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Sjögren Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The CXCR5 (chemokine [C-X-C motif] receptor 5, in association with the neighboring gene DDX6) gene encodes a membrane-bound protein present on some memory B cells and on follicular helper T cells. CXCR5 acts as a receptor for CXCL13, which directs B cells to lymphoid follicles, and which is expressed in 90% of pSS patients and only 10% of healthy individuals. CXCR5 pathogenic variants are implicated in multiple sclerosis and primary biliary cirrhosis. CXCR5 dysregulation has been observed in B cells of the salivary gland and periphery tissues from Sjögren syndrome patients [5].
Chemokines and Chemokine Receptor Interactions and Functions
Published in Thomas R. O’Brien, Chemokine Receptors and AIDS, 2019
Philip L. Shields, David H. Adams
Chemokines act via specific cell surface, seven transmembrane spanning G-protein-linked receptors (Figure 2). Five CXC chemokine receptors (CXCR1 to CXCR5), ten CC chemokine receptors (CCR1 to CCR10), and one CXXXC receptor have been identified so far in humans (Table 1). Most chemokine receptors are shared by more than one chemokine, such as CXCR3 which binds IP-10, MIG or IFN-inducible T cell alpha chemoattractant (I-TAC). A few have a restricted number of ligands such as CCR6 which binds MEP-3α and CXCR1, which binds IL-8 and granulocyte chemoattractant protein-2 (GCP-2). Some chemokines can also interact with more than one receptor (e.g., MIP-1α) suggesting a degree of redundancy and flexibility in the chemokine/chemokine receptor system. Engagement of chemokine receptors is associated with a calcium flux and G-protein dependent activation of phospholipases. The details of the downstream signals differ between cell types, so, for instance, IL-8 causes phospholipase D activation in lymphocytes, but not in neutrophils. There is also evidence that the consequences of receptor engagement is determined by the intracellular signals., Thus cytoskeletal rearrangement is a consequence of phospholipase C and Rho activation, whereas activation of protein tyrosine kinases is involved in cell activation and proliferation (11).
Lymphocyte homing and immunology of extranodal lymphoid tissues
Published in Franco Cavalli, Harald Stein, Emanuele Zucca, Extranodal Lymphomas, 2008
Mariagrazia Uguccioni, James J Campbell, Katrin Kuscher, Marshall E Kadin
Many publications have shown CXCL13 and its selective receptor CXCR5, in different extranodal B-cell lymphomas, as the primary central nervous system lymphoma (PCNSL).99 PCNSL is a rare, but often rapidly fatal form of non-Hodgkin’s B-cell lymphomas which arises in the CNS, involves the brain, spinal cord, meninges, and/or eye, and has a low propensity to metastasize. Gene expression profiling, using cDNA microarrays for cytokines/chemokines and their receptors, has been utilized to assess the role of the dysregulation of the endogenous immune system in PCNSL, extranodal and nodal lymphomas. This study, although employing few cases of each subtype, has underlined the importance of CXCL13, in addition to the chemokines active on monocytes and T lymphocytes.100 CXCL13, a B-cell-attracting chemokine, has been the first chemokine identified in malignant B lymphocytes of PCNSL.99 The protein, but not its mRNA, has been detected also on vascular endothelium, within the tumor mass. It has been hypothesized that there is an active mechanism of transport from the source to endothelial cells. Indeed, an active transport from the stroma to endothelial cells has been reported for other chemokines.101 In addition, malignant B cells express CXCR5, the selective CXCL13 receptor.99 This latter feature suggests a role for CXCL13 in the pathogenesis of PCNSL. Recent publications report that malignant B lymphocytes in PCNSL express CXCL12, as well as its selective receptor CXCR4.102–104 These data need confirmation at the mRNA level, but corroborate the need for thoughtful studies to assess the role of chemokines in PCNSL development and localization.
Poor clinical outcomes and immunoevasive contexture in CXCL13+CD8+ T cells enriched gastric cancer patients
Published in OncoImmunology, 2021
Kaifeng Jin, Yifan Cao, Yun Gu, Hanji Fang, Yuchao Fei, Jieti Wang, Xin Liu, Kunpeng Lv, Xudong He, Chao Lin, Hao Liu, He Li, Hongyong He, Ruochen Li, Heng Zhang, Jiejie Xu
It is generally believed that CD8+ T cells act as a positive prognosticator in most cancer types, as they could attack cancer cells directly.38 However, emerging studies have reported that several certain subtypes of intratumoral CD8+ T cells are associated with poor clinical outcomes,39 which attributes to T cell dysfunction.32 Previous studies, which investigate T cells in human melanoma and hepatocellular carcinoma, have identified CXCL13 as a significantly upregulated gene in dysfunctional CD8+ T cells.28,29,40 Until now, few studies have investigated the mechanism of CXCL13 up-regulation in malignancies. Some studies indicated that CXCL13 expression might be regulated by phosphatidylinositol 3-kinase (PI3K)-AKT pathway41 or Wnt/β-Catenin signal pathway.42 The up-regulated CXCL13 could interact with its specific receptor C-X-C motif chemokine receptor 5 (CXCR5), and form the CXCL13-CXCR5 axis, which plays an important role in tumor proliferation and migration.16 Although previous studies reported that the expression of CXCL13 receptor CXCR5 was significantly up-regulated in gastric cancer,43 and CXCR5 could be expressed on CD8+ T cell,44 CD4+ TFH cells45 and myeloid-derived suppressor cells (MDSCs),46 the clinical significance and the potential impact of CXCR5 on gastric cancer was still obscure, and would be further investigated in our following studies.
CXCL13-producing PD-1hiCXCR5− helper T cells in chronic inflammation
Published in Immunological Medicine, 2020
While Tph and Tfh cells share phenotype and functions in B-cell helper activities and CXCL13 production, these cells have a big difference in the expression of chemokine receptor CXCR5 that is crucial for the localization of cells in lymphoid follicle. CXCR5 expressing Tfh cells migrate into lymphoid follicle and exert B-cell helper activities with the functions of transcription factor BCL-6 [19]. These processes are finely regulated to produce extremely high affinity antibodies [20], and probably are acquired and optimized during long evolution of mammals. Therefore, CXCR5-negative Tph cells are supposed to be outside of lymphoid follicle and to exert biological functions different from Tfh cells. Indeed, in RA synovium, Tph cells and their transcription factor Sox4 localize in outside area of lymphoid follicle [6,10], and Tph and Tfh cells have different B-cell helper activities against naïve B cells [14]. Biological and immunological significance and molecular background for these differences remain to be determined.
Associations of circulating CXCR3–PD-1+CD4+T cells with disease activity of systemic lupus erythematosus
Published in Modern Rheumatology, 2019
Lei Han, Xue Yang, Yiyun Yu, Weiguo Wan, Ling Lv, Hejian Zou
Although elevated cTfh cells (characterized as CXCR5+PD-1highCD4+, CXCR5+ICOShighCD4+ or CXCR5highICOShighPD-1highCD4+ T cells) were observed in lupus patients and were associated with titers of autoantibodies and severity of end-organ involvement [4,10]. However, the relationship and function of circulating CXCR5– T cells in lupus remain unclear. Given these identified functional subsets in cTfh cells, we also wondered whether these subsets (CXCR3–PD-1+, ICOS+PD-1+, CCD7loPD-1hi) in CXCR5– cells had association with SLE disease activity index 2000 (SLEDAI) or autoantibody production. In this study, we assessed these subsets in circulating antigen-experienced CXCR5+/CXCR5–T cells and their correlation with disease activity. We found that the increased frequency of CXCR3–PD-1+CD4+ T cells was highly correlated with SLEDAI, anti-dsDNA and anti-nucleosome antibody production independently of CXCR5 expression. We also identified that CXCR3–PD-1+CD4+ T cells have better potential to B cell help. Our study suggests that percentage of CXCR3–PD-1+CD4+T cells in SLE patients is a sensitive indicator to assess SLE disease activity, and CXCR3–PD-1+CD4+T cells might contribute B cell help and the generation of autoantibodies in patients.