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Systemic lupus erythematosus: interface between immunodeficiency, immunosuppressant therapy and infection

Abstract

Introduction: Several immunologic abnormalities reported in Systemic Lupus Erythematosus (SLE) have been reported, including abnormalities in the frequency and function of the various lymphocyte subsets, Complement system, and regulation of immunoglobulins. Recently, we have demonstrated that 28% of SLE patients present decreased IgM and IgG subclass serum levels, suggesting a subclinical immunodeficiency state. It is not clear if these abnormalities are primary or secondary to the underlying inflammatory process and immunosuppressive therapy. SLE patients are frequently treated with immunosuppressant drugs that aim to reduce the inflammatory activity. Some of these patients become vulnerable to opportunistic infections due to the immune depression caused by immunosuppressant, whereas others seem to cope well with the immunosuppressant treatment. Taken together, these observations suggest that the heterogeneity in the occurrence of opportunistic infections in SLE patients under immunosuppressant therapy may be directly associated with some degree of individual heterogeneity in the susceptibility of various lymphocyte subsets to the effects of immunosuppressant drugs. Objectives: This study has two arms: one to investigate the nature of the immunoglobulin deficiency in the context of SLE; the other one to analyze possible heterogeneity in the susceptibility of the immune system of SLE patients under immunosuppressant therapy. The study will include 330 SLE patients to be retrieved from the Rheumatology Outpatient Clinic at UNIFESP, 160 first-degree relatives of these patients (estimated guess) and 60 healthy blood donors. In the first arm (SLE & immunodeficiency), we will determine immunoglobulin serum levels, evaluate the immune phenotypic profile of peripheral blood mononuclear cells (PBMC), quantify the in vitro production of immunoglobulins, and determine the vaccine response to protein and polysaccharide antigens. In the second arm (SLE & immunosuppressant therapy), we will study patients with active lupus nephritis at the beginning of combined therapy with cyclophosphamide and methylprednisolone. Patients will be evaluated at baseline (before starting treatment) and after the fourth monthly intravenous pulse application. At these time points we will assess the immunophenotypic profile of T and B lymphocytes, monocytes and neutrophils, as well as neutrophil function, serum immunoglobulins and the vaccine response to protein and polysaccharide antigens. Material and Methods: The following parameters will be analyzed: enumeration of subsets of T and B lymphocytes, monocytes and neutrophils in PBMC; proliferation assay for B and T lymphocytes; in vitro synthesis of immunoglobulins; vaccine response to tetanus and pneumococcal antigens. For SLE patients starting immunosuppressant therapy, the analysis was performed at baseline and after 4 months of intravenous pulse therapy, except for the vaccine response that was evaluated only after the 4th month of therapy. Preliminary results: SLE patients from our cohort evaluated in the 2010 study have been followed and will be evaluated for the stability of the immunoglobulin status. We already have the serum immunoglobulin estimation for some of them. Those with low IgM or IgA serum levels in 2010 maintained the low serum level status in the evaluation performed now. In contrast, some of those originally with low IgG subclass serum levels reverted to normal serum levels in the recent evaluation. This preliminary result with a few patients suggest a different basis for IgM/IgA versus IgG subclass deficiency in SLE. The extension of this analysis will allow clarification of this interesting pathophysiologic aspect of the disease. (AU)