Introduction
Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease that develops in genetically susceptible individuals in response to environmental factors(1). The pathogenesis remains to be fully elucidated. Autoantibodies are key mediators in determining the clinical manifestations of SLE. The mechanisms by which antibodies may be harmful to self-tissues encompassed complement mediated inflammation, cell apoptosis and immune-complexes mediated damage. However, the precise cooperation of antibodies in SLE have not been unraveled so far(2).
Apoptosis is an energy-dependent process that leads to the programmed destruction of cells. It is tightly regulated by the expression of cell surface molecules such as Fas and intracellular protooncogenes including Bcl-2 and the Bax family members(3). It has been proved that apoptotic signaling pathway is obviously disordered in SLE patients. Abnormal expression of a large number of apoptotic signaling molecules such as TNF-related apoptosis inducing ligand (TRAIL), TNF-like weak inducer of apoptosis (TWEAK) and death ligand FasL (Fas ligand) leads to abnormal increase of apoptotic cells(4, 5). In addition, the body of SLE patients also has obstacles to the removal of apoptotic cells. Cell death, including apoptosis, necrosis and NETosis (special cell death of neutrophil through NETs), is the major potential resource of self-dsDNA which activates the immune system and leads finally to autoimmune disease(6).
Natural immunity is responsible for identification and elimination of damaged and apoptotic cells. Meanwhile, it also complete the intricate regulation of inflammatory response and enhance immune tolerance. Natural IgM(nIgM) is an important component of the body’s innate immune system. nIgM is an evolutionarily conserved molecule and reacts with a variety of epitopes expressed on both self-and non-self antigens (7). nIgM deficiency is associated with an increased tendency toward the development of autoimmune disease. It plays a key role in the clearance of apoptotic cells and prevents apoptotic cells from inducing abnormal autoimmunity.
B-1 cells and innate-like B cells (ILBs) are proved to be the major producer of natural IgM. Early transfer experiments showed that more than 80% of serum natural IgM is derived from B1 cells(8). ILBs are heterogeneous populations of unconventional B cells with innate sensing and responding properties. In mice, ILBs are composed of B1 cells, marginal zone (MZ) B cells and other related B cells. CD19+CD27+IgD+B cells which are also termed as un-switched memory B cells have been proposed to be a kind of human ILBs(9). ILBs maintain natural IgM levels at steady state, and they can rapidly acquire immune regulatory activities through the secretion of natural IgM and IL-10 after innate activation(10). Our previous study indicated that CD27+IgD+B cells were impaired in rheumatoid arthritis (RA) with dysfunctional features, which might contribute to the disease perpetuation(11). Nevertheless, the characteristics of CD27+IgD+ B cells and their potential role in SLE are largely unknown.
In this study, we determined the frequencies and natural antibody-like IgM-producing capacity of CD27+IgD+B cells in SLE patients. In addition, we also analyzed their clinical associations and revealed their tendency after therapy.