Low Urine Secretion of Semaphorin3A in Lupus Patients with Proteinuria

Inflammation - Immune semaphorins are important in controlling both innate and adaptive immune responses. The regulatory role of semaphorin3A (sema3A) in systemic lupus erythematosus (SLE),...     

Plexin A3 is involved in semaphorin 3F-mediated oligodendrocyte precursor cell migration

Class 3 semaphorins are expressed in the neurodevelopmental or damage repair phase of the central nervous system (CNS). They play an important role in guiding axon growth and directing cell migration, including the migration of oligodendrocyte precursor cells (OPCs). As co-receptors for semaphorin 3F(sema3F), the expression and role of neuropilin-2 (NRP2) and plexin A3 in OPC migration are unclear. Using RT-PCR, Western blot analysis, and immunofluorescence, we demonstrated that primary OPCs and immature oligodendrocytes from neonatal rats express NRP2 and plexin A3. After transfection with NRP2 siRNA and plexin A3 siRNA, the number of migrating OPCs attracted to sema3F remarkably decreased. These results suggest that plexin A3 is expressed in OPCs and immature oligodendrocytes and is involved in OPC migration.     

Diverse roles for semaphorin-plexin signaling in the immune system

Semaphorins were originally identified as axon guidance factors involved in the development of the neuronal system. However, accumulating evidence indicates that several semaphorins, so-called 'immune semaphorins', are crucially involved in various phases of both physiological and pathological immune responses; some regulate immune cell activation or differentiation, whereas others navigate the trafficking of immune cells. Plexin family members are one of the most representative semaphorin receptors and the semaphorin-plexin complex structures were recently determined in crystallization studies. Here, we review the rapidly emerging functions of semaphorins and their receptors in the immune system.     

Plexin-A4 negatively regulates T lymphocyte responses

Semaphorins and their receptors play crucial roles not only in axon guidance during neuronal development but also in the regulation of immune responses. Plexin-A4, a member of the plexin-A subfamily, forms a receptor complex with neuropilins and transduces signals for class III semaphorins in the nervous system. Although plexin-A4 is also expressed in the lymphoid tissues, the involvement of plexin-A4 in immune responses remains unknown. To explore the role of plexin-A4 in the immune system, we analyzed immune responses in plexin-A4-deficient (plexin-A4-/-) mice. Among immune cells, plexin-A4 mRNA was detected in T cells, dendritic cells and macrophages but not in B cells and NK cells. Plexin-A4-/- mice had normal numbers and cell surface markers for each lymphocyte subset, suggesting that plexin-A4 is not essential for lymphocyte development. However, plexin-A4-/- mice exhibited enhanced antigen-specific T cell responses and heightened sensitivity to experimental autoimmune encephalomyelitis. Plexin-A4-/- T cells exhibited hyperproliferative responses to anti-CD3 stimulation and to allogeneic dendritic cells in vitro. Furthermore, this hyperproliferation was also observed in both T cells from neuropilin-1 mutant (npn-1(Sema-)) mice, in which the binding site of class III semaphorins is disrupted, and T cells from Sema3A-deficient (Sema-3A-/-) mice. Collectively, these results suggest that plexin-A4, as a component of the receptor complex for class III semaphorins, negatively regulates T cell-mediated immune responses.     

Structure and function of the immune semaphorin CD100/SEMA4D

Semaphorins are a large family of membrane-bound and secreted molecules involved in numerous functions, including axon guidance, morphogenesis, carcinogenesis, and immunomodulation. A growing number of semaphorins--namely, human CD100/SEMA4D, CD108/SEMA7A, and SEMA3A; viral semaphorins, SemaVA and SemaVB; and, very recently, mouse Sema4A--were reported to regulate immune cell responses. Among them, the role of CD100 has been well documented in both humans and mice. CD100, in particular, has been shown to influence monocyte migration, T-cell activation, B-cell survival as well as T/B and T/dendritic cell cooperation. In contrast to other semaphorins, CD100 is the only semaphorin for which membrane and soluble forms are endowed with functional properties, and for which bidirectional signaling has been suggested. The human membrane-bound CD100 engagement triggers costimulatory signals to T cells through its interaction with membrane protein tyrosine phosphatase CD45 and an intracellular serine kinase. Its soluble extracellular region acts most likely through its receptors, human PlexinB1 and mouse CD72, to promote T-cell priming, B-cell survival and antibody production in response to T-dependent antigens. Human soluble CD100 also induces monocyte paralysis and the arrest of its spontaneous and chemokine-induced migration by signaling through an as yet unknown receptor that is different from PlexinB1 and CD72. In this review, we discuss recent advances in research studies on human and murine CD100, and we describe the relationship of CD100 function to its expression and structure. The signaling events that support CD100 function are also discussed.     

Innate immune-responses and their role in driving autoimmunity

Autoimmunity and autoimmune diseases were always considered to be driven mainly by adaptive immune responses, namely by auto-reactive B and T cell over-activity. The continuous stimulation of dendritic cells by autoantigens increases B cell activity, driving auto-reactive B cells to increase the production of autoantibodies and of pro-inflammatory cytokines. On the other hand, a subset of dendritic cells is established being of tolerogenic properties thus becoming important in maintaining self-tolerance. However, early innate immune responses are continuously appreciated to be highly important in the development of immune-mediated inflammation in general and autoimmunity in particular. The innate immune system is a complex network of structured cells/proteins such as antigen presenting cells (macrophages and dendritic cells), the complement cascade, and many receptors/cytokines/proteins. Of these, one may mention the high expression of toll-like receptors 7 and 9 in antigen presenting cells, and B cells of systemic lupus erythematosus patients contributing to the expansion of auto-reactive B cells. C-reactive protein (CRP) and C1q are crucially important for efficient uptake of apoptotic cells. However, CRP is appreciated to have a role in maintaining anti-inflammatory responses and in altering autoimmunity. Natural killer cells (NK) are responsible for cytotoxicity responses but some of them (mainly CD56high), are important in maintaining peripheral self-tolerance, thus considered to be immune-regulatory cells. In this review we will cover most of the new data on innate immune system and discuss its importance in the development of autoimmunity. New treatments were developed following our better understanding of these pathways, the targeting of which, opened new therapeutic avenues in treating autoimmune diseases.     

Targeting B cells and plasma cells in autoimmune diseases: From established treatments to novel therapeutic approaches

Autoimmune diseases are characterized by the recognition of self-antigens by the immune system, which leads to inflammation and tissue damage. B cells are directly and indirectly involved in the pathophysiology of autoimmunity, both via antigen-presentation to T cells and production of proinflammatory cytokines and/or autoantibodies. Consequently, B lineage cells have been identified as therapeutic targets in autoimmune diseases. B cell depleting strategies have proven beneficial in the treatment of rheumatoid arthritis (RA), systemic lupus erythematous (SLE), ANCA-associated vasculitis (AAV), multiple sclerosis (MS), and a wide range of other immune-mediated inflammatory diseases (IMIDs). However, not all patients respond to treatment or may not reach (drug-free) remission. Moreover, B cell depleting therapies do not always target all B cell subsets, such as short-lived and long-lived plasma cells. These cells play an active role in autoimmunity and in certain diseases their depletion would be beneficial to achieve disease remission. In the current review article, we provide an overview of novel strategies to target B lineage cells in autoimmune diseases, with the focus on rheumatic diseases. Both advanced therapies that have recently become available and more experimental treatments that may reach the clinic in the near future are discussed.     

Regulatory T cells in the central nervous system

Regulatory T cells (Tregs) are critical to the human immune system, providing appropriately scaled immune responses and mediating peripheral tolerance. A central role for forkhead box protein 3 (FoxP3)(+) Tregs has been shown in the pathogenesis of mechanistically diverse central nervous system (CNS) diseases from autoimmune diseases such as multiple sclerosis to glioblastomas. Understanding how tumors induce Treg function to escape immune surveillance in marked contrast to autoimmune diseases, where there is loss of Treg function, will provide valuable lessons regarding Treg biology and potential therapeutic targets for CNS diseases.     

Homeostasis and T cell regulation

Homeostatic regulation of cell numbers is an important principle in biology. Mechanisms that function to maintain or re-establish homeostasis in the immune system include interactions among antigen-presenting cells, regulatory T cells and cytokines. The vital role that homeostatic regulation plays in maintaining a functionally intact immune system is illustrated by the perturbation of the peripheral T cell repertoire that occurs after lymphopenic incidents, which frequently provoke either exacerbated immune or autoimmune responses. Recent studies show that transient states of lymphopenia occur in viral infections and in the neonatal state and might be involved in the development of autoimmune diseases. On the positive side, lymphopenia-provoked T cell expansion might enhance weak immune responses and thereby aid the rejection of tumours or the elimination of parasites.     

Selfie: Autoimmunity,boon or bane

The immune system provides protection to tissues damaged by infectious microrganisms or physical damage. In autoimmune diseases, the immune system recognizes and attacks its own tissues, i.e., self-destruction. Various agents such as genetic factors and environmental triggers are thought to play a major role in the development of autoimmune diseases. A common feature of all autoimmune diseases is the presence of autoantibodies and inflammation, including mononuclear phagocytes, autoreactive T lymphocytes, and autoantibody producing B cells (plasma cells). It has long been known that B cells produce autoantibodies and, thereby, contribute to the pathogenesis of many autoimmune diseases. Autoimmune diseases can be classified as organ-specific or non-organ specific depending on whether the autoimmune response is directed against a particular tissue or against widespread antigens as in chronic inflammatory autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Both SLE and RA are characterized by the presence of autoantibodies which play a major role in their etiopathogenesis. SLE is characterized by circulating antibodies and immune complex deposition that can trigger an inflammatory damage in organs. RA is a progressive inflammatory disease in which T cells, B cells, and pro-inflammatory cytokines play a key role in its pathophysiology.     

NK cells in autoimmune diseases: Linking innate and adaptive immune responses

The pathogenesis of autoimmunity remains to be fully elucidated, although the contribution of genetic and environmental factors is generally recognized. Despite autoimmune conditions are principally due to T and B lymphocytes, NK cells also appear to play a role in the promotion and/or maintenance of altered adaptive immune responses or in peripheral tolerance mechanisms.Although NK cells are components of the innate immune system, they shows characteristics of the adaptive immune system, such as the expansion of pathogen-specific cells, the generation of long-lasting “memory” cells able to persist upon cognate antigen encounter, and the possibility to induce an increased secondary recall response to re-challenge.Human NK cells are generally identified as CD56⁺ CD3^?, conversely CD56⁺ CD3⁺ cells represent a mixed population of NK-like T (NK T) cells and antigen-experienced T cells showing the up-regulation of several NK cell markers. CD56^dim constitute about 90% of NK cells in the peripheral blood, they are mature and involved in cytotoxicity responses; CD56^bright instead are more immature, mostly involved in cytokine production, having only a limited role in cytolytic responses, keen to leave the blood vessels as the principal population observed in lymph nodes. NK cells have been identified also in non-lymphoid tissues since, in pathologic conditions, they can quickly reach the target organs. A cross-talk between NK with dendritic cells and T cells is established throughout different receptor-ligand bindings.Several studies support the correlation between NK cell number and/or functional alterations, such as a defective cytotoxic activity and several autoimmune conditions. Among the different autoimmune pathologies and even within the same disease, NK cell function is significantly different either promoting or even protecting against the onset of the autoimmune condition.In this Review, we discuss recent literature supporting the role played by NK cells, as a bridge between innate and adaptive immunity, in the onset of autoimmune diseases.     

T-cell costimulation blockade in immunologic diseases: role of CD28 family members

The destruction of many immune-mediated diseases is a result of T-cell responses against usually harmless antigens. Extensive research has been conducted to discover new mechanisms to specifically modulate harmful effector T cells while leaving normal immune responses intact. Since proteins of the CD28 family members are expressed on T cells, blockade of these proteins has become a possible target for potential therapies. The CD28 family contains proteins that have the ability to both enhance and diminish T-cell responses. Therefore, blockade of targets that enhance T-cell signaling may reduce destructive autoimmune responses, while blockade of targets that diminish T-cell signaling may enhance antitumor responses. In this article, the function of these proteins will be reviewed and a sample of clinical trials highlighting the potential efficacy and drawbacks of their use in humans will be described briefly. Finally, inducible costimulator and programmed death-1, two future targets of T-cell therapies, will be highlighted.     

Translational mini-review series on the immunogenetics of gut disease: immunogenetics of coeliac disease

Recent advances in immunological and genetic research in coeliac disease provide new and complementary insights into the immune response driving this chronic intestinal inflammatory disorder. Both approaches confirm the central importance of T cell-mediated immune responses to disease pathogenesis and have further begun to highlight other relevant components of the mucosal immune system, including innate immunity and the control of lymphocyte trafficking to the mucosa. In the last year, the first genome wide association study in celiac disease led to the identification of multiple new risk variants. These risk regions implicate genes involved in the immune system. Overlap with autoimmune diseases is striking with several of these regions being shown to confer susceptibility to other chronic immune-mediated diseases, particularly type 1 diabetes.     

Immunomodulatory and Immunosuppressive Roles of 1α,25(OH)2D3 in Autoimmune Diseases

Autoimmune diseases are pathological conditions characterized by abnormal responses, accompanied by autoantibodies to self‐molecules. The role of vitamin D in autoimmune diseases has increased significantly in the recent past from its functions in calcium and phosphate homoeostasis, and it is now involved in the regulations and proliferations of Th1 and Th17 lymphocyte. 1α,25(OH)2D3 is very important in ameliorations of inflammatory disorders arising from autoimmune diseases, but the mechanism by which this is performed is still a bone of contentions. This review aimed to highlight the existing facts about the roles of Vitamin D in the treatment and management of autoimmune diseases. An extensive online literature search was conducted using PubMed, MEDLINE and Scopus. Accumulated bodies of research evidence are available which demonstrates that Vitamin D has a very important part to play in the regulation of immune responses in autoimmune diseases. Some of the authors suggested that Vitamin D3 carry‐out its immunosuppressive and immune modulatory action, through its actions on antigen‐presenting cells and activated T and B cells with the help of Vitamin D receptors present on the each of these cells. Vitamin D supplementation assists in autoimmune disorders by making qualitative and quantitative changes in the immune system (downregulation of Th1 and upregulations of Th2 cells). This resulted in the body to be more tolerant of self and less likely to mount autoimmune responses.     

Regulatory B cells and allergic diseases

B cells are generally considered to positively regulate immune responses by producing antigen-specific antibodies. B cells are classified into classical CD5(-) conventional B cells and CD5(+) B1 cells. The latter produce multi-specific autoantibodies and are thought to be involved in autoimmune diseases. However, evidence supporting a B cell negative regulatory function has accumulated over the past 30 years. Multiple reports have suggested that absence, or loss, of regulatory B cells exacerbates symptoms of both allergic (including contact hypersensitivity and anaphylaxis) and autoimmune (such as experimental autoimmune encephalomyelitis, chronic colitis, and collagen-induced arthritis) diseases, and in lupus-like models of autoimmunity. Regulatory B cells are characterized by production of the negative regulatory cytokines, IL-10 and TGF-β. IL-10-producing B cells were the first regulatory B cells to be recognized and were termed 'B10' cells. IL-10-producing regulatory B cells are of the CD19(+)CD5(+)IgM(hi)IgD(lo)CD1d(hi) type. Recently, a TGF-β-producing regulatory B cell subset, Br3, has been shown to be related to immune tolerance in food allergies. Moreover, forkhead box P3 (Foxp3)-expressing B cells have also been identified in humans and may act as regulatory B cells (Bregs). The functional image of regulatory B cells is similar to that of regulatory T cells. Because of the proliferative and apoptotic responses of Br1 and Br3 cells in immune tolerance in non-IgE-mediated food allergy, reciprocal roles and counter-regulatory mechanisms of Br1 and Br3 responses are also suspected. Additionally, different roles for regulatory B and T cells at different time points during initiation and progression of autoimmune disease are described.     

Leptin in immuno-rheumatological diseases

Leptin is one of the most important hormones secreted by adipocytes, with a variety of physiological roles related to the control of metabolism and energy homeostasis. Since its discovery in 1994, leptin has attracted increasing interest in the scientific community for its pleiotropic actions. One of these functions is the relationship between nutritional status and immune competence. It structurally resembles proinflammatory cytokines, such as IL-6 and IL-12. The cytokine-like structural characteristic of leptin is implicative of its function in regulating immune responses. The role of leptin in regulating immune responses has been assessed in vitro as well as in clinical studies. It has been shown that disease conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders, such as autoimmune diseases, are associated with the increased secretion of leptin and the production of proinflammatory pathogenic cytokines. In this paper, we review the most recent advances of the role of leptin in immune-rheumatological diseases, and we discuss whether strategies aimed at modifying leptin levels could represent innovative and therapeutic tools for autoimmune disorders.     

Innate lymphoid cells are pivotal actors in allergic,inflammatory and autoimmune diseases

Innate lymphoid cells (ILCs) are lymphoid cells that do not express V(D)J-rearranged receptors and play a role in the innate immune system. ILCs are categorized into three groups with respect to their function in the immune system. ILC1 induces production of IFN-γ via T-box expressed on T cells, ILC2 promotes production of type 2 cytokines via GATA-binding protein-3 and ILC3 promotes IL-17 and IL-22 production via retinoic acid receptor-related orphan receptor-γt. ILCs can maintain homeostasis in epithelial surfaces by responding to locally produced cytokines or direct recognition of danger patterns. Altered epithelial barrier function seems to be a key point in inappropriate activation of ILCs to promote inflammatory and allergic responses. ILCs play an essential role in initiation and maintenance of defense against infections as well as immune-mediated diseases. In this paper, we discuss the role of ILCs in inflammatory, allergic and autoimmune diseases.     

Suppression of immune-mediated liver injury after vaccination with attenuated pathogenic cells

Cell vaccination via immunization with attenuated pathogenic cells is an effective preventive method that has been successfully applied in several animal models of inflammatory or autoimmune diseases. Concanavalin A (Con A)-induced hepatitis (CIH) is a commonly used experimental model to study immune-mediated liver injury. Multiple cell types including T lymphocytes, macrophages and neutrophils have been found to be involved in the pathogenesis of CIH. In this study, we used attenuated spleen lymphocytes or peripheral blood lymphocytes as vaccines to investigate whether they could induce protective immune responses to prevent mice from developing CIH. We found that mice receiving such vaccination before CIH induction developed much milder diseases, exhibited a lower level of alanine aminotransferase (ALT) released into their plasma and had less inflammatory lesions in their livers. Such CIH-suppression is dose- and frequency-dependent. The suppressive effect was associated with inhibition of several major inflammatory mediators, pro-inflammatory cytokines and chemokines.     

The Role of T cell Immunoglobulin and Mucin Domain‐3 in Immune Thrombocytopenia

T cell immunoglobulin and mucin domain‐3 (TIM‐3), originally identified as a T helper (Th) 1‐specific type I membrane protein, plays a vital role in Th1 immunity and tolerance induction through interaction with its ligand, galectin‐9. The binding of TIM‐3 by galectin‐9 serves to downregulate Th1 responses. Moreover, the regulatory function of TIM‐3 has been extended to other cells, such as Th17 cells, CD4⁺CD25⁺ regulatory T cells (Tregs), CD8⁺ T cells and certain innate immune cells. Previous studies have acknowledged that the TIM‐3 pathway is involved in the pathogenesis of several human autoimmune diseases, such as systemic lupus erythematous, rheumatoid arthritis and aplastic anaemia. Moreover, genetic data suggest a role for TIM‐3 in human autoimmune diseases. However, in immune thrombocytopenia (ITP), a common Th1‐ and possibly Th17‐biased autoimmune disorder, the role of TIM‐3 has not been explored. Recently, our data have demonstrated that TIM‐3 expression is reduced in ITP patients, and we have found a potential link between ITP and the TIM‐3 pathway. In this article, we discuss and speculate on the role of the TIM‐3 pathway in ITP.