Changes in peripheral B cell subsets under immunosuppressive therapy
Normal homeostasis of the immune system is critical for the maintenance of immunological tolerance and immunocompetence. Failure of self-tolerance results in autoimmune reactions which may progress to chronic autoimmune diseases. B cells play an important role in the pathogenesis of autoimmune diseases and influence autoimmunity through multiple pathways. With the availability of informative B cell surface markers it is now possible to identify within the circulating B cell compartment (CD19+) at least 4 subsets: naive B cells (CD27-), IgM memory B cells (CD27+IgM/D+), switched memory B cells (CD27+IgM/D-) and plasma cells (CD27+CD38+CD24-). For the first time this B cell subset analysis was performed in three established autoimmune conditions (systemic lupus erythematosus (SLE), wegener's granulomatosis (WG), chronic graft versus host disease (GvHD)) with special emphasis on changes induced by immunosuppressive therapy (disease modifying antirheumatic drugs (DMARDs)) and cyclophosphamide (CYC) treatment. There was a significant impact of immunosuppressive treatment on peripheral B cell subsets in SLE and WG patients. Absolute lymphocyte numbers and CD19+ B cell counts were significantly decreased, as were naive B cells and switched memory B cells. Plasma cells tended to show a relative but not an absolute increase. In SLE patients the most significant decrease was observed for IgM memory B cells after CYC and DMARD therapy: absolute and relative cell counts were very low and remained so for a mean period of over 3 years after the last CYC treatment. Untreated SLE patients showed no significant decrease of IgM memory B cells. It is suggested that remission inducing therapy with CYC has a profound and long-lasting impact on total lymphocytes and peripheral B cell subsets in SLE and WG patients. Notably the IgM memory B cells are seriously hit. In contrast, plasma cells which can hide in protected niches of bone marrow and lamina propria intestini appear to be quite resistant to conventional immunosuppressive therapy. As IgM memory B cells provide the first T cell independent humoral immune response to bacterial polysaccharides from Streptococcus pneumoniae and Hemophilus influenzae it may be predicted that primary immune responses against these bacterial antigens are severely compromised in CYC and DMARD treated patients. It has recently been shown that splenectomy and congenital asplenia cause a profound and long-lasting loss of IgM memory B cells together with an impairment of the immune response to pneumococcal polysaccharides. As successful allogeneic stem cell transplantation (allo-SCT) patients with stable chimerism often show signs of functional asplenia with appearance of Howell-Jolly bodies in erythrocytes we were interested to study B cell subsets in those patients. After a mean follow-up of 4.7 years 12 clinically stable allo-SCT recipients (five with positive Howell-Jolly bodies) exhibited a profound decrease of IgM memory B cells similar to splenectomized or CYC treated SLE and WG patients. There was no difference in IgM memory B cells numbers between allo-SCT recipients with and without functional asplenia as evidenced by the occurence of Howell-Jolly bodies. Ten of the 12 patients have an ongoing mild to moderate GvHD, suggesting that this process may impede IgM memory formation in the spleen. In any case the presented findings underline that the generation of IgM memory B cells is critically dependent on a functional spleen and is highly susceptible to CYC and DMARD treatment.
systemische Lupus erythematodes (SLE), Wegener-Granulomatose (WG), chronische Transplantat-gegen-Wirt -Reaktion (GvHD), systemic lupus erythematosus (SLE), Wegener's granulomatosis (WG), chronic graft versus host disease (GvHD)
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