Immune regulation: FcγRIIB—regulating the balance between protective and autoreactive immune responses
Year: 2008
Type: article
Abstract: The magnitude of immune responses is regulated by concomitant triggering of activating and inhibitory signalling pathways in vivo. Impaired negative regulation results in overwhelming inflammation and in the worst case leads to the destruction of healthy tissues and development of chronic autoimmune diseases. In a new study published in the Journal of Experimental Medicine, Brownlie and colleagues now show a surprising cell type-specific impact of negative regulation by the inhibitory Fcγ-receptor IIB (FcγRIIB) with respect to controlling autoimmunity and infection.1 The family of FcγRs which recognise the Fc-fragment of IgG antibodies consists of one inhibitory (FcγRIIB) and three different activating receptors in mice (FcγRI, III, IV) and humans (FcγRIA, IIA, IIIA). One hallmark of this family is the paired expression of activating and inhibitory receptors on innate immune effector cells such as mast cells, neutrophils and macrophages, thereby regulating cell activation and the resulting effector responses.2 FcγRIIB is also expressed on B cells where it regulates activating signals transduced by the B cell receptor. The generation of FcγRIIB knockout mice and the crossing of this strain to transgenic or knockin-mice expressing autoreactive B cell receptors demonstrated that the inhibitory FcR is a late peripheral checkpoint of humoral tolerance regulating the follicular exclusion of autoreactive B cells, expansion of IgG positive autoreactive plasma blasts and homeostasis of plasma cells.3, 4, 5, 6 Moreover, autoimmune-prone mouse strains express lower levels of this regulator on B cells due to polymorphisms in the FcγRIIB promoter.2 In humans functionally impaired FcγRIIB alleles or mutations in the FcγRIIB promoter are associated with the development and/or severity of autoimmune diseases.7, 8, 9 Importantly, however, FcγRIIB deletion also leads to a lower threshold for innate immune effector cell activation which might contribute to the severity of autoimmune disease.5 Thus, it was of utmost importance to delineate the contribution of these two cell types—that is B cells and innate immune cells—with respect to the development and severity of autoimmune disease. In previous studies Bolland et al. and McGaha et al. either used bone marrow chimeras or retroviral overexpression systems to demonstrate that correction of FcγRIIB levels mainly on B cells suppresses disease development in autoimmune-prone mouse strains and FcγRIIB-deficient animals.10, 11 Using the retroviral system, the greatest level of FcγRIIB overexpression was seen on B cells, although increased FcγRIIB expression on macrophages might have contributed to the observed phenotype. In the present study, Brownlie et al., substantially extended these studies by using cell type-specific promoters to achieve either a B cell or macrophage-specific overexpression of the inhibitory Fc-receptor (Figure 1).1 Targeted overexpression of FcγRIIB on B cells heightened the threshold for B cell activation and resulted in the suppression of autoimmune disease. Strikingly, T cell dependent but not T cell independent B cell responses were suppressed and this effect was largely seen in the late IgG but not the early IgM response, in line with data obtained in other in vivo model systems.3 Moreover, FcγRIIB overexpression resulted in a shift towards antibodies with a higher affinity after antigenic challenge emphasising the important role of this negative regulator in controlling B cell activation and shaping the antibody repertoire. Surprisingly, however, overexpression on macrophages—which resulted in decreased triggering of activating signalling pathways—did not result in significant suppression of autoimmune disease in models of arthritis and systemic lupus erythematosus. However, these animals became more susceptible to bacterial infections due to impaired bacterial phagocytosis, which was not the case for mice with increased FcγRIIB expression on B cells (Figure 1). These findings unequivocally identify FcγRIIB on B cells as a major regulator of humoral tolerance and suggest that novel therapeutic strategies for autoimmune diseases should focus on the correction of FcγRIIB expression levels on B cells. On the other hand, bypassing the negative regulatory effects of FcγRIIB on macrophages could be a promising strategy to increase the efficacy of passive antibody therapy. Nonetheless, there is good evidence that by either blocking activating FcγRs or changing the expression level of activating and inhibitory FcγRs on innate immune effector cells is able to suppress autoantibody-induced inflammation in mice and humans.2, 12 In addition, the anti-inflammatory activity of high doses of intravenously administered IgG preparations (IVIG therapy) was shown to be essentially dependent on the presence and upregulation of the inhibitory FcγRIIB on effector macrophages.13 An explanation of why overexpressing FcγRIIB on macrophages was not sufficient to achieve more dramatic anti-inflammatory activities compared to IVIG therapy might be that in addition to upregulation of FcγRIIB, IVIG treatment induced the simultaneous downregulation of activating FcγRs, thus dramatically changing the threshold for innate immune effector cell activation.14 Moreover, the level of FcγRIIB-mediated negative regulation varies greatly for the different IgG subclasses with the greatest level of inhibition seen for IgG1.15 In the model systems used in the study by Brownlie et al. IgG2a dominates the response which might require a higher level of FcγRIIB overexpression on macrophages.1 To further address this question, the generation of B cell or macrophage-specific FcγRIIB-knockout mouse strains will be of great importance. Taken together, early and late events responsible for the initiation and maintenance of autoimmune disease are regulated by the inhibitory FcγRIIB. In contrast to blocking autoantibody production by B cells, therapeutic approaches focusing on innate immune effector cells block inflammation only transiently (although very effectively) and do not have long lasting or curative effects. The results of Brownlie and coworkers emphasise that relatively minor changes in the expression level of negative regulatory proteins can have dramatic effects on the ensuing immune response and maintenance of tolerance.1, 11 Based on this tightly balanced regulation of antibody activity by the family of FcγRs in mice and humans, several novel therapeutic approaches aiming at either enhancing the activity of therapeutic antibodies or blocking the self-destructive potential of autoantibodies are currently under development providing hope for better and safer therapeutic approaches for the treatment of infections and autoimmune diseases in the future. Outcome of cell type-specific overexpression of FcγRIIB on autoimmunity and the control of infection. (a) Overexpression of FcγRIIB on B cells results in a reduced level of autoantibody producing plasma cells, a lower level of class-switched autoantibodies (shown in black) and thus to no recruitment of innate immune effector cells to tissues expressing potential autoantigens (shown in green). In contrast, no effect on the control of bacterial infections was observed indicating that B cells were still able to mount an antigen-specific immune response (pathogen-specific antibodies are shown in blue). (b) Macrophage-specific overexpression resulted in a decreased capacity to phagocytose opsonised bacteria resulting in a decreased survival rate of infected animals. The level of FcγRIIB overexpression was not sufficient to block autoantibody mediated inflammation and tissue destruction.
Source: Immunology and Cell Biology
DOI: 10.1038/icb.2008.34
Authors: Anne Baerenwaldt, Falk Nimmerjahn
Institution: Friedrich-Alexander-Universität Erlangen-Nürnberg
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2327593719