Activation of innate immunity accelerates sialoadenitis in a mouse model for Sjögren's syndrome-like disease

Oral Diseases (2011) 17 , 801–807 Objective: Sjögren’s syndrome is a chronic autoimmune disorder characterized by progressive lymphocytic infiltration within the salivary and lacrimal glands. This study was undertaken to investigate the effects of innate immunity activation on sialoadenitis in a mouse strain genetically susceptible for development of SS‐like disease. Methods: Female New Zealand Black X New Zealand White F1 mice were repeatedly treated with toll‐like 3 receptor agonist poly(I:C). Submandibular glands were investigated at different time points for sialoadenitis by immunohistochemistry and for gene expression of different chemokines by quantitative PCR. Submandibular gland–infiltrating cells were characterized by flow cytometry. Results: Poly(I:C) treatment significantly upregulated the expression of multiple chemokines within the submandibular glands. The severity and incidence of sialoadenitis was considerably higher in poly(I:C)‐treated mice. There was a preponderance of dendritic cells and NK cells in the initial inflammatory cell infiltrates, and these were followed by CD4+ T cells. Conclusions: Our data clearly demonstrate that systemic activation of innate immunity accelerates sialoadenitis in a mouse model for SS‐like disease. These findings suggest that chronic activation of innate immunity can influence certain features of SS.     

Review: Pathogen-induced inflammation at sites distant from oral infection: bacterial persistence and induction of cell-specific innate immune inflammatory pathways

A hallmark of infection with the gram‐negative pathogen Porphyromonas gingivalis is the induction of a chronic inflammatory response. P. gingivalis induces a local chronic inflammatory response that results in oral inflammatory bone destruction, which manifests as periodontal disease. In addition to chronic inflammation at the initial site of infection, mounting evidence has accumulated supporting a role for P. gingivalis‐mediated periodontal disease as a risk factor for several systemic diseases including, diabetes, preterm birth, stroke, and atherosclerotic cardiovascular disease. A growing number of in vitro studies have demonstrated that P. gingivalis infection stimulates cell activation commensurate with expected responses paralleling inflammatory atherosclerotic‐type responses. Furthermore, various mouse models have been used to examine the ability of P. gingivalis to stimulate chronic inflammatory plaque accumulation and recent studies have pointed to a pivotal role for innate immune signaling via the Toll‐like receptors in the chronic inflammation associated with P. gingivalis infection. In this review we discuss the pathogen and host cell specificity of these responses and discuss possible mechanisms by which this oral pathogen can induce and maintain a chronic state of inflammation at sites distant from oral infection.     

Immunohistochemical identification of antigen presenting cells in rat salivary glands

Mucosal dendritic cells affect immune responses through secretion of cytokines and exposure of na?ve B- and T-lymphocytes to foreign matter as antigen presenting cells (APCs). APC in oral tissues may play a role in the development of local and secretory immune responses [Crit. Rev. Oral Biol. Med. 7 (1996) 36]. Previous studies have shown that APC are present in the interstitial tissues of rat salivary glands [Arch. Oral Biol. 40 (1995) 1015]. This study sought to further define the distribution of APC in salivary glands. The major glands and ducts of male Sprague-Dawley and Wistar rats were fixed with 4% paraformaldehyde and prepared for immunofluorescence and pre- and post-embedding immunoelectron microscopy. Monoclonal antibodies to the dendritic cell marker Ia antigen (OX-6 antibody), monocyte lineage cytoplasmic antigen (ED-1), and resident tissue macrophage antigen (ED-2) were visualized with FITC-conjugated secondary antibodies for light microscopy and HRP- and gold-labelled secondary antibodies for electron microscopy. Light microscopy revealed numerous OX-6-positive cells with branching processes in the epithelium of striated and excretory ducts of both rat strains, as well as in the connective tissue stroma. ED-1-positive cells had a similar distribution but exhibited a more compact shape with fewer processes. ED-2-positive cells were found only in the connective tissue. Acinar and duct epithelial cells were unreactive. Electron microscopy confirmed that both OX-6-positive and ED-1-positive, non-epithelial cells were present within the duct epithelium. The presence of APC in the duct epithelium suggests that these ducts may be exposed to antigens, possibly by retrograde access from the oral cavity, and that APC located in the salivary gland epithelium may participate in local immune responses.     

细菌素免疫蛋白调控变形链球菌抗菌敏感性及生物膜形成的实验研究

目的 观察细菌素免疫蛋白相关基因对变形链球菌抗菌敏感性及生物膜形成的影响,探讨细菌素免疫蛋白与细菌抗菌剂耐受性的关系,为生物膜抗菌敏感性的研究提供基础数据.方法筛选培养细菌素免疫蛋白基因突变株,绘制生长曲线.酶标仪检测不同质量浓度氨苄青霉素(0.04、0.05、0.06、0.07及0.08 mg/L)、氟化钠(50、100、150、200及250 mg/L)及不同质量分数的次氯酸钠(0.078%、0.156%、0.313%、0.625%及1.250%)作用下变形链球菌标准株、△immA-和△immB-突变株菌液的吸光度值.应用最小生物膜清除浓度(minimal biofilm eradicatin concentration,MBEC)桩钉96孔板以连续稀释法检测醋酸氯己定对3种菌株生物膜的MBEC.应用激光共聚焦扫描显微镜(confocal laser scanning microscope,CLSM)定量分析标准株和突变株生物膜结构.结果 △immA-和△immB-突变株的迟缓期和稳定生长期均比标准株延时1 h.氨苄青霉素为0.06 mg/L时,标准株、△immA-突变株和△immB-突变株菌液吸光度值分别为0.334±0.016、0.027±0.016及0.047±0.018;氟化钠质量浓度为150 mg/L时,3种菌株菌液吸光度值分别为0.254±0.018、0.129±0.011及0.167±0.01;当次氯酸钠质量分数为0.313%时,3种菌株菌液吸光度值分别为0.467±0.008、0.017±0.006及0.050±0.006,以上各组抗菌剂中,标准株与突变株吸光度值差异均有统计学意义(P<0.01).醋酸氯己定对3种菌株的MBEC分别为6.25、1.57及3.13 mg/L.标准株生物膜厚度显著高于△immA-和△immB-突变株(P<0.01);标准株各层活菌比例均高于△immA-突变株(P<0.05);标准株中、外层活菌比例高于△immB-突变株(P<0.01),但内层活菌比例差异无统计学意义(P=0.191).结论细菌素免疫蛋白参与调控浮游细菌生长,尤其在生长初期;细菌素免疫蛋白相关基因缺陷使浮游态变形链球菌抗菌敏感性提高、抗菌剂MBEC降低及生物膜结构不成熟.     

The impact of lipids on the cancer–immunity cycle and strategies for modulating lipid metabolism to improve cancer immunotherapy

Lipids have been found to modulate tumor biology, including proliferation, survival, and metastasis. With the new understanding of tumor immune escape that has developed in recent years, the influence of lipids on the cancer–immunity cycle has also been gradually discovered. First, regarding antigen presentation, cholesterol prevents tumor antigens from being identified by antigen presenting cells. Fatty acids reduce the expression of major histocompatibility complex class I and costimulatory factors in dendritic cells, impairing antigen presentation to T cells. Prostaglandin E2 (PGE2) reduce the accumulation of tumor-infiltrating dendritic cells. Regarding T-cell priming and activation, cholesterol destroys the structure of the T-cell receptor and reduces immunodetection. In contrast, cholesterol also promotes T-cell receptor clustering and relative signal transduction. PGE2 represses T-cell proliferation. Finally, regarding T-cell killing of cancer cells, PGE2 and cholesterol weaken granule-dependent cytotoxicity. Moreover, fatty acids, cholesterol, and PGE2 can improve the activity of immunosuppressive cells, increase the expression of immune checkpoints and promote the secretion of immunosuppressive cytokines. Given the regulatory role of lipids in the cancer–immunity cycle, drugs that modulate fatty acids, cholesterol and PGE2 have been envisioned as effective way in restoring antitumor immunity and synergizing with immunotherapy. These strategies have been studied in both preclinical and clinical studies.     

黄龙止咳颗粒联合孟鲁司特钠治疗小儿急性支气管炎的临床研究

目的 探讨黄龙止咳颗粒联合孟鲁司特钠治疗小儿急性支气管炎的临床疗效。方法 选取2021年8月—2022年8月在南京医科大学第四附属医院治疗的急性支气管炎患儿126例,随机分为对照组和治疗组,每组各63例。对照组患儿口服孟鲁司特钠咀嚼片,2～5岁患儿4 mg/次,6～13岁患儿5 mg/次,1次/d。治疗组患儿在对照组的基础上口服黄龙止咳颗粒,2～3岁患儿3 g/次,4～7岁患儿6 g/次,8～13岁患儿10 g/次,3次/d。两组患儿均连续治疗7 d。观察两组患儿临床疗效,比较治疗前后两组患儿临床症状消失时间,血清C反应蛋白（CRP）、白细胞介素-1β（IL-1β）和降钙素原（PCT）水平,及免疫功能。结果 治疗后,治疗组的总有效率为95.24%,明显高于对照组的84.13%（P＜0.05）。治疗后,治疗组咳痰、咳嗽、肺部湿啰音消失时间明显短于对照组（P＜0.05）。治疗后,两组血清CRP、IL-1β、PCT水平降低,而免疫球蛋白A（IgA）、IgG水平明显升高（P＜0.05）,且治疗组血清炎性因子水平和免疫功能明显好于对照组（P＜0.05）。结论 黄龙止咳颗粒联合孟鲁司特钠治疗小儿急性支气管炎具有较好的临床疗效,且可有效降低血清炎症因子水平,提升患儿的免疫功能。     

Impact of oral resuscitation on circulating and splenic leukocytes after burns

BackgroundHemodynamic aberrations after severe burns are treated with aggressive intravenous (IV) fluid resuscitation however, oral resuscitation has been proposed in resource poor scenarios. Previously we have shown that animals receiving oral fluid following burns were able to recover kidney function. However, immune function such as circulating and splenic immune cell populations after oral or intravenous fluid administration was not examined. Herein, we perform a follow up analysis of splenic tissue and plasma from the previous animal study to examine the splenic response following these resuscitation strategies after burn injury.MethodsEighteen anesthetized Yorkshire swine receiving 40%TBSA contact burns were randomized to receive either: (1) no fluids (Fluid Restricted; negative control), (2) 70 mL/kg/d Oral Rehydration Salt solution (Oral), or (3) 2 mL/kg/%TBSA/d of lactated Ringer’s solution IV. Blood was drawn for blood cell analysis, and CT scans were performed before and 48 h post-burn, at which point spleens were harvested for histological, Western blot, and RT-PCR analyses.ResultsSplenic artery diameter decreased by −0.97 ± 0.14 mm in fluid-restricted animals, while IV led to an increase of 0.68 ± 0.30 mm. No significant differences were detected in white and red pulp. IV fluids reduced the population of splenic monocytes (CD163; P = 0.001) and neutrophils (MPO protein; P = 0.13), as well as cytokines IL-8 (P = 0.003), IFN-γ (P = 0.11) and TNFα (P = 0.05). Additionally, withholding IV fluids consistently decreased the expression of FoxP3, CCR6, and IL17β in spleen, suggesting a shift in T-cell phenotype with IV resuscitation.ConclusionsThe route of fluid administration has a minor influence on the changes in circulating and splenic leukocytes post-burn in the acute phase. Further research is needed to help guide resuscitation approaches using immunologic markers of splenic function following burns.     

Role of Inflammation and the Immune System in the Progression of Osteoarthritis

Understanding the molecular drivers and feedback loops of osteoarthritis (OA) may provide future therapeutic strategies to modulate the disease progression. The current paradigm of OA is evolving from a purely mechanical disease caused by cartilage wear toward a complex biological response connecting biomechanics, inflammation, and the immune system. The view of OA as a chronic wound highlights the role inflammation plays and also the body's attempts to repair an ongoing injury. Inflammatory signals, including cytokines such as interleukin-1 and tissue necrosis factor α, surface-expressed pattern recognition receptors such as toll-like receptors 2 and 4, complement factors such as C5, as well as pathogen-associated molecular patterns and damage-associated molecular patterns drive the enzymatic cascade that degrades cartilage matrix in OA. Considering the joint as an entire organ, interactions between the cells that reside in the synovium including macrophages and other immune cells, appear to drive enzymatic activity in cartilage, which, in turn, feeds signals back to the synovium that continues stimulating degradation in a feed-forward loop. This review will explore the potential roles of immune cells such as macrophages and T cells in the synovium in both stimulating and modulating the inflammatory response in OA. © 2019 Orthopedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:253-257, 2020     

Extracellular nucleotide signaling in solid organ transplantation

The role of extracellular purine nucleotides, including adenosine triphosphate (ATP) and adenosine, as modulators of posttransplantation outcome and ischemia‐reperfusion injury is becoming increasingly evident. Upon pathological release of ATP, binding and activation of P2 purinergic surface receptors promote tissue injury and inflammation, while the expression and activation of P1 receptors for adenosine have been shown to attenuate inflammation and limit ischemia‐induced damage, which are central to the viability and long‐term success of allografts. Here we review the current state of the transplant field with respect to the role of extracellular nucleotide signaling, with a focus on the sources and functions of extracellular ATP. The connection between ischemia reperfusion, purinergic signaling, and graft preservation, as well as the role of ATP and adenosine as driving factors in the promotion and suppression of posttransplant inflammation and allograft rejection, are discussed. We also examine novel therapeutic approaches that take advantage of the ischemia‐reperfusion‐responsive and immunomodulatory roles for purinergic signaling with the goal of enhancing graft viability, attenuating posttransplant inflammation, and minimizing complications including rejection, graft failure, and associated comorbidities.