Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Cellular and Serological Changes Following B Cell Repopulation after Rituximab Therapy Suggest Antibody-Independent Roles for B Cells in Systemic Lupus Erythematosus.
N. Lazarus, Mark, Fester, Andrew, Turner-Stokes, Tabitha, A. Isenberg, David, R. Ehrenstein, Michael
For the last ten years B cell depletion therapy (BCDT) has been used in the treatment of systemic lupus erythematosus (SLE). However, the clinical improvements that follow BCDT are not always associated with a reduction in autoantibody titres suggesting that B cells might also induce disease via antibody-independent mechanisms.
The aim of this study was to investigate whether B cells exert an effect on other immune cells which are known to be low in the blood of patients with active disease.
We analysed changes in the titres of anti-dsDNA antibodies, C3 and lymphocyte and monocyte numbers in the blood of 55 patients with SLE during B cell depletion and over a 52 week period following repopulation. PBMCs were obtained from 53 rituximab treated patients and analysed by flow cytometry for the expression of the activation markers CD69 and HLA-DR by CD4+ T cells. Chemokines were measured in the serum of 19 rituximab treated patients using a cytometric bead assay. In vitro experiments were carried out using PBMCs from 5 healthy controls and 5 patients with SLE.
Our results showed that in patients with high anti-dsDNA antibody titres (above 100 IU/L) pre BCDT titres only fell in patients who remained in remission at 52 weeks following B cell repopulation (p<0.05) but did not change in patients that relapsed, either during the B cell depletion phase or during repopulation. C3 levels rose during B cell depletion and fell again during relapse but only in patients with high anti-dsDNA antibodies pre-BCDT (p<0.01; p=0.07). Lymphocyte numbers increased during repopulation in all patients (p<0.05) but fell during relapse only in patients who had low titres of anti-dsDNA antibody pre-BCDT (p<0.05). The fall in lymphocytes was paralleled by an increase in the expression of HLA-DR by CD4+CD49d+ T cells (p<0.05). Expression of CD69 was increased in all lupus patients and did not change following B cell depletion. In vitro experiments revealed that B cell activation directly led to increased expression of HLA-DR, but not CD69, on CD4+ T cells. Finally, monocyte numbers increased during depletion and fell during relapse in all groups (p<0.05). These changes in monocyte numbers coincided with a reduction in the serum levels of the monocyte recruiting chemokine, MCP-1 (p<0.05). MCP-1 production increased in vitro when PBMCs were stimulated through the B cell receptor (p<0.05).
These results demonstrate that changes in anti-dsDNA antibody and C3 correlate with response to BCDT but only in patients with high titres of anti-dsDNA antibody pre-BCDT. In patients with low anti-dsDNA titres pre-BCDT changes in lymphocyte and moncyte numbers may be more important. These changes in lymphocyte and monocyte numbers correlated with changes in HLA-DR expression by CD4+ T cells and MCP-1 levels respectively, suggesting that B cells might also induce the migration of T cells and monocytes to sites of inflammation in addition to producing autoantibodies. In conclusion, these results suggest that responses to rituximab may be partly governed by antibody independent mechanisms providing an explanation for some of the heterogeneous responses to BCDT that have been observed in SLE.
To cite this abstract, please use the following information:
N. Lazarus, Mark, Fester, Andrew, Turner-Stokes, Tabitha, A. Isenberg, David, R. Ehrenstein, Michael; Cellular and Serological Changes Following B Cell Repopulation after Rituximab Therapy Suggest Antibody-Independent Roles for B Cells in Systemic Lupus Erythematosus. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :740