Immune Mechanisms Of Diabetes Flashcards
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
Function of HLA in T1D
Presents antigen
Haplotypes allow APC to present antigens in a way that is foreign to T cells, therefore inducing inflammatory response
Non-HLA genes involved in autoimmunity
CTLA4
Tyrosine phosphatase
CD25
AIRE
FOXP3
FAS
Describe the function of AIRE and what happens when it is mutated
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
Where are mutations in the insulin gene located?
What do they cause?
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
What does a defect in CTLA4 expression on Tregs and activated T cells cause?
Decrease the ability to down-regulate immune response and maintain tolerance
Perinatal and intrauterine risk factors for T1D
Decreased transplacental transmission of antibodies
Increased birthweight
Genetics and HLA genotype
Postnatal environmental factors of T1D
Breastfeeding: decreased breast-feeding can lead to T1D because breast milk has more insulin than cows milk
Dietary risk factors of T1D
Wheat gluten (potent diabetogen)
Vitamin D deficiency (Type 1 and 2)
Infectious risk factors to developing T1D
How?
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
Processing and presentation and activation of T1D immune mechanism
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)
What are ICA (islet cell autoantibody)?
Examples?
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)
How are beta cells destroyed by CD8 and CTLs?
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
Are TH1 or TH2 more prevalent in T1D?
What does this cause?
TH1; TH 1 suppresses TH2 response therefore have higher prevalence of allergies in T1D pt
Prevalence is TH1 due to dysregulation of T regs
Effect of T1D on T reg cells
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
How do you prevent diabetes?
T1D cannont be prevented
Lifestyle changes can help T2D
