Which MHC (Major Histocompatibility Complex) allele is associated with type 1 diabetes, Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), Goodpasture's syndrome, Graves' disease, Sjogren's syndrome, and Rheumatoid Arthritis?

MHC Allele Associations with Autoimmune Diseases

Specific MHC alleles are strongly associated with various autoimmune diseases, with HLA-DRB104-DQA103:01-DQB103:02 (DR4-DQ8) and HLA-DRB103-DQA105:01-DQB102:01 (DR3-DQ2.5) being the predominant associations for type 1 diabetes, while other autoimmune conditions have distinct HLA associations.

Type 1 Diabetes

• HLA-DRB104-DQA103:01-DQB1*03:02 (DR4-DQ8) and HLA-DRB103-DQA105:01-DQB1*02:01 (DR3-DQ2.5) are the primary MHC associations 1
• These haplotypes, alone or in combination, may account for up to 90% of children and young adults with type 1 diabetes 1
• The HLA DQ and DR genes are the most important determinants for developing β-cell autoantibodies following environmental exposure 1
• Protective effect: HLA DQB1*06:02 allele protects against progression to diabetes onset in children 1

Systemic Lupus Erythematosus (SLE)

• Associated with MHC class II molecules, particularly HLA-DR3 2
• The polymorphic regions unique to these predisposing HLA alleles influence susceptibility 3

Multiple Sclerosis (MS)

• Strongly associated with HLA-DR2 4
• MHC class II alleles play a significant role in disease susceptibility 3

Goodpasture's Syndrome

• Associated with HLA-DR2 4
• Previously not found to be associated with HLA-A, -B, and -C antigens 4

Graves' Disease

• Associated with MHC class II molecules 2
• Specific HLA associations contribute to autoimmune thyroid disease development

Sjögren's Syndrome

• MHC class II associations similar to other autoimmune diseases
• Part of the spectrum of HLA-associated autoimmune conditions

Rheumatoid Arthritis (RA)

• Associated with HLA-DR4 4
• Polymorphisms in the amino acid sequence of HLA-DRB1 change the capability to present autoantigens or increase the number of autoreactive T cells during thymic selection 1

Mechanisms of MHC Association with Autoimmune Disease

Antigen Presentation

• MHC molecules present short peptides derived from pathogens or autoantigens to T cells to initiate the adaptive immune response 1
• MHC class II molecules are expressed primarily on antigen-presenting cells and present processed extracellular pathogens to CD4 T cells 1
• The antigen-binding groove of MHC class II is open-ended and accommodates peptides of variable length 1

Genetic Inheritance

• HLA genes are inherited as complete haplotypes from each parent 5
• Recombination between HLA loci is rare due to their close proximity on chromosome 6 5
• The HLA-A, B, and C loci are closely linked and generally inherited together 5

Environmental Triggers

• Genetic predisposition is only one risk factor; environmental factors, particularly infections, play a critical role in triggering autoimmune diseases 2
• Low concordance rates in monozygotic twins suggest environmental factors are important 2

Clinical Implications

• HLA typing has limited value in the routine diagnosis or management of type 1 diabetes 1
• However, typing for genetic markers and using genetic risk scores are recommended for individuals who cannot be clearly classified as having type 1 or type 2 diabetes 1
• Understanding HLA haplotype inheritance is crucial for predicting possible HLA phenotypes in siblings, which has significant implications for transplantation medicine and donor selection 5

Important Caveats

• While specific MHC alleles increase susceptibility, they are not causative for autoimmune diseases 1
• Many susceptibility alleles are common in the general population (30-40% for some T1D-associated haplotypes) 1
• Once autoimmunity has developed, HLA genes do not seem to contribute significantly to disease progression in some conditions like T1D 1
• Multiple genetic factors beyond HLA, including genes for insulin (INS), PTPN22, CTLA-4, and others, contribute to autoimmune disease risk 1