Abstract
Antibody-mediated allograft rejection (AMR) hinders patient prognosis after organ transplantation. Current studies concerning AMR have mainly focused on the diagnostic value of immunoglobulin G (IgG)-type donor-specific antihuman leukocyte antigen antibodies (DSAs), primarily because of their antigen specificity, whereas the clinical significance of immunoglobulin M (IgM)-type DSAs has not been thoroughly investigated in the context of organ transplantation because of their nonspecificity against antigens. Although consensus regarding the clinical significance and role of IgM antibodies is not clear, as discussed in this review, recent findings strongly suggest that they also have a huge potential in novel diagnostic as well as therapeutic application for the prevention of AMR. Most serum IgM antibodies are known to comprise natural antibodies with low affinity toward antigens, and this is derived from B-1 cells (innate B cells). However, some of the serum IgM-type antibodies reportedly also produced by B-2 cells (conventional B cells). The latter are known to have a high affinity for donor-specific antigens. In this review, we initially discuss how IgM-type antibodies of different origins participate in the pathology of various diseases, directly or through cell surface receptors, complement activation, or cytokine production. Then, we discuss the clinical applicability of B-1 and B-2 cell-derived IgM-type antibodies for controlling AMR with reference to the involvement of IgM antibodies in various pathological conditions.
Highlights
Many reports have described the close relationship between donor-specific antihuman leukocyte antigen antibodies (DSAs) and the development of antibody-mediated allograft rejection (AMR) and the difficulties in eliminating long-lived bone marrow plasma cells (PCs), which are known to produce immunoglobulin G (IgG)-type DSAs [1,2]
The clinical significance of immunoglobulin M (IgM) antibodies has been evaluated in fields such as infection, autoimmune diseases and cancers, and their potential organ-protective and antiinflammatory effects, as well as utility in evaluating pathological conditions, have been reported
The clinical significance of IgM antibodies has not received substantial attention because no consensus has yet been reached regarding the mechanism by which IgM antibodies participate in the survival of transplanted grafts
Summary
Many reports have described the close relationship between donor-specific antihuman leukocyte antigen antibodies (DSAs) and the development of antibody-mediated allograft rejection (AMR) and the difficulties in eliminating long-lived bone marrow plasma cells (PCs), which are known to produce IgG-type DSAs [1,2]. Antibodies against ABO blood group antigens, which are representative of IgM and IgG antibodies, induce the development of AMR, causing transplanted graft failure in ABO-incompatible liver transplant recipients [13,14,15]. B-1a cells play a remarkably protective role against acute lung injury induced by sepsis by controlling exaggerated inflammation and infiltration of neutrophils in lungs [46] These cells reportedly produce IL-10, which suppresses the proinflammatory response and contributes to the resolution of inflammation-induced injury These reports indicate that B-1a cells could play a crucial role in immunoprotection against inflammation, tissue injury and immunological attacks, either by secreting natural IgM antibodies or IL-10 as well as other immunoregulatory molecules [47,48,49,50,51,52,53,54,55]. The possibility of B1-b cell differentiation into cells with these diverse functions plays an important role as a bridge between innate and adaptive of immunity [27,41,64,65,66] (Figure 1)
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