Production of Autoantibodies against Citrullinated Antigens/Peptides by Human B Cells

Abstract

Autoantibodies against citrullinated protein Ags (ACPA) are associated with the development of rheumatoid arthritis (RA). This immune response against citrullinated protein Ags, which is thought to be facilitated by certain MHC HLA-DR alleles, is highly specific for this disease and has been speculated to be involved in the pathogenesis. We have previously studied cultures of B cells for the production of Abs against HLA Ags. The aim of the current study was to examine the role of B cells in the production of ACPA in patients with RA. Peripheral blood B cells from RA patients and healthy people were cultured with EL4-B5, a murine cell line expressing human CD40L, and with T cell factors to stimulate the in vitro production of Abs by B cells isolated from peripheral blood. ACPA were produced by cultured B cells from RA patients, as determined by reactivity to cyclic citrullinated peptide (CCP). The results showed that 22% of the healthy persons tested also had B cells that could produce ACPA. Patients with HLA-DR alleles carrying the RA-associated shared epitope appeared to have more B cells with autoimmune potential for CCP than those without such HLA alleles (odds ratio 8.1, p = 0.001). In healthy individuals, anti-CCP–producing B cells were also observed more frequently if the RA-associated MHC genes were present (odds ratio 8.0, p = 0.01). Analysis of B cells in cultures may shed light on the interaction of genetic and environmental factors in the development of RA.

Circulating plasmablasts/plasmacells as a source of anticitrullinated protein antibodies in patients with rheumatoid arthritis

“…A single study detected ACPA production in cultures of synovial fluid mononuclear cells 9. Another study identified ACPA production by peripheral blood B cells upon stimulation 10. However, it remained unclear whether ACPA detected in this latter study originated primarily from stimulated, otherwise resting memory B cells, or from circulating, differentiated plasmablasts/cells (PB/PC).…”

The role of anti-cyclic citrullinated peptide (CCP) antibodies in early detection of rheumatoid arthritis: an overview of the INOVA Diagnostics, Inc. QUANTA Lite CCP assays

“…Bellatin et al [31] demonstrated that B cells from RA patients produce IgG anti-CCP3 antibodies (INOVA Diagnostics, Inc.), and this production occurred in patients who had detectable anti-CCP antibodies in serum. However, normal subjects who did not have anti-CCP antibodies in serum produced anti-CCP antibodies in B-cell cultures.…”

The effect of targeted rheumatoid arthritis therapies on anti-citrullinated protein autoantibody levels and B cell responses

“…In addition, a DR1 allele is present in many Caucasian RA patients who are negative for DR4 alleles. All the RA-associated HLA alleles share a region of highly similar amino acid sequences (amino acids [67][68][69][70][71][72][73][74] called the shared epitope (SE), which has been postulated to control susceptibility to disease [5]. Among the important potential pathogenic peptides presented by the SE are citrullinated peptides.…”

“…The changes in lymphoid architecture mediated by TNF antagonists may contribute to the reductions in memory B cells noted in RA patients treated with these therapies [62,65,66], which may be important, as memory B cells in RA patients express anti-CCP autoantibodies [67]. In addition, TNF antagonists decrease the proportion of memory B cells expressing CD86 after 6 months of therapy [68].…”