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. 2005 May 16;201(10):1659-67.
doi: 10.1084/jem.20042321.

Impaired early B cell tolerance in patients with rheumatoid arthritis

Jonathan Samuels  1 , Yen-Shing Ng, Claire Coupillaud, Daniel Paget, Eric Meffre
Affiliations

Impaired early B cell tolerance in patients with rheumatoid arthritis

Jonathan Samuels et al. J Exp Med. .

Abstract

Autoantibody production is a characteristic of most autoimmune diseases including rheumatoid arthritis (RA). The role of these autoantibodies in the pathogenesis of RA remains elusive, but they appear in the serum many years before the onset of clinical disease suggesting an early break in B cell tolerance. The stage of B cell development at which B cell tolerance is broken in RA remains unknown. We previously established in healthy donors that most polyreactive developing B cells are silenced in the bone marrow, and additional autoreactive B cells are removed in the periphery. B cell tolerance in untreated active RA patients was analyzed by testing the specificity of recombinant antibodies cloned from single B cells. We find that autoreactive B cells fail to be removed in all six RA patients and represent 35-52% of the mature naive B cell compartment compared with 20% in healthy donors. In some patients, RA B cells express an increased proportion of polyreactive antibodies that can recognize immunoglobulins and cyclic citrullinated peptides, suggesting early defects in central B cell tolerance. Thus, RA patients exhibit defective B cell tolerance checkpoints that may favor the development of autoimmunity.

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Figures

Figure 1.
Figure 1.
RA B cells express antibodies with unusually long CDR3s. Increased frequency of Igκ genes with unusually long ≥11−amino acid CDR3s in new emigrant B cells from RA patients. Differences in frequency of Igκ genes with ≥11−amino acid CDR3s between healthy donors and RA patients were found to be statistically significant (P = 0.008).
Figure 2.
Figure 2.
RA B cells can express an antibody repertoire consistent with either decreased or increased secondary V(D)J recombination. (A) Increased Jκ1 usage in new emigrant B cells from RA01, RA02, and RA08 patients. Pie charts show the proportion of different Jκ genes. The number of sequences analyzed in each fraction is indicated below the pie charts. Control healthy donor new emigrant B cells from HD01, HD02, and HD03 were previously reported (13, 14). *, Indicates statistically significant difference (RA01: 53.1%, P = 0.025; RA02: 51.4%, P = 0.02; and RA08: 47.9%, P = 0.027). (B) Decreased upstream (5′) Vκ usage in RA01, RA02, and RA08 new emigrant B cells. The proximal Vκ locus involved in 95% of Vκ−Jκ rearrangements is shown clustered into four groups of Vκ genes. Genes from the distal locus were combined to the upstream Vκ group. The percent of each Vκ group is indicated on the Y axis. *, Indicates statistically significant difference (RA02: P = 0.044; combined RA01, RA02, RA08: P = 0.0042). (C) The new emigrant B cell Igκ repertoire in RA06 is consistent with increased secondary V(D)J recombination in developing B cells. Patients' and healthy donor controls' upstream Vκ usage frequency was plotted against that of downstream Jκ3-4-5 usage. Increased upstream Vκ usage in RA06 was found to be statistically significant (P = 0.033). (D) Increased Jκ1 usage in some RA patients is associated with a lower frequency of ≥11–amino acid–long Igκ CDR3s in new emigrant B cells. Patients' and healthy donor controls' Jκ1 usage frequency was plotted against that of ≥11–amino acid–long Igκ CDR3s.
Figure 3.
Figure 3.
Increased frequency of HEp-2–reactive antibodies in mature naive B cells from RA patients. Data shown are from ELISAs for anti–HEp-2 cell reactivity of recombinant antibodies cloned from (A) new emigrant and (B) mature naive B cells from RA patients. Dotted lines show ED38 positive control (13, 17). The percentage of autoreactive clones for each fraction and their p-values for differences with controls are indicated. *, The controls for new emigrant and mature naive B cells isolated from HD01, HD02, HD03, and HD04 were previously reported (13, 14).
Figure 4.
Figure 4.
RA B cells express polyreactive antibodies. Antibodies from (A) new emigrant and (B) mature naive B cells from RA patients were tested by ELISAs for reactivity with single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), insulin, and lipopolysaccharide (LPS). Dotted lines show ED38-positive control (13, 17). Percentages represent frequency of polyreactive antibodies in each fraction. *, The controls for new emigrant and mature naive B cells isolated from HD01, HD02, HD03, and HD04 were previously reported (13, 14).
Figure 5.
Figure 5.
RA peripheral B cells contain rheumatoid factor and anti-CCP clones. Antibodies from new emigrant and mature naive B cells from RA patients were tested by ELISAs for reactivity against IgG (A and B) and CCP (C and D). Dotted lines show either ED38-positive control (A and B) or serum anti-CCP IgG-positive control (C and D). Percentages represent frequency of anti-CCP antibodies in each fraction. P-values are in comparison to control new emigrant B cells (13, 14).
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