HLA shared epitope and ACPA: just a marker or an active player?

Area of Science:

• Immunogenetics
• Rheumatology
• Molecular Biology

Background:

• Autoantibody production, including anti-citrullinated protein/peptide antibodies (ACPA), is genetically influenced.
• ACPA are specific biomarkers for rheumatoid arthritis (RA) and correlate with disease severity.
• ACPA production is strongly associated with Human Leukocyte Antigen (HLA)-shared epitope (SE) positive individuals.

Purpose of the Study:

• To investigate the role of HLA-SE alleles in the genetic control of ACPA production.
• To explore the mechanisms by which HLA-DRB1 alleles influence ACPA specificity and quantity.
• To determine if the presentation of citrullinated antigens is the sole mechanism behind HLA-DRB1 effects on ACPA.

Main Methods:

• Analysis of genetic control of autoantibody production.
• Association studies between HLA-DRB1 alleles (sharing SE) and ACPA production.
• In vitro binding assays of HLA-SE alleles with citrullinated peptides from various proteins.

Main Results:

• HLA-SE alleles act as immune response genes, dictating ACPA specificity and levels.
• SE alleles demonstrate selective binding to citrullinated peptides from joint-associated proteins.
• EBV-derived citrullinated peptides show limited binding to SE alleles, despite genetic control of immune response.

Conclusions:

• HLA-DRB1 SE alleles play a crucial role in regulating ACPA production in RA.
• While SE alleles bind citrullinated antigens, this interaction is not the exclusive mechanism for HLA-DRB1's influence on ACPA.
• Additional molecular mechanisms likely contribute to the genetic predisposition to ACPA formation in RA.