Winning Abstracts from the 2006 National Medical Student Poster Competition: Potential Role for IFN-a Therapy in Erosive Arthritis
.Author:
Kofi A. Mensah, University of Rochester School of Medicine & Dentistry, 2011
Introduction:
Patients with systemic lupus erythematosus (SLE), an enigmatic autoimmune condition characterized by diverse clinical features and end-organ involvement, frequently develop painful joint inflammation but, on plain x-ray, rarely manifest erosive changes like those common in rheumatoid arthritis (RA). Peripheral blood mononuclear cells (PBMC) from SLE patients have an alpha-interferon (IFN-a) signature, which stimulates their differentiation into dendritic cells (DC). Interestingly, this stimulation inhibits the differentiation of PBMC into osteoclasts (OC), the cellular mediator of erosive arthritis. Here we test the hypothesis that systemic IFN-a prevents erosive arthritis by biasing myelopoiesis towards precursor DC (pDC) and away from OC precursors (OCP) in a mutually exclusive fashion that can be characterized by the expression of unique surface molecules on the plasma membrane of precursor cells.
Methods:
The RAW 264.7 monocyte (Mo) cell line was used to evaluate the effects of 500 U/mL of recombinant IFN-a on pDC, OCP and OC in-vitro before or after culture with 100 ng/mL of the OC differentiation factor RANK-ligand (RANKL). The amounts of IFN-a and RANKL were based on published data. After culture, the cells were analyzed by fluorescence-activated cell scanning (FACS) with labeled antibodies against immune cell surface markers: c-Fms, FcgRIII, CD11b and CD11c.
Results:
OC development in RAW cell cultures was observed after two days of treatment with RANKL, while untreated cells remained as Mos. OCP presence was confirmed by FACS. OCPs were defined as c-Fms (M-CSF receptor) positive since the M-CSF cytokine stimulates Mo differentiation into OCs. When expression of FcgRIII (a Mo marker down-regulated in OCs) and CD11c (a DC marker) was compared in untreated RAW 264.7 Mo, none of the cells were CD11c+/FcgRIII– or CD11c–/FcgRIII–, 30% were CD11c–/FcgRIII+ and 70% were CD11c+/FcgRIII+. Treatment with RANKL resulted in a shift to 25% CD11c+/FcgRIII–, 7% CD11c–/FcgRIII+ and 40% CD11c+/FcgRIII+. When treated with RANKL followed by IFN-a there was no change in the percentage of double-positive cells. Treatment with IFN-a before RANKL, however, resulted in 87% double-positive cells.
Conclusion:
The CD11c+/FcgRIII+ populations decrease following RANKL treatment. In contrast, pre-treatment with IFN-a before RANKL results in a marked increase in double-positive cells, even above the level seen with neither treatment. This study suggests the potential for IFN-a therapy in treatment of erosive inflammatory arthritis based on the shift in cell populations described.
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