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The capacity of lymphocytes continuously home to lymphoid structures is remarkable for cancer immunosurveillance and immunotherapy. Lymphocyte homing and recirculation within the tumor microenvironment (TME) are now understood to be adaptive processes that are regulated by specialized cytokines and adhesion molecule signaling cascades. Restricted lymphocyte infiltration and recirculation have emerged as key mechanisms contributing to poor responses in cancer immunotherapies like chimeric antigen receptor (CAR)-T cell therapy and immune checkpoint blockades (ICBs). Uncovering the kinetics of lymphocytes in tumor infiltration and circulation is crucial for improving immunotherapies. In this review, we discuss the current insights into the adhesive and migrative molecules involved in lymphocyte homing and transmigration. The potential mechanisms within the TME that restrain lymphocyte infiltration are also summarized. Advanced on these, we outline the determinates for tertiary lymphoid structures (TLSs) formation within tumors, placing high expectations on the prognostic values of TLSs as therapeutic targets in malignancies. [ABSTRACT FROM AUTHOR]

Lymphocyte homing to peripheral lymph nodes (PLN) is critical for immune surveillance. However, autoimmune diseases such as multiple sclerosis (MS) can occur due to excessive immune responses in the PLN. Here we show that 6-sulfo sialyl Lewis X (6-sulfo sLex) glycans on high endothelial venules that function as ligands for l -selectin on lymphocytes play a critical role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In N -acetylglucosamine-6- O -sulfotransferase (GlcNAc6ST)-1 and GlcNAc6ST-2 double-knockout mice lacking the expression of 6-sulfo sLeX glycans, the EAE symptoms and the numbers of effector Th1 and Th17 cells in the draining lymph nodes (dLN) and spinal cords (SC) were significantly reduced. To determine whether 6-sulfo sLeX could serve as a target for MS, we also examined the effects of anti-glycan monoclonal antibody (mAb) SF1 against 6-sulfo sLeX in EAE. Administration of mAb SF1 significantly reduced EAE symptoms and the numbers of antigen-specific effector T cells in the dLN and SC in association with suppression of critical genes including Il17a and Il17f that are involved in the pathogenesis of EAE. Taken together, these results suggest that 6-sulfo sLeX glycan would serve as a novel target for MS. [ABSTRACT FROM AUTHOR]

Sjögren's syndrome (SS) is a chronic systemic autoimmune disease that typically presents with lymphocyte, dendritic cell, and macrophage infiltration of exocrine gland ducts and the formation of ectopic germinal centers. The interactions of lymphocyte homing receptors and addressins and chemokines and their receptors, such as a4b7/MAdCAM-1, LFA-1/ICAM-1, CXCL13/CXCR5, CCL25/ CCR9, CX3CL1/CX3CR1, play important roles in the migration of inflammatory cells to the focal glands and the promotion of ectopic germinal center formation in SS. A variety of molecules have been shown to be involved in lymphocyte homing, including tumor necrosis factor-a, interferon (IFN)-a, IFN-b, and B cell activating factor. This process mainly involves the Janus kinase-signal transducer and activator of transcription signaling pathway, lymphotoxin-b receptor pathway, and nuclear factor-kB signaling pathway. These findings have led to the development of antibodies to cell adhesion molecules, antagonists of chemokines and their receptors, compounds interfering with chemokine receptor signaling, and gene therapies targeting chemokines and their receptors, providing new targets for the treatment of SS in humans. The aim of this study was to explore the relationship between lymphocyte homing and the pathogenesis of SS, and to provide a review of recent studies addressing lymphocyte homing in targeted therapy for SS. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial tissue inflammation, substantially impacting the quality of life of patients. The interaction between L-selectin and its glycoprotein ligands modified with 6-sulfo sialyl Lewis x (6-sulfo sLex) is known to mediate lymphocyte homing to initiate immune responses. Thus, this process could be a potential therapeutic target for RA. Herein, we explored the preventive effects of an anti-6-sulfo sLex monoclonal antibody (mAb), SF1, on collagen-induced arthritis (CIA) in DBA/1 mice. Mice were administered SF1 from day 21 postfirst immunization with type II collagen (CII), and the effects of SF1 on both clinical and histopathological disease progression evoked by the second immunization were examined. SF1 significantly suppressed clinical features and histological levels associated with arthritis severity. Enzyme-linked immunosorbent assay consistently indicated that SF1 inhibited the production of CII-specific IgG2a. Based on the reverse transcription-quantitative PCR analysis, SF1 suppressed the expression of interferon-γ, a T helper 1 cytokine, as well as that of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, in draining lymph nodes. Collectively, these results indicate that SF1, an anti-sulfated glycan mAb, could be beneficial in preventing CIA in mice and may afford as a novel agent to treat RA. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) reside in nonlymphoid tissues where they carry out unique functions. The molecular mechanisms responsible for Treg accumulation and maintenance in these tissues are relatively unknown. Using an unbiased discovery approach, we identified LAYN (layilin), a C-type lectin-like receptor, to be preferentially and highly expressed on a subset of activated Tregs in healthy and diseased human skin. Expression of layilin on Tregs was induced by TCR-mediated activation in the presence of IL-2 or TGF-β. Mice with a conditional deletion of layilin in Tregs had reduced accumulation of these cells in tumors. However, these animals somewhat paradoxically had enhanced immune regulation in the tumor microenvironment, resulting in increased tumor growth. Mechanistically, layilin expression on Tregs had a minimal effect on their activation and suppressive capacity in vitro. However, expression of this molecule resulted in a cumulative anchoring effect on Treg dynamic motility in vivo. Taken together, our results suggest a model whereby layilin facilitates Treg adhesion in skin and, in doing so, limits their suppressive capacity. These findings uncover a unique mechanism whereby reduced Treg motility acts to limit immune regulation in nonlymphoid organs and may help guide strategies to exploit this phenomenon for therapeutic benefit.

Extranodal lymphoma occurs in one-third of lymphoma patients and is a key indicator of the international prognostic index, associated with unfavorable outcomes. Due to the lack of ideal models, the causes and characteristics of extranodal lymphoma are greatly underexplored. Recently, we observed a high incidence of extranodal lymphoma in two types of mouse models with tropism for the brain and kidneys. These findings prompt us to rethink the pathological progression of lymphoma colonization in lymph nodes and non-lymphoid organs. Nodal lymphoma, primary extranodal lymphoma and secondary extranodal lymphoma should be biologically and clinically distinctive scenarios. Based on the observations in mouse models with extranodal lymphoma, we propose that lymphoma dissemination can be seen as lymphoma losing the ability to home to lymph nodes. The pathological process of nodal lymphoma should be referred to as lymphoma homing to distinguish it from benign hyperplasia. Lymphoma dissemination, defined as a pathological process that lymphoma can occur in almost any part of the body, is a key pathological hallmark for malignant progression of B-cell lymphoma. Reshaping cellular plasticity is a promising strategy to allow transformed cells to homing back to lymph nodes and re-sensitize tumor cells to treatment. From this perspective, we provide new insights into the pathological progression of lymphoma dissemination and its inspiration on therapeutic interventions. We believe that establishing extranodal lymphoma mouse models, identifying molecular mechanism governing lymphoma dissemination, and developing therapies to prevent lymphoma dissemination will become emerging topics for fighting relapsed and refractory lymphoma. [ABSTRACT FROM AUTHOR]

AIOLOS, encoded by IKZF3, is a member of the IKZF family of proteins that plays an important role in regulating late B-cell differentiation. Human individuals heterozygous for the AIOLOS p.N160S variant displayed impaired humoral immune responses as well as impaired B and T cell development. We have previously reported that a mouse strain harboring an Ikzf3N159S allele that corresponds to human IKZF3N160S recapitulated immune-deficient phenotypes, such as impaired B cell development and loss of CD23 expression. In this study, we investigated the effect of the Ikzf3N159S variant and found that B1a cell development was impaired in Ikzf3N159S/N159S mice. In addition, CD62L expression was severely decreased in both B and T lymphocytes by the Ikzf3N159S mutation, in a dose-dependent manner. Mixed bone marrow chimera experiments have revealed that most immunodeficient phenotypes, including low CD62L expression, occur in intrinsic cells. Interestingly, while Ikzf3N159S/N159S lymphocytes were still present in the spleen, they were completely outcompeted by control cells in the lymph nodes, suggesting that the capacity for homing or retention in the lymph nodes was lost due to the Ikzf3N159S mutation. The homing assay confirmed severely decreased homing abilities to lymph nodes of Ikzf3N159S/N159S B and T lymphocytes but selective enrichment of CD62L expressing Ikzf3N159S/N159S lymphocytes in lymph nodes. This finding suggests that impaired CD62L expression is the major reason for the impaired homing capacity caused by the Ikzf3N159S mutation. Interestingly, an excess amount of Ikaros, but not Aiolos, restored CD62L expression in Ikzf3N159S/N159S B cells. Together with the loss of CD62L expression due to Ikaros deficiency, the AiolosN159S mutant protein likely interferes with Ikaros function through heterodimerization, at least in activating the Sell gene encoding CD62L expression. Thus, our results revealed that AiolosN159S causes some immunodeficient phenotypes via the pathogenesis referred to as the heterodimeric interference as observed for AiolosG158R variant. [ABSTRACT FROM AUTHOR]

AIOLOS, encoded by IKZF3, is a member of the IKZF family of proteins that plays an important role in regulating late B-cell differentiation. Human individuals heterozygous for the AIOLOS p.N160S variant displayed impaired humoral immune responses as well as impaired B and T cell development. We have previously reported that a mouse strain harboring an Ikzf3N159S allele that corresponds to human IKZF3N160S recapitulated immune-deficient phenotypes, such as impaired B cell development and loss of CD23 expression. In this study, we investigated the effect of the Ikzf3N159S variant and found that B1a cell development was impaired in Ikzf3N159S/N159S mice. In addition, CD62L expression was severely decreased in both B and T lymphocytes by the Ikzf3N159S mutation, in a dose-dependent manner. Mixed bone marrow chimera experiments have revealed that most immunodeficient phenotypes, including low CD62L expression, occur in intrinsic cells. Interestingly, while Ikzf3N159S/N159S lymphocytes were still present in the spleen, they were completely outcompeted by control cells in the lymph nodes, suggesting that the capacity for homing or retention in the lymph nodes was lost due to the Ikzf3N159S mutation. The homing assay confirmed severely decreased homing abilities to lymph nodes of Ikzf3N159S/N159S B and T lymphocytes but selective enrichment of CD62L expressing Ikzf3N159S/N159S lymphocytes in lymph nodes. This finding suggests that impaired CD62L expression is the major reason for the impaired homing capacity caused by the Ikzf3N159S mutation. Interestingly, an excess amount of Ikaros, but not Aiolos, restored CD62L expression in Ikzf3N159S/N159S B cells. Together with the loss of CD62L expression due to Ikaros deficiency, the AiolosN159S mutant protein likely interferes with Ikaros function through heterodimerization, at least in activating the Sell gene encoding CD62L expression. Thus, our results revealed that AiolosN159S causes some immunodeficient phenotypes via the pathogenesis referred to as the heterodimeric interference as observed for AiolosG158R variant.

Central memory T cells (TCM) patrol lymph nodes, providing central immunosurveillance against known pathogens, but have not been described as conducting primary tissue immunosurveillance. We analyzed the expression of tissue-homing addressins in human TCM vs effector memory T cells (TEM) from the same donors. In humans, the majority of human TCM were tropic for either skin or gut, and the overall tissue tropism of TCM was comparable to that of TEM TCM were present in healthy, noninflamed human skin, lung, colon, and cervix, suggesting a role for TCM in the primary immunosurveillance of peripheral tissues. TCM also had potent effector functions; 80% of CD8+ TCM produced TC1/TC2/TC17/TC22 cytokines. TCM injected into human skin-grafted mice migrated into skin and induced inflammatory eruptions comparable to TEM-injected mice. In summary, human TCM express peripheral tissue-homing receptors at levels similar to their effector memory counterparts, are found in healthy human tissues, have impressive effector functions, and can act alone to induce skin inflammation in human engrafted mice. Our studies support a novel role for human TCM in primary immunosurveillance of peripheral tissues and highlight the important role of this long-lived cell type in tissue-based immune responses.

With growing molecular evidence for correlations between spatial arrangement of blood vasculature and fundamental immunological functions, carried out in distinct compartments of the subdivided lymph node, there is an urgent need for three-dimensional models that can link these aspects. We reconstructed such models at a 1.84 µm resolution by the means of X-ray phase-contrast imaging with a 2D Talbot array in a short time without any staining. In addition reconstructions are verified in immunohistochemistry staining as well as in ultrastructural analyses. While conventional illustrations of mammalian lymph nodes depict the hilus as a definite point of blood and lymphatic vessel entry and exit, our method revealed that multiple branches enter and emerge from an area that extends up to one third of the organ’s surface. This could be a prerequisite for the drastic and location-dependent remodeling of vascularization, which is necessary for lymph node expansion during inflammation. Contrary to corrosion cast studies we identified B-cell follicles exhibiting a two times denser capillary network than the deep cortical units of the T-cell zone. In addition to our observation of high endothelial venules spatially surrounding the follicles, this suggests a direct connection between morphology and B-cell homing. Our findings will deepen the understanding of functional lymph node composition and lymphocyte migration on a fundamental basis. [ABSTRACT FROM AUTHOR]

The onset of an adaptive immune response provides the signals required for differentiation of antigen-specific lymphocytes into effector cells and imprinting of these cells for re-circulation to the most appropriate anatomical site (i.e., homing). Lymphocyte homing is governed by the expression of tissue-specific lymphocyte homing receptors that bind to unique tissue-specific ligands on endothelial cells. In this study, a whole-parasite malaria vaccine (radiation-attenuated sporozoites (RAS)) was used as a model system to establish homing receptor signatures induced by the parasite delivered through mosquito bite to provide a benchmark of desirable homing receptors for malaria vaccine developers. This immunization regimen resulted in the priming of antigen-specific B cells and CD8+ T cells for homing primarily to the skin and T/B cell compartments of secondary lymphoid organs. Infection with live sporozoites, however, triggers the upregulation of homing receptor for the liver and the skin, demonstrating that there is a difference in the signal provided by attenuated vs. live sporozoites. This is the first report on imprinting of homing routes by Plasmodium sporozoites and, surprisingly, it also points to additional, yet to be identified, signals provided by live parasites that prime lymphocytes for homing to the liver. The data also demonstrate the utility of this method for assessing the potential of vaccine formulations to direct antigen-specific lymphocytes to the most relevant anatomical site, thus potentially impacting vaccine efficacy. [ABSTRACT FROM AUTHOR]

With growing molecular evidence for correlations between spatial arrangement of blood vasculature and fundamental immunological functions, carried out in distinct compartments of the subdivided lymph node, there is an urgent need for three-dimensional models that can link these aspects. We reconstructed such models at a 1.84 µm resolution by the means of X-ray phase-contrast imaging with a 2D Talbot array in a short time without any staining. In addition reconstructions are verified in immunohistochemistry staining as well as in ultrastructural analyses. While conventional illustrations of mammalian lymph nodes depict the hilus as a definite point of blood and lymphatic vessel entry and exit, our method revealed that multiple branches enter and emerge from an area that extends up to one third of the organ’s surface. This could be a prerequisite for the drastic and location-dependent remodeling of vascularization, which is necessary for lymph node expansion during inflammation. Contrary to corrosion cast studies we identified B-cell follicles exhibiting a two times denser capillary network than the deep cortical units of the T-cell zone. In addition to our observation of high endothelial venules spatially surrounding the follicles, this suggests a direct connection between morphology and B-cell homing. Our findings will deepen the understanding of functional lymph node composition and lymphocyte migration on a fundamental basis.

Inflammatory bowel diseases (IBDs) are characterized by chronic inflammatory disorders that are a result of an abnormal immune response mediated by a cytokine storm and immune cell infiltration. Proinflammatory cytokine therapeutic agents, represented by TNF inhibitors, have developed rapidly over recent years and are promising options for treating IBD. Antagonizing interleukins, interferons, and Janus kinases have demonstrated their respective advantages in clinical trials and are candidates for anti-TNF therapeutic failure. Furthermore, the blockade of lymphocyte homing contributes to the excessive immune response in colitis and ameliorates inflammation and tissue damage. Factors such as integrins, selectins, and chemokines jointly coordinate the accumulation of immune cells in inflammatory regions. This review assembles the major targets and agents currently targeting proinflammatory cytokines and lymphatic trafficking to facilitate subsequent drug development. [ABSTRACT FROM AUTHOR]

Objective To investigate the etiology, diagnosis and treatment of granulomatous cheilitis（GC）. Methods For a patient with recurrent granulomatous cheilitis for more than 1 year in whom no medical treatment was used, only systemic treatment of the teeth was performed, and its efficacy was observed. We also reviewed the relevant literature. Results The vermilion of the right lower lip of the patient was obviously swollen and soft. There was rebound and no pitting edema with palpation. A large dark red rash with local desquamation was observed on the skin over the right mandible. There were residual roots in tooth 35, 46, and 47, a porcelain bridge on 11-24, deep caries in 15, 16, 26, and 36, and many calculi in the whole mouth, and the gingival margin was obviously congested and swollen. Histopathological examination showed many lymphocytes infiltrated the superficial dermis, and granulation tissue, plasma cells and eosinophils infiltrated locally. The diagnosis was as follows: ① GC; ② 35, 46, and 47 residual roots; ③ 15, 16, 26, and 36 deep caries; ④ gingivitis. The treatment included extraction of 35, 46, and 47 residual roots, periodontal basic treatment, and fillings for 15, 16, 26, and 36. No drugs were administered except for 3 days after tooth extraction. After 5 weeks of treatment, the swelling of the lower lip and the skin rash completely disappeared. There was no recurrence in the follow-up observation at six months. Through a literature review and analysis, we found that GC may be related to various factors such as immunity, infection, and genetics. Local oral infections may be closely related to the incidence of GC. Conclusion Resolution of local oral infections is effective for the treatment of granulomatous cheilitis, and local oral infections may be closely related to the onset of granulomatous cheilitis. In the treatment of granulomatous cheilitis, attention should be paid to the systematic examination of the oral condition, and the treatment of suspected lesions in the oral cavity should begin in the early stages of treatment.

The capacity of lymphocytes continuously home to lymphoid structures is remarkable for cancer immunosurveillance and immunotherapy. Lymphocyte homing and recirculation within the tumor microenvironment (TME) are now understood to be adaptive processes that are regulated by specialized cytokines and adhesion molecule signaling cascades. Restricted lymphocyte infiltration and recirculation have emerged as key mechanisms contributing to poor responses in cancer immunotherapies like chimeric antigen receptor (CAR)-T cell therapy and immune checkpoint blockades (ICBs). Uncovering the kinetics of lymphocytes in tumor infiltration and circulation is crucial for improving immunotherapies. In this review, we discuss the current insights into the adhesive and migrative molecules involved in lymphocyte homing and transmigration. The potential mechanisms within the TME that restrain lymphocyte infiltration are also summarized. Advanced on these, we outline the determinates for tertiary lymphoid structures (TLSs) formation within tumors, placing high expectations on the prognostic values of TLSs as therapeutic targets in malignancies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tian, Wei, Qin, Bao, Tong, Zhou, Xue, Zhang and Shao.)

The onset of an adaptive immune response provides the signals required for differentiation of antigen-specific lymphocytes into effector cells and imprinting of these cells for re-circulation to the most appropriate anatomical site (i.e., homing). Lymphocyte homing is governed by the expression of tissue-specific lymphocyte homing receptors that bind to unique tissue-specific ligands on endothelial cells. In this study, a whole-parasite malaria vaccine (radiation-attenuated sporozoites (RAS)) was used as a model system to establish homing receptor signatures induced by the parasite delivered through mosquito bite to provide a benchmark of desirable homing receptors for malaria vaccine developers. This immunization regimen resulted in the priming of antigen-specific B cells and CD8+ T cells for homing primarily to the skin and T/B cell compartments of secondary lymphoid organs. Infection with live sporozoites, however, triggers the upregulation of homing receptor for the liver and the skin, demonstrating that there is a difference in the signal provided by attenuated vs. live sporozoites. This is the first report on imprinting of homing routes by Plasmodium sporozoites and, surprisingly, it also points to additional, yet to be identified, signals provided by live parasites that prime lymphocytes for homing to the liver. The data also demonstrate the utility of this method for assessing the potential of vaccine formulations to direct antigen-specific lymphocytes to the most relevant anatomical site, thus potentially impacting vaccine efficacy.

Summary: Differentiation of intestinal T helper 17 (Th17) cells, which contribute to mucosal barrier protection from invasive pathogens, is dependent on colonization with distinct commensal bacteria. Segmented filamentous bacteria (SFB) are sufficient to support Th17 cell differentiation in mouse, but the molecular and cellular requirements for this process remain incompletely characterized. Here, we show that intestine-draining mesenteric lymph nodes (MLNs), not intestine proper, are the dominant site of SFB-induced intestinal Th17 cell differentiation. Subsequent migration of these cells to the intestinal lamina propria is dependent on their upregulation of integrin β7. Stat3-dependent induction of RORγt, the Th17 cell-specifying transcription factor, largely depends on IL-6, but signaling through the receptors for IL-21 and IL-23 can compensate for absence of IL-6 to promote SFB-directed Th17 cell differentiation. These results indicate that redundant cytokine signals guide commensal microbe-dependent Th17 cell differentiation in the MLNs and accumulation of the cells in the lamina propria.

Caramel color is a widely used food pigment, and 2-Acetyl-4-tetrahydroxybutylimidazole (THI) is a by-products of Class III caramel color. Some studies have shown that THI can reduce the number of peripheral blood lymphocytes. However, the comprehensive mechanism of THI immunotoxicity requires further study. In this study, the effects of THI on lymphocyte count, humoral immunity, cellular immunity and nonspecific immunity were determined and the effect of the nutritional status of VB6 on THI immunotoxicity was evaluated. Female BALB/c mice were divided into 3 groups and fed chow containing different doses of VB6: VB6-normal (6 mg/kg VB6), VB6-deprived (0.5 mg/kg VB6) or VB6-enhanced (12 mg/kg VB6) feed. Each group was further divided into 4 subgroups and treated with THI (0.5, 2.5 or 12.5 mg/kg bw) or the solvent control by gavage for 30 days. The thymic cortical thickness was measured with ViewPoint; the proportions of major immune cells and T cells in peripheral blood and tissues were detected via flow cytometry; the transformation and proliferation abilities of T and B cells were detected via T and B lymphocyte proliferation assays; NK cell activity was assessed via lactate dehydrogenase assays; humoral immune function was assessed via plaque-forming cell assays; and the immune function of T lymphocytes was assessed via delayed type hypersensitivity assays. The results showed that compared with those in the corresponding control group, the white blood cell count and lymphocyte count decreased significantly in all the VB6-deprived groups, in the 2.5 and 12.5 mg/kg VB6 groups, and in the 12.5 mg/kg VB6-enhanced group. With increasing THI dose, the thymic cortical layer became thinner. In the thymus, THI increased the proportions of CD3+ T cells and mature CD8+ T cells and decreased the proportions of immature double-positive, double-negative T cells and CD69-expressing lymphocytes. The proportions of naïve T cells and Tcm (central memory T) cells related to homing decreased. The proportion of mature T cells in the spleen decreased significantly. The proliferation of T cells stimulated by ConA decreased after THI exposure. VB6-deficient mice were more sensitive to THI immunotoxicity, and supplementation with VB6 had a certain protective effect on these mice. The results of the PFC and NK cell activity assays indicated that THI exposure might not affect humoral immune or innate immune function. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases (IBDs) are characterized by chronic inflammatory disorders that are a result of an abnormal immune response mediated by a cytokine storm and immune cell infiltration. Proinflammatory cytokine therapeutic agents, represented by TNF inhibitors, have developed rapidly over recent years and are promising options for treating IBD. Antagonizing interleukins, interferons, and Janus kinases have demonstrated their respective advantages in clinical trials and are candidates for anti-TNF therapeutic failure. Furthermore, the blockade of lymphocyte homing contributes to the excessive immune response in colitis and ameliorates inflammation and tissue damage. Factors such as integrins, selectins, and chemokines jointly coordinate the accumulation of immune cells in inflammatory regions. This review assembles the major targets and agents currently targeting proinflammatory cytokines and lymphatic trafficking to facilitate subsequent drug development.

The addition of sulfate to glycan structures can regulate their ability to serve as ligands for glycan-binding proteins. Although sulfate groups present on the monosaccharides glucosamine, uronate, N-acetylglucosamine and N-acetylgalactosamine are recognized by defined receptors that mediate important functions, the functional significance of galactose-6-O-sulfate (Gal6S) is not known. However, in vitro studies using synthetic glycans and sulfotransferase overexpression implicate Gal6S as a binding determinant for the lymphocyte homing receptor, L-selectin. Only two sulfotransferases have been shown to generate Gal6S, namely keratan sulfate galactose 6-O-sulfotransferase (KSGal6ST) and chondroitin 6-O-sulfotransferase-1 (C6ST-1). In the present study, we use mice deficient in KSGal6ST and C6ST-1 to test whether Gal6S contributes to ligand recognition by L-selectin in vivo. First, we establish that KSGal6ST is selectively expressed in high endothelial venules (HEVs) in lymph nodes and Peyer's patches. We also determine by mass spectrometry that KSGal6ST generates Gal6S on several classes of O-glycans in peripheral lymph nodes. Furthermore, KSGal6ST, but not C6ST-1, is required for the generation of the Gal6S-containing glycan, 6,6'-disulfo-3'sLN (Siaα2→3[6S]Galβ1→4[6S]GlcNAc) or a closely related structure in lymph node HEVs. Nevertheless, L-selectin-dependent short-term homing of lymphocytes is normal in KSGal6ST-deficient mice, indicating that the Gal6S-containing structures we detected do not contribute to L-selectin ligand recognition in this setting. These results refine our understanding of the biological ligands for L-selectin and introduce a mouse model for investigating the functions of Gal6S in other contexts.

Sjögren's syndrome (SS) is a chronic systemic autoimmune disease that typically presents with lymphocyte, dendritic cell, and macrophage infiltration of exocrine gland ducts and the formation of ectopic germinal centers. The interactions of lymphocyte homing receptors and addressins and chemokines and their receptors, such as α4β7/MAdCAM-1, LFA-1/ICAM-1, CXCL13/CXCR5, CCL25/CCR9, CX3CL1/CX3CR1, play important roles in the migration of inflammatory cells to the focal glands and the promotion of ectopic germinal center formation in SS. A variety of molecules have been shown to be involved in lymphocyte homing, including tumor necrosis factor-α, interferon (IFN)-α, IFN-β, and B cell activating factor. This process mainly involves the Janus kinase-signal transducer and activator of transcription signaling pathway, lymphotoxin-β receptor pathway, and nuclear factor-κB signaling pathway. These findings have led to the development of antibodies to cell adhesion molecules, antagonists of chemokines and their receptors, compounds interfering with chemokine receptor signaling, and gene therapies targeting chemokines and their receptors, providing new targets for the treatment of SS in humans. The aim of this study was to explore the relationship between lymphocyte homing and the pathogenesis of SS, and to provide a review of recent studies addressing lymphocyte homing in targeted therapy for SS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liao, Yu, Huang, He, Yang, Zhang, Chen, Song, Luo and Tao.)

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We report the case of an 84-year-old woman with poorly differentiated non-small cell carcinoma of the right parotid who presented with headache, was found to have a primary right parotid gland cancer as well as metastatic disease, and underwent palliative radiotherapy to the primary site. The patient received no chemotherapy or immunotherapy, but both the primary site and several non-irradiated foci in the lungs regressed or completely resolved. The patient remained free of disease for about one year before progression. The case is a rare instance of abscopal regression of metastatic disease in the absence of pharmacologic immunomodulation. A literature review surveys the history of the abscopal effect of radiation therapy, attempts to understand the mechanisms of its successes and failures, and points to new approaches that can inform and improve the outcomes of radioimmunotherapy. [ABSTRACT FROM AUTHOR]

Objectives: Human papillomavirus (HPV) ranks the first cause of cervical cancer. Cervical cancer has high prevalence rates in women around the world. The HPV-E7 oncoprotein is expressed in cervical cancer and is a target of developing immunotherapies against HPV-associated tumors. However, the antigenicity of this protein is low. Due to this reason, potent adjuvants are required to enhance its therapeutic efficacy. This preliminary study aims to evaluate whether lymphotoxin (LT) could act as an effective immune adjuvant for HPV infection in mice models. Material and methods: Intranasal immunization was used to explore the effect of HPV-E7 and/or LT immune response. After the third intranasal immunization, the titer for the HPV-E7 antibody was detected in serum and vaginal washing fluid. Also, we assessed the expression of chemokine ligand 13 (CXCL13) and Peripheral Node Addressin (PNAd) in the lymph nodes after intranasal immunization with immunohistochemical analysis. Results: compared to HPV-E7 immunization, intranasal immunization with HPV-E7 plus LT significantly increased HPV-E7-specific serum IgG and vaginal IgA titers. Furthermore, the combined use of HPV-E7 and LT strongly induced E7-specific CTL responses. Conclusions: LT can be effective for intranasal immunized HPV-E7 to improve E7-specific immune responses to HPV infection. It is new approach to eradicate chronic HPV infection capable of inducing an effective anti-infection method. [ABSTRACT FROM AUTHOR]

The mechanisms operating in lymphocyte recruitment and homing to liver are reviewed. A literature review was performed on primary biliary cirrhosis (PBC), progressive sclerosing cholangitis (PSC), and homing mechanisms; a total of 130 papers were selected for discussion. Available data suggest that in addition to a specific role for CCL25 in PSC, the CC chemokines CCL21 and CCL28 and the CXC chemokines CXCL9 and CXCL10 are involved in the recruitment of T lymphocytes into the portal tract in PBC and PSC. Once entering the liver, lymphocytes localize to bile duct and retain by the combinatorial or sequential action of CXCL12, CXCL16, CX3CL1, and CCL28 and possibly CXCL9 and CXCL10. The relative importance of these chemokines in the recruitment or the retention of lymphocytes around the bile ducts remains unclear. The available data remain limited but underscore the importance of recruitment and homing.

BackgroundThe recruitment of lymphocytes to secondary lymphoid organs relies on interactions of circulating cells with high endothelial venules (HEV). HEV are exclusive to these organs under physiological conditions, but they can develop in chronically-inflamed tissues. The interaction of L-selectin on lymphocytes with sulfated glycoprotein ligands on HEV results in lymphocyte rolling, which represents the initial step in lymphocyte homing. HEV expression of GlcNAc6ST-2 (also known as HEC-GlcNAc6ST, GST-3, LSST or CHST4), an HEV-restricted sulfotransferase, is essential for the elaboration of L-selectin functional ligands as well as a critical epitope recognized by MECA-79 mAb.ResultsWe examined the expression of GlcNAc6ST-2 in relationship to the MECA-79 epitope in rheumatoid arthritis (RA) synovial vessels. Expression of GlcNAc6ST-2 was specific to RA synovial tissues as compared to osteoarthritis synovial tissues and localized to endothelial cells of HEV-like vessels and small flat-walled vessels. Double MECA-79 and GlcNAc6ST-2 staining showed colocalization of the MECA-79 epitope and GlcNAc6ST-2. We further found that both TNF-alpha and lymphotoxin-alphabeta induced GlcNAc6ST-2 mRNA and protein in cultured human umbilical vein endothelial cells.ConclusionThese observations demonstrate that GlcNAc6ST-2 is induced in RA vessels and provide potential cytokine pathways for its induction. GlcNAc6ST-2 is a novel marker of activated vessels within RA ectopic lymphoid aggregates. This enzyme represents a potential therapeutic target for RA.

BackgroundThe recruitment of lymphocytes to secondary lymphoid organs relies on interactions of circulating cells with high endothelial venules (HEV). HEV are exclusive to these organs under physiological conditions, but they can develop in chronically-inflamed tissues. The interaction of L-selectin on lymphocytes with sulfated glycoprotein ligands on HEV results in lymphocyte rolling, which represents the initial step in lymphocyte homing. HEV expression of GlcNAc6ST-2 (also known as HEC-GlcNAc6ST, GST-3, LSST or CHST4), an HEV-restricted sulfotransferase, is essential for the elaboration of L-selectin functional ligands as well as a critical epitope recognized by MECA-79 mAb.ResultsWe examined the expression of GlcNAc6ST-2 in relationship to the MECA-79 epitope in rheumatoid arthritis (RA) synovial vessels. Expression of GlcNAc6ST-2 was specific to RA synovial tissues as compared to osteoarthritis synovial tissues and localized to endothelial cells of HEV-like vessels and small flat-walled vessels. Double MECA-79 and GlcNAc6ST-2 staining showed colocalization of the MECA-79 epitope and GlcNAc6ST-2. We further found that both TNF-alpha and lymphotoxin-alphabeta induced GlcNAc6ST-2 mRNA and protein in cultured human umbilical vein endothelial cells.ConclusionThese observations demonstrate that GlcNAc6ST-2 is induced in RA vessels and provide potential cytokine pathways for its induction. GlcNAc6ST-2 is a novel marker of activated vessels within RA ectopic lymphoid aggregates. This enzyme represents a potential therapeutic target for RA.

The interaction of L-selectin expressed on lymphocytes with sulfated sialomucin ligands such as CD34 and GlyCAM-1 on high endothelial venules (HEV) of lymph nodes results in lymphocyte rolling and is essential for lymphocyte recruitment. HEC-GlcNAc6ST-deficient mice lack an HEV-restricted sulfotransferase with selectivity for the C-6 position of N-acetylglucosamine (GlcNAc). HEC-GlcNAc6ST-/- animals exhibit faster lymphocyte rolling and reduced lymphocyte sticking in HEV, accounting for the diminished lymphocyte homing. Isolated CD34 and GlyCAM-1 from HEC-GlcNAc6ST-/- animals incorporate approximately 70% less sulfate than ligands from wild-type animals. Furthermore, these ligands exhibit a comparable reduction of the epitope recognized by MECA79, a function-blocking antibody that reacts with L-selectin ligands in a GlcNAc-6-sulfate-dependent manner. Whereas MECA79 dramatically inhibits lymphocyte rolling and homing to lymph nodes in wild-type mice, it has no effect on HEC-GlcNAc6ST-/- mice. In contrast, in vitro rolling on purified GlyCAM-1 from HEC-GlcNAc6ST-/- mice, although greatly diminished compared with that on the wild-type ligand, is inhibited by MECA79. Our results demonstrate that HEC-GlcNAc6ST contributes predominantly, but not exclusively, to the sulfation of HEV ligands for L-selectin and that alternative, non-MECA79-reactive ligands are present in the absence of HEC-GlcNAc6ST.

The steps involved in lymphocyte homing to the white pulp cords of the spleen are poorly understood. We demonstrate here that the integrins lymphocyte function associated (LFA)-1 and alpha 4 beta 1 make essential and mostly overlapping contributions necessary for B cell migration into white pulp cords. T cell entry to the white pulp is also reduced by blockade of LFA-1 and alpha 4 beta 1. The LFA-1 ligand, intercellular adhesion molecule 1 is critical for lymphocyte entry and both hematopoietic cells and radiation-resistant cells contribute to this requirement. Vascular cell adhesion molecule 1 contributes to the alpha 4 beta 1 ligand requirement and a second ligand, possibly fibronectin, also plays a role. By contrast with the entry requirements, antigen-induced movement of B cells from follicles to the outer T zone is not prevented by integrin blocking antibodies. Comparison of the distribution of integrin-blocked B cells and B cells treated with the G alpha i inhibitor, pertussis toxin, early after transfer reveals in both cases reduced accumulation in the inner marginal zone. These observations suggest that chemokine receptor signaling and the integrins LFA-1 and alpha 4 beta 1 function together to promote lymphocyte transit from the marginal zone into white pulp cords.

A small fraction of HIV-1-infected T cells forms populations of latently infected cells when they are a naive T-cell subset or in transit to a resting memory state. Latently HIV-1-infected cells reside in lymphoid tissues and serve as viral reservoirs. However, whether they systemically recirculate in the body and re-enter the lymphoid nodes are unknown. Here, we employed two in-vitro cell coculture systems mimicking the lymphatic endothelium in lymph nodes and investigated the homing potential, specifically the transendothelial migration (TEM), of two latently HIV-1-infected cell lines (J1.1 and ACH-2). In trans-well coculture systems, J1.1 and ACH-2 showed higher TEM efficiencies than their parental uninfected and acutely infected cells. The efficiency of TEM was enhanced by the presence of stromal cells, such as HS-5 and fibroblastic reticular cells. In an in-vitro reconstituted, three-dimensional coculture system in which stromal cells are embedded in collagen matrices, J1.1 showed slightly higher TEM efficiency in the presence of HS-5. In accordance with these phenotypes, latently infected cells adhered to the endothelial cells more efficiently than uninfected cells. Together, our study showed that latently HIV-1-infected cells enhanced cell adhesion and TEM abilities, suggesting their potential for efficient homing to lymph nodes.

B cell entry to lymph nodes and Peyer's patches depends on chemokine receptor signaling, but the principal chemokine involved has not been defined. Here we show that the homing of CXCR4-/- B cells is suppressed in CCL19 (ELC)- and CCL21 (SLC)-deficient paucity of lymph node T cells mice, but not in wild-type mice. We also find that CXCR4 can contribute to T cell homing. Using intravital microscopy, we find that B cell adhesion to high endothelial venules (HEVs) is disrupted when CCR7 and CXCR4 are predesensitized. In Peyer's patches, B cell entry is dependent on CXCR5 in addition to CCR7/CXCR4. CXCL12 (SDF1) is displayed broadly on HEVs, whereas CXCL13 (BLC) is found selectively on Peyer's patch follicular HEVs. These findings establish the principal chemokine and chemokine receptor requirements for B cell entry to lymph nodes and Peyer's patches.

Sphingosine-1-phosphate receptor subtype 1 (S1P1) is essential for lymphocyte egress from lymphoid organs into systemic circulation and provides a well-defined drug target for autoimmune disorders. IMMH001, also called SYL930, is a specific S1P1/S1P4/S1P5 modulator. Here, we investigated the potential therapeutic effect of IMMH001 on rheumatoid arthritis (RA). IMMH001 rendered periphery blood lymphocytes insensitive to the egress signal from secondary lymphoid organs. Importantly, in both rat adjuvant-induced arthritis and collagen-induced arthritis models, IMMH001 treatment significantly inhibited the progression of RA and RA-associated histological changes in the joints of Sprague-Dawley rats, including hind paw swelling and arthritic index, and thus reduced the pathological score. Furthermore, IMMH001 markedly decreased proinflammatory cytokine and chemokine release from the damaged joints. These data demonstrated that IMMH001 is a promising drug candidate for RA treatment.

Lymphocyte homing into the intestine is mediated by binding of leukocytes to mucosal addressin cell adhesion molecule 1 (MAdCAM-1), expressed on endothelial cells. Currently, the immune system of the gut is considered a major modulator not only of inflammatory bowel disease, but also of extra-intestinal autoimmune disorders, including multiple sclerosis (MS). Despite intense research in this field, the exact role of the intestine in the pathogenesis of (neuro-)inflammatory disease conditions remains to be clarified. This prompted us to investigate the role of MAdCAM-1 in immunological processes in the intestine during T cell-mediated autoimmunity of the central nervous system (CNS). Using the experimental autoimmune encephalomyelitis model of MS, we show that MAdCAM-1-deficient (MAdCAM-1-KO) mice are less susceptible to actively MOG35−55-induced disease. Protection from disease was accompanied by decreased numbers of immune cells in the lamina propria and Peyer's patches as well as reduced immune cell infiltration into the spinal cord. MOG35−55-recall responses were intact in other secondary lymphoid organs of MAdCAM-1-KO mice. The composition of specific bacterial groups within the microbiome did not differ between MAdCAM-1-KO mice and controls, while MAdCAM-1-deficiency severely impaired migration of MOG35−55-activated lymphocytes to the gut. Our data indicate a critical role of MAdCAM-1 in the development of CNS inflammation by regulating lymphocyte homing to the intestine, and may suggest a role for the intestinal tract in educating lymphocytes to become encephalitogenic.

Hericium erinaceus polysaccharide (HEP) is a bioactive substance present in the fruiting bodies of H. erinaceus. Previously we have shown that HEP can repair the intestinal injury caused by Muscovy duck reovirus (MDRV) infection in Muscovy ducklings. To examine the effect of HEP on intestine mucosal MDRV immunity and explore its possible mechanisms, an MDRV contact-infection model in the Muscovy ducklings was established. Transcriptome sequencing analysis was then performed to investigate the mechanism of action of HEP on intestine mucosal MDRV immunity. During the infection, the expression levels of genes involved in cellular activities (protein translation and binding, cytokine interaction, and adhesion molecules activities) in the infected ducklings were increased. The expression levels of adhesion molecules (α4β7, LFA-1) and chemotaxis cytokine receptors (CCR7, CCR9, and CCR10) were also significantly upregulated. Following HEP treatment, cellular activities and cytokines upregulated to various degrees play crucial roles in the immune defenses and antiviral activities of Muscovy ducklings. ELISA analysis results were consistent with the results of the transcriptome analysis. Overall, our results provide a basis for further studying the underlying mechanisms of HEP in regulating mucosal immunity and for the clinical application of HEP in controlling MDRV infection in the Muscovy duck industry. • Sequence information in the Muscovy duck remains scant, and this study enriches the available data in the Muscovy duck. • HEP regulates the lymphocyte homing in Muscovy ducklings in response to MDRV infection. • Our results provide a basis for the clinical application of HEP in controlling MDRV infection in the Muscovy duck industry. [ABSTRACT FROM AUTHOR]

Lymphocytic infiltration into melanoma tissue is an important prerequisite for effective antitumoral immunity. However, analysis of human metastatic melanoma has shown that leucocyte adhesion receptor expression on melanoma blood vessels is very low or absent, thereby impairing the entry of cytotoxic lymphocytes into tumor tissue. We hypothesized that adhesion molecules can be induced on melanoma vasculature allowing better infiltration of cytotoxic lymphocytes. Quantitative real‐time PCR and immunofluorescence staining indicated that the adhesion molecules ICAM‐1 (CD54) and E‐selectin (CD62E) can be significantly induced by intralesional application of TNF alpha in tissue from human melanoma metastases either in vitro or in vivo when grafted onto immunodeficient NSG (NOD.Cg‐PrkdcscidIl2rgtm1Wjl/SzJ) mice that preserved human vessels. Furthermore, activated human autologous CD3+ lymphocytes were injected intravenously into mice bearing melanoma xenografts treated with TNF‐α or PBS in addition to the leucocyte chemoattractant TARC (CCL17). Significantly increased numbers of CD8+ cells were detected in TNF‐α–treated melanoma metastases compared with PBS‐treated controls. In addition, tumor cell apoptosis was enhanced and melanoma cell proliferation reduced as shown by TUNEL assay and KI‐67 staining. We conclude that adhesion molecules can be induced on human melanoma vasculature resulting in significantly improved homing of activated autologous cytotoxic T cells to melanoma tissue and inhibition of melanoma cell proliferation. These observations should be considered when designing protocols for immunotherapy of malignant melanoma. [ABSTRACT FROM AUTHOR]

Sphingosine-1-phosphate receptor subtype 1 (S1P1) is essential for lymphocyte egress from lymphoid organs into systemic circulation and provides a well-defined drug target for autoimmune disorders. IMMH001, also called SYL930, is a specific S1P1/S1P4/S1P5 modulator. Here, we investigated the potential therapeutic effect of IMMH001 on rheumatoid arthritis (RA). IMMH001 rendered periphery blood lymphocytes insensitive to the egress signal from secondary lymphoid organs. Importantly, in both rat adjuvant-induced arthritis and collagen-induced arthritis models, IMMH001 treatment significantly inhibited the progression of RA and RA-associated histological changes in the joints of Sprague-Dawley rats, including hind paw swelling and arthritic index, and thus reduced the pathological score. Furthermore, IMMH001 markedly decreased proinflammatory cytokine and chemokine release from the damaged joints. These data demonstrated that IMMH001 is a promising drug candidate for RA treatment. [ABSTRACT FROM AUTHOR]

Highlights • Study the pathogenicity of DTMUV from infection to recovery in duck spleen using HE staining. • Study the pathological change of duck spleen infected by DTMUV in using TEM for the first time. • Study the molecular mechanism of DTMUV infecting duck spleen from infection to recovery by RNA-seq. Abstract Duck Tembusu virus (DTMUV) is a novel member of flavivirus with the highest viral loads in the spleen. Six-month egg-laying shelducks were intramuscularly injected with DTMUV strain XZ-2012. Morphological analysis revealed the presence of vacuolar degeneration in the periellipsoidal lymphatic sheaths (PELS) of spleen white pulp following infection, especially from 12 hpi to 3 dpi. Ultrastructural images showed an obvious swelling of cells and their mitochondria and endoplasmic reticulum. Using RNA-seq analysis, the expression levels of RIG-I like receptors (RLRs), downstream IRF7 and proinflammatory cytokines IL-6 from RIG-I signaling pathway were non-apparently upregulated at 2 hpi and apparently at 3 dpi, while MHC-II expression was obviously downregulated at 2 hpi. The expression levels of downstream antiviral cytokines type-I IFNs, anti-inflammatory cytokines IL-10, cell adhesion molecules (CAMs), chemokines and their receptors associated with lymphocyte homing were significantly upregulated at 3 dpi. The population of lymphocyte was increased at 6 dpi. The immune function of spleen was recovered starting from 9 dpi. These findings of this study suggest that DTMUV invaded into the spleen via RIG-I signaling pathway and enhanced immune evasion by inhibiting MHC-II expression during the early stage of infection. Additionally, DTMUV induced PELS lesions through activating IL-6 expression. Furthermore, DTMUV increased the expression levels of RLRs, antiviral type-I IFNs, lymphocyte homing-related genes and proteins as well as the number of lymphocytes in the infected duck spleen. Taken altogether, this study provides new insights into the cellular and molecular mechanisms of DTMUV infection in duck spleen. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) mediate tolerance to food antigens, limit reactivity to the gut microbiota and are required for optimal response to intestinal pathogens. Intestinal DCs are heterogeneous but collectively generate both regulatory and effector T cell responses. The balance of outcomes is determined by the activity of functionally distinct DC subsets and their modulation by environmental cues. DCs constantly sample luminal content to monitor for pathogens; the significance of the various pathways by which this occurs is incompletely understood. Intestinal DC have distinctive properties shaped by local host, dietary and microbial signals. These properties include the ability to produce all-trans retinoic acid (RA) and imprint gut tropism on T cells they activate. In the steady-state, subsets of intestinal DC are potent generators of inducible Treg, aided by their ability to activate TGFβ and produce RA. However, responses induced by steady-state intestinal DCs are not exclusively regulatory in nature; effector T cells with specificity for commensal bacterial can be found in the healthy mucosa and these can be locally controlled to prevent inflammation. The ability of intestinal DCs to enhance effector responses in infection or sustain inflammation in disease is likely to involve both modulation of the local DC population and recruitment of additional populations. Immune pathways in the pathogenesis of inflammatory bowel disease can be mapped to DCs and in inflamed intestinal tissue, DCs show increased expression of microbial recognition machinery, activation, and production of key immunological mediators. Intestinal DCs may be targeted for disease therapy or to improve vaccine responses.

The leukocyte homing receptor (HR), the endothelial leukocyte adhesion molecule, and gmp140/platelet activation-dependent granule membrane protein are members of a family of adhesion molecules, termed the lectin cell adhesion molecules (LEC-CAMS) which are unified by a multi-domain structure containing a lectin motif, an epidermal growth factor-like (egf) motif, and variable numbers of a complement binding-like (CB) motif. Previous data have indicated a predominant role for the lectin motif in cell adhesion directed by the LEC-CAMS, although the egf-like domain of the HR may also play a potential role in cell binding. While the role(s) of the CB domains in the LEC-CAMS is currently not understood, they have been hypothesized to act as rigid spacers or stalks for lectin and perhaps, egf domain presentation. In this paper, we analyze the functional characteristics of murine HR-IgG chimeras containing the lectin, lectin plus egf, and lectin plus egf plus CB domains. The Mel 14 mAb, an adhesion blocking antibody which recognizes a conformational determinant in the N-terminus of the HR lectin domain, shows a significantly decreased affinity for a HR construct which lacks the CB motifs, consistent with the possibility that the CB domains are involved with lectin domain structure. In agreement with this conjecture, HR mutants lacking the CB domains show a profound decrease in lectin-specific interaction with the carbohydrate polyphosphomannan ester, suggesting that the changes in Mel 14 affinity for the lectin domain are reflected in lectin functionality. Various assays investigating the interactions between the HR deletion mutants and the peripheral lymph node high endothelium, including cell blocking, immunohistochemical staining, and radioactively labeled ligand binding, all showed that removal of the CB domains results in a lack of HR adhesive function. These results imply that the CB domains of the HR, and, by analogy, the other members of the LEC-CAM family, may play important structural roles involving induction of lectin domain conformation and resultant functionality.

Lymphocyte attachment to high endothelial venules within lymph nodes is mediated by the peripheral lymph node homing receptor (pnHR), originally defined on mouse lymphocytes by the MEL-14 mAb. The pnHR is a calcium-dependent lectin-like receptor, a member of the LEC-CAM family of adhesion proteins. Here, using a soluble recombinant form of the homing receptor, we have identified an endothelial ligand for the pnHR as an approximately 50-kD sulfated, fucosylated, and sialylated glycoprotein, which we designate Sgp50 (sulfated glycoprotein of 50 kD). Recombinant receptor binding to this lymph node-specific glycoprotein requires calcium and is inhibitable by specific carbohydrates and by MEL-14 mAb. Sialylation of the component is required for binding. Additionally, the glycoprotein is precipitated by MECA-79, an adhesion-blocking mAb reactive with lymph node HEV. A related glycoprotein of approximately 90 kD (designated as Sgp90) is also identified.

The entry of blood-borne lymphocytes into most secondary lymphoid organs is initiated by a highly specific adhesive interaction with the specialized cuboidal endothelial cells of high endothelial venules (HEV). The adhesive receptors on lymphocytes that dictate interactions with HEV in different lymphoid organs are called homing receptors, signifying their critical role in controlling organ-selective lymphocyte migration. Considerable work has established that the mouse peripheral lymph node homing receptor (pnHR), defined by the mAb MEL-14, functions as a lectin-like adhesive protein. We have previously shown that sialidase treatment of peripheral lymph node (PN) HEV abrogates lymphocyte attachment to the HEV both in vivo and in vitro. We extend this evidence by demonstrating that Limax agglutinin (LA), a sialic acid-specific lectin, when reacted with HEV exposed in cryostat-cut tissue sections, blocks lymphocyte attachment to PN HEV and, unexpectedly, to the HEV of Peyer's patches (PP) as well. Using a recombinant form of the pnHR as a histochemical probe for its cognate adhesive site (HEV-ligand) on PN HEV, we demonstrate that both sialidase and Limax agglutinin functionally inactive this ligand. It is concluded that the requirement for sialic acid is at the level of the pnHR interaction with its HEV ligand. A distinct sialyloligosaccharide may encode the recognition determinant of a PP HEV ligand.

The binding of lymphocytes to high endothelial venules (HEV) within peripheral lymph nodes (pln) is thought to be mediated by a lectinlike adhesion molecule termed the pln homing receptor (pln HR). The cloning and sequencing of cDNAs encoding both murine and human pln HR revealed that these adhesion molecules contain protein motifs that are homologous to C-type or calcium dependent lectin domains as well as to epidermal growth factor (egf) and complement-regulatory protein domains. We have produced a novel, antibody-like form of the murine HR by joining the extracellular region of the receptor to a human IgG heavy chain. This antibody-like molecule is capable of recognizing carbohydrates, blocking the binding of lymphocytes to pln HEV, and serving as a histochemical reagent for the staining of pln HEV. This murine HR-IgG chimera should prove useful in analyzing the distribution of the HR ligand(s) in normal as well as in inflammatory states.

Extranodal lymphoma occurs in one-third of lymphoma patients and is a key indicator of the international prognostic index, associated with unfavorable outcomes. Due to the lack of ideal models, the causes and characteristics of extranodal lymphoma are greatly underexplored. Recently, we observed a high incidence of extranodal lymphoma in two types of mouse models with tropism for the brain and kidneys. These findings prompt us to rethink the pathological progression of lymphoma colonization in lymph nodes and non-lymphoid organs. Nodal lymphoma, primary extranodal lymphoma and secondary extranodal lymphoma should be biologically and clinically distinctive scenarios. Based on the observations in mouse models with extranodal lymphoma, we propose that lymphoma dissemination can be seen as lymphoma losing the ability to home to lymph nodes. The pathological process of nodal lymphoma should be referred to as lymphoma homing to distinguish it from benign hyperplasia. Lymphoma dissemination, defined as a pathological process that lymphoma can occur in almost any part of the body, is a key pathological hallmark for malignant progression of B-cell lymphoma. Reshaping cellular plasticity is a promising strategy to allow transformed cells to homing back to lymph nodes and re-sensitize tumor cells to treatment. From this perspective, we provide new insights into the pathological progression of lymphoma dissemination and its inspiration on therapeutic interventions. We believe that establishing extranodal lymphoma mouse models, identifying molecular mechanism governing lymphoma dissemination, and developing therapies to prevent lymphoma dissemination will become emerging topics for fighting relapsed and refractory lymphoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Jiang and Qian.)