Patients with IgG4-RD often have allergic disorders such as bronchial asthma and allergic rhinitis . Indeed, levels of Th2 cells and Th2 cytokines including interleukin (IL)-4, IL-5, and IL-10 are frequently increased in affected tissues or peripheral blood of patients with IgG4-RD [2–5,7]. Of note, Culver et al. reported associations of IgG4-RD with allergy, atopy, eosinophilia, increased serum levels of IgE, and IgE-positive mast cells in lymphoid and affected tissues. They concluded that levels of IgE could be used for diagnosis and predicting relapse . Taken together, the results suggest that Th2 cells and IgE-mediated allergic response play a role in the pathogenesis of IgG4-RD.
Histopathologically, infiltration of IgG4-positive plasma cells accompanied by storiform fibrosis is usually observed in affected tissues of IgG4-RD [1,23]. It is well known that IL-10 and TGF-β are key cytokines for IgG4 class-switching and fibrosis, respectively [24–26]. Therefore, regulatory T (Treg) cells have been focused on from the early period of IgG4-RD research as a pathognomonic source of IL-10 and TGF-β. Indeed, several studies have shown an increased number of Treg cells and increased expression level of their master regulator, Foxp3, in both affected sites and circulating leukocytes in patients with IgG4-RD [2,4,7–10]. We also found increased levels of Treg cells in blood and affected tissues of patients with IgG4-RD (F. Ito, R. Kamekura, unpublished data). Taken together, the results of these studies suggest that Treg cells are preferentially involved in IgG4 class-switching and fibrosis in lesions of IgG4-RD; however, no direct evidence regarding the function of Treg cells in IgG4-RD was shown in those reports. Further studies are probably required to clarify IgG4 class-switching and fibrosis caused by Treg cells in IgG4-RD.
As mentioned above, abundant infiltration of IgG4-positive plasma cells is usually observed in tissue lesions of IgG4-RD . This suggests that dysregulation of the IgG4 class-switch underlies the pathogenesis of IgG4-RD. Tfh cells, which are postulated as a specialized class of effector helper CD4+ T cells, assist B cells to form germinal centers of lymphoid follicles, and Tfh cells thereby contribute to the class switch recombination of B cells and the selection of high-affinity B cells in germinal centers [30,31]. Importantly, Tfh cells have the capacity to secrete IL-4 and IL-10, which are key cytokines for IgG4 class-switching . Tfh cells have been considered as a potential key player in the development of IgG4-RD.
A more recent study on rheumatoid arthritis (RA) has revealed an unidentified subset of CD4+ T cells named Tph cells (PD-1hiCXCR5-CD4+ cells) [42▪▪]. Tph cells present Tfh cell-like features to produce factors associated with B-cell help, including IL-21 and CXCL13 in the inflamed synovium of RA. Unlike Tfh cells, Tph cells in the synovium of RA do not express high levels of Bcl6 and instead show elevated levels of Blimp1, which opposes the actions of Bcl6 as a counter-regulator . Tph cells also have a unique expression profile of chemokine receptors, such as CCR2, CCR5, and CX3CR1 (a fractalkine receptor), that ignite their migration to inflamed sites [42▪▪]. Thus, Tph cells show substantial differences from Tfh cells in their surface phenotypes, migratory capacity, and transcriptional regulation [42▪▪]. Recent studies have shown an increased percentage of Tph cells in blood from patients with primary Sjögren's syndrome . In addition, Gu-Trantien et al. reported that CD4+ T cells with a Tph cell-like phenotype were found in breast cancer tissues and that they have a possible regulatory function in immune responses against tumor cells. Based on these observations, we have first reported a possible pathological role of Tph cells in IgG4-RD [19▪▪]. Our results have shown that circulating PD-1+CXCR5− cells (including PD-1hiCXCR5− cells, thus collectively named Tph-like cells here) were significantly increased within CD4+ T cells in patients with IgG4-RD compared to those in healthy volunteers. We also found that their percentage was positively correlated with serum levels of IgG4 and soluble IL-2 receptor and with the number of involved organs in IgG4-RD patients. In addition, we found that such Tph-like cells frequently expressed GZMA, which is related to a cytotoxic property. Clinical remission achieved by treatment with glucocorticoids clearly led to a numerical reduction of Tph-like cells [19▪▪]. Taken together, our findings strongly suggest that circulating Tph-like cells play a pivotal role in the pathogenesis of IgG4-RD.
In peripheral tissues of chronic inflammation such as IgG4-RD and RA, aggregations of T cells and B cells (so-called ectopic lymphoid structures, ELSs) frequently develop  [Figure 1]. In ELSs, T cell–B cell interactions result in uncontrolled somatic hypermutation, class switch recombination, and differentiation of plasma cells , the functional interplay of which accelerates the development of the disease. Our previous observations revealed abundant infiltration of PD-1hiICOShi Tfh cells in lesional ELSs of IgG4-DS [13▪▪], suggesting that activated Tfh cells interact and strongly induce B cells to produce IgG4 in ELSs of IgG4-RD. The appearance of a new player, Tph cells, in the research field of chronic inflammation, might lead to a deeper understanding of the immunological mechanisms of ELS formation in lesions of chronic inflammation including IgG4-RD. Based on results of previous studies and our recent findings regarding IgG4-RD, we presume the following relationship between Tph cells and Tfh cells in the pathogenesis of IgG4-RD. Owing to the high expression levels of chemokine receptors including CCR2, CCR5, and CX3CR1, Tph cells are preferentially prone to infiltration of inflamed tissues in patients with IgG4-RD. Production of CXCL13 by Tph cells may subsequently provide early stimuli for the recruitment of CXCR5+ immune cells including both Tfh cells and B cells. As a result, it is possible that Tfh cells and B cells accumulate to form ELSs in the lesions and eventually provide an immune microenvironment in which the production of IgG4 is further induced. Because fractalkine, which is a ligand of CX3CR1, is highly expressed by endothelial cells in submandibular glands of IgG4-DS (H. Yabe, R. Kamekura R, unpublished data), Tph cells might have a role in the initiation of inflammation and maintenance of chronic fibroinflammation in IgG4-RD, although influencing vascularities in the lesions . Given that destructive inflammation is observed in IgG4-RD [Figure 1], our experimental evidence indicates that Tph-like (PD-1+CXCR5-CD4+) cells, which preferentially contain cytotoxic granules of GZMA, are responsible for such pathological changes in IgG4-RD [19▪▪]. In this study, we could not see abundant expression of IL21 mRNAs in Tph-like cells compared with those in Tfh cells from patients with IgG4-RD [19▪▪]. Taken together, the results suggest that Tph-like cells in IgG4-RD play a pathological role as CD4+ CTLs rather than as B cell helpers such as Tfh cells [Figure 2].
Several questions remain to be answered to understand the mechanisms of the origin and differentiation of Tfh cell in lesions of IgG4-RD and the developmental relationship between Tfh cells and Tph cells.
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