ImmunologyTier 1Medical Sciences concept

Autoantigens in type 1 diabetes (insulin, GAD65, IA-2)

Core concept

T-cell-mediated destruction of beta cells; the antibodies are markers of the process, not the effectors

Autoantigen	Notes
Insulin (IAA)	The ONLY beta-cell-SPECIFIC autoantigen - the first to appear in young children; uninterpretable more than ~2 weeks after starting exogenous insulin
GAD65	Also expressed in brain (GABAergic neurons) and other neuroendocrine tissue -> also found in stiff-person syndrome, cerebellar ataxia, limbic encephalitis
IA-2 (ICA512) and IA-2beta	Tyrosine phosphatase-like, also neuroendocrine
ZnT8 (SLC30A8)	Zinc transporter; adds sensitivity, especially in those negative for the others
ICA (islet cell cytoplasmic)	The historical immunofluorescence assay

Insulin being the only truly beta-cell-restricted antigen is the exam point, and explains why the others turn up in neurological autoimmunity

Prevalence at diagnosis: ~90-95% have at least one antibody; ~70-80% have two or more
- Age shapes the profile: IAA dominates in young children, GAD65 in adolescents and adults
- GAD65 is the antibody to order in a suspected adult (LADA) - it is the most persistent over time
Staging of type 1 diabetes (ADA/JDRF)

Stage	Definition
1	>=2 autoantibodies, NORMOGLYCAEMIC
2	>=2 autoantibodies + dysglycaemia, still asymptomatic
3	Clinical, symptomatic hyperglycaemia

Two or more antibodies -> ~85% progress to clinical diabetes within 15 years, and near 100% lifetime - the basis for screening relatives and for pre-clinical intervention
Genetics: HLA-DR3-DQ2 / DR4-DQ8 account for ~50% of genetic risk, highest in the DR3/DR4 heterozygote; INS, PTPN22, CTLA4, IL2RA contribute
- HLA-DQB106:02 is strongly PROTECTIVE*
C-peptide measures endogenous insulin - low/undetectable C-peptide with concurrent hyperglycaemia supports T1DM; preserved C-peptide years after diagnosis points to MODY or T2DM

Antibody testing is for classification, not for diagnosis of diabetes - use it when the phenotype is ambiguous
- Adult with "type 2 diabetes" failing oral agents quickly, lean, other autoimmune disease -> GAD65 and C-peptide (LADA)
- Antibody-negative, young, strong family history over generations, mild stable hyperglycaemia -> think MODY and test genetically; sulfonylurea-responsive HNF1A/HNF4A, no treatment needed for GCK
Teplizumab (anti-CD3) delays progression from stage 2 to stage 3 by around 2 years - the first disease-modifying therapy, and the reason autoantibody screening of relatives now has a therapeutic consequence
Screen for the associated autoimmune conditions: coeliac disease (tTG-IgA with total IgA), autoimmune thyroid disease (TSH, TPO), Addison's if unexplained hypoglycaemia or falling insulin requirement, pernicious anaemia
GAD antibodies at very high titre with neurological features - think stiff-person syndrome or autoimmune cerebellar ataxia, not just diabetes

HLA-disease associations; complex/polygenic disease genetics
Central and peripheral T-cell tolerance (AIRE and insulin expression in the thymus)
Diabetes drug mechanisms of action by class
Autoimmune polyglandular syndromes; Addison's disease
Counter-regulatory hormone response to hypoglycaemia

3 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.