Regulatory macrophages produce high levels of IL-10 and low levels of IL-12, thereby dampening the immune response and limiting inflammation (108, 109). regulate immune disorders. In this review, we spotlight the role of regulatory immune cells and molecules in the pathogenesis of pemphigus vulgaris and bullous pemphigoid, the two most representative forms of AIBD, and indicate issues that should be resolved in future investigations. gene mutations, lacked functional Treg cells, displayed severe erosive skin lesions similar to that in BP, and produced autoantibodies targeting murine BP230 and BP180. Moreover, the transfer of CD4+ T cells from scurfy mice to immunodeficient mice induced the expression of autoantibodies targeting BP230 and BP180, and this phenomenon was ameliorated in gene knockout mice (60). An additional study had discovered that the formation of sub-epidermal blisters in scurfy mice is usually caused by the monoclonal antibody (mAb) 20B12, which could cross-react with human BP230 (61). These studies together suggest that the absence of FoxP3+ Treg cells prospects to the BP phenotype in mice by inducing the expression of pathogenic autoantibodies targeting BP antigens (Physique 2). Further research is required to clarify the immunological mechanisms controlling the inhibition of autoantibody production by CD4+ Treg cells and to understand why this function is usually lost in BP. Another study had shown that CD25high Treg cells were in comparable proportions to that of CD4+ T cells in BP and healthy blood, and that Mertk the ability of CD4+ CD25high Treg cells to suppress T cell proliferation and interferon- (IFN-) secretion in patients with BP was comparable to that in normal individuals (62). Even though results seemed to be contradictory, CD4 and CD25, by themselves, are not sufficient to identify Treg cells. CD4+ CD25bright cells may represent not only Treg cells, but also FoxP3?activated T cells. The inconsistent results may have been caused by the different phenotypes of Treg cells. Induced Treg (iTreg) Cells Besides thymus-derived FoxP3+ nTreg cells, there are several other types of Treg cells that can be induced from peripheral naive T lymphocytes in the periphery, including FoxP3+ iTreg cells (63), IL-10-generating T regulatory type 1 (Tr1) cells 7-Methyluric Acid 7-Methyluric Acid (64), TGF–secreting Th3 cells (65), and B-cell-induced Foxp3? regulatory T cells (Treg-of-B cells) (66). Among them, Tr1 cells are the most extensively analyzed type. Tr1 cells were first reported in 1997 and could produce high levels of IL-10 and TGF-, which played a key role in suppressing antigen-specific T cell responses (67). Veldman et al. had shown that Dsg3-responsive Tr1 cells, isolated from healthy carriers of two PV-associated HLA class II alleles (DRB1*0402 and DQB1*0503), were present in significantly higher proportions than in patients with PV. This population of cells secreted IL-10, TGF-, and IL-5 in response to Dsg-3, and inhibited the proliferation of Dsg3-reactive Th cells (68). The Dsg3-responsive Tr1 cells could be divided into two subpopulations based on their cell size and granularity. The smaller subset expressed FoxP3 and secreted IL-10 and TGF- in response to Dsg3 stimulation. The larger subset, on the other hand, did not express FoxP3, exhibited a Th cell-like phenotype, and secreted IL-2 (69) (Figure 2). Inhibition of mRNA in Tr1, using antisense oligonucleotides resulted in the cells showing features similar to those of Th2 cells, such as the secretion of IL-2 and loss of anergy in response to Dsg3 antigen stimulation (70). After treatment with rituximab, the mean count of Tr1 cells increased in 2 weeks, and gradually declined over the remaining period (51). In summary, alterations in the growth 7-Methyluric Acid and function of Dsg3- responsive Tr1 cells in PV, as 7-Methyluric Acid well as their inhibitory effect on Th cells, indicate their relevance in PV pathogenesis. Future studies should focus on 7-Methyluric Acid the underlying mechanisms.