Background/Purpose:

A skewed B cell receptor (BCR) repertoire was observed in some RA patients. In these patients, BCR κ light chains contain a higher percentage of downstream Vκ and upstream Jκ gene segments rather than the broader utilization of Vκ-Jκ gene segments seen in healthy donor (HD) controls. How this BCR phenotype occurs and whether it relates to erosive disease is unclear.

Methods:

Peripheral blood B cells were obtained from 40 seropositive RA patients meeting ACR classification criteria. Vκ and Jκ gene segment usage was determined by PCR and allowed patients to be separated into two groups. Erosive disease prevalence was compared between the groups. Gene microarray was done on B cells from each group to determine candidate genes for further investigation and we developed in vitro and in vivo models based on this to investigate mechanisms for the observed differences.

Results:

We identified a subgroup of RA patients whom we call group I in which BCR κ light chains contain a higher percentage of downstream Vκ and upstream Jκ gene segments compared to HD controls suggesting abnormalities in RAG-mediated BCR V(D)J rearrangement. BCRs in a second subgroup, group II, had broader utilization of Vκ-Jκ gene segments similar to that of HD. B cell gene array showed decreased ataxia-telangiectasia mutated (ATM) in group I vs group II. ATM is a key regulator of DNA double-strand break repair, RAG expression, and BCR κ locus allelic exclusion during RAG-induced V(D)J rearrangement. Intriguingly, group I RA patients had a higher prevalence of erosive disease despite no differences in age, disease duration, RF, or ACPA titers between the groups. To determine if lack of functional ATM independent of other RA disease factors could explain the increased erosive prevalence in group I, we pharmacologically inhibited ATM in vitro in HD control B cells and found increased pro-osteoclastogenic B cell RANKL, IL6 and TNF expression and decreased anti-osteoclastogenic OPG and anti-inflammatory IL10 expression. To determine if decreased B cell ATM expression in the absence of RA disease could account for the skewed BCR Vκ-Jκ segment usage in RA group I, we examined B cells from ataxia-telangiectasia (A-T) patients lacking ATM. BCRs from A-T patients showed the same skewed Vκ-Jκ gene segment usage seen in group I RA patients. We utilized the NSG “humanized” mouse model transplanted with non-RA human hematopoietic stem cells to examine developing human bone marrow B cells undergoing V(D)J recombination. ATM inhibition led to an increased immature B cell CD69+CXCR4+ phenotype indicative of retention in the bone marrow and an increased proportion of BCRs expressing λ light chains with evidence of κ chain deletion.

Conclusion:

We have identified a novel way of subgrouping RA patients. Group I RA patients lack broad BCR Vκ-Jκ gene segment utilization, which can be explained by relatively insufficient B cell ATM expression. Lack of sufficient functional B cell ATM can also explain the increased erosive disease prevalence in group I compared to group II RA patients. Thus, subgrouping RA patients in the manner presented here has important implications for diagnosis, prognosis and treatment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/decreased-b-cell-ataxia-telangiectasia-mutated-expression-and-receptor-diversity-identify-a-subset-of-rheumatoid-arthritis-patients-with-increased-joint-erosion-prevalence/