Elevated IgA Plasmablast Levels in Subjects at Risk of Developing Rheumatoid Arthritis.
The disease process in rheumatoid arthritis (RA) starts years before the clinical diagnosis is made, and elevated levels of disease-specific autoantibodies can be detected during this period. Early responses to known or novel autoantigens likely drive the eventual production of pathogenic autoimmunity. Importantly, the presence of disease-specific autoantibodies can identify individuals who are at high risk of developing RA but who do not currently have arthritis. The goal of the current study was to characterize plasmablasts from individuals at risk of developing RA.



We investigated antibody-secreting plasmablasts derived from a well-characterized cohort of individuals who were at risk of developing RA, based on RA-related serum autoantibody positivity, as compared to patients with early (<1 year) seropositive RA as well as healthy control subjects. The plasmablast antibody repertoires of at-risk subjects were analyzed using DNA barcode-based methods with paired heavy- and light-chain gene sequencing. Cells were single-cell sorted, the cell- and plate-specific DNA barcodes were sequentially added, and next-generation sequencing was performed.



Total plasmablast levels were similar in the antibody-positive (1%) and control (0.4-1.6%) groups. However, increased frequencies of IgA+ versus IgG+ plasmablasts were observed in the antibody-positive group (39% IgA+ and 37% IgG+) as compared to other groups (1-9% IgA+ and 71-87% IgG+). Paired antibody sequences from antibody-positive subjects revealed cross-isotype clonal families and similar sequence characteristics in the IgA and IgG plasmablast repertoires. Antibody-positive individuals also demonstrated elevated serum levels of IgA isotype anti-cyclic citrullinated peptide 3 antibodies.



The IgA plasmablast dominance in these antibody-positive individuals suggests that a subset of RA-related autoantibodies may arise from mucosal immune responses and may be involved in early disease pathogenesis in individuals who are at risk of developing RA.
University of Colorado School of Medicine, Aurora.
Jennifer D
JD
Kinslow
Stanford University, Stanford, California, and VA Palo Alto Health Care System, Palo Alto, California.
Lisa K
LK
Blum
University of Colorado School of Medicine, Aurora.
Kevin D
KD
Deane
University of Colorado School of Medicine, Aurora.
M Kristen
MK
Demoruelle
University of Colorado School of Medicine, Aurora.
Yuko
Y
Okamoto
University of Colorado School of Medicine, Aurora.
Mark C
MC
Parish
Stanford University, Stanford, California, and VA Palo Alto Health Care System, Palo Alto, California.
Sarah
S
Kongpachith
Stanford University, Stanford, California, and VA Palo Alto Health Care System, Palo Alto, California.
Lauren J
LJ
Lahey
Colorado School of Public Health and University of Colorado, Aurora.
Jill M
JM
Norris
Stanford University, Stanford, California, and VA Palo Alto Health Care System, Palo Alto, California.
William H
WH
Robinson
University of Colorado School of Medicine, Aurora. Michael.Holers@ucdenver.edu.
V Michael
VM
Holers
D000328:Adult; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology; D005260:Female; D050438:Genes, Immunoglobulin Heavy Chain / Q000235:genetics; D050439:Genes, Immunoglobulin Light Chain / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007070:Immunoglobulin A / Q000235:genetics / Q000276:immunology*; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology*; D010950:Plasma Cells / Q000276:immunology*; D012217:Rheumatoid Factor / Q000276:immunology*; D012306:Risk; D017422:Sequence Analysis, DNA
D001323:Autoantibodies; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D012217:Rheumatoid Factor