Background Rheumatoid arthritis (RA) is a common, destructive and non-curable autoimmune disease that affects approximately 0.5-1% of the population of the Western world. The importance of B cells in RA has regained interest in the last decade following the discovery of highly disease-specific antibodies against citrullinated proteins (ACPA) and the success of treating RA with B-cell depleting therapy. It is known that the B cell memory compartment is altered in RA, however, the kinetics, phenotype and function of the various B cell populations are not. We, and others, have uncovered an autoreactive B cell subpopulation in both mice and RA patients, which lacks the expression of the CD21 and CD23 markers and most likely belong to the memory B cell pool (1,2).
Objectives To investigate whether different B-cell subpopulations in RA patients correlate to disease activity, erosivity, autoantibody profile and clinical response, which could provide biomarkers for treatment response or even provide new treatment targets.
Methods In a cross-sectional study, female patients with manifest RA according to ACR1987 criteria (n=30, mean age: 56 y) were stratified into two groups: with and without autoantibodies (ACPA, Rheumatic Factor and/or Anti-Nuclear Antibodies). Patients with other autoimmune diseases, rituximab treatment, cancer or infections were excluded.
In an ongoing longitudinal prospective study, a spin-off project from the Scandinavian study Nord-Star (n=800), incident RA-patients (according to ACR/EULAR 1987/2010) at our site (n=50, age and sex so far not analyzed) are randomized to head-to-head treatment with methotrexate and either a) certilizumab; b) tocilizumab; c) abatacept or d) prednisolone and assessed at diagnosis and after 1, 3, 6 and 12 months.
Clinical response (DAS28), joint erosivity (X-ray), autoantibodies and B-cells are assessed. Flow cytometry is used for the analysis of the following surface markers on leukocytes in peripheral blood: CD19, CD27, CD21, CD23, CD24, CD27, CD38, PD-1, PD-L1, IgG, IgD and IgM.
Results The crossectional study indicates a pronounced variation in B-cells lacking CD21 and CD23 (CD21-CD23-). In RA patients with autoantibodies the frequency of switched memory B cells, i.e. not expressing IgM or IgD, in the CD21-CD23- subgroup is decreased compared to patients lacking autoantibodies. In addition, the absolute number of memory B cells is decreased in patients with autoantibodies and coincides with increased joint erosivity.
The ongoing longitudinal study indicates alterations particularly in the CD21-CD23 subpopulation. The difference was most pronounced between the untreated RA patients and healthy matched controls: memory B cells were decreased at diagnosis of RA but increased with treatment, while both plasmablasts and immature B cells were increased at diagnosis but decreased with treatment.
Conclusions Our data suggest that the B cell compartment is disturbed already early in the disease and that there are differences in B-cell subpopulations between RA patients with and without autoantibodies.
Keenan, R.A., de Riva, A., Martensson, I.L. et al 2008. Censoring of autoreactive b cell development by the pre-b cell receptor. Science 321:696-699.
Isnardi, I., Ng, Y.S., Menard, I., Meyers, G., et al. 2010. Complement receptor 2/cd21- human naive b cells contain mostly autoreactive unresponsive clones. Blood 115:5026-5036.
Disclosure of Interest : None declared
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