Immuno

Question 1

Describe the role of environmental factors in Type 1 DM (6)

Answer 1

• 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

Question 2

TQ

Explain susceptibility factors (genetics) in the development of Type 1 DM (4)

Answer 2

18 genes:

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

Question 3

List auto-Ags and auto-Abs found in patients with Type 1 DM and explain their role in disease diagnostic pathogenesis

Answer 3

-Islet cell autoantibodies (ICA):
GAD65
IA-2
IAA
-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

Question 4

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–>
Stimulates IFN-gamma–>
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.

Answer 4

IL-12

IFN-gamma

Question 5

How is central tolerance to insulin established normally?

Answer 5

In the thymus insulin-Ags are presented within Class II MHC–>negative selection!

Treg–>peripheral tolerance

Question 6

Which HLA alleles put individuals at high risk for T1DM?

Answer 6

DQ2/DQ8 (adults)
DR3/DR4 (children <5)
MHC II lacking Asp57 of B chain

Question 7

Which HLA class II–>protection?

Answer 7

DR2/DQ6

Question 8

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?

Answer 8

Lower insulin mRNA synthesis-->
Low insulin Ag synthesis-->
Low Ag presentation in thymus-->
Failure of deleting self-reactive CD8 T cells-->
Periphery

Central tolerance is broken with class I allleles

Question 9

Transcriptional expression of insulin in the thymus is controlled by ____. Malfunctioning results in lower levels of insulin mRNA–>failure of central tolerance!

Answer 9

AIRE

Question 10

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

Tx: sCTLA4

Answer 10

CD28

Question 11

Explain the role of cell-mediated immunity in the pathogenic mechanisms of Type 1 DM

Answer 11

-Susceptibility to T1D may be greatly enhanced when CD4+/CD25+ TReg cells fail to prevent activation/expansion of auto-reactive T cells

Question 12

Asthma is more prevalent in children with T1D than non-diabetic children.
What is the common denominator?

Answer 12

Failure of regulatory mechanisms controlled by CD4+/CD25+TReg cells

-The Ags can activate damaging CD4+ and CD8+ T cells.

Question 13

Mechs of suppression by CD4+/CD25+ Treg in normal individuals?

Answer 13

• 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

Question 14

The loss Treg in IPEX syndrome leads to neonatal diabetes:
Immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, a rare disease linked to the dysfunction of the transcriptional activator _____.

Answer 14

FoxP3 (the master regulator in the development and function of regulatory T cells…resistance to apop)