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

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

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.

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).

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.