Anti-citrullinated protein antibodies arise during affinity maturation of germline antibodies to carbamylated proteins in rheumatoid arthritis
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Abstract
Why autoantibodies in rheumatoid arthritis (RA) primarily target physiologically modified proteins, called citrullinated proteins, is unknown. Recognizing the inciting event in the production of anti-citrullinated protein antibodies (ACPAs) may shed light on the origin of RA. Here, we demonstrate that ACPAs originate from germline-encoded antibodies targeting a distinct but structurally similar modification, called carbamylation, which is pathogenic and environmentally driven. The transition from anti-carbamylated protein (anti-CarP) antibodies to ACPAs results from somatic hypermutations, indicating that the change in reactivity is acquired via antigen-driven affinity maturation. During this process, a single germline anti-CarP antibody transitions from anti-CarP to double positive (anti-CarP/ACPA) to ACPA according to the pattern and number of somatic hypermutations, explaining their coexistence and diverse specificity in RA. Artificial intelligence-based structural modeling revealed that an ACPA and its germline precursor exhibit distinct structural and biophysical properties, and pointed to heavy-chain tryptophan 48 (H-W48) as a critical residue in the differential recognition of citrullinated vs. carbamylated proteins. Indeed, a single methionine substitution in H-W48 changes the antibody specificity from ACPA to anti-CarP. These data indicate that the existence of germline-encoded anti-CarP antibodies is most likely the first event in the production of ACPAs during the early stages of RA development.
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somatic hypermutations create pathogenic antibodies, some of which exhibit multiple autoreactivities
Is it possible that this mechanism could apply to other autoantibody-driven IMIDs like SLE?
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Thus, the data suggest that somatic hypermutations in germline-encoded anti-CarP antibodies can favor either specificity (ACPA, anti-CarP and/or anti-CarP/ACPA), which is likely determined by the type of antigen that dominates during the process of affinity maturation.
If the affinity matured antibodies no longer recognize carbamated proteins, does this suggest that follicular DCs are presenting citrullinated, non-carbamylated self-antigen in the germinal center? Does this involve a secondary tolerance break at the level of fDC antigen presentation?
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Antibodies to citrullinated and carbamylated proteins are of particular interest in RA because of their high prevalence, specificity, association with erosive disease, and appearance during the preclinical phase of RA
Are ACPAs universal in RA, or do they generally appear in a subset of cases? Do you think that autoantibodies against other antigens in RA may have similar properties?
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