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The regulatory functions of G protein-coupled receptors signaling pathways in B cell differentiation and development contributing to autoimmune diseases

Cell & Bioscience volume 15, Article number: 57 (2025) Cite this article

Abstract

Autoimmune diseases are characterized by a dysfunction of the immune system. Disruptions in the balance of B-cell dynamics and the increase in auto-antibody levels are pivotal in the triggering of several autoimmune disorders. All of this is inextricably linked to the differentiation, development, migration, and functional regulation of B cells in the human immune response. G protein-coupled receptors (GPCR) are recognized as crucial targets in drug development and play pivotal roles in both B cell differentiation and the underlying mechanisms of autoimmune diseases. However, there has been an inadequate comprehension of how GPCR intricately modulate B cell development and impact the pathogenesis of autoimmune diseases. Ligands and functions of GPCR—chemokine receptors including CXCR3, CXCR4, CXCR5 and CCR7, lipid receptors including S1PR1-5, cannabinoid receptor CB2 as well as orphan GPCR including GPR132, GPR183, GPR174, and P2RY8 in B cell differentiation and development, will be elaborated in this review. The roles these GPCR play in mediating B cells in several autoimmune diseases will also be discussed. The elucidation of the multifaceted mechanisms controlled by GPCR not only enriches our comprehension of immune responses but also provides a promising avenue for therapeutic interventions in the domain of autoimmune disorders.

Introduction

B cell-driven humoral immune abnormalities represent a crucial pathogenic factor in various autoimmune diseases [1, 2]. Current research continues to elucidate the variety of human B cell subpopulations implicated in disease processes, as well as identifying novel pathways that activate B cells in the context of autoimmunity [3]. From the perspective of the mechanism of B cells targeted drug therapy, although drugs such as rituximab, belizumab, tataxipril, and eramod have varying mechanisms of action, all of those drugs have a common feature which directly or indirectly block certain key pathways of B cells development towards plasma cells (PC), thereby reducing the level of PC that produce autoimmune antibodies [4]. G protein-coupled receptors (GPCR), as an important family of membrane receptors involved in the differentiation and development of B cells, blocking some of these processes can achieve the aforementioned effects and mitigate the severity of autoimmune responses.

GPCR represent the dominant of membrane receptors found in eukaryotic cells [5]. These receptors have the capacity to detect and bind to various chemical molecules present in their environment, triggering a cascade of intracellular signaling events [6]. Many GPCR are associated with innate or adaptive immunity, such as chemokine protein receptors and inflammatory peptide receptors, and are involved in immune cell differentiation and development. The abnormal expression or activation of certain GPCR is the foundation of the pathogenesis of inflammatory response, immune deficiency and autoimmune diseases. Members of the GPCR superfamily have been have emerged as prime candidates for pharmaceutical intervention, with a significant portion, approximately 34%, of contemporary medicinal compounds being directed at one or several of the 800 known human GPCRs [7].

GPCRs contribute to the regulation of B-cell migration and positioning within germinal centers (GCs) and within the peripheral bloodstream (Fig. 1). Certain GPCR-targeted therapies have already been approved for the treatment of multiple sclerosis(MS) [8], while others have demonstrated effectiveness in animal experiments, holding promise for further development and clinical application. Therefore, we are justified in believing that insights into a deeper understanding of GPCRs’ involvement in B cell maturation and development can help the creation of targeted drugs for the management of autoimmune illnesses.

Fig. 1
figure 1

The role of GPCRs in the development of B cells. G2A is highly expressed in pre-B cells, and then down-regulates in pre-B and immature B cells. CXCR4 promotes the retention of precursor B cells within BM, and down-regulation of CXCR4 allows B cells to exit the BM and enter the periphery. Naive recirculating B cells migrate to B cell follicles or EF regions via the CXCL13-CXCR5 axis. The entry of B cells into lymphoid tissue through HEV is mediated by CCR7 and CXCR4. EBI2 and P2RY8 play roles in B cells clustering in follicles and forming GC. In GC, Centroblasts with high expression of CXCR4 are distributed in DZ. When CXCR4 is down-regulated, they enter the LZ to become centrocytes. P2RY8 and S1PR mediate the movement and retention of B cells within GC, ultimately giving rise to memory B cells or PC. MZ B cells and memory B cells are present in the marginal zone. S1PR1, S1PR3, CXCR5, and CB2 mediate the localization and shuttling of MZ B cells within the MZ

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GPCR regulate B cell differentiation and development

GPCR in early B cell differentiation and development

G2A, an orphan GPCR encoded by Gpr132 gene, is an anti-proliferative cell cycle regulator that is mainly expressed in lymphoid progenitor cells. The G2A protein may contribute to the protection of cells against genomic instability, given its high expression in thymocytes and pro-B cells that are engaged in the process of antigen receptor gene recombination [9]. This suggests a role for G2A in the context of lymphoid cell development and maturation. Conversely, G2A levels are comparatively low in pre-B cells and immature B cells. Additionally, the BCR-ABL protein, which is associated with certain forms of cancer, can induce G2A expression in pre-B cells, thereby potentially impacting the normal development of pro-B cells into pre-B cells [9, 10].

CXCR4, a GPCR, plays a key role in various biological processes such as hematopoiesis, B cell lymphogenesis, myelopoiesis, and the maintenance of germinal centers (GC). CXCR4 monogamously recognizes CXC chemokine ligand 12 (CXCL12). When mice were found to be deficient in CXCR4, there was a significant reduction in pre-B cells in their BM and an increase of pre-B cells in the blood [11], This suggests that CXCR4 contributes to the retention of pre-B cells in the BM, preventing them from moving into the bloodstream. Sphingosine 1-phosphate (S1P) has also been shown to interact synergistically with CXCL12 in mouse BM, When S1PR4, the receptor for S1P, was deficient, the populations of pro-B and pre-B cells were diminished [12]. The precise interplay between CXCL12-CXCR4 and S1P-S1PR4 requires additional validation. Elevated expression of CXCL12 in BM facilitates B cell proliferation, and CXCL12 levels are attenuated during inflammatory states, preferentially inhibiting B lymphopoiesis and promoting granulopoiesis [13]. Moreover, because of down-regulating the expression of CXCR4 in B cells, B cell motility was reduced which potentially resulted in the expulsion of B cells from BM. The engagement of antigens by immature B cells antagonizes this process, which is presumed to occur after negative selection. This antigen-induced BCR signaling prevents the down-regulation of CXCR4, enhances B lineage cell motility, and inhibits their egress from the BM [14].

Human BLR1 gene, which is also known as CXCR5, is specifically expressed in lymphocyte lineages [15]. When B cells express the IgD, B cells up-regulate the chemokine receptor CXCR5 [16], and recirculating naive B cells overexpress CXCR5 in response to the chemokine CXCL13, which encourages their migration towards B cell follicles [17].

GPCR play a role in the EF and GC response of B cells

The localization of B cells within lymphoid tissue is a highly dynamic process that is critical for the effective functioning of the immune system. This process is coordinated by an intricate network of chemokines, cytokines, and additional secreted substances.

High endothelial venules (HEV) are the structures that allow B cells to enter lymphoid tissue like spleen and lymph node (LN) from the peripheral blood, and CCR7 as well as CXCR4 are the main chemokine receptors that mediate migration process. Researches indicated that CCR7 and CXCR4 mediated the majority of GPCR signaling pathways that are essential for B cells to migrate to LN. Blocking of signals via neither CCR7 nor CXCR4 pathways caused a diminution in B cell accumulation in LN by approximately 90% [18].

From the B–T boundary, activated B cells migrate to the extrafollicular (EF) region, where they undergo rapid proliferation and differentiation to produce plasmablasts (PB) or PC. Alternatively, antigen-activated B cells could be localized in follicular central regions that are abundant in follicular dendritic cells (FDCs) to form the GC and differentiate into long-lived plasma cells (LLPC) or memory B cells, then egressing from GC.

In secondary lymphoid tissues, the migration of activated B cells to EF or interfollicular regions is regulated by Epstein-Barr virus-induced molecule 2 (EBI2) which is also named GPR183. Additionally, EBI2 is vital for the production of GC and EF responses. The up-regulation of EBI2 expression is vital for activated B to relocate to the external site of the follicle and for inducing EF responses. In contrast, B cells can penetrate the follicular center and encourage the development of GC when EBI2 is downregulated[19].

The two separate zones into which GCs are polarized are the dark zone (DZ) and the light zone (LZ). The B cells that divide rapidly are called centroblasts. They have high expression of CXCR4 and CXCR5 on their cytomembrane surface and low expression of immunoglobulin and mainly distribute in the DZ where the density of B cells is relatively high. Centroblasts go through cycles of somatic hypermutation and rapid proliferation, later their division rate slows down and their expression of CXCR4 is down-regulated, but immunoglobulins of them gradually began to be highly expressed, and then they migrate to LZ where the B cell density is relatively low. Centrocytes that are able to bind antigen and obtain assistance from T cells survive and exit the GC as LLPC or memory B cells [20].

CXCL13 exhibits a distinct pattern of distribution within GC compared to CXCL12, with a higher abundance in LZ than DZ. This suggests that CXCL13, along with its receptor CXCR5, is involved in guiding B cells to the LZ. However, CXCL13 is not a key factor in the separation of DZ and LZ, nor does it only rely on centrocytes migration to CXCL13 to mediate the separation of centrocytes from centroblasts. Moreover, CXCL13 serves to facilitate LZ localization in the pole of the GC distal to the T zone. It appears that the CXCR4-CXCL12 axis might be enough to distinguish between centroblasts and centrocytes [21].

Down-regulation of EBI2 expression mediated by BCL-6 is critical in the differentiation of GC B cells, which facilitates B cells to enter the follicle center and promote GC formation. BCL-6-induced alteration in EBI2 expression causes activated B cells to become less sensitive to its ligand 7a,25-dihydroxycholesterol, resulting in the movement of GC B cell precursors to the follicular center [22]. Moreover, GC B cells in DZ did not express as much EBI2 as those in LZ did [23]. Changes in EBI2 expression guide GC B cells towards higher concentrations of 7a,25-dihydroxycholesterol in LZ [24].

However, EBI2 signaling pathway is not the only one to promote the clustering of GC-precursors at the follicle center. The intracellular and extracellular levels of S1P are spatially altered, allowing it to function as an autocrine or paracrine factor respectively, which is widely distributed in lymph and blood circulation and is believed to exist in the attenuation gradient from blood to tissues. It has been found that S1P concentrations increase in LN during an immune response [25]. S1P has multiple effects, including involvement in cell growth, angiogenesis, immunity, and neuroprotection [26]. S1P signaling pathway plays vital roles in categorizing immune cells into lymphatic organs and regulating their entry into the periphery blood and LN. Five GPCR, S1PR1–5, have S1P as their ligand. GC B cells have an up-regulation of S1PR2 expression. S1PR2 can regulate the size of GC and induce GC B cells to aggregate towards the follicular center by inhibiting their tendency to migrate to in S1Phi extracellular follicles driven by CXCL13 and other attractants [27]. Furthermore, it was shown that over-expression of S1PR1 inhibited S1PR2 and enhanced GC-type B-cell migration, indicating that the dynamic modulation and balance of S1PR1 and S1PR2 is a pivotal mechanism for the formation of GC [22]. S1PR4 is highly expressed in follicular B cells and marginal zone (MZ) B cells. Additionally, the fact that S1PR4 increases the chemotaxis of splenic B cells to CXCL13, suggesting that a unified mechanism underlies the process of B cell migration that is orchestrated by both S1P-mediated signaling and CXC chemokines [12].

P2RY8, an orphan Gα13-coupled receptor, exerts a high expression in GC B cells, triggers B cells clustering and inhibits the growth of GC B cells [28]. P2RY8 ligand S-geranylgeranyl-L-glutathione (Ggg), antagonizes chemokine-mediated migration of GC B cells and follicular helper T cells (Tfh). Similar to S1P, Ggg also forms a concentration gradient from outside to inside in GC. Researches found that FDCs could produce gamma-glutamyltransferase-5 (Ggt5), which converted Ggg to an inactive form for the receptor. The capacity of P2RY8 to encourage B cells confinement to GCs was interfered with when this enzyme was overexpressed, suggesting that it is involved in the formation of a Ggg gradient in lymphoid tissues [29]. Besides, B cell trafficking to BM was adversely controlled by P2RY8 and GGG [28].

CB2, a peripheral cannabinoid receptor subtype of GPCR, is a prevalent immune cannabinoid subtype in the human body. Of all the leukocyte subsets, the bulk expression of CB2 occurs in tonsillar B cells and peripheral blood. 2-AG functions as a chemokinetic agent that preferentially draws unstimulated naïve B cells [30]. CB2 is highly expressed in mantle zones and slightly in GC of follicles. Moreover, during B cell development, there is a definite down-regulation of CB2 receptor expression. Centroblasts that were proliferating in GC had the lowest level of CB2 expression [31].

GPCR and PC

Coordination of changes in chemokine reactivity during B cell development into PC controls the B cell migration within secondary lymphatic organs and encourages their deposition in BM. PC exhibited a greater chemotactic sensitivity to CXCL12 compared to B cell precursors. While concurrently, they down-regulate CXCR5 and CCR7 receptors [32] and reduce the reactivity to the chemokines CXCL13, CCL19 and CCL21, which appears to be a crucial component of the process in the spleen and lung that encourages PC migration out of the B and T zones. The CXCR4-CXCL12 axis is instrumental in orchestrating the positioning of PC within the splenic red pulp and their deposition in BM. A deficiency in CXCR4 renders PC unable to correctly localize within the spleen, leading to an increased presence in the periphery blood and a suboptimal accumulation in BM. However, while the CXCR4-CXCL12 axis is a pivotal regulator of PC distribution, various other factors participate in the comprehensive spatial arrangement of these cells, suggesting a multifaceted control mechanism [16].

The capacity of PC produced from B cells that are lack of CXCR4 to enter EF regions and gather at follicle boundaries may depend on chemotaxis to EBI2 ligands concentrated in this region [16]. Early antibody production is significantly decreased in B cells lacking EBI2 because they are unable to develop into PB and move to EF regions [19]. It seems improbable that the binding of EBI2 to its ligand will have a direct impact on PC formation. Conversely, EBI2 could exert its functions by guiding B cells to particular microenvironments that either facilitate B cell maturation and differentiation or support the survival of PC [33].

GPCR and memory B cells

Upon subsequent exposure to systemic antigens, IgG+ PC precursors migrate towards CXCR3 ligands, which may facilitate their migration to BM and inflamed tissue respectively [34]. The up-regulation of CXCR3 has been detected on a subset of memory B cells. The retention of this receptor throughout their maturation into PC implies that the utilization of CXCR3 in immune reactions may be a determinant of B-cell memory functionality, potentially influencing B-cell homing to inflammatory tissue.

GPCR and MZ B cells

B cells located in MZ engage in ongoing encounters with antigens within the bloodstream and migrate bidirectionally between the marginal zone and the follicles, which helps to exert immune effects in a timely manner [35]. CXCR5 is mainly detected in MZ that contains a large number of long-lived circulating B cells, while just a tiny percentage of cells in GC express CXCR5. Moreover, CXCR5 is mainly expressed in resting B cells and down-regulated in B cells with strong proliferation activity [36, 37]. MZ B cells highly express S1PR1 and S1PR3, and whether MZ B cells are concentrated in MZ or within the follicle depends on the dynamic modulation and balance of S1PR1 and CXCR5. S1PR1 signaling is usually dominant to prevent MZ B cells from responding to CXCL13 and moving towards the follicle. The signal mediated by S1PR3 has also been shown to contribute to the high S1PR1 chemotactic property of MZ B cells, thereby affecting the trafficking of MZ B cells. When MZ B cells contact with antigens such as LPS, the expression of S1PR1 and S1PR3 are decreased and MZ B cells re-enter the white pulp [38].

Furthermore, B cells are able to be directed to MZ through the mediation of CB2, which also inhibits their migration into the peripheral circulation. CB2 antagonism leads to the displacement of MZ B cells into follicles when S1PR is absent and B cells can be positioned in the splenic MZ by simply up-regulating CB2 expression [39].

GPR174 is universally expressed on immune cells, is transduced by Gαs signaling in follicular B cells [40]. The ligands for GPR174 are CCL19 and CCL21 [41]. Gpr174 and Gαs deficiencies have been associated with enhanced B cell activity in vitro and a reduced compartment of MZ B cells in mice [41,42,43]. Gpr174 is a receptor that can significantly influence B cell gene expression. Notably, CCR7 is up-regulated in naive B cells through a Gpr174 and Gαs-dependent mechanism, and Gpr174 may exert a synergistic effect with CCR7 during B cell activation [43].

Potential application of these GPCR in autoimmune diseases

Some GPCRs and their ligand levels differ between patients with autoimmune diseases and healthy individuals, playing a role in the pathogenesis of autoimmune diseases (Fig. 2). Drugs targeting GPCRs have been developed as effective treatments for autoimmune diseases. Additionally, some inhibitors and agonists have been developed for experimental purposes, with expectations for their clinical feasibility in the future (Table 1).

Fig. 2
figure 2

The current research progress of GPCRs and its ligands in autoimmune diseases. A multitude of GPCRs and their ligands exhibit altered expression levels in various B cell subsets during autoimmune disorders. In SLE, S1PR1 agonists prompt receptor internalization and degradation, hindering the migration of lymphocytes in response to S1P. This manipulation may mitigate the entry of autoreactive B cells into the peripheral blood, Consequently, it can attenuate the inflammatory response. The CXCR4 antagonist AMD3100 and the CTCE-9908 compound have been found to alleviate lupus nephritis; AMD3100 was shown to maintain a reduced population of LLPC and anti-dsDNA IgG in BM. In RA synovial tissue, CXCL13 expression is upregulated in TLS. In addition, its receptor CXCR5 has been shown to be widely expressed in infiltrating B cells. These studies suggest that CXCL13 may be involved in the formation of TLS in chronic arthritis by attracting B cells. Evobrutinib, a BTK inhibitor, deregulates BTK and CXCR3 expression, thereby affecting the migration of CXCR3+ B cells and reducing the inflammation

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Table 1 GPCRs and their role in autoimmune diseases
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S1PR

S1PR1 is highly expressed on non-activated B cells. Inactivated B cells migrate efficiently towards S1P in a concentration-dependent mode. S1PR1 modulators, most of which are S1PR1 agonists, result in receptor internalization, followed by ubiquitination and proteasome degradation, which prevents lymphocytes from tracking the S1P gradient to egress from LN [44, 45]. This modification can diminish the influx of auto-reactive B cells into the periphery blood, consequently lessening the inflammatory response, making S1PR1 a prospective therapeutic target for managing diverse immune-associated diseases. The targeting of S1PR for therapeutic purposes was initially employed in the treatment of MS [8]. Numerous modulators of S1PR were advancing through clinical development to treat multiple sclerosis (MS), and their efficacy in treating other autoimmune conditions was also being assessed. These conditions included systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and psoriasis [45]. It has been shown that individuals with psoriasis had a considerably higher serum S1P concentration [46], and that patients with SLE also have heightened S1P levels. Elevated S1P levels in lupus murine models were linked to disease activity and organ impairment [47]. Experimental studies have shown that multiple S1PR modulators could alleviate symptoms of experimental SLE. One such modulator, cenerimod that effectively inhibits B cell migration towards S1P [48], was currently the subject of a Phase II clinical trial for the treatment of SLE [49]. Additionally, a Phase II trial demonstrated that the S1PR agonist ponesimod markedly decreased the lesion size and PASI scores in patients with chronic plaque psoriasis, suggesting its potential utility in managing psoriasis [50, 51].

The up-regulation of autotoxin, which changes sphingosylphosphorylcholine (SPC) into S1P in response to LPS, coincided with the differentiation of PC. SPC was shown to significantly inhibit B cell development toward PC and antibody production, which was mediated by S1PR3, one of the receptors of S1P. Moreover, SPC showed therapeutic outcomes against experimental autoimmune encephalomyelitis (EAE), which indicated SPC maybe have a potential to control MS [52]. In addition, S1PR3 demonstrated a strong positive connection with immune cells, exhibited excellent specificity and sensitivity, and was up-regulated in the synovium of RA patients, thus qualifying it as a biomarker for the early detection of RA [53]. Inhibition of S1PR3 could alleviate symptoms of arthritis in experimental mice, although the precise mechanism was not fully elucidated [54]. Considering the anti-apoptosis role of S1P in B cells of patients with RA [55], it is proposed that the mechanism of S1PR3 signaling pathway in RA is associated with its capability to mediate B cell regulation.

CXCR3

CXCR3 expression was up-regulated in the patients with neuromyelitis optica spectrum disorder (NMOSD) [56], IBD [57] and MS [58]. Synthetic antagonists of CXCR3 helped alleviate central nervous system (CNS) inflammation by inhibiting lymphocyte entry into the CNS [59]. Memory B cells exhibit high phenotypic variety. Changes of subgroup characteristics from B cells correlate with disease activity in various autoimmune diseases, such as RA and SLE [60]. In patients with long-standing type 1 diabetes, a reduction in CXCR3 expression on memory B cells has been identified, but the level of B cell activating factor and CXCR3 ligands CXCL10 and CXCL11 in serum were elevated [61]. Both autoreactive memory B cells and PC from RA highly expressed CXCR3, which promote secreting autoantibodies recognizing proteins with posttranslational modifications [62].

Additionally, evobrutinib is a new and highly specific antagonist of Bruton’s tyrosine kinase (BTK) that has yielded encouraging outcomes in phase II clinical trial for relapsing MS, SLE and RA [63, 64]. Furthermore, it has been found to inhibit B cell development and antigen-presenting function in EAE [65]. A positive correlation between BTK and CXCR3 expression suggests that the mechanism of evobrutinib to treat autoimmune disease was through affecting the migration of CXCR3+ B cells [66]. It has been reported that the aggregation of B cells in CNS induced by dopamine receptor D3 (DRD3) is also mediated by the upregulation of CXCR3 expression. Knocking out Drd3 in mouse B cells reduces the expression of CXCR3, thereby inhibiting the progression of EAE [67]. These findings suggest that CXCR3 plays a pivotal role in the aggregation of B cells and the onset and development of diseases. However, the efficacy of targeting CXCR3 in autoimmune diseases needs further exploration. Studies have shown that the percentage of GC B cells and PC decreases in lupus mice with CXCR3 knockout, and the CXCR3 antagonist AMG487 reduces the level of serum anti-dsDNA IgG in the lupus mice [68]. Additionally, AMG487 can effectively down-regulate inflammatory B cell signaling and exert an anti-arthritic effect in RA mice [69], indicating that CXCR3 is a potential therapeutic target for treating autoimmune diseases.

CXCR4

When immature B cells encountered auto-antigens, BCR-induced CXCR4 expression was increased, and more B cells were remained in BM parenchyma, indicating that CXCR4 functionally contributes to central B cell tolerance [70]. In the lupus mouse model, there was an increased CXCR4 expression in B cells from BM and several B cell subsets from the spleen, including MZ B cells, follicular B cells PC and PB [14, 71]. The proportion of CXCR4+ B cells was less observed in the peripheral blood from lupus mice and SLE patients than in BM [72]. However, compared to control groups, an increase in CXCR4 + B cells was found in lupus mice [73]. In the peripheral blood of SLE patients, ASC cells exhibited high expression of both CXCR4 and CXCR3, and these pathogenic B cells can migrate to inflamed lupus kidneys [74]. In addition to promoting migration towards CXCL12, increased expression of CXCR4 on B cells can provide a prolonged survival advantage to these potentially auto-reactive cells. This could potentially result in a break of peripheral B cell tolerance. The enhanced signaling triggered by CXCL12 extends the lifespan of auto-reactive GC B cells and PC, which may result in higher levels of auto-antibodies [75]. Furthermore, studies have shown that the Janus kinase 1 specific inhibitor upadacitinib can be used to treat experimental autoimmune uveitis by inhibiting the CXCR4-mediated migration pathway [76]. Inhibiting the connection between CXCR4 and CXCL12 is a promising strategy for diminishing the renewal of the pool of auto-reactive LLPC.Thus it may be applicable in the management of autoimmune illnesses [77].

CXCR4 antagonists include CTCE-9908 and AMD3100. When CXCR4 blockade CTCE-9908 was instituted late in lupus mouse model, it was successful in retarding the progression of renal pathology and extending the survival rate of the mice in question [71]. Treatment with AMD3100 in mice decreased the population of short-lived PC and LLPC, including cells that secrete anti-dsDNA antibodies in the spleen and BM. These effects are strongly associated with delayed development of proteinuria and prolonged survival, and they may inhibit the progression of lupus nephritis [78]. Kidney immune cells highly expressed chemokine receptors CXCR4, suggesting it may serve as potential therapeutic target [79].

CXCR4 antagonist may also be used for the treatment of bullous pemphigoid (BP). In patients with BP, the abundance of CXCR4 on peripheral B cells was significantly elevated in comparison to healthy controls. The presence of CXCR4 + B cells and the production of secretory antibodies were markedly enhanced within BP lesions, which correlated with increased levels of the CXCL12 in both the vesicular fluid and serum of these patients. In addition, CXCL12 activates c-Myc, a factor that influences B cells to differentiate into antibody-secreting cells (ASCs) and enhances the generation of auto-antibodies, both of which can be inhibited by CXCR4 inhibitors in vitro [80].

CXCR5

CXCL13 is elevated in various autoimmune diseases, including SLE [81], RA [82], primary Sjögren’s syndrome (pSS) [83, 84], MS [85] and IBD [86]. The expression of CXCL13 is upregulated in tertiary lymphoid structures (TLS), particularly in areas characterized with significant B cell accumulation [82].. CXCR5, expressed at high levels in infiltrating B cells [87] and Tfh, facilitates their migration towards CXCL13, which is crucial for promoting T cell-B cell interactions. This migration is instrumental in facilitating B cell proliferation, differentiation, and the subsequent generation of antibodies [88]. These studies indicate that the elevation of CXCL13 recruits CXCR5+ B cells and T cells to aggregate and proliferate, leading to tissue inflammation and clinical symptoms.

However, whether CXCR5 can be a viable target requires further development of inhibitors and exploration in animal models and clinical trials. In lymphoma, studies have utilized CXCR5-targeted CAR-T cells to eliminate pathogenic B cells and Tfh cells, suggesting that a similar approach might be attempted in autoimmune diseases with high expression of CXCR5 [89]. Double-negative B cells (IgD−CD27−CXCR5−) have also been found to expand significantly in various autoimmune diseases [90], such as SLE. It has been reported that a subset of B cells with the phenotype CXCR5−CD19low are precursors of PB [91], suggesting that CXCR5 may only play a partial role in the pathogenesis of autoimmune diseases.

CCR7

Among the factors involved in the formation of TLS, CCL21 and CCL19, the ligands for CCR7 emerge as key players, in addition to CXCL13 as previously described. Research has shown that the deficiency of CCR7 resulted in impaired lymphocytic recirculation, which in turn caused lymphocytes to accumulate in nonlymphoid tissues [92]. This accumulation may have extended the stay for presumed autoreactive lymphocytes at mucosal locations, thereby promoting the formation of gastric TLS, and the TLS in CCR7−/− mice contained classic B2 lymphocytes in autoimmune gastritis [93]. Furthermore, researches have demonstrated that CCL19 and CCL21 are up-regulated in the synovium of RA [94]. Treatment with anti-human CCR7 mAb 8H3-16A12 prevents the induction of collagen-induced arthritis in humanized CCR7 mice [95]. Nonetheless, the majority of studies leveraging CCR7 as a therapeutic candidate for RA have primarily concentrated on its mechanism of action in T cells and DCs. It was reported that there was no substantial evidence to show 8H3-16A12, an anti-human CCR7 antibody, regulated GC B cells or follicular B cells in RA [95].

Graves disease (GD) and Hashimoto thyroiditis (HT) are included within the spectrum of autoimmune thyroid disease (AITD). Significant expression of chemokines such as CCL21, CXCL12, and CXCL13 have been significantly observed in AITD glands [96]. The proportion of circulating CCR7+ and CXCR5+ B cells in TLS of AITD patients has significantly decreased. These phenotypic alterations might be valuable indicators of the cellular immune response to thyroid auto-antigens and aid in the clinical evaluation of the patients [97].

EBI2

Compared with healthy controls, the plasma levels of 7α, 25‐OHC was increased in SLE patients [98], while EBI2 expression in many peripheral blood lymphocyte subsets were reduced, including naïve B cells, memory B cells, and PC. The presence of EBI2 on circulating CD27-IgD + B cells has been found to be predictive of SLE disease activity, differentiating between those with quiescent and active disease. Furthermore, stimulation with type I interferon has been observed to suppress EBI2 expression in peripheral blood T and B cells. The disrupted EBI2 expression may provide insights into the prediction of disease activity and understanding the underlying pathogenesis of SLE [99].

P2RY8

P2RY8 promots GC confinement and restrains the maturation of PC. The absence of P2RY8 may compromise B-cell tolerance and contribute to the onset of lupus. Investigations have shown that B cells from certain SLE patients exhibited substantially reduced levels of P2RY8, with an even more pronounced decrease observed in patients with lupus nephritis [100]. SLE patients with diminished P2RY8 expression not only had a higher incidence of nephritis but also an increased number of age-associated B cells (ABCs), which are recognized as pathological in lupus nephritis and a significant source of autoantibody-producing cells [15]. P2RY8 may have a protective effect in autoimmune diseases and be served as a biomarker of renal lupus.

G2A

In G2A−/− (G2A gene knockout) mice, it was noted that their secondary lymphoid organs increasingly swelled as they aged, accompanied by a pathological polyclonal expansion of lymphocytes that severely altered their structural integrity. At around 1 year old, these elderly G2A−/− mice ultimately developed an autoimmune syndrome, with the onset of this condition occurring relatively late in their life expectancy. The pathological hallmarks of the autoimmune syndrome in these mice closely resemble those seen in humans with SLE [101, 102]. The lymphadenopathy seen in these aging G2A−/− mice is correlated with a rise in both T and B cell populations, and the activation of auto-reactive B cells [102]. G2A may thus contribute to a protective role against the onset of autoimmune diseases, indicating that modulating its function could be therapeutic benefit in human patients.

CB2

CB2 plays a protective role in MS [103], IBD [104] and other autoimmune diseases and inflammatory responses. The activation of CB2 enhances the expression of IgE by B cells [102, 105]. However, the specific mechanism of CB2 regulating B cells in the inflammatory response remains unclear.

Gpr174

It is reported that the variants in Gpr174 were a risk factor for GD [106] and HT [107]. Gpr174 curtails the inherent functionality of male B cells, but not female B cells, to form GC and generate PC, which was consistent with the fact that autoimmune diseases tend to occur more in women than men. It was a possible reason that Gpr174 deregulate the production and ability of autoimmune B cell in males, contributing to sexual dimorphism to humoral immunity [41]. Additionally, the deletion of Gpr174 resulted in an elevation of MZ B cells within the spleenic compartment, thereby mitigating systemic inflammation in the context of sepsis [42]. This observation stands in contrast to another study, which reported that the in vivo ablation of GPR174 culminated in a reduction of MZ B cells in the murine spleen [43]. Such discrepancy may be ascribed to experimental variability or the utilization of distinct mouse strains. Additionally, Researches posited that GPR174, in concert with its ligand, orchestrates the upregulation of gene expression encoding CD86 in B cells via the Gαs signaling pathway. The molecule CD86 is noted for its ability to stimulate the proliferation of B cells and to augment the secretion of antibodies [108]. This finding aligns with the attenuation of the inflammatory response observed in the absence of Gpr174 [42]. Therefore, antagonists of Gpr174 could potentially function as a therapeutic strategy for autoimmune diseases.

Conclusion

B cells are fundamentally tasked with the generation of immunoglobulins, colloquially known as antibodies. In BM, lymphoid progenitor cells give rise to pro-B cells. These pro-B cells transition to pre-B cells upon the onset of heavy chain expression. Pre-B cells then undergo V-J recombination for the light chains and begin expressing IgM, marking their advancement to immature B cells. Subsequently, B cells that survive negative selection and start expressing IgD are deemed naive B cells. These cells enter the lymphatic circulation and are equipped to respond to encountered antigens.

G2A is highly expressed in IgD-J gene reprogrammed pre-B cells. It may be expressed to protect cells from genomic instability. CXCR4 is essential for the retention of pre-B cells in BM, where its chemokine CXCL12 promotes B cell generation. When CXCR4 expression is reduced, B cells are able to exit BM and move into the peripheral circulation. Naive recirculating B cells migrate to to either the follicles or the EF regions through the CXCL13-CXCR5 axis. B cell entry into lymphoid tissue from high endothelial venules is mediated by CCR7 and CXCR4, where they form GC within follicles. Centroblasts with high expression of CXCR4 are distributed in DZ, upon CXCR4 down-regulation, they enter the LZ to become centrocytes. P2RY8 and S1PR mediate the retention and migration of B cells within GC, ultimately developing into memory B cells or PC. Additionally, EBI2 is crucial for GC and EF responses that facilitate B cell proliferation and development into PB. High expression of EBI2 redirects B cells towards EF regions and initiates early plasmablast responses, while EBI2 down-regulation drives B cells into the follicular centers for GC reactions. MZ B cells and memory B cells reside in the MZ, with S1PR1, S1PR3, CXCR5, and CB2 involved in the localization and distribution of MZ B cells. Gpr174 is associated with the MZ B cell compartment.

B cells have been recognized anew as more than just incidental observers, they are active contributors in autoimmune processes. As a transmembrane molecular protein, GPCR are important drug targets. These GPCR, which are crucial in the differentiation and development of B cells, undoubtedly offer fresh insights and potential therapeutic avenues. Research has established the pivotal role of various GPCRs in autoimmune diseases. P2RY8, CB2, EBI2, and Gpr174 may serve as protective receptors, warranting further exploration as potential disease biomarkers. S1PR, CXCR3, CXCR4, CXCR5, and CCR7, among others, exhibit promise for the development of targeted therapeutics, with several candidates expected to enter clinical trials within the next few years and eventually be translated into clinical practice. However, the mechanisms of GPCR action in autoimmune diseases remain incompletely understood, and current drugs often lack specificity, potentially leading to adverse effects or unintended consequences on other immune cells. The future of GPCR targeting in autoimmune diseases hinges on the development of more selective therapeutic agents, further clinical trials to evaluate safety and efficacy, and exploration of optimal dosing regimens. In summary, while the potential of GPCR-targeted therapies in autoimmune diseases is vast, challenges persist. With ongoing research and technological advancements, these therapies are poised to herald a transformative era in the treatment of autoimmune disorders.

Data availability

Data shared here is available upon request.

Abbreviations

GPCRs:

G protein-coupled receptors

PC:

Plasma cell

MS:

Multiple sclerosis

BM:

Bone marrow

CXCR:

CXC chemokine receptor

CXCL:

CXC chemokine ligand

S1P:

Sphingosin-1-phosphate

Ggg:

S-geranylgeranyl-L-glutathione

CCR:

C–C chemokine receptor

CCL:

C–C motif chemokine

HEV:

High endothelial venule

LN:

Lymph node

GC:

Germinal Center; DZ: dark zone

LZ:

Light zone

Tfh:

Follicular helper T cells

PB:

Plasmablast

FDCs:

Follicular dendritic cells

LLPC:

Long-lived plasma cells

Ggt5:

Gamma-glutamyltransferase-5

CB:

Cannabinoid

2-AG:

2-Arachidonoylglycerol

EBI2:

Epstein–Barr virus-induced molecule 2

EF:

Extrafollicular

MZ:

Marginal zone

BLR1:

Burkitt's lymphoma receptor 1

IBD:

Inflammatory bowel disease

BTK:

Bruton's tyrosine kinase

RA:

Rheumatoid arthritis

SLE:

Systemic lupus erythematosus

SPC:

Sphingosylphosphorylcholine

LPS:

Lipopolysaccharide

EAE:

Experimental allergic encephalomyelitis

NMOSD:

Neuromyelitis optical spectrum disorder

CNS:

Central Nervous System

ASCs:

Antibody-secreting cells

BP:

Bullous pemphigoid

TLS:

Tertiary lymphoid structure

BCR:

B-cell receptor

pSS:

Primary Sjogren’s syndrome

AITD:

Autoimmune thyroid disease

HT:

Hashimoto thyroiditis

GD:

Graves’ disease

ABCs:

Age-associated B cells

G2A −/− :

G2A gene knockout

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Acknowledgements

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Funding

This work was supported by Natural Science Foundation of China (No.82173425, No.82373488, No.82473530), Major Scientific Research Program for High-Level Health Personnel in Hunan Province Health and Family Planning Commission (No.2023041), National Key R&D Program of China (2021YFC2702004), Health research project of Hunan Provincial Health Commission of China (No. W20243055), Natural Science Foundation of Hunan Province of China (No.2024JJ4077, No.2024JJ9199), Central South University Innovation-Driven Research Programme (No.2023CXQD046).

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  1. Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China

    Yongqi Shao, Yang Mei, Yixin Tan, Ming Yang & Haijing Wu

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  2. Yang Mei
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YQ S wrote the manuscript, Y M contributed to the conception, YX T, M Y and HJ W revised the manuscript.

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Shao, Y., Mei, Y., Tan, Y. et al. The regulatory functions of G protein-coupled receptors signaling pathways in B cell differentiation and development contributing to autoimmune diseases. Cell Biosci 15, 57 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13578-025-01398-7

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Cell & Bioscience

ISSN: 2045-3701

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