Single-cell immunomics reveals the immunological hallmarks about the onset and different outcomes for ankylosing spondylitis patients.

Abstract

Objectives: The immunological hallmarks associated with ankylosing spondylitis (AS) occurrence and development were unclear.

Method: After recruiting healthy donors and patients in different stages, we performed single-cell RNA sequencing for peripheral blood mononuclear cells (PBMCs) and relied on T-cell receptor (TCR) and B-cell receptor (BCR) analyses to explore the immunological patterns causing AS onset and different outcomes.

Results: Effector T/B cells possessed marked clonal expansion and AS lesions were characterized by B-cell clonal expansion. However, patients in remission showed weak T/B-cell clonal expansion. The usage of top 10 CDR3 sequences and the rearrangement of V(D)J genes in AS remission was less diverse. BCR-V(D)J rearrangement in healthy donors was more specific. AS different stages all exhibited preferred TRA genes (TRAV17 for onset, TRAV9-2 for aggravation, and TRAV23/DV6 and TRAJ56 for remission) and TRBV12-5 was overrepresented in remission. The top two paired TCR-V/J genes for AS different stages were all different (TRBV20-1/TRBJ2-1 and TRAV14/DV4/TRAJ53 for onset, TRBV7-9/TRBJ2-5 and TRBV20-1/TRBJ2-3 for aggravation, and TRBV27/TRBJ2-1 and TRBV28/TRBJ2-1 for remission). IGHV3-30 and IGHV4-30-2 were overrepresented in remission and the top two paired BCR-V/J genes for AS different stages were also different (IGHV3-23/IGHJ4 and IGHV3-7/IGHJ3 for onset, IGLV1-44/IGLJ2 and IGHV3-7/IGHJ4 for aggravation, and IGHV3-74/IGHJ4 and IGLV3-1/IGLJ2 for remission).

Conclusion: These findings provide insights into the dynamic immune-response features of AS onset and outcomes, suggesting that there is an important connection between driving AS lesions and B-cell clonal expansion, and decreased V(D)J usage diversity in remission has guiding value for inducing rapid remission in AS patients. Key Points • Differential immunodominant epitopes in T/B-cell responses are associated with AS onset and different outcomes. • The specificity of BCR-V(D)J in AS patients determines the driving effect of B-cell clonal expansion on AS lesions. • Decreased V(D)J-usage diversity in remission results in the contribution of inadequate clonal expansion to AS remission.