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Endo Final > Immune Mechanism of Diabetes > Flashcards

Immune Mechanism of Diabetes Flashcards

1
Q

Genetic susceptibility, sedentary lifestyle, high fat diet and psychological stress have complementary effecs on the development of which type of diabetes

A

T2D

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2
Q

How is adipose tissues, macrophage types and immune cell types different in person with lean adipose tissues vs person who is obese?

A

Lean adipose tissues have greater M2/M1, more Tregs. Obesity leads to adipocyte necrosis, and increase in M1 macrophages. Treg cells are reduced and there is an increase in B cells, CD4 TH1 cells and CD8 T cells.

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3
Q

What are the anti-inflammaory cytokines as seen in lean adipose tissues.

A

IL10, IL4, IL13

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4
Q

What are some pro-inflammatory cytokines and chemokines as seen in obese insulin resitant adipose tissues.

A

IL-1b, TNF-a, Il6, CCL2, CCL3, and CXCL8

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5
Q

In the immediate instructional pancreatic beta cells resulting in an insulin deficiency is what type of diabetes

A

Type one diabetes

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6
Q

Patients with what type of diabetes are more prone to ketoacidosis

A

Type I diabetes

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7
Q

Type I diabetes is what kind of automated disorder?

A

T cells mediated automated disorder

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8
Q

The onset of type I diabetes is associated with infiltration of islets of Langerhans has by what cell?

A

mononuclear cells and CD8 cells

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9
Q

What is meant by unsulitis?

A

Infiltration of islets of hangerhans by mononuclear cells and CD8 T cells.

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10
Q

True or false

; type one diabetes mainly involves genetic factors

A

False it involves genetic and environmental factors such as birth delivery mode use of antibiotics and diet.

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11
Q

What role does gut microbiota play in developing type I diabetes

A

It could be the link between environmental factors and development of autoimmunity and T1D

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12
Q

The fact that type I diabetes has additional non-genetic influences was seen in studies done in monozygotic twins that shows what?

A

It shows concordance rate of about 30-50% vs. 100%.

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13
Q

True or false: There is an increased likelihood of developing T1D risk in infants who drink cows milk vs. breast milk.

A

True.

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14
Q

Gluten, bovine milk and high-fat diet, and infections all contribute to mucine degradation which leads to _ .

A

Leaky gut, (increased paracellular permeability) so now bacterias (eg. bacteriodes) can now enter lamina propria and cause inflamamtion, decrease insulin sensitivity and cause autoimmunity

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15
Q

True or false. Wheat gluten is a diabetogen

A

True

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16
Q

How does Vitamin D affect risk of T1D?

A

Vitamin D is an immune modulator and suppressant and so people with vitamin D deficiency are at higher risk of developing T1D.

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17
Q

which bacterial products of streptomyeces are cytotoxic for beta cells?

A

Stretozocin and bafilomycin A1.

18
Q

Which viruses have been implicated in T1D?

A

Mumps and rubella

19
Q

True or False: there are no specific diabetes gene, but just a wrong combination of normal polymorphisms.

A

True

20
Q

Of the up to 18 possible genes with varying potencies associated with susceptibility to T1D, which ones are most significant?

A
  1. HLA region (chromosome 6) - presentation of insulin Ags for CD8 T cells
  2. Insulin gene (Chromosome 11) - Ag for autoimmune response
  3. Regulators of insulin gene expression in the thymus (AIRE)
  4. CTLA-4 gene (chromosome 2) - regulation of autoimmune response
21
Q

Which HLA alleles are considered high risk alleles that play a role in T1D?

A

DQ2/DQ8 and DR3/DR4

22
Q

Which HLA alleles are found in more than 90% of individuals with T1D

A

DW2/DQ8

23
Q

Which HLA alleles are associated with childhood T1D (ages 5 or younger) - shown in 50% of cases

A

DR3/DR4

24
Q

HLA class II molecules that lack _ of the beta chain are often found among individuals with T1D.

A

Asp57

25
Q

Which class II HLA haplotyes are conferred as dominant protection against T1D?

A

DR2/DQ6

26
Q

Which VTNR polymorphism class in the insulin gene (IDDM2) is most prevalent in T1D?

A

Class II

27
Q

What makes the Class I VTNR polymorphism susceptible which are associated with lower insulin mRNA synthesis resulting in Low Ag synthesins, and thus presentation to thymus and failure of deleting self-reactive CD8 T cells.

A

Central tolerance is broken in class I alleles.

28
Q

Explain how AIRE is involved in potentiating a person for T1D?

A

Normally transcriptional expression of insulin the thymus is controlled by AIRE. Manufacturing of IRE results in lower level of mRNA in the thymus. With absence of insulin results in failure of delelting insulin-reactive T cells and the central tolerance gets broken. Once central tolerance is broken insulin is recognized as an antigen.

29
Q

What is the function of CTLA-4?

A

suppression of T cell activation and activation of it’s apoptosis. It counter-regulate the CD28-dependent TCR activation of T cells

30
Q

On what chromosome is the susceptiblity locus associated with T1D of CTLA4 found?

A

Chromosome 2

31
Q

What is the mechanism of action of CTLA in blocking T cell activation?

A

Engagement of CTLA-4 on T cell deliver inhibitory signals that terminate further activation of that cell (intrinsic function of CTLA4). CTLA-4 on regulatory or responding T cells binds to B7 molecules from the surface of APC making the B7 costimuators unavailble to CD28 and blocking T cell activation CTLA4 competes with CD28 for binding CD80 leading to cell-cycle arrest that prevents expansion of acivated T cells.

32
Q

what is sCTLA4 used for in clinical trials?

A

treatment of autoimmune disease

33
Q

Failure of T cells to expression CTLA-4 gene due to mutations contributes to _

A

aberrant immune responses seen in T1D

34
Q

GAD65, IA,2 tyrosine phopshtase, IAA are all specifities of several identified _, presence of which confirms a diagnosis of Type 1A diabetes.

A

Islet cell autoantibodies (ICA)

35
Q

T or F. Presence of Auto-abs against beta cells is indicative T1D.

A

False. autoantibodes may contribute but is not absolutely required to get the disease. They may affect the time course, but there has to be other components added before a person develops the disease.

36
Q

Explain the pathogenic role of T cells in developing T1D.

A

T cells are activated in lymph nodes that drain the pancreas. Once activated islet specific T cells traffic to the pancreas where they proliferate and accumulate resulting in organ specific inflammation. Local APC presents Ag to class II MHC and secretes IL12. These APCs activate Ag-specific CD4 T cells and further stimulates IFN-gamma. INF-gamma inhibits Th2 cytokines production (IL4, 5, 10) and enhance Il1b, TNF-a, free radical production by macrophages and all other toxic to islet beta cells.

37
Q

What role do Treg cell play in suppressing T1D?

A

Islet-specific pathogenic clones of T cells are found in healhty indivuals but T1D is prevented and the peripheeral self tolerance is maintained by T reg cells. In other words, failure of Treg cells adds to the susceitibility of T1D.

38
Q

What is the MOA of Treg in suppressing autoimmunity?

A

They suppress immune response by direclty suppressing B cell activation and inhibit the proliferation and differentiation of NK cells. They produce immunosuppressive cytokines IL-10 and TGF-8; reduce ability of APC to stimulate T cells (could be via CTLA actions); and consumption of IL-2 and thus cells that need IL-2 are not made.

39
Q

In NOD mice, Treg was shown to prevent diabetes by preventing activation of which cells?

A

CD4 and CD8 T cells.

40
Q

What transcriptional activator is shown to be a specific marker of T reg cells and is a master regulator in the development and function of Treg cells.

A

FOXP3

41
Q

What are the three major islet auto_ags in T1D?

A
  1. Insulin/proinsulin
  2. Glutamic acid decarboxylase 65 (GAD65)
  3. Islet protein tyrosine phosphtases (PTPs IA-2 and IA-2beta
42
Q

Which autoantigen causing T1D is most prevalent in chidlren? in adults?

A

Insulin/prosinulin autantigen is prevalent in children

GAD65 is prevalent in adults

Endo Final (14 decks)

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