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Endo/Repro Midterm > Immune Mechanisms Of Diabetes > Flashcards

Immune Mechanisms Of Diabetes Flashcards

1
Q

Types of tolerance:

Central?

Peripheral?

A

Developing lymphocytes (central lymphoid organs)

Mature lymphocytes (peripheral tissues)

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2
Q

Describe the role of AIRE in central tolerance for T cells in the thymus

Defects in AIRE cause what?

A

Presences of AIRE:
Presents self antigen to the developing T cells, if they respond, the T cells are deleted; simulates the expression of peripheral “tissue-restricted” self androgens in the thymus

Autoimmune diseases like polyendocrinopathy and Type 1 diabetes

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3
Q

What has a big role in peripheral T cell tolerance?

What do they express?

What do they secrete?

Function?

A

Regulatory T cells

CD4; TGF-beta; FoxP3; *CD25 (high affinity IL2 receptor on surface so it can respond immediately and start proliferating); *CTLA4 (regular T regs express it after activation)

IL10 and TGF-beta

Inhibit T cell response and other cels in the periphery

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4
Q

Loss of FoxP3 causes what?

A

Widespread autoimmunity

IPEX: immune dysregulation polyendocrinopathy, enteropathy, X-linked

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5
Q

In what two ways are T cells activated due to T cell anergy of peripheral T cell tolerance?

What happens in the absence of infection?

A

TCR binds to HLA complex

Binding of B7 to CD28

W/o infection: T cells activated, express CTLA4; outcompete CD28 to bind to B7 with a higher affinity; T cell has built in mechanism to shut itself down

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6
Q

Factors that contribute to autoimmunity

Lead to what?

A

Genes, infections, environmental factors

Breakdown of tolerance

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7
Q

Inhibitory receptors to peripheral B cell tolerance

A

Self antigen; angergy (functional inactivation)

IgG

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8
Q

T/F: Type 1 diabetes is immune meditated

Type 2 diabetes is not gestational

A

TRUE

FALSE

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9
Q

Describe type 1 DM

type 2 DM

A

Autoimmune; leaders to destruction of beta cells; need insulin for survival

Insulin resistance due to lifestyle changes leading to insulin insensitivity

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10
Q

Adipose tissue normally release what?

What immune cells are normally contained in adipose tissue?

What do they normally secrete in low levels?

A

FFA

Alternatively activated macrophages normally there (M2; inhibit inflammatory response)

Secrete IL1 and IL1 receptor

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11
Q

What is the number one cause of Type2 DM?

How does obesity course insulin resistance?

A

Obesity

Increases lipolysis and macrophage accumulation (not M2; therefore increasing inflammatory state);

Increases glucose, triglyceride, and acute phase protein secretion

Decreases insulin, beta cell function, and inflammatory changes in the pancreas -> all leading to insulin resistance

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12
Q

Risk factors for type 2 DM

A 
Obesity
Microbiome/diet
Vitamin D
Maternal disease
High birth weight babies
Pollution, pesticides
Sleep deprivation
Chronic inflammation
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13
Q

Genetic risk factors of type 2 DM

A

Race

Parents with T2D, risk increases (independent of personal lifestyle)

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14
Q

How does obesity produce and inflammatory state?

A

Lean adipose tissue has a lot of Tregs and M2 macrophages (anti inflammatory)

Overtime more adipocytes do lipolysis, destruction, and go into a chronic inflammatory state; M1 enter the area secreting IL6, IL1, TNF which promote a true phase inflammation (recruit more inflammatory mediators)

CD8 T cells move in

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15
Q

Function of IL6

A

Acute phase inflammatory response

Stimulates liver to release acute phase proteins

Pyrogen

Plays role in insulin resistance by increasing lipolysis, stimulating malabsorption in intestine

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16
Q

Free fatty acid (FFA) role in adipose inflammation

A

Long chain FFA palmitate is a ligand for toll like receptor TLR4 present on adipocytes

Receptor ligand binding leads to proinflammatory cytokines release and production from adipocytes

Recruits M1 macrophages

Increased inflammatory state causes sustained beta cell dysfunction

17
Q

These cytokines increase in response to obesity.

What cytokines decrease?

A

Recruiting M1 macrophages, mast cells, B cells antibodies

Treg and M2 decrease

18
Q

Long term changes to pancreatic cells because of insulin resistance

A

Increase of beta cell dysfunction and loss of mass

19
Q

Describe type 1 DM

What is required?

Prone to what disease?

A 
Autoimmunity
Tcell mediated (hypersensitivity type 4) destruction of beta cells -> insulin deficiency
Autoantibody production used as markers for B-cell destruction

Insulin therapy

Ketoacidosis

20
Q

Symptoms of T1D

A

High blood sugar
Weight loss
Increased hunger
Increased thirst

21
Q

Immune response to type 1 DM

A

Autoantigens form on beta cells and presented by APC to Tcells that will respond to selfantigen (breakdown in central tolerance)

Activation of T helper 1 lymphocytes which secrete:
INFgamma: activate macrophages with release of IL1 and TNF alpha
IL2: activation of autoantigen specific T cytotoxic (CD8)

Activation of T helper 2 which secrete:
IL4: activation of B lymphocytes to produce autoantibodies

All work to destroy beta cells therefore decreased insulin secretion

22
Q

What are the genetic risks of T1D?

What another autoimmune diseases can occur?

A

Risk if parents and sibling have T1D

Celiacs disease

Thyroid autoimmunity (because highly vascularized organ)

23
Q

What genes can causes T1D?

A 
HLA
INS-insulin gene
AIRE
CTLA4
IL10
IL2
24
Q

HLA class II (high risk) haplotypes in T1D

A

DQ2/DQ8: more than 90% of people with T1D

DR3/DR4: most common in children diagnosed prior to age 5

HLA class II that lacks Asp57 of beta chains common

25
Q

Function of HLA in T1D

A

Presents antigen

Haplotypes allow APC to present antigens in a way that is foreign to T cells, therefore inducing inflammatory response

26
Q

Non-HLA genes involved in autoimmunity

A

CTLA4

Tyrosine phosphatase

CD25

AIRE

FOXP3

FAS

27
Q

Describe the function of AIRE and what happens when it is mutated

A

Expression and presentation of insulin in the thymus to developing T cells; critical to protecting against development of T1D

If AIRE cannot express insulin, autoreactive T cells will react with beta cells

28
Q

Where are mutations in the insulin gene located?

What do they cause?

A

Located in the variable number tandem repeats (VNTR) in promoter regions

Lead to lower expression of insulin; even if AIRE is present, cannot express insulin to T cells, so autoreactive T cells are produced because reduction in tolerance

29
Q

What does a defect in CTLA4 expression on Tregs and activated T cells cause?

A

Decrease the ability to down-regulate immune response and maintain tolerance

30
Q

Perinatal and intrauterine risk factors for T1D

A

Decreased transplacental transmission of antibodies

Increased birthweight

Genetics and HLA genotype

31
Q

Postnatal environmental factors of T1D

A

Breastfeeding: decreased breast-feeding can lead to T1D because breast milk has more insulin than cows milk

32
Q

Dietary risk factors of T1D

A

Wheat gluten (potent diabetogen)

Vitamin D deficiency (Type 1 and 2)

33
Q

Infectious risk factors to developing T1D

How?

A

Mumps, rubella, cytomegalovirus, enterovirus, retrovirus

Streptomyces (fungus) secretes proteins that are cytotoxic to beta cells: streptozocin and bafilomycin A1

Viruses lead to destruction of beta cells by: direct cytotoxicity, molecular mimicry

34
Q

Processing and presentation and activation of T1D immune mechanism

A

Autoantigens are being processed and presented by dendritic cells using HLA -> activate autoreactive T cells

Cross presentation allows the CD4 cells to activate CD8; caused by a TH1 response

Also gets B cells involved making IgG autoantibodies (class 1)

35
Q

What are ICA (islet cell autoantibody)?

Examples?

A

Detected in pts with T1D

Antibody production appears months to years in advance of metabolic changes from beta-cell destruction and can be used to predict and confirm T1D

GAD65, IAA, IA-2 (tyrosine phosphatase)

36
Q

How are beta cells destroyed by CD8 and CTLs?

A

Destruction of beta cells -> TH1 are supporting B cells and sustaining inflammatory response; CD8 are destroying the cell

Release of beta cell antigens are processed by dendritic cells -> present antigen autoreactive CD4 cells -> cross present to autoreactive CD8 -> CD4/CD8 cells migrate to place of destruction

CD8 -> apoptosis (FAS)
Granzyme/perforin

37
Q

Are TH1 or TH2 more prevalent in T1D?

What does this cause?

A

TH1; TH 1 suppresses TH2 response therefore have higher prevalence of allergies in T1D pt

Prevalence is TH1 due to dysregulation of T regs

38
Q

Effect of T1D on T reg cells

A

Lead to change in T reg population and effector function (become unstable) and lose Foxp3

Some produce inflammatory cytokines INFgamma and IL17

T helper cells are resistant to T reg mechanisms

39
Q

How do you prevent diabetes?

A

T1D cannont be prevented

Lifestyle changes can help T2D

Endo/Repro Midterm (11 decks)

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