Immune Mechanisms Of Diabetes Flashcards
(39 cards)
Types of tolerance:
Central?
Peripheral?
Developing lymphocytes (central lymphoid organs)
Mature lymphocytes (peripheral tissues)
Describe the role of AIRE in central tolerance for T cells in the thymus
Defects in AIRE cause what?
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
What has a big role in peripheral T cell tolerance?
What do they express?
What do they secrete?
Function?
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
Loss of FoxP3 causes what?
Widespread autoimmunity
IPEX: immune dysregulation polyendocrinopathy, enteropathy, X-linked
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?
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
Factors that contribute to autoimmunity
Lead to what?
Genes, infections, environmental factors
Breakdown of tolerance
Inhibitory receptors to peripheral B cell tolerance
Self antigen; angergy (functional inactivation)
IgG
T/F: Type 1 diabetes is immune meditated
Type 2 diabetes is not gestational
TRUE
FALSE
Describe type 1 DM
type 2 DM
Autoimmune; leaders to destruction of beta cells; need insulin for survival
Insulin resistance due to lifestyle changes leading to insulin insensitivity
Adipose tissue normally release what?
What immune cells are normally contained in adipose tissue?
What do they normally secrete in low levels?
FFA
Alternatively activated macrophages normally there (M2; inhibit inflammatory response)
Secrete IL1 and IL1 receptor
What is the number one cause of Type2 DM?
How does obesity course insulin resistance?
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
Risk factors for type 2 DM
Obesity Microbiome/diet Vitamin D Maternal disease High birth weight babies Pollution, pesticides Sleep deprivation Chronic inflammation
Genetic risk factors of type 2 DM
Race
Parents with T2D, risk increases (independent of personal lifestyle)
How does obesity produce and inflammatory state?
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
Function of IL6
Acute phase inflammatory response
Stimulates liver to release acute phase proteins
Pyrogen
Plays role in insulin resistance by increasing lipolysis, stimulating malabsorption in intestine
Free fatty acid (FFA) role in adipose inflammation
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
These cytokines increase in response to obesity.
What cytokines decrease?
Recruiting M1 macrophages, mast cells, B cells antibodies
Treg and M2 decrease
Long term changes to pancreatic cells because of insulin resistance
Increase of beta cell dysfunction and loss of mass
Describe type 1 DM
What is required?
Prone to what disease?
Autoimmunity Tcell mediated (hypersensitivity type 4) destruction of beta cells -> insulin deficiency Autoantibody production used as markers for B-cell destruction
Insulin therapy
Ketoacidosis
Symptoms of T1D
High blood sugar
Weight loss
Increased hunger
Increased thirst
Immune response to type 1 DM
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
What are the genetic risks of T1D?
What another autoimmune diseases can occur?
Risk if parents and sibling have T1D
Celiacs disease
Thyroid autoimmunity (because highly vascularized organ)
What genes can causes T1D?
HLA INS-insulin gene AIRE CTLA4 IL10 IL2
HLA class II (high risk) haplotypes in T1D
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
