with lower insulin mRNA synthesis. How does this affect central tolerance?
Lower insulin mRNA synthesis-->
Low insulin Ag synthesis-->
Low Ag presentation in thymus-->
Failure of deleting self-reactive CD8 T cells-->
Central tolerance is broken with class I allleles
Transcriptional expression of insulin in the thymus is controlled by ____. Malfunctioning results in lower levels of insulin mRNA-->failure of central tolerance!
CTLA4 (cytotoxic T lymphocyte antigen-4) is the susceptibility locus on chromosome 2. It encodes a glycoprotein that is a _____ homologue and binds the B7 protein (CD80/86) on the APC. Therefore, CTLA4 may counter-regulate/inhibit the activation of T cells.
The function of CTLA4 is essential to suppress T cell activation and induce apoptosis. Therefore CTLA4 controls peripheral tolerance. No CTLA4-->aberrant immune response
Explain the role of cell-mediated immunity in the pathogenic mechanisms of Type 1 DM
-Susceptibility to T1D may be greatly enhanced when CD4+/CD25+ TReg cells fail to prevent activation/expansion of auto-reactive T cells
Asthma is more prevalent in children with T1D than non-diabetic children.
What is the common denominator?
Failure of regulatory mechanisms controlled by CD4+/CD25+TReg cells
-The Ags can activate damaging CD4+ and CD8+ T cells.
Mechs of suppression by CD4+/CD25+ Treg in normal individuals?
-Production of immunosupp cytokines IL-10 and TGFB
-Reduces ability of APC to stimulate T cells (dependent on binding CTLA4 on regulatory cells to B7 on APC)
-Consumption of IL-2 bc of the high level of IL-2R these cells absorb IL-2 and deprive other T cell pop of this GF leading to reduced prolif of other cells