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Distinct lymphocyte subpopulations in bone marrow from rheumatoid arthritis and osteoarthritis patients: a role for IL-15?
Arthritis Res Thervolume 6, Article number: 85 (2004)
Recent data indicate that bone marrow plays an important role not only as a primary lymphoid organ responsible for haemopoiesis, but also as a secondary lymphoid organ with capability of antigen presentation exceeding that of lymph nodes. Although in chronic inflammatory/immune disease, like rheumatoid arthritis (RA), bone marrow participates in the initiation and/or perpetuation of the disease, there is little information about the real number of lymphocyte subpopulations in bone marrow of these patients and how they can be modulated by T-cell growth factors. IL-15 acting through IL-15 receptors (including the high-affinity IL-15R alpha chain) is a key cytokine influencing the development of natural killer cells in bone marrow, and proliferation and maintenance of the memory T-cell pool. However, there is no information about the levels of IL-15 in bone marrow.
In the present study we measured the real numbers of lymphocyte subsets in bone marrow isolated from RA and osteoarthritis (OA) patients in correlation with the levels of soluble IL-15 and surface-expressed IL-15R alpha.
Bone marrow samples, obtained from nine RA and nine OA patients (mean age 53.1 ± 10.6 years and 54.3 ± 13.6 years, respectively) undergoing joint replacement surgery, were diluted four times in heparinized PBS. Bone marrow plasma samples were obtained by centrifugation and levels of IL-15 were measured using specific ELISA. The real number of lymphocytes stained for CD3+, CD4+, CD8+ and CD19+ were counted in the presence of TruCount beads using flow cytometry. Surface-expressed IL-15R was done on cells separated by gradient centrifugation, acid wash of surface-bound IL-15 and flow cytometric analysis.
The real number of CD3+, CD4+, CD8+ T cells and CD19+ B cells, and statistical significance of these data are presented in Table 1. There were twice as many T (CD3+) cells in RA in comparison with OA bone marrow. In contrast, only 42% of B (CD19+) cells present in OA were observed in RA. Interestingly, lymphocytes isolated from RA patients expressed a significantly higher level of surface IL-15R alpha chain, indicating their activation status. In addition, there is a tendency (although not statistically significant, P = 0.08) for elevated levels of IL-15 in bone marrow plasma from RA in comparison with OA patients (2390 ± 1687 pg/ml and 1292 ± 457 pg/ml, respectively).
A highly significant increase of CD3+ (both CD4+ and CD8+) T-cell numbers in RA in comparison with OA suggest that T cells in RA are actively trafficking to bone marrow or vigorously proliferate in situ, or both. Since lymphocytes from RA, in contrast to OA, express IL-15 receptors, and since there is a tendency to higher levels of IL-15 in RA, it is likely that T cells actively proliferate in bone marrow in response to locally produced IL-15. Significantly lower B-cell numbers in RA than in OA suggest that these cells actively emigrate from RA bone marrow to peripheral blood and affected joints.