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.
Lipid-Antigen Presentation by CD1d B Cells Is Essential for the Maintenance of Inkt Cells: Aberrant B Cells From Patients with Systemic Lupus Erythematosus Impair Inkt Cell Homeostasis.
Bosma1, Anneleen, Abdel-Gadir1, Azza, Isenberg2, David A., Mauri1, Claudia, Jury1, E.C.
Systemic lupus erythematosus (SLE) is characterized by a profound breakdown in immune-regulatory mechanisms. Disease pathogenesis is complex but recent research has centred on the role of B cells secreting pathogenic auto-antibodies. However, B cells have other essential functions including CD1d-mediated lipid-antigen presentation to invariant natural killer T (iNKT) cells, a specialised T cell subset with regulatory function in both innate and adaptive immunity. Very few studies have examined the role of B cells on the maintenance of iNKT cells in the context of lupus. Profound reductions in iNKT cell frequency have been reported in SLE patients. To consider the in vivo role that B cells play in iNKT cell homeostasis and whether B cell dysfunction drives iNKT cell abnormality in lupus patients, we exploited B cell depletion therapy (rituximab) as an in vivo human model.
Peripheral blood mononuclear cells (PBMC) were collected from 250 patients with SLE and 90 healthy controls. Patients had active disease (BILAG>6) before rituximab treatment. Patients were considered B cell depleted (BCD) when B cell levels were below 5 cells/ml and in most cases their disease became inactive (BILAG <6). Responding patients remained in remission with inactive disease after B cell repopulation; non-responding patients developed active disease when B cells repopulated. B cell and iNKT cell phenotyping was determined by flow cytometry. To assess iNKT cell function PBMC were stimulated with a-galactocylceramide (aGC) for 7 days and iNKT cell proliferation and aGC driven cytokine profiles determined.
SLE iNKT cells displayed an activated phenotype with clustered invariant (i)TCRs compared with dispersed iTCR distribution in iNKT cells from healthy individuals. In addition, compared to healthy, lupus iNKT cells expressed increased levels of CD69 paralleled by enhanced expression of surface Annexin V. Furthermore, we show that while healthy iNKT cells proliferate in response to in vitro a- aGC stimulation, SLE iNKT cells lack this capacity. When lupus patients were treated with rituximab, iNKT cell numbers remained low in the absence of B cells and in patients who had repopulated their B cell populations but did not respond clinically to treatment. However, iNKT cell numbers increased in patients with repopulated B cells responding to treatment, iNKT cells from these patients also regained their capacity to proliferate in response to aGC. We found that B cells from patients with SLE display significantly reduced levels of surface CD1d, compared to the levels expressed by healthy B cells. The expression of CD1d on B cells was exclusively recovered on B cell-repopulated patients responding to rituximab therapy and directly correlated with iNKT frequency.
These findings support our hypothesis that auto-reactive B cells in SLE patients impair iNKT cell-mediated responses and that B cell depletion therapy may restore this interaction by "resetting" the balance of B cell-iNKT cell homeostasis.
Funded by Arthritis Research UK Career Development award to ECJ (18106) and programme grant to CM (MP/17707) and Nuffield Foundation Oliver Bird Rheumatism Programme (AB). ECJ and CM share senior authorship.
To cite this abstract, please use the following information:
Bosma, Anneleen, Abdel-Gadir, Azza, Isenberg, David A., Mauri, Claudia, Jury, E.C.; Lipid-Antigen Presentation by CD1d B Cells Is Essential for the Maintenance of Inkt Cells: Aberrant B Cells From Patients with Systemic Lupus Erythematosus Impair Inkt Cell Homeostasis. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1662