Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.


B Cell Function and Cytokine Secretion After B Cell Depletion Therapy in SLE and Rheumatoid Arthritis.

Palanichamy,  Arumugam, Roger,  James, Wang,  Wensheng, Barnard,  Jennifer, Biear,  Jamie, Wei,  Chungwen, Sanz,  Iñaki

Background/Purpose:

The physiological complexity of B cell subsets and functions has been highlighted by the variable success of rituximab (anti-CD20) based B cell depletion therapy (BCDT) in multiple autoimmune diseases including systemic lupus (SLE) and rheumatoid arthritis (RA). We have previously described that a B cell reconstitution with transitional cells is associated with sustained clinical remission while a quick resurgence of memory cells portends a poor outcome. One critical question that remains to be addressed is whether the benefit of BCDT is directly mediated by the expanded transitional cells, a putative regulatory subset, or instead reflects the absence of effector B cells or a combination of both.

Methods:

B cells from SLE (n=11) and RA patients (n11) were analyzed by multi-color flow cytometry at various times after BCDT or in untreated subjects. An additional 10 subjects were studied at baseline, 2 month, 4 month, and q4 months after BCD. Expression of CXCR3, CD21, CD95, and anchor markers (IgD, CD19, CD27, CD38, CD24 and live/dead/T-cell exclusions) were used to subset memory B cells. Expression of MitoTracker Green extrusion, CD10, IgM, CD23 and anchor markers were used to subset transitional B cells. Cytokine expression in distinct B cell subsets was examined by flow cytometry after 48 hours CpG stimulation (5 ug/ml) and 5 hr culture with PMA and ionomycin (both 500 ng/ml).

Results:

Early after BCD (<6 month) residual B cells were detectable and consisted predominantly of memory B cell populations: switched CD27+IgD- memory, CD27-IgD- memory, and plasma cells. The residual memory B cells displayed a high fraction of CD95+ and CD21- compared to pre-depletion suggesting some resistance of these activated populations to anti-CD20. In patients who had previously received rituximab but were being re-treated because of disease relapse, memory B cells were overwhelmingly CD95+, CD21-, suggesting that disease is driven by these effector memory populations. In previously rituximab naïve patients, reconstitution occurred with a variable distribution of transitional, naïve, and memory B cells, with a memory dominant profile more common in SLE and associated with a less robust clinical response. In memory vs. transitional dominant patients, there was a significantly higher fraction of activated, effector B cell populations (CD21– 51.2+21.9 vs. 12.5+7.6%; CD24– 58.5+9.7 vs. 20.5+15.9%, CD95+ 76.9+24.4 vs. 17.6+7.2%, CXCR3+ 17.2+4.8 vs. 6.6+4.5%, p<0.05). In RA the predominant IL10 producing B cell populations were naïve/transitional, but the unswitched memory had the highest relative content of IL10+ cells. In untreated SLE IL10 production shifted to include more memory B cell populations, whereas the naïve/transitional compartment became the predominant IL10 producer after BCD. IL10 production in the unswitched memory compartment also increased after BCD in this group (4.7+3.3 vs. 1.2+1.1, p=0.03).

Conclusion:

Our results support the hypothesis that the clinical and immunological outcome of BCDT depends on the relative balance of protective and pathogenic B cell subsets established after BCD and upon B cell repopulation.

To cite this abstract, please use the following information:
Palanichamy, Arumugam, Roger, James, Wang, Wensheng, Barnard, Jennifer, Biear, Jamie, Wei, Chungwen, et al; B Cell Function and Cytokine Secretion After B Cell Depletion Therapy in SLE and Rheumatoid Arthritis. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1739
DOI:

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