Citrullination of self-proteins and autoimmunity

Area of Science:

• Immunology
• Autoimmunity
• Rheumatoid Arthritis Research

Background:

• Citrullination (post-translational modification of arginine to citrulline) of self-proteins is implicated in rheumatoid arthritis (RA) pathogenesis.
• The role of citrullinated autoantigens, like fibrinogen, in initiating autoimmune responses requires further investigation.

Purpose of the Study:

• To investigate the immune response to citrullinated human fibrinogen (hFBG) in mouse models with varying susceptibility to RA.
• To determine if the induced immune response to citrullinated hFBG can trigger arthritis in these mouse models.

Main Methods:

• Immunization of mouse strains expressing MHC class II antigens similar to RA-susceptible or non-susceptible HLA-DR4 alleles with normal or deiminated hFBG.
• Analysis of anti-FBG and anti-citrulline antibody production, including crossreactivity with mouse FBG (mFBG).
• Assessment of arthritis development in over 600 investigated mice.

Main Results:

• Immunization with deiminated hFBG induced high levels of anti-FBG antibodies but low levels of anti-citrulline antibodies and limited crossreactivity with mFBG across all mouse strains.
• Mice with RA-susceptible MHC class II molecules produced higher levels of crossreactive anti-mFBG antibodies compared to those with non-susceptible alleles.
• Despite robust antibody responses, no mice developed arthritis, indicating the induced immune response was insufficient to cause the disease.

Conclusions:

• The quality and quantity of autoantibodies generated against citrullinated fibrinogen in this model are insufficient to induce arthritis.
• While citrullination of fibrinogen elicits an immune response, it may not be the sole or sufficient trigger for RA development in this context.