T-regulatory cells exhibit a biphasic response to prolonged endurance exercise in humans.

PURPOSE: T-regulatory cells (Tregs) are a sub-population of lymphocytes that act to suppress aberrant immune responses. We investigated changes in the numbers of naïve and terminally differentiated Tregs in the peripheral blood to establish their role in the immuno-suppressive response to prolonged exercise. METHODS: Blood was drawn from seventeen experienced runners (age 40 ± 12 years; height 1.75 ± 0.08 m; mass 71.4 ± 10.8 kg) before, ~1 h after (POST-1h), and on the day following the marathon (POST-1d). Tregs (CD3+CD4+Foxp3+CD25++CD127-) were analysed in peripheral blood mononuclear cells using flow cytometry. The markers CD45RA and HLA-DR were included to define naïve and terminally differentiated Tregs, respectively. RESULTS: The absolute number of Tregs decreased (27%) POST-1h marathon (P < 0.001) but increased (21%) at POST-1d (P < 0.01). Naïve CD45RA+ Tregs fell by 39% POST-1h (P < 0.01) but were unaffected POST-1d (P > 0.05). In contrast, an increased number of Tregs expressing HLA-DR was observed at POST-1d (P < 0.01). Interleukin (IL)-1ß, IL-6, IL-8 and IL-10 levels in the serum all increased POST-1h (P > 0.05) but returned to pre-exercise levels POST-1d. The suppressive cytokine, transforming growth factor-beta, was unaffected by the marathon (P > 0.05). CONCLUSIONS: These results suggest that Tregs do not play a major role in immune suppression in the early hours of recovery from a marathon. However, terminally differentiated HLA-DR+ Tregs are mobilized the following day, which could represent a compensatory attempt by the host to restore immune homeostasis and limit excessive cell damage.

Induction of long-term B-cell depletion in refractory rheumatoid arthritis patients preferentially affects autoreactive more than protective humoral immunity.

INTRODUCTION: B-cell depletion has become a common treatment strategy in anti-TNF-refractory rheumatoid arthritis (RA). Although the exact mechanism of how B-cell depletion leads to clinical amelioration in RA remains to be elucidated, repetitive treatment with B-cell-depleting agents leading to long-term B-cell depletion has been reported to be beneficial. The latter has led to the hypothesis that the beneficial effects of B-cell depletion might act through their influence on pathogenic autoreactive plasma cells. METHODS: In this study, we investigated the effects of a fixed retreatment regimen with anti-CD20 mAbs on the humoral (auto)immune system in a cohort of therapy-refractory RA patients. RESULTS: Fixed retreatment led to long-term B-cell depletion in peripheral blood, bone marrow and, to a lesser extent, synovium. Also, pathologic autoantibody secretion (that is, anticitrullinated peptide antibodies (ACPAs)) was more profoundly affected by long-term depletion than by physiological protective antibody secretion (that is, against measles, mumps and rubella). This was further illustrated by a significantly shorter estimated life span of ACPA-IgG secretion compared to total IgG secretion as well as protective antibody secretion. CONCLUSION: By studying plasma cell function during an extensive 2-year period of B-cell depletion, autoantibody secretion was significantly shorter-lived than physiologically protective antibody secretion. This suggests that the longevity of autoreactive plasma cells is different from protective long-lived plasma cells and might indicate a therapeutic window for therapies that target plasma cells.