The soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells.

Pentraxin 3 (PTX3) is a fluid-phase pattern recognition receptor of the humoral innate immune system with ancestral antibody-like properties but unknown antibody-inducing function. In this study, we found binding of PTX3 to splenic marginal zone (MZ) B cells, an innate-like subset of antibody-producing lymphocytes strategically positioned at the interface between the circulation and the adaptive immune system. PTX3 was released by a subset of neutrophils that surrounded the splenic MZ and expressed an immune activation-related gene signature distinct from that of circulating neutrophils. Binding of PTX3 promoted homeostatic production of IgM and class-switched IgG antibodies to microbial capsular polysaccharides, which decreased in PTX3-deficient mice and humans. In addition, PTX3 increased IgM and IgG production after infection with blood-borne encapsulated bacteria or immunization with bacterial carbohydrates. This immunogenic effect stemmed from the activation of MZ B cells through a neutrophil-regulated pathway that elicited class switching and plasmablast expansion via a combination of T cell-independent and T cell-dependent signals. Thus, PTX3 may bridge the humoral arms of the innate and adaptive immune systems by serving as an endogenous adjuvant for MZ B cells. This property could be harnessed to develop more effective vaccines against encapsulated pathogens.

Microbiota regulate the ability of lung dendritic cells to induce IgA class-switch recombination and generate protective gastrointestinal immune responses.

Protective immunoglobulin A (IgA) responses to oral antigens are usually orchestrated by gut dendritic cells (DCs). Here, we show that lung CD103(+) and CD24(+)CD11b(+) DCs induced IgA class-switch recombination (CSR) by activating B cells through T cell-dependent or -independent pathways. Compared with lung DCs (LDC), lung CD64(+) macrophages had decreased expression of B cell activation genes and induced significantly less IgA production. Microbial stimuli, acting through Toll-like receptors, induced transforming growth factor-ß (TGF-ß) production by LDCs and exerted a profound influence on LDC-mediated IgA CSR. After intranasal immunization with inactive cholera toxin (CT), LDCs stimulated retinoic acid-dependent up-regulation of α4ß7 and CCR9 gut-homing receptors on local IgA-expressing B cells. Migration of these B cells to the gut resulted in IgA-mediated protection against an oral challenge with active CT. However, in germ-free mice, the levels of LDC-induced, CT-specific IgA in the gut are significantly reduced. Herein, we demonstrate an unexpected role of the microbiota in modulating the protective efficacy of intranasal vaccination through their effect on the IgA class-switching function of LDCs.

SORT1 Mutation Resulting in Sortilin Deficiency and p75(NTR) Upregulation in a Family With Essential Tremor.

*These authors contributed equally to this work.Essential tremor (ET) is the most prevalent movement disorder affecting millions of people in the United States. Although a positive family history is one of the most important risk factors for ET, the genetic causes of ET remain unknown. In this study, whole exome sequencing and subsequent approaches were performed in a family with an autosomal dominant form of early-onset ET. Functional analyses including mutagenesis, cell culture, gene expression, enzyme-linked immunosorbent, and apoptosis assays were also performed. A disease-segregating mutation (p.Gly171Ala), absent in normal population, was identified in the SORT1 gene. The p.Gly171Ala mutation was shown not only to impair the expression of its encoding protein sortilin but also the mRNA levels of its binding partner p75 neurotrophin receptor that is known to be implicated in brain injury, neuronal apoptosis, and neurotransmission.

CEACAM1-S: the virtues of alternative splicing in gut immunity.

Immunoglobulin A (IgA) is the main intestinal antibody. In this issue of Immunity, Chen et al. (2012) show that intestinal T cells enhance protective IgA responses by expressing a short isoform of the CEACAM1 protein.

Regulation of frontline antibody responses by innate immune signals.

Mature B cells generate protective immunity by undergoing immunoglobulin (Ig) class switching and somatic hypermutation, two Ig gene-diversifying processes that usually require cognate interactions with T cells that express CD40 ligand. This T-cell-dependent pathway provides immunological memory but is relatively slow to occur. Thus, it must be integrated with a faster, T-cell-independent pathway for B-cell activation through CD40 ligand-like molecules that are released by innate immune cells in response to microbial products. Here, we discuss recent advances in our understanding of the interplay between the innate immune system and B cells, particularly "frontline" B cells located in the marginal zone of the spleen and in the intestine.

B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen.

Neutrophils use immunoglobulins to clear antigen, but their role in immunoglobulin production is unknown. Here we identified neutrophils around the marginal zone (MZ) of the spleen, a B cell area specialized in T cell-independent immunoglobulin responses to circulating antigen. Neutrophils colonized peri-MZ areas after postnatal mucosal colonization by microbes and enhanced their B cell-helper function after receiving reprogramming signals, including interleukin 10 (IL-10), from splenic sinusoidal endothelial cells. Splenic neutrophils induced immunoglobulin class switching, somatic hypermutation and antibody production by activating MZ B cells through a mechanism that involved the cytokines BAFF, APRIL and IL-21. Neutropenic patients had fewer and hypomutated MZ B cells and a lower abundance of preimmune immunoglobulins to T cell-independent antigens, which indicates that neutrophils generate an innate layer of antimicrobial immunoglobulin defense by interacting with MZ B cells.

Immunoglobulin responses at the mucosal interface.

Mucosal surfaces are colonized by large communities of commensal bacteria and represent the primary site of entry for pathogenic agents. To prevent microbial intrusion, mucosal B cells release large amounts of immunoglobulin (Ig) molecules through multiple follicular and extrafollicular pathways. IgA is the most abundant antibody isotype in mucosal secretions and owes its success in frontline immunity to its ability to undergo transcytosis across epithelial cells. In addition to translocating IgA onto the mucosal surface, epithelial cells educate the mucosal immune system as to the composition of the local microbiota and instruct B cells to initiate IgA responses that generate immune protection while preserving immune homeostasis. Here we review recent advances in our understanding of the cellular interactions and signaling pathways governing IgA production at mucosal surfaces and discuss new findings on the regulation and function of mucosal IgD, the most enigmatic isotype of our mucosal antibody repertoire.

Innate signaling networks in mucosal IgA class switching.

The past 20 years have seen a growing interest over the control of adaptive immune responses by the innate immune system. In particular, considerable attention has been paid to the mechanisms by which antigen-primed dendritic cells orchestrate the differentiation of T cells. Additional studies have elucidated the pathways followed by T cells to initiate immunoglobulin responses in B cells. In this review, we discuss recent advances on the mechanisms by which intestinal bacteria, epithelial cells, dendritic cells, and macrophages cross talk with intestinal T cells and B cells to induce frontline immunoglobulin A class switching and production.

Ghrelin protects against experimental sepsis by inhibiting high-mobility group box 1 release and by killing bacteria.

Sepsis, a life-threatening complication of infections and the most common cause of death in intensive care units, is characterized by a hyperactive and out-of-balance network of endogenous proinflammatory cytokines. None of the current therapies are entirely effective, illustrating the need for novel therapeutic approaches. Ghrelin (GHR) is an orexigenic peptide that has emerged as a potential endogenous anti-inflammatory factor. In this study, we show that the delayed administration of GHR protects against the mortality in various models of established endotoxemia and sepsis. The therapeutic effect of GHR is mainly mediated by decreasing the secretion of the high mobility box 1 (HMGB1), a DNA-binding factor that acts as a late inflammatory factor critical for sepsis progression. Macrophages seem to be the major cell targets in the inhibition of HMGB1 secretion, in which GHR blocked its cytoplasmic translocation. Interestingly, we also report that GHR shows a potent antibacterial activity in septic mice and in vitro. Remarkably, GHR also reduces the severity of experimental arthritis and the release of HMGB1 to serum. Therefore, by regulating crucial processes of sepsis, such as the production of early and late inflammatory mediators by macrophages and the microbial load, GHR represents a feasible therapeutic agent for this disease and other inflammatory disorders.

Neuropeptides rescue mice from lethal sepsis by down-regulating secretion of the late-acting inflammatory mediator high mobility group box 1.

Originally described as a nuclear protein that bends DNA, the high mobility group box 1 protein (HMGB1) has recently emerged as a necessary and sufficient late mediator of severe sepsis. HMGB1 is therefore a molecular target that provides a wide window for clinical intervention in sepsis. Vasoactive intestinal peptide (VIP) and urocortin are two well known anti-inflammatory neuropeptides that protect against several immune disorders by regulating a wide panel of inflammatory mediators. In this study, we demonstrate the therapeutic effect of VIP and urocortin in various models of established sepsis: both agents reduced lethality induced by cecal ligation and puncture or by injection of live Escherichia coli. The therapeutic effect of VIP and urocortin was accompanied by a decrease in systemic levels of HMGB1. In addition, administration of recombinant HMGB1 completely reversed the protective effect of VIP and urocortin in experimental sepsis. In vitro and ex vivo studies show that both VIP and urocortin down-regulate translocation of HMGB1 from the nucleus to the cytoplasm and its subsequent secretion by activated macrophages, suggesting that macrophages are major targets in the inhibitory activity of these neuropeptides. To our knowledge, VIP and urocortin are the first endogenous inhibitors of HMGB1 secretion shown to improve sepsis survival in a clinically relevant time frame.

Tuning immune tolerance with vasoactive intestinal peptide: a new therapeutic approach for immune disorders.

The induction of immune tolerance is essential for the maintenance of immune homeostasis and to limit the occurrence of exacerbated inflammatory and autoimmune conditions. Multiple mechanisms act together to ensure self-tolerance, including central clonal deletion, cytokine deviation and induction of regulatory T cells. Identifying the factors that regulate these processes is crucial for the development of new therapies of autoimmune diseases and transplantation. The vasoactive intestinal peptide (VIP) is a well-characterized endogenous anti-inflammatory neuropeptide with therapeutic potential for a variety of immune disorders. Here, we examine the latest research findings, which indicate that VIP participates in maintaining immune tolerance in two distinct ways: by regulating the balance between pro-inflammatory and anti-inflammatory factors, and by inducing the emergence of regulatory T cells with suppressive activity against autoreactive T-cell effectors.

Therapeutical approaches of vasoactive intestinal peptide as a pleiotropic immunomodulator.

The vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two neuropeptides belonging to the VIP/secretin/glucagon family of peptides. VIP/PACAP are present and released from both innervation and immune cells, particularly Th2 cells, and exert a wide spectrum of immunological functions controlling the homeostasis of immune system through different receptors expressed in various immunocompetent cells. VIP/PACAP have a general anti-inflammatory effect, both in innate and adaptive immunity. In innate immunity, VIP/PACAP inhibit the production of pro-inflammatory cytokines and chemokines from macrophages, microglia and dendritic cells. In addition, VIP/PACAP reduce the expression of costimulatory molecules (particularly CD80 and CD86) on the antigen-presenting cells, and therefore reduce stimulation of antigen-specific CD4(+) T cells. In terms of adaptive immunity, VIP/PACAP promote Th2-type responses, and reduce the pro-inflammatory Th1-type responses. Several of the molecular mechanisms involved in the inhibition of cytokine and chemokine expression, and in the preferential development and/or survival of Th2 effectors, are perfectly known. Therefore, VIP/PACAP and analogues have been recently proposed as very promising candidates, alternative to other existing treatments, for treating acute and chronic inflammatory and autoimmune diseases, such as septic shock, rheumatoid arthritis, multiple sclerosis, Parkinson's disease, Crohn disease, or autoimmune diabetes. The aim of this review is firstly to update our knowledge of the cellular and molecular events relevant to VIP function on the immune system; and secondly to gather together recent data that support its role as a type 2 cytokine. Recognition of the central functions VIP plays in cellular processes is focusing our attention on this "very important peptide" as an exciting new candidate for therapeutic intervention and drug development.

Tuning inflammation with anti-inflammatory neuropeptides.

The immune system is confronted with the daunting task of defending the organism against invading pathogens while at the same time remaining self-tolerant to the body's own constituents and preserving its integrity. The loss of immune tolerance stemming from an unbalance in pro-inflammatory factors versus anti-inflammatory cytokines, or of autoreactive/inflammatory T helper 1 cells versus regulatory/suppressive T cells, results in the breakdown of immune homeostasis and the subsidiary appearance of exacerbated inflammatory and autoimmune diseases. Some neuropeptides have been shown to have anti-inflammatory properties and to participate in maintaining immune tolerance. Here the authors examine the most recent developments in this field and highlight the effectiveness of using neuropeptides in treating several inflammatory and autoimmune disorders.

Therapeutic effect of urocortin on collagen-induced arthritis by down-regulation of inflammatory and Th1 responses and induction of regulatory T cells.

OBJECTIVE: To investigate the potential therapeutic action of the immunomodulatory neuropeptide urocortin (UCN) in an experimental model of rheumatoid arthritis (RA). METHODS: After disease onset, DBA/1J mice with collagen-induced arthritis (CIA) were treated with UCN, and the incidence, severity (clinical score), and joint histopathology were evaluated. The inflammatory response was determined by measuring the levels of different mediators of inflammation (cytokines and chemokines) in the joints and sera. The Th1-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with the autoantigen and by assaying the content of serum autoantibodies. The number of regulatory CD4+,CD25+ T cells and their capacity to suppress self-reactive Th1 cells were determined in joints and lymph nodes. RESULTS: UCN treatment significantly reduced the incidence and severity of CIA, completely abrogating joint swelling and cartilage and bone destruction. The therapeutic effect of UCN was associated with a striking reduction of the 2 deleterious components of the disease: the Th1-driven autoimmune response and the inflammatory response. UCN also induced the generation and/or activation of efficient interleukin-10/transforming growth factor beta1-producing Treg cells in arthritis with the capacity to suppress the autoreactive response and to restore immune tolerance, thus playing a pivotal role in the therapeutic effect of UCN. CONCLUSION: Our findings provide a powerful rationale for assessing the efficacy of UCN as a novel multistep therapeutic approach to the treatment of RA in humans.

Adrenomedullin protects from experimental arthritis by down-regulating inflammation and Th1 response and inducing regulatory T cells.

Rheumatoid arthritis is a chronic autoimmune disease of unknown etiology characterized by chronic inflammation in the joints and subsequent destruction of the cartilage and bone. The present study proposes a new strategy for the treatment of arthritis: the administration of the immunomodulatory neuropeptide adrenomedullin. Treatment with adrenomedullin significantly reduced incidence and severity of collagen-induced arthritis, an experimental model of rheumatoid arthritis, completely abrogating joint swelling and destruction of cartilage and bone. The therapeutic effect of adrenomedullin was associated with a striking reduction of the two deleterious components of the disease, ie, the Th1-driven autoimmune and inflammatory responses. Adrenomedullin also induced the generation and/or activation of efficient CD4+ CD25+ regulatory T cells in arthritis with capacity to suppress autoreactive response and restore immune tolerance, which could play a pivotal role in the therapeutic effect of adrenomedullin on experimental arthritis contributing to the restoration of immune tolerance.

Therapeutic effect of cortistatin on experimental arthritis by downregulating inflammatory and Th1 responses.

BACKGROUND: Rheumatoid arthritis is a chronic autoimmune disease of unknown aetiology characterised by chronic inflammation in the joints and subsequent destruction of the cartilage and bone. AIM: To propose a new strategy for the treatment of arthritis based on the administration of cortistatin, a newly discovered neuropeptide with anti-inflammatory actions. METHODS: DBA/1J mice with collagen-induced arthritis were treated with cortistatin after the onset of disease, and the clinical score and joint histopathology were evaluated. Inflammatory response was determined by measuring the levels of various inflammatory mediators (cytokines and chemokines) in joints and serum. T helper cell type 1 (Th1)-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with collagen and by assaying the content of serum autoantibodies. RESULTS: Cortistatin treatment significantly reduced the severity of established collagen-induced arthritis, completely abrogating joint swelling and destruction of cartilage and bone. The therapeutic effect of cortistatin was associated with a striking reduction in the two deleterious components of the disease-that is, the Th1-driven autoimmune and inflammatory responses. Cortistatin downregulated the production of various inflammatory cytokines and chemokines, decreased the antigen-specific Th1-cell expansion, and induced the production of regulatory cytokines, such as interleukin 10 and transforming growth factor beta1. Cortistatin exerted its effects on synovial cells through both somatostatin and ghrelin receptors, showing a higher effect than both peptides protecting against experimental arthritis. CONCLUSION: This work provides a powerful rationale for the assessment of the efficacy of cortistatin as a novel therapeutic approach to the treatment of rheumatoid arthritis.

Regulation of immune tolerance by anti-inflammatory neuropeptides.

The induction of antigen-specific tolerance is essential to maintain immune homeostasis, control autoreactive T cells, prevent the onset of autoimmune diseases and achieve tolerance of transplants. Inflammation is a necessary process for eliminating pathogens, but can lead to serious deleterious effects in the host if left unchecked. Identifying the endogenous factors that control immune tolerance and inflammation is a key goal in the field of immunology. In the last decade, various neuropeptides that are produced by immune cells with potent anti-inflammatory actions were found to participate in the maintenance of tolerance in different immunological disorders.

Regulation of dendritic cell differentiation by vasoactive intestinal peptide: therapeutic applications on autoimmunity and transplantation.

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) involved in the defense of the body and in the maintenance of the immune tolerance. The regulation of their maturation, migration, and expression of stimulatory and costimulatory molecules has major consequences on the immune response. The endogenous factors that regulate DC function are poorly known. Vasoactive intestinal peptide (VIP) is a neuropeptide with potent anti-inflammatory actions. This anti-inflammatory profile is maintained partially through effects on DC differentiation/function. Thus, VIP has differential effects on DCs, depending on the differentiation and stimulatory states. Immature DCs treated with VIP exhibit increased CD86 expression and induce CD4(+) T cell proliferation. In addition, the CD4(+) T cells activated in vitro or in vivo by VIP-treated iDCs exhibit a Th2 phenotype. In contrast, VIP reduces both CD86 and CD80 expression on lipopolysaccharide (LPS)-stimulated DCs, and inhibits the capacity of DCs to induce in vitro or in vivo T cell proliferation. However, addition of VIP in the early states of DC differentiation results in the generation of DCs that cannot mature following inflammatory stimuli that exhibit a tolerogenic phenotype, characterized by low expression of costimulatory molecules (CD40, CD80, and CD86), low production of proinflammatory cytokines, increased production of IL-10, and capacity to induce regulatory T cells with suppressive actions. The effect of VIP on the DC-Treg axis represents an additional mechanism for their general anti-inflammatory role, particularly relevant in autoimmunity and transplantation.