Genetics & Immunology of Diabetes Flashcards
HLA class II alleles in DM1
DR3 & DR4 halotypes are major risk factors (both together = higher risk)
DR3: HLA-DQA1, HLA-DQB1
DR4: HLA-DRB1
DM1 in families linked to variation on locus of …
Chromosome 11
Variable number of tandem repeats (VNTR polymorphism)
Upstream of insulin gene (INS)
5’ INS gene VNTR
Two polymorphisms at this site are common:
small VNTR (26-63 repeats) –> increased risk of DM1
large VNTR (160-243 repeats) –> protective
Large VNTR
Protective
May promote negative selection of insulin-specific T-cells in thymus
Increased thymus INS gene expression –> lower risk
Environmental role DM1
Important component of DM1 variation
“clean” environment associated w/ increased risk for DM1
May have less antigenic exposure during childhood
Most individuals have islet-directed autoimmunity
Though to arise after immunological trigger event
Environmental factors/precipitating agents DM1
- Viruses: rubella, mumps, CMV, coxsackie (enteroviruses)
- Bacteria: Mycobacterium avium via molecular mimicry
- Cow’s milk: albumin component (islet autoimmunity)
DM1: Cow’s milk
Albumin component (islet autoimmunity)
Cross reactivity between serum antibodies to albumin & ICA-1, a B-cell surface protein
Breastfeeding – protective
DR3: HLA-DQA1, HLA-DQB1
HLA class II alleles in DM1
DR4: HLA-DRB1
HLA class II alleles in DM1
Genetic susceptibility DMI
PTPN22
Protein Tyrosine Phosphatase non-receptor 22
Important regulator of TCR signaling
LOF –> Lower threshold autoreactive T-cell activation in periphery
Genetic susceptibility DMI
CTLA4
Cytotoxic T-lymphocyte associated protein 4
Important for negative regulation of immune responses
Competitively binds B7 (inplace of B7/CD28) to INHIBIT T-cell activation
Genetic susceptibility DMI
IL2RA
IL-2 receptor a OR CD25
Tregs express IL2RA –affects function and ability of FoxP3 TREGS
Higher levels –> better immune suppression
Lower levels –> poorer immune suppression
Gene associated with DM2
TCF7L2 gene
TFx in wnt signal pathway
B-catenin involved in increased growth
B-cell turnover
MODY (maturity diabetes of the young)
AD diabetes
Onset late childhood (<25) Not obese
Defect in glucose-induced insulin release
Mutation MODY 2 –> Glucokinase protein not functioning as glucose monitor
MODY 2 Mutation
Glucokinase protein not functioning as glucose monitor
MODY
Small VNTR
Increased risk of DM1
Large VNTR
Protective, may promote negative selection of insulin-specific T-cells in thymus
DR3 & DR4
HLA MHC II
DMI genes
T1D – destructive process in cell-mediated & organ specific manner
Type IV hypersensitivity
Proinflammatory Cytokines released in islets once infiltrated by T-cells/macrophages
IL-1B
TNFa
TNFy
Autoantibodies associated with T1D
Anti-insulin
Anti-glutamic acid decarboxylase (GADA/GAD65)
Anti-islet cell antigen 2 (IA-2)
Anti-zinc transporter (ZnT8)
Honeymoon phase
Remission after dx – B-cell stress relieved 2/2 admin of insulin
Type II DM hypersensitivity
Non-cytotoxic
Type II Hypersensitivity
Anti-glutamic acid decarboxylase (GADA or GAD65)
Anti-islet-cell antigen 2 (IA-2)
Autoantibodies associated with T1D
