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Arthritis Rheumatol. 2018 Nov;70(11):1732-1744. doi: 10.1002/art.40578. Epub 2018 Sep 24.

T Cell-Dependent Affinity Maturation and Innate Immune Pathways Differentially Drive Autoreactive B Cell Responses in Rheumatoid Arthritis.

Author information

1
Stanford University, Stanford, California, and VA Palo Alto Health Care System, Palo Alto, California.
2
University of Rochester Medical Center, Rochester, New York.
3
Stanford University, Stanford, California.
4
Fred Hutchinson Cancer Research Center, Seattle, Washington.

Abstract

OBJECTIVE:

Rheumatoid arthritis (RA) is characterized by the activation of B cells that produce anti-citrullinated protein antibodies (ACPAs) and rheumatoid factors (RFs), but the mechanisms by which tolerance is broken in these B cells remain incompletely understood. We undertook this study to investigate whether ACPA+ and RF+ B cells break tolerance through distinct molecular mechanisms.

METHODS:

We developed antigen-tetramers to isolate ACPA+ and RF+ B cells and performed single-cell RNA sequencing on 2,349 B cells from 6 RA patients and 1 healthy donor to analyze their immunoglobulin repertoires and transcriptional programs. Prominent immunoglobulins were expressed as monoclonal antibodies and tested for autoantigen reactivity.

RESULTS:

ACPA+ and RF+ B cells were enriched in the peripheral blood of RA patients relative to healthy controls. Characterization of patient-derived monoclonal antibodies confirmed ACPA and RF targeting of tetramer-specific B cells at both antigen-inexperienced and affinity-matured B cell stages. ACPA+ B cells used more class-switched isotypes and exhibited more somatic hypermutations relative to RF+ B cells, and these differences were accompanied by down-regulation of CD72 and up-regulation of genes that promote class-switching and T cell-dependent responses. In contrast, RF+ B cells expressed transcriptional programs that stimulate rapid memory reactivation through multiple innate immune pathways. Coexpression analysis revealed that ACPA+ and RF+ B cell-enriched genes belong to distinct transcriptional regulatory networks.

CONCLUSION:

Our findings suggest that ACPA+ and RF+ B cells are imprinted with distinct transcriptional programs, which suggests that these autoantibodies associated with increased inflammation in RA arise from 2 different molecular mechanisms.

PMID:
29855173
PMCID:
PMC6203609
[Available on 2019-11-01]
DOI:
10.1002/art.40578

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