In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 40 ( 2012-10-02)
Abstract:
Our results define a unique pathway for regulating immunity and tolerance. We propose that IgM antibodies promote humoral immune responses to foreign antigen yet suppress autoantibody production through at least the complement activation cascade and FcμR signaling pathway ( Fig. P1 ). We do not know whether FcμR and CR on B cells work independently, or cooperate or compete with each other, to regulate immunity and tolerance of B cells under different circumstances. Our results also suggest an autoregulatory mechanism of B-cell activation by the kinetics of antibodies they produce and their isotypes. In addition to FcμR, B cells express an IgG Fc receptor, FcγRIIB, which inhibits B-cell activation on binding of IgG antibody–antigen complexes. Therefore, B cells express two types of Fc receptors with opposing functions. We propose that during the early phase of the response, when IgM production is dominant, B-cell activation is favored and is augmented through the FcμR. However, later in the response, when IgG production becomes dominant, further B-cell activation is attenuated by FcγRIIB-mediated inhibition. This mechanism has significant implications for understanding the etiology of immunological disorders where there is altered production of IgM vs. IgG antibodies, such as in the hyper-IgM syndrome. Patients with hyper-IgM syndrome are immunodeficient due to defects in the production of IgG and other class-switched antibodies. Paradoxically, these patients frequently develop autoimmune diseases. Our results suggest that on infection, these patients produce increased levels of IgM but little IgG, resulting in sustained or prolonged activation of B cells, some of which may produce antibodies that cross-react with self-antigens and cause autoimmunity. Blocking the IgM/FcμR interaction with specific antibodies and/or inhibitors may provide therapeutic benefit for the treatment of autoimmunity in these patients. How does FcμR enhance humoral immune responses? We found that the survival of FcμR-deficient B cells was reduced compared with WT B cells following BCR cross-linking and that cross-linking FcμR alone had no effect. This finding suggests that FcμR alone cannot trigger a biological response without BCR cross-linking. We conclude that this mechanism ensures that FcμR only functions in antigen-stimulated B cells, allowing it to enhance the activation of antigen-specific B cells reactive with foreign antigens and to promote deletion, anergy, or both, of self-reactive B cells. Despite the reduced antibody production against foreign antigens, an unexpected intriguing phenotype of the FcμR-deficient mice is that they produce autoantibodies as they age in the absence of additional genetic defects or experimental manipulations. Mice lacking complement components produce increased levels of autoantibody by at least two possible mechanisms as follows: ( i ) Complement facilitates the removal of apoptotic cells that can otherwise trigger autoantibody production, and ( ii ) complement receptors (CRs) are involved in the anergy of autoreactive B cells. Increased autoantibody production was also observed in mice lacking secretory IgM ( 2 , 3 ), which was thought to be due to their inability to activate complement, although an increased frequency of B1 cells and augmented IgG responses to type II T-independent antigens may play a role. In contrast, our results demonstrate a unique pathway mediated by the FcμR to prevent autoantibody synthesis and maintain self-tolerance. Although the precise mechanisms remain to be discovered, one likely possibility is that IgM–autoantigen complexes trigger the deletion, anergy, or both, of autoreactive B cells by cross-linking FcμR to the B-cell receptor (BCR) on the surface of these cells. The existence of an IgM Fc receptor was first suggested 40 y ago, but the identity of its gene was revealed only recently ( 5 ). FcμR is unique among FcRs in that it is expressed only by lymphoid cells, B cells in mice, and B and T cells in humans. To test whether FcμR is involved in humoral immune responses, we generated mice lacking FcμR. The mutant mice had significantly increased levels of serum IgM, suggesting that some portion of the IgM in WT mice binds to the FcμR, whereupon it is sequestered or degraded. Therefore, FcμR is normally involved in the homeostasis of IgM. The mutant mice produced reduced levels of antibody against protein antigens, and this immune deficiency was accompanied by impaired B-cell expansion in the germinal centers and decreased numbers of memory B and antibody-secreting plasma cells. This observation indicates that normal humoral immune responses require FcμR. IgM is the first antibody isotype produced during an immune response and functions as a primary barrier against pathogens. IgM also regulates immune responses. Thus, antigen-specific IgM administered before immunization enhances antibody response, which depends on complement ( 1 ). These and other observations suggest that IgM enhances antibody production by activating complement and facilitating B-cell activation and/or antigen trapping ( 1 – 3 ). However, mice expressing mutant IgM that is unable to activate complement maintain normal antibody responses ( 4 ). Therefore, IgM-enhanced antibody production cannot be solely explained by complement activation by the classic pathway. Here, we present an alternative explanation; mice lacking the recently identified Fc receptor for IgM (FcμR) are impaired in antibody production.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1210706109
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2012
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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