Subcapsular Sinus Of Lymph Node Research Articles

The cell surface hyaluronidase TMEM2 is essential for systemic hyaluronan catabolism and turnover

As a major component of the extracellular matrix, hyaluronan (HA) plays an important role in defining the biochemical and biophysical properties of tissues. In light of the extremely rapid turnover of HA and the impact of this turnover on HA biology, elucidating the molecular mechanisms underlying HA catabolism is key to understanding the in vivo functions of this unique polysaccharide. Here, we show that TMEM2, a recently identified cell surface hyaluronidase, plays an essential role in systemic HA turnover. Employing induced global Tmem2 knockout mice (Tmem2iKO), we determined the effects of Tmem2 ablation not only on the accumulation of HA in bodily fluids and organs, but also on the process of HA degradation in vivo. Within 3 weeks of tamoxifen-induced Tmem2 ablation, Tmem2iKO mice exhibit pronounced accumulation of HA in circulating blood and various organs, reaching levels as high as 40-fold above levels observed in control mice. Experiments using lymphatic and vascular injection of fluorescent HA tracers demonstrate that ongoing HA degradation in the lymphatic system and the liver is significantly impaired in Tmem2iKO mice. We also show that Tmem2 is strongly expressed in endothelial cells in the subcapsular sinus of lymph nodes and in the liver sinusoid, two primary sites implicated in systemic HA turnover. Our results establish TMEM2 as a physiologically relevant hyaluronidase with an essential role in systemic HA catabolism in vivo, acting primarily on the surface of endothelial cells in the lymph nodes and liver.

Clinicopathological features and prognosis of nodal nevi

Objective: To investigate the clinicopathological characteristics, differential diagnosis and prognosis of nodal nevi (NN). Methods: Eighteen cases of NN diagnosed at Fudan University Shanghai Cancer Center, Shanghai, China from 2009 to 2019 were collected. The clinicopathological characteristics and follow-up data were retrospectively analyzed. Histopathologic evaluation and immunohistochemical studies were carried out. The Vysis Melanoma FISH Probe Kit, combined with 9p21(CDKN2A) and 8q24(MYC) assays were performed in 2 cases. Results: There were 2 males and 16 females in the case series. The age of the patients ranged from 36 to 70 years (average 48.2 years). Fifteen cases located in axillary lymph nodes, 1 in inguinal lymph node, 1 in cervical lymph node, and 1 in external iliac lymph node. NN was found in only one lymph node in each case. Histologically, the nevus cell aggregates were found in capsule of lymph nodes in all cases. Nevus cells grew along the capsule into trabeculae in 8 cases, with 3 of them scattered in parenchyma. In one of these 8 cases, nevus cell aggregates massively occupied the parenchyma of the lymph node. The largest lesions in the 18 NN cases measured from 0.2 to 6.5 mm. All of the NN cases were classified as conventional nevi. The majority of the cases were composed of uniform nevus-like cells and identical to cutaneous pigmented nevi without atypia, necrosis, or mitosis. In the NN case that massively occupied parenchyma, some areas had abundant nevus cells and displayed atypical cytologic features, including increased nucleo-cytoplasmic ratio, small nucleoli, and occasional mitotic figures. Immunohistochemistry was performed in 13 cases. All of them were positive for S-100, SOX10, Melan A, and p16. HMB45 showed weak staining in rare cells of only one case out of 13 cases. Ki-67 labeling index <1% was found in all 13 cases. Additionally, the results of FISH assay were both negative. All patients were followed up for 13 to 129 months (median 31.5 months). Except that one patient died of the salivary gland carcinoma, the other patients all survived without tumor during the follow-up period. Conclusions: NN is a benign melanocytic lesion in lymph node. It is important to distinguish NN from metastatic melanoma when nevus cells occur in parenchyma and subcapsular sinus of lymph nodes, or show some atypical cytologic features. The morphology of bland nevus cells in capsule and trabeculae is a valuable clue. Besides, immunohistochemical profiling and FISH assay are helpful in the differential diagnosis.

Do carbon nanoparticles really improve thyroid cancer surgery? A retrospective analysis of real-world data

BackgroundParathyroid protection and central neck dissection (CND) are basic points of thyroid cancer surgery and draw persistent concern. We aimed to evaluate the value of carbon nanoparticles (CNs) for parathyroid gland protection and CND in thyroid surgery for thyroid cancer patients.MethodsA total of 386 consecutive thyroid cancer patients were enrolled in the retrospective study. Three hundred thirty-four patients using CNs intraoperatively were included in the CN group, and 52 patients without using CNs or any other helping agent were included in the control group. Intact parathyroid hormone (iPTH) was examined. Medical records and histopathologic reports were reviewed. Histopathologic examination was performed.ResultsThere were no statistical significances in demographic and basic surgical information, preoperative iPTH, and serum calcium between the two groups (P > 0.05). In the CN group, the thyroid tissue and central neck lymph nodes were stained black by CNs, while the parathyroid glands were not. Histopathological examination showed that the carbon nanoparticles might accumulated in the subcapsular sinus of lymph nodes compared with the none-stained samples. The staining with CNs did not impact the histopathological examination. There were no significant differences in postoperative hypocalcemia and hypoPT at day 1, 1 month, and half year after surgery between the two groups, respectively. There was a big decline of iPTH level after surgery, whereas the perioperative decreasing amplitude of PTH was not statistically different between the CNs and control group (57.2 ± 28.6 vs 55.7 ± 27.8, P = 0.710). There were 43 patients occurring incidental parathyroidectomy in the CN group (43/334, 12.9%) and 7 patients in the control group (7/52, 13.5%), without significant difference (P = 0.907). There was no significant difference in the number of lymph nodes identified by pathology per patient between the CNs and control group regardless of unilateral and bilateral CND.ConclusionsCarbon nanoparticles help highlight parathyroid glands and lymph nodes in thyroidectomy, but generate no significant benefit for parathyroid glands protection and lymph node dissection. The value of carbon nanoparticles in thyroid cancer surgery should not be exaggerated and needs further evaluation.

Immune Response of A Novel ATR-AP205-001 Conjugate Anti-hypertensive Vaccine

We developed a virus-like particle (VLP)-based therapeutic vaccine against angiotensin II receptor type 1, ATR-AP205-001, which could significantly reduce the blood pressure and protect target organs of hypertensive animals. In this study, we focused on the immunological effect and safety of the VLP-based vaccine. By comparing to the depolymerized dimeric vaccine ATR-Dimer-001, we found that ATR-AP205-001 reached subcapsular sinus of lymph node shortly after administration, followed by accumulation on follicle dendritic cells via follicle B cell transportation, while ATR-Dimer-001 vaccine showed no association with FDCs. ATR-AP205-001 vaccine strongly activated dendritic cells, which promoted T cells differentiation to follicular helper T cells. ATR-AP205-001 vaccine induced powerful germinal center reaction, which was translated to a boost of specific antibody production and long-lasting B cell memory, far superior to ATR-Dimer-001 vaccine. Moreover, neither cytotoxic T cells, nor Th1/Th17 cell-mediated inflammation was observed in ATR-AP205-001 vaccine, similar to ATR-Dimer-001 vaccine. We concluded that ATR-AP205-001 vaccine quickly induced potent humoral immunity through collaboration of B cells, follicular dendritic cells and follicular helper T cells, providing an effective and safe intervention for hypertension in the future clinical application.

The identification and developmental requirements of colonic CD169⁺ macrophages.

CD169-positive macrophages in the marginal zone of the spleen and subcapsular sinus of lymph nodes play an important role as gatekeepers, strategically located to capture pathogens. Here we identified a population of CD169-positive macrophages in the colon and investigated which factors influenced their development. Murine colonic CD115+ F4/80(lo) CD11c(lo) macrophages expressing CD169 were present in the lamina propria, mainly surrounding the crypts. In spite of the high levels of bacterial flora in the colon and the importance of Toll-like receptor signalling in mucosal homeostasis, the presence of CD169+ macrophages was not affected in mice that were deficient in MyD88-mediated Toll-like receptor signalling and in mice in which the bacterial flora was eradicated. Whereas the development of splenic CD169+ macrophages was dependent on lymphotoxin α, colonic CD169+ macrophages were present in normal numbers in lymphotoxin α-deficient mice. In contrast, reduced numbers of CD169+ macrophages were found in the colon of mice deficient in vitamin A, whereas CD169+ macrophages in the spleen were unaffected. In conclusion, we identified a new macrophage subset in the lamina propria of the colon characterized by the expression of CD169. Its differentiation, unlike CD169+ macrophages in lymphoid organs, is independent of lymphotoxin α signalling, but requires vitamin A.

Targeting to porcine sialoadhesin receptor improves antigen presentation to T cells.

Antibody-mediated targeting of antigen to specific antigen presenting cells (APC) receptors is an attractive strategy to enhance T cell immune responses to weak immunogenic antigens. Here, we describe the characterization of two monoclonal antibodies (mAb) against different epitopes of porcine sialoadhesin (Sn) and evaluate in vitro the potential of targeting this receptor for delivery of antigens to APC for T cell stimulation. The specificity of these mAb was determined by amino acid sequence analysis of peptides derived from the affinity purified antigen. Porcine Sn is expressed by macrophages present in the border between white and red pulp of the spleen and in the subcapsular sinus of lymph nodes, an appropriate location for trapping blood and lymph-borne antigens. It is also expressed by alveolar macrophages and monocyte-derived dendritic cells (MoDC). Blood monocytes are negative for this molecule, but its expression can be induced by treatment with IFN-a. MAb bound to Sn is rapidly endocytosed. MAb to sialoadhesin induced in vitro T cell proliferation at concentrations 100-fold lower than the non-targeting control mAb when using T lymphocytes from pigs immunized with mouse immunoglobulins as responder cells and IFN-a treated monocytes or MoDC as APC, suggesting a role of sialoadhesin in antigen uptake and/or delivery into the presentation pathway in APC.

Organizer-Like Reticular Stromal Cell Layer Common to Adult Secondary Lymphoid Organs

Mesenchymal stromal cells are crucial components of secondary lymphoid organs (SLOs). Organogenesis of SLOs involves specialized stromal cells, designated lymphoid tissue organizer (LTo) in the embryonic anlagen; in the adult, several distinct stromal lineages construct elaborate tissue architecture and regulate lymphocyte compartmentalization. The relationship between the LTo and adult stromal cells, however, remains unclear, as does the precise number of stromal cell types that constitute mature SLOs are unclear. From mouse lymph nodes, we established a VCAM-1(+)ICAM-1(+)MAdCAM-1(+) reticular cell line that can produce CXCL13 upon LTbetaR stimulation and support primary B cell adhesion and migration in vitro. A similar stromal population sharing many characteristics with the LTo, designated marginal reticular cells (MRCs), was found in the outer follicular region immediately underneath the subcapsular sinus of lymph nodes. Moreover, MRCs were commonly observed at particular sites in various SLOs even in Rag2(-/-) mice, but were not found in ectopic lymphoid tissues, suggesting that MRCs are a developmentally determined element. These findings lead to a comprehensive view of the stromal composition and architecture of SLOs.

Initial steps in lymph node metastasis formation in an experimental system: possible involvement of recognition by macrophage C-type lectins.

We used histological observations and experiments with fluorescent cell tracers to investigate the roles of tissue macrophages in recognition through a galactose/N-acetylgalactosamine-specific C-type lectin (mMGL) in lymph node metastasis formation by mouse ovarian tumor OV2944-HM-1 (HM-1) cells. Lymph node metastasis from subcutaneous sites was shown to be initiated by the entry of tumor cells into the subcapsular sinus of lymph nodes where mMGL-positive cells were mainly located. To investigate whether mMGL-positive cells contributed to host resistance against lymph node metastasis, we repeatedly treated mice bearing transplanted tumors with an mMGL-blocking monoclonal antibody that was known to inhibit mMGL binding to its ligands. The number of HM-1 cells recovered from lymph nodes 2 weeks after subcutaneous injections was significantly greater when the mice were treated with the blocking anti-mMGL antibody. These results suggested that mMGL-positive macrophages contributed to the host's defense against lymph node metastasis.

Axillary Node Micrometastases: Detection and Biologic Significance.

Axillary lymph node status is the single most important predictor of overall survival in patients with breast cancer. Standard histopathologic examination of regional lymph nodes relies on one microscopic section of each node to detect metastatic disease. The spectrum of metastatic disease in a lymph node ranges from complete replacement of the node by tumor to isolated nests of tumor cells in the subcapsular sinus. The clinical significance of micrometastases in axillary lymph nodes has changed over time. Micrometastases are defined by the American Joint Committee on Cancer as tumor foci less than or equal to 2 mm in greatest dimension. Retrospective studies of node-negative breast cancer patients employing intensive histopathologic examination of the axillary lymph nodes consistently show that up to a third of these patients are actually node positive. Studies published through the mid-1980s failed to show any significant effect of these micrometastases on survival. More recent studies (mid-1980s-1997) with more than 10 years of clinical follow-up have come to a different conclusion. It now appears that micrometastases are associated with a small, but statistically significant, decrease in tumor-free survival and overall survival, as compared with truly node-negative breast cancer patients. Additional slides stained with hematoxylin and eosin ("levels"), immunohistochemistry for cytokeratin proteins (found only in epithelial cells), and reverse transcriptase polymerase chain reaction for cytokeratin protein mRNA have all been used to detect micrometastases in recently published studies. The methodology utilized to detect micrometastases clearly affects the sensitivity of their detection. The current issue is the most appropriate method of detection of these small foci of tumor, given technical and cost considerations. The clinical significance of single malignant cells in the subcapsular sinus of lymph nodes, identified only by immunohistochemistry or molecular techniques, remains unclear.

Concomitant Lymphoma and Carcinoma

Concomitant Lymphoma and Carcinoma

Retention of lymphocytes in the subcapsular sinus of lymph nodes: A physiological event?

This study examined the lymphocyte content of the subcapsular sinus of lymph nodes of diverse anatomical sites, from euthymic and athymic animals of various ages. One unusual feature which prevailed in young euthymic animals consisted of the accumulation of lymphocytes on the outer wall of the subcapsular sinus, following differential patterns with respect to diverse domains or areas of the subcapsular sinus of a node compartment. It is concluded that such an accumulation is due to the retention of lymphocytes on the sinus outer wall. Whether the retention reflects a step in unspecific defence mechanisms, in an immunological reaction pathway, or a transient state of the misfunctioning of lymph-carried cells, is considered. Some findings favor the latter possibility. In this case, retention would be due to a mild form of lymphocyte alteration caused by the emergence of an abnormal milieu in a drained tissue, and conceivably involving mast cell products. Whatever the case, the retention on the outer wall of the subcapsular sinus, instead of on its inner wall, would prevent any hindering of the usual activity of the latter wall.