B cells as under-appreciated mediators of non-auto-immune inflammatory disease

B lymphocytes play roles in many auto-immune diseases characterized by unresolved inflammation, and B cell ablation is proving to be a relatively safe, effective treatment for such diseases. B cells function, in part, as important sources of regulatory cytokines in auto-immune disease, but B cell cytokines also play roles in other non-auto-immune inflammatory diseases. B cell ablation may therefore benefit inflammatory disease patients in addition to its demonstrated efficacy in auto-immune disease. Current ablation drugs clear both pro- and anti-inflammatory B cell subsets, which may unexpectedly exacerbate some pathologies. This possibility argues that a more thorough understanding of B cell function in human inflammatory disease is required to safely harness the clinical promise of B cell ablation. Type 2 diabetes (T2D) and periodontal disease (PD) are two inflammatory diseases characterized by little autoimmunity. These diseases are linked by coincident presentation and alterations in toll-like receptor (TLR)-dependent B cell cytokine production, which may identify B cell ablation as a new therapy for co-affected individuals. Further analysis of the role B cells and B cell cytokines play in T2D, PD and other inflammatory diseases is required to justify testing B cell depletion therapies on a broader range of patients.     

Vascular cells contribute to atherosclerosis by cytokine- and innate-immunity-related inflammatory mechanisms

Cardiovascular diseases are the human diseases with the highest death rate and atherosclerosis is one of the major underlying causes of cardiovascular diseases. Inflammatory and innate immune mechanisms, employing monocytes, innate receptors, innate cytokines, or chemokines are suggested to be involved in atherogenesis. Among the inflammatory pathways the cytokines are central players. Plasma levels of cytokines and related proteins, such as CRP, have been investigated in cardiovascular patients, tissue mRNA expression was analyzed and correlations to vascular diseases established. Consistent with these findings the generation of cytokine-deficient animals has provided direct evidence for a role of cytokines in atherosclerosis. In vitro cell culture experiments further support the suggestion that cytokines and other innate mechanisms contribute to atherogenesis. Among the initiation pathways of atherogenesis are innate mechanisms, such as toll-like-receptors (TLRs), including the endotoxin receptor TLR4. On the other hand, innate cytokines, such as IL-1 or TNF, or even autoimmune triggers may activate the cells. Cytokines potently activate multiple functions relevant to maintain or spoil homeostasis within the vessel wall. Vascular cells, not least smooth muscle cells, can actively contribute to the inflammatory cytokine-dependent network in the blood vessel wall by: (i) production of cytokines; (ii) response to these potent cell activators; and (iii) cytokine-mediated interaction with invading cells, such as monocytes, T-cells, or mast cells. Activation of these pathways results in accumulation of cells and increased LDL- and ECM-deposition which may serve as an 'immunovascular memory' resulting in an ever-growing response to subsequent invasions. Thus, vascular cells may potently contribute to the inflammatory pathways involved in development and acceleration of atherosclerosis.     

间充质干细胞在疾病治疗中的应用潜力

间充质干细胞（mesenchymal stem cell,MSCs）是衍生自中胚层的多能细胞,可产生多种间充质谱系,包括成骨细胞、脂肪细胞、成软骨细胞和肌细胞。MSCs还具有分泌多种细胞因子的能力,可促进血管生成、上皮再生等,在再生医学领域具有巨大的潜力。研究证实,MSCs可通过分化为多种细胞类型促进组织再生,加速伤口愈合;通过分泌细胞因子改善组织纤维化;还可通过携带载体药物诱导肿瘤细胞的凋亡,抑制肿瘤的发展。然而MSCs的成纤维化潜能和促进肿瘤生长的能力降低了MSCs应用于临床治疗的安全性。总结了MSCs在肿瘤、慢性难愈合伤口、纤维化等疾病发展过程中的作用,并进一步讨论了MSCs在临床相关疾病治疗中的潜在应用价值及挑战,以期为间充质干细胞的临床应用提供参考。     

Intracellular trafficking and secretion of inflammatory cytokines

The secretion of cytokines by immune cells plays a significant role in determining the course of an inflammatory response. The levels and timing of each cytokine released are critical for mounting an effective but confined response, whereas excessive or dysregulated inflammation contributes to many diseases. Cytokines are both culprits and targets for effective treatments in some diseases. The multiple points and mechanisms that have evolved for cellular control of cytokine secretion highlight the potency of these mediators and the fine tuning required to manage inflammation. Cytokine production in cells is regulated by cell signaling, and at mRNA and protein synthesis levels. Thereafter, the intracellular transport pathways and molecular trafficking machinery have intricate and essential roles in dictating the release and activity of cytokines. The trafficking machinery and secretory (exocytic) pathways are complex and highly regulated in many cells, involving specialized membranes, molecules and organelles that enable these cells to deliver cytokines to often-distinct areas of the cell surface, in a timely manner. This review provides an overview of secretory pathways – both conventional and unconventional – and key families of trafficking machinery. The prevailing knowledge about the trafficking and secretion of a number of individual cytokines is also summarized. In conclusion, we present emerging concepts about the functional plasticity of secretory pathways and their modulation for controlling cytokines and inflammation.     

Mechanisms of unconventional secretion of IL-1 family cytokines

One of the most poorly understood processes in cell biology is the peculiar ability of specific leaderless proteins to be secreted via ER/Golgi-independent mechanisms (‘unconventional protein secretion’). One such leaderless protein is the major immune-activating cytokine, interleukin-1β (IL-1β). Unusual amongst cytokines, IL-1β is expressed in the cytosol as an inactive precursor protein. It requires maturation by the caspase-1 protease, which itself requires activation upon immune cell sensing of infection or cell stress. Despite 25 years of intensive research into IL-1β secretory mechanisms, how it exits the cell is still not well understood. Here we will review the various mechanisms by which macrophages have been proposed to secrete IL-1 family cytokines, and the potential involvement of caspase-1 therein. Since aberrant IL-1β production drives inherited and acquired human diseases (e.g. autoinflammatory diseases, arthritic diseases, gout, Alzheimer’s disease), elucidation of the IL-1β secretory pathway may offer new therapeutic opportunities for treatment across this wide range of human conditions.     

Immunological Consequences of Macrophage-Mediated Clearance of Apoptotic Cells

Apoptosis and the rapid clearance of apoptotic cells by professional or non-professional phagocytes are normal and coordinated processes that ensure controlled cell growth with a non-pathological outcome. Defects in clearance of apoptotic cells by macrophages have serious consequences often resulting in autoimmune disorders. Phagocyte-derived immunoregulatory cytokines such as Interleukin-12 and Interleukin-10 play pivotal roles in the etiology and pathology of many autoimmune diseases. Elucidation of the apoptotic cell-mediated signaling mechanisms involved in the control of pro- and anti-inflammatory cytokines during cell turnovers under normal and pathological conditions may help us counter the cytokine dysregulation and control inappropriate host immune reactions in pathological situations such as autoimmunity, infectious diseases, graft-versus-host disease, and cancer.     

Molecular regulation of mast cell development and maturation

Mast cells play a crucial role in the pathogenesis of allergic diseases. In recent years, tremendous progresses have been made in studies of mast cell origination, migration, proliferation, maturation and survival, and the cytokines regulating these activities. These advances have significantly improved our understandings to mast cell biology and to the molecular mechanisms of mast cells in the pathogenesis of allergic diseases.     

Cytokine mediated apoptosis of granulocyte eosinophils in expressed blood eosiniphilia

Programmed cell death induced by recombinant cytokines (IL-5, IL-3 and eotaxin) of eosinophils isolated from patients with expressed blood eosinophilia (malignant diseases of the blood system, opisthorchosis) has been examined. It was demonstrated that an initially low level of spontaneous apoptosis is registered in all surveyed patients. r-IL-5, r-IL-3 and r-eotaxin treatment of eosinophils isolated from the peripheral blood of opisthorchosis patients and cultivated in vitro suppressed apoptosis. However, eosinophils isolated from patients with malignant diseases associated with expressed blood eosinophilia were insensitive to the cytokines.     

外泌体对睾丸微环境调控机制研究及应用进展

外泌体（exsomes）是一类具有生物活性的双层脂质组成的小囊泡,可携带不同类型的信息物质与受体细胞结合,通过信息传递与物质交换,促发受体细胞的表型发生变化。本文总结了在睾丸微环境中,外泌体通过调节细胞因子促进睾丸微环境中细胞增殖、调节细胞免疫维持睾丸免疫环境、调节氧化应激修复受体细胞功能、调节细胞自噬改善生精能力、调节细胞凋亡改善精子发生、调节细胞因子影响睾酮分泌等机制维持睾丸微环境稳态,并对外泌体在男科相关疾病预防、诊断、治疗中的作用进行归纳,外泌体在男性不育、勃起功能障碍、精索静脉曲张、性腺功能减退、前列腺癌等疾病诊疗中具备明显优势。外泌体作为一种新兴的应用物质,随着外泌体工程和提取工艺的不断优化,以及相关机制研究的不断深入,外泌体在男科疾病中的临床运用成为可能,有望成为治疗男科疾病的新手段。     

Interleukin 12 (IL-12) family cytokines: Role in immune pathogenesis and treatment of CNS autoimmune disease

Cytokines play crucial roles in coordinating the activities of innate and adaptive immune systems. In response to pathogen recognition, innate immune cells secrete cytokines that inform the adaptive immune system about the nature of the pathogen and instruct naïve T cells to differentiate into the appropriate T cell subtypes required to clear the infection. These include Interleukins, Interferons and other immune-regulatory cytokines that exhibit remarkable functional redundancy and pleiotropic effects. The focus of this review, however, is on the enigmatic Interleukin 12 (IL-12) family of cytokines. This family of cytokines plays crucial roles in shaping immune responses during antigen presentation and influence cell-fate decisions of differentiating naïve T cells. They also play essential roles in regulating functions of a variety of effector cells, making IL-12 family cytokines important therapeutic targets or agents in a number of inflammatory diseases, such as the CNS autoimmune diseases, uveitis and multiple sclerosis.     

Current directions of studies for development of methods for specific diagnostics of allergic diseases in vitro

Results of studies as well as perspectives for development and use of modern in vitro methods of allergic diseases diagnostics are presented. High prevalence of allergic diseases dictates the need of high-quality etiologic diagnosis for conducting relevant etiopathogenetic treatment - allergen-specific immunotherapy and prophylactic measures. Interest to in vitro diagnostic methods due to their high specificity and commonality is rising. They are directed to identification of various elements of "material substrate" of allergic reaction - specific antibodies, cell elements, cytokines as well as genes, which encode them. Intensively developing methods based on immunoenzyme, immunofluorescent, and immunochemiluminescent reactions are widely used now. Methods based on the use of various monoclonal antibodies for identification of lymphocytic markers, cytokines, antigen-presenting cells by laser flowcytometry are also very promising. ELISPOT technology is also intensively used for diagnostics of allergic diseases. From immunogenetic methods great potential belongs to molecular biologic methods of assessment of genome specificity characterizing sensitization to given antigen.     

Cross-talk between apoptosis and cytokines in the regulation of parasitic infection

Parasitic diseases have worldwide medical and economical impact. Host T lymphocytes and the cytokines they produce determine the outcome of parasitic infections. Programmed cell death by apoptosis is induced in the course of parasitic infections, and affects cytokine production by removing activated effector T and B cells. In addition, engulfment of apoptotic cells promotes the secretion of cytokines that regulate intracellular replication of protozoan parasites. In this review, we discuss how the cross-talk between apoptosis and cytokines regulates parasitic infection.     

CYTOKINE- AND NEUROPEPTIDE-MEDIATED DIFFERENTIATION IN RETINAL PIGMENT EPITHELIAL CELLS IN VITRO

To determine the mechanism of growth and differentiation of retinal pigment epithelial (RPE) cells it is important to understand the pathogenesis of several retinal diseases. Recently it has been reported that several cytokines and neuropeptides regulate the growth of RPE cells. In this study, the role of cytokines and neuropeptides in melanin synthesis, which is one indication of the RPE cell differentiation, was examined using chick RPE cells in vitro IL-1β, TNF-α, substance P, β-endorphin and methionine-enkephalin stimulated the melanin synthesis of RPE cells in a dose-dependent manner. The most effective concentrations of these agents on RPE cell melanin synthesis were not the same as that for RPE cell proliferation. These results indicate that cytokines and neuropeptides play an important role not only for the growth but also for the differentiation of RPE cells.     

Interleukin-17 contributes to cardiovascular diseases

Interleukin (IL)-17 (also known as IL-17A), as the signature cytokine of the newly described T helper 17 (Th17) cell population, is the founding member of a new subclass of cytokines that have highly proinflammatory properties. Recently there is accumulating evidence that stipulates the involvement of IL-17 in the pathogenesis of cardiovascular diseases via amplifying the inflammation induced by other cytokines in synergistic interactions. The present review provides a summary of the potential roles of IL-17 in the context derived from both animal models and clinical settings in cardiovascular diseases, and perspectives for IL-17-targeted cytokine therapy.     

Expression of CD1d molecules by human schwann cells and potential interactions with immunoregulatory invariant NK T cells

CD1d-restricted NKT cells expressing invariant TCR alpha-chains (iNKT cells) produce both proinflammatory and anti-inflammatory cytokines rapidly upon activation, and are believed to play an important role in both host defense and immunoregulation. To address the potential implications of iNKT cell responses for infectious or inflammatory diseases of the nervous system, we investigated the expression of CD1d in human peripheral nerve. We found that CD1d was expressed on the surface of Schwann cells in situ and on primary or immortalized Schwann cell lines in culture. Schwann cells activated iNKT cells in a CD1d-dependent manner in the presence of alpha-galactosylceramide. Surprisingly, the cytokine production of iNKT cells stimulated by alpha-galactosylceramide presented by CD1d+ Schwann cells showed a predominance of Th2-associated cytokines such as IL-5 and IL-13 with a marked deficiency of proinflammatory Th1 cytokines such as IFN-gamma or TNF-alpha. Our findings suggest a mechanism by which iNKT cells may restrain inflammatory responses in peripheral nerves, and raise the possibility that the expression of CD1d by Schwann cells could be relevant in the pathogenesis of infectious and inflammatory diseases of the peripheral nervous system.     

Th细胞亚群在自身免疫病的发病及治疗中作用的实验研究进展

本文回顾了Ｔｈ细胞亚群的功能、交互调节、影响其分化的因素以及Ｔｈ细胞亚群在自身免疫病发病中的可能作用;概括了通过调节Ｔｈ细胞亚群来治疗自身免疫病的方法,包括：上调ＣＤ１ｄ治疗、给予相关细胞因子治疗、佐剂治疗、用抗细胞因子、细胞因子受体、ＣＤ４０配体和Ｂ７分子的单克隆抗体治疗以及ＣＴＬＡ和ＣＴＬＡＩｇ治疗。这些方法为自身免疫病的治疗提供了新的思路。     

Th细胞亚群自身免疫病的发病及治疗中作用的实验研究进展

本文回顾了Ｔｈ细胞亚群的功能、交互调节、影响其分化的因素以及Ｔｈ细胞亚群自身免疫病发病中的可能作用;概括了通过调节Ｔｈ细胞亚群来治疗自身免疫病的方法,包括：上调ＣＤ１ｄ治疗、给予相关细胞因子治疗、佐剂治疗、用抗细胞因了、细胞因了受体、ＣＤ４０配体和Ｂ７分子的单克隆抗体治疗以及ＣＴＬＡ和ＣＴＬＡＩｇ治疗。这些方法为自身免疫病的治疗提供了新的思路。     

Regulatory B cells and T cell Regulation in Cancer

Recent researches shed light on B cell role on various autoimmune diseases, including autoantibody-mediated diseases as well as T cell-mediated autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. B cells play a critical role in the immune response beyond the production of antibodies through mechanisms such as antigen presentation and cytokine production. Furthermore, B cells have recently been recognized to play a role in promoting tumor immunity against cancer. However, not all B cells positively regulate immune responses. Regulatory B cells negatively regulate immune responses by the production of anti-inflammatory cytokines such as interleukin (IL)-10, IL-35, and transforming growth factor-beta. Thus, a balance between effector and regulatory B cells regulates the immune response through the release of cytokines. In this review, we highlight the main emerging roles of B cells in tumor immunity with a focus on the T cell response. These findings can guide a protocol for selectively depleting regulatory B cells as a potential therapeutic strategy for patients with cancer.     

T cell, Ig domain, mucin domain-2 gene-deficient mice reveal a novel mechanism for the regulation of Th2 immune responses and airway inflammation

The development of asthma and other atopic diseases is influenced by cytokines produced by Th2 effector T cells. How effector T cell responses are regulated once these cell populations are established remains unclear. The recently described T cell and airway phenotype regulator locus, containing the T cell, Ig domain, mucin domain (TIM) genes, is genetically associated with Th2 cytokine production and Th2-dependent immune responses. In this study, we report the phenotype of the TIM-2 gene-deficient mouse, and demonstrate exacerbated lung inflammation in an airway atopic response model. Immune responses in the TIM-2-deficient mouse reveal disregulated expression of Th2 cytokines, and adoptive transfer experiments show that the T cell compartment is responsible for the heightened inflammatory phenotype. These studies show that TIM-2 is a novel and critical regulator of effector T cell activity.