Pregnancy enables antibody protection against intracellular infection.

Adaptive immune components are thought to exert non-overlapping roles in antimicrobial host defence, with antibodies targeting pathogens in the extracellular environment and T cells eliminating infection inside cells1,2. Reliance on antibodies for vertically transferred immunity from mothers to babies may explain neonatal susceptibility to intracellular infections3,4. Here we show that pregnancy-induced post-translational antibody modification enables protection against the prototypical intracellular pathogen Listeria monocytogenes. Infection susceptibility was reversed in neonatal mice born to preconceptually primed mothers possessing L. monocytogenes-specific IgG or after passive transfer of antibodies from primed pregnant, but not virgin, mice. Although maternal B cells were essential for producing IgGs that mediate vertically transferred protection, they were dispensable for antibody acquisition of protective function, which instead required sialic acid acetyl esterase5 to deacetylate terminal sialic acid residues on IgG variable-region N-linked glycans. Deacetylated L. monocytogenes-specific IgG protected neonates through the sialic acid receptor CD226,7, which suppressed IL-10 production by B cells leading to antibody-mediated protection. Consideration of the maternal-fetal dyad as a joined immunological unit reveals protective roles for antibodies against intracellular infection and fine-tuned adaptations to enhance host defence during pregnancy and early life.

Human IL-10-producing B cells have diverse states that are induced from multiple B cell subsets.

Regulatory B cells (Bregs) suppress immune responses through the secretion of interleukin-10 (IL-10). This immunomodulatory capacity holds therapeutic potential, yet a definitional immunophenotype for enumeration and prospective isolation of B cells capable of IL-10 production remains elusive. Here, we simultaneously quantify cytokine production and immunophenotype in human peripheral B cells across a range of stimulatory conditions and time points using mass cytometry. Our analysis shows that multiple functional B cell subsets produce IL-10 and that no phenotype uniquely identifies IL-10+ B cells. Further, a significant portion of IL-10+ B cells co-express the pro-inflammatory cytokines IL-6 and tumor necrosis factor alpha (TNFα). Despite this heterogeneity, operationally tolerant liver transplant recipients have a unique enrichment of IL-10+, but not TNFα+ or IL-6+, B cells compared with transplant recipients receiving immunosuppression. Thus, human IL-10-producing B cells constitute an induced, transient state arising from a diversity of B cell subsets that may contribute to maintenance of immune homeostasis.

Dynamic Number and Function of IL-10-Producing Regulatory B Cells in the Immune Microenvironment at Distinct Stages of Type 1 Diabetes.

The critical role of IL-10-producing B cells (B10 cells) with a unique CD1dhiCD5+ phenotype in suppressing autoimmune responses and relieving inflammation has been demonstrated in several models of autoimmune diseases. However, the regulatory role of B10 cells in T cell-mediated autoimmune responses during the natural history of type 1 diabetes is unclear. In this study, we used the NOD mouse model of autoimmune diabetes to clarify the changes and potential mechanisms of B10 cells for disease. Compared with B10 cells present in the 4-wk-old normoglycemic NOD mice, the frequency of B10 cells was increased in the insulitis and diabetic NOD mice, with the highest proportion in the insulitis NOD mice. The changes in the relative number of B10 cells were most pronounced in the pancreas-draining lymph nodes. The pathogenic T cells, including Th1 and Th17 cells, remarkably increased. The assays in vitro showed that B10 cells in the NOD mice did not inhibit the proliferation of CD4+CD25- T cells. They also had no regulatory effect on IFN-γ and IL-4 secretion or on Foxp3 expression of T cells. B10 cells suppressed T cell-mediated autoimmune responses via an IL-10-dependent pathway. In contrast, B10 cells in the NOD mice exhibited a significant reduction in IL-10 production. In summary, a defect in the number and function of B10 cells may participate in the development and progression of type 1 diabetes.

Poor Clinical Outcomes and Immunoevasive Contexture in Intratumoral IL-10-Producing Macrophages Enriched Gastric Cancer Patients.

OBJECTIVE: To investigate the clinical significance of IL-10+ tumor-associated macrophages (TAMs) in gastric cancer. BACKGROUND: Due to the plasticity and diversity of TAMs, it is necessary to phenotypically and functionally classify subsets of TAMs to better understand the critical role of TAMs in cancer progression. TAMs expressing interleukin-10 (IL-10) have been found to facilitate immune evasion in many malignancies, but the role of IL-10+ TAMs in gastric cancer remains obscure. METHODS: Four hundred and sixty-eight tumor tissue microarray specimens, 52 fresh tumor tissue samples of gastric cancer patients from Zhongshan Hospital, and data of 298 gastric cancer patients from the Cancer Genome Atlas (TCGA) were analyzed. IL-10+ TAM level and immune contexture were examined by CIBERSORT, immunohistochemistry, and flow cytometry. Clinical outcomes were analyzed by Kaplan-Meier curves and Cox model. RESULTS: Gastric cancer patients with high IL-10+ TAM infiltration exhibited poor prognosis and inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy. IL-10+ TAM infiltration yielded an immunoevasive tumor microenvironment featured by regulatory T cell infiltration and CD8+ T cell dysfunction. The combinational analysis of IL-10+ TAM and CD8+ T cell infiltration stratified patients into distinct risk groups with different clinical outcomes. Moreover, IL-10+ TAM infiltration was correlated with tumor-intrinsic characteristics including EBV status, PD-L1 expression, and genome stability in gastric cancer. CONCLUSIONS: This study revealed that IL-10+ TAMs might drive an immunoevasive microenvironment and determine poor prognosis and inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy, indicating IL-10+ TAMs could be applied as a potential target for immunotherapeutic approach in gastric cancer.

Assessment of Allergen-Responsive Regulatory T Cells in Experimental Asthma Induced in Different Mouse Strains.

BACKGROUND: Regulatory T cells (Tregs) are important in regulating responses to innocuous antigens, such as allergens, by controlling the Th2 response, a mechanism that appears to be compromised in atopic asthmatic individuals. Different isogenic mouse strains also have distinct immunological responses and susceptibility to the experimental protocols used to develop lung allergic inflammation. In this work, we investigated the differences in the frequency of Treg cell subtypes among A/J, BALB/c, and C57BL/6, under normal conditions and following induction of allergic asthma with ovalbumin (OVA). METHODS: Subcutaneous sensitization followed by 4 consecutive intranasal OVA challenges induced asthma characteristic changes such as airway hyperreactivity, inflammation, and production of Th2 cytokines (IL-4, IL-13, IL-5, and IL-33) in the lungs of only A/J and BALB/c but not C57BL/6 strain and evaluated by invasive whole-body plethysmography, flow cytometry, and ELISA, respectively. RESULTS: A/J strain naturally showed a higher frequency of CD4+IL-10+ T cells in the lungs of naïve mice compared to the other strains, accompanied by higher frequencies of CD4+IL-4+ T cells. C57BL/6 mice did not develop lung inflammation and presented higher frequency of CD4+CD25+Foxp3+ Treg cells in the bronchoalveolar lavage fluid (BALF) after the allergen challenge. In in vitro settings, allergen-specific stimulation of mediastinal LN (mLN) cells from OVA-challenged animals induced higher frequency of CD4+IL-10+ Treg cells from A/J strain and CD4+CD25+Foxp3+ from C57BL/6. CONCLUSIONS: The observed differences in the frequencies of Treg cell subtypes associated with the susceptibility of the animals to experimental asthma suggest that CD4+CD25+Foxp3+ and IL-10-producing CD4+ Treg cells may play different roles in asthma control. Similar to asthmatic individuals, the lack of an efficient regulatory response and susceptibility to the development of experimental asthma in A/J mice further suggests that this strain could be preferably chosen in experimental models of allergic asthma.

IL-17-dependent fibroblastic reticular cell training boosts tissue protective mucosal immunity through IL-10-producing B cells.

Prior experience of pathogen-associated stimuli reduces morbidity and mortality to newly encountered infections through innate immune training, which can be enhanced by childhood vaccination. Fibroblastic reticular cells (FRCs) are stromal cells in lymphoid organs that support lymphocyte localization and survival and modulate adaptive immune responses. IL-17 signaling is important for FRC metabolism and proliferation during inflammatory responses. Here, we show that FRC-intrinsic IL-17 signaling was required for protective antibody-mediated immunity to the gut bacterial pathogen Citrobacter rodentium. We asked whether prior activation of FRC through nonspecific inflammatory "training" of the gut would alter subsequent immune response to C. rodentium. Inflammatory training increased the number of activated FRC in mesenteric LN (MLN) and enhanced the antibody response to C. rodentium in an IL-17­dependent manner. FRC demonstrated cardinal features of innate immune training, including increased epigenetic markers of activation and increased metabolic response to infection. Enhanced responses were still evident 6 weeks after training. The kinetics of bacterial infection were not changed by inflammatory training, but colon inflammation was paradoxically reduced. Mechanistically, IL-10 production by activated B cells was required for colon protective effects of inflammatory training. Enhancing tissue protective B cell responses thus led to increased production of antibody and IL-10, allowing clearance of infection with reduced tissue inflammation. These data identify a new mode of immune training through FRC to modulate future adaptive responses and better preserve host health.

IL-21 Rescues the Defect of IL-10-Producing Regulatory B Cells and Improves Allergic Asthma in DOCK8 Deficient Mice.

Mutations in human DOCK8 cause a combined immunodeficiency syndrome characterized by allergic diseases such as asthma and food allergy. However, the underlying mechanism is unclear. Regulatory B (Breg) cells that produce IL-10 exert potent immunosuppressive functions in patients with allergic and autoimmune disorders. DOCK8-deficient B cells show diminished responses to TLR9 signaling, suggesting a possible defect in IL-10-producing Breg cells in those with DOCK8 deficiency, which may contribute to allergies. Here, we isolated peripheral blood mononuclear cells from DOCK8-deficient patients and generated a Dock8 KO mouse model to study the effect of DOCK8 deficiency on Breg cells. DOCK8-deficient patients and Dock8 KO mice harbored quantitative and qualitative defects in IL-10-producing Breg cells; these defects were caused by abnormal Dock8-/- CD4+ T cells. We found that recombinant murine (rm)IL-21 restored the function of Bregs both in vitro and in Dock8 KO mice, leading to reduced inflammatory cell infiltration of the lungs in a murine asthma model. Overall, the results provide new insight into the potential design of Breg-based or IL-21-based therapeutic strategies for allergic diseases, including asthma associated with DOCK8 deficiency.

Porcine-Stimulated Human Tr1 Cells Showed Enhanced Suppression in Xenoantigen Stimulation Response.

Type 1 regulatory T (Tr1) cells play a fundamental role in maintaining and inducing immune tolerance. Our preliminary study demonstrated that an interleukin- (IL-) 10-mediated pathway is a possible regulatory mechanism underlying the xenoantigen-specific human Treg enhanced suppressive capacity. Here, we developed a feasible protocol for expanding IL-10-induced xenoantigen-specific human Tr1 cells in vitro which would be more efficient in transplantation immunotherapy efficiency. In this study, xenoantigen-specific Tr1 cells are generated from human naive CD4+ T cells expanded for two subsequent xenoantigen-stimulation cycles with recombinant human IL-10. The phenotype and suppressive capacity of xenoantigen-stimulated Tr1 cells are assessed, and the mechanism of their suppression is studied. Tr1 cells can be induced by porcine xenoantigen stimulation combined with IL-10, IL-2, and IL-15, displaying an increased expression of CD49b, CTLA-4, and LAG-3 without expressing Foxp3 which also showed an effector memory Treg phenotype and expressed high levels of CD39. After xenoantigen stimulation, the IL-10 and IL-5 gene expression in Tr1 cells increased, secreting more IL-10, and xenoantigen-stimulated Tr1 cells changed their T cell receptor (TCR) Vß repertoire, increasing the expression of TCR Vß2, TCR Vß9, and TCR Vß13. In a pig to human mixed lymphocyte reaction (MLR), xenoantigen-stimulated Tr1 cells displayed enhanced suppressive capacity via CD39 in a dose-dependent manner. Moreover, IL-5 could affect the proliferation of xenoantigen-specific Tr1 cells, but not their phenotypes' expression. This study provides a theory and feasible method for immune tolerance induction in clinical xenotransplantation.

The Effect of Homocysteine on the Secretion of Il-1ß, Il-6, Il-10, Il-12 and RANTES by Peripheral Blood Mononuclear Cells-An In Vitro Study.

The contemporary theory of the inflammatory-immunological pathomechanism of atherosclerosis includes the participation of interleukin-1ß (Il), Il-6, Il-10, Il-12, RANTES, and homocysteine in this process. The knowledge on the direct effect of hyperhomocysteinemia on inflammatory-state-related atherosclerosis is rather scarce. Our study is the first to account for the effects of homocysteine on the secretion of Il-10 and RANTES in vitro conditions. For this purpose, human mitogen-stimulated peripheral blood mononuclear cells (PBMNCs) were cultured in vitro and exposed to homocysteine at high concentrations. Subsequently, the concentrations of cytokines were assayed in the cell culture supernatant using flow cytofluorimetry. It has been shown that, in the presence of homocysteine, the secretion of IL-1, IL-6 and RANTES by PBMNCs was increased, whereas IL-10 concentration was significantly lower than that of the supernatant derived from a mitogen-stimulated cell culture without homocysteine. The secretion of Il-12 by PBMNCs exposed exclusively to mitogen, did not differ from homologous cells also treated with homocysteine. Therefore, in our opinion, high-concentration homocysteine affects the progression of atherosclerosis by increasing the secretion of proinflammatory cytokines secreted by PBMNCs, such as Il-1ß, Il-6, RANTES, and by attenuating the secretion of Il-10.

Regulatory B Cells: Role in Type 1 Diabetes.

Regulatory B cells (Bregs) have an anti-inflammatory role and can suppress autoimmunity, by employing both cytokine secretion and cell-contact mediated mechanisms. Numerous Breg subsets have been described and have overlapping phenotypes in terms of their immune expression markers or cytokine production. A hallmark feature of Bregs is the secretion of IL-10, although IL-35 and TGFß-producing B cells have also been identified. To date, few reports have identified an impaired frequency or function of Bregs in individuals with type 1 diabetes; thus our understanding of the role played by these Breg subsets in the pathogenesis of this condition is limited. In this review we will focus on how regulatory B cells are altered in the development of type 1 diabetes, highlighting both frequency and function and discuss both human and animal studies.

An inhibitory immunoreceptor, Allergin-1, suppresses FITC-induced type 2 contact hypersensitivity.

Although allergic contact dermatitis (ACD) is the most common T cell-mediated inflammatory responses against an allergen in the skin, the pathogenesis of ACD remains incompletely understood. In the sensitization phase in ACD, hapten-bearing dermal dendritic cells (DCs) play a pivotal role in the transport of an antigen to the lymph nodes (LNs), where they present the antigen to naïve T cells. Here we report that Allergin-1, an inhibitory immunoreceptor containing immunoreceptor tyrosine-based inhibitory motif (ITIM) in the cytoplasmic region, is highly expressed on dermal DCs. Mice deficient in Allergin-1 exhibited exacerbated fluorescein isothiocyanate (FITC)-induced type 2 contact hypersensitivity (CHS) such as ear swelling and skin eosinophilia. Allergin-1-deficient mice also showed larger numbers of CD4+ T cells and FITC-bearing DCs and greater expressions of type 2 cytokines, including IL-5, IL-10 and IL-13, in the draining LNs than did wild type mice. In sharp contrast, Allergin-1-deficient mice showed comparable level of type 1 CHS induced by 2,4-dinitrofluorobenzene (DNFB). These results suggest that Allergin-1 on dermal DC inhibits type 2, but not type 1, immune responses in the sensitization phase of CHS.

Inosine monophosphate and inosine differentially regulate endotoxemia and bacterial sepsis.

Inosine monophosphate (IMP) is the intracellular precursor for both adenosine monophosphate and guanosine monophosphate and thus plays a central role in intracellular purine metabolism. IMP can also serve as an extracellular signaling molecule, and can regulate diverse processes such as taste sensation, neutrophil function, and ischemia-reperfusion injury. How IMP regulates inflammation induced by bacterial products or bacteria is unknown. In this study, we demonstrate that IMP suppressed tumor necrosis factor (TNF)-α production and augmented IL-10 production in endotoxemic mice. IMP exerted its effects through metabolism to inosine, as IMP only suppressed TNF-α following its CD73-mediated degradation to inosine in lipopolysaccharide-activated macrophages. Studies with gene targeted mice and pharmacological antagonism indicated that A2A , A2B, and A3 adenosine receptors are not required for the inosine suppression of TNF-α production. The inosine suppression of TNF-α production did not require its metabolism to hypoxanthine through purine nucleoside phosphorylase or its uptake into cells through concentrative nucleoside transporters indicating a role for alternative metabolic/uptake pathways. Inosine augmented IL-ß production by macrophages in which inflammasome was activated by lipopolysaccharide and ATP. In contrast to its effects in endotoxemia, IMP failed to affect the inflammatory response to abdominal sepsis and pneumonia. We conclude that extracellular IMP and inosine differentially regulate the inflammatory response.

Photobiomodulation therapy improved functional recovery and overexpression of interleukins-10 after contusion spinal cord injury in rats.

Following severe Spinal Cord Injury (SCI), regeneration is inadequate, and functional recovery is incomplete. The occurrence of oxidative stress and the spread of inflammation play a crucial role in the failure to regenerate the injury site. In this way, we explored the neuroprotective effects of PhotoBioModulation (PBM), as the main factor in controlling these two destructive factors, on SCI. fifty-four female adult Wistar rats divided into three groups: sham group (just eliminate vertebra lamina, n = 18), SCI group (n = 18), and SCI-PBM group which exposed to PBM (150 MW, 50 min/day, 14 days, n = 18). After SCI induction at the endpoint of the study (the end of 8 week), we took tissue samples from the spinal cord for evaluating the biochemical profiles that include Catalase (CAT), Malondialdehyde (MDA), Superoxide Dismutase (SOD), Glutathione Peroxidase (GSH-PX) levels, immunohistochemistry for Caspase-3, gene expressions of Interleukin-1ß (IL-1ß), Tumor Necrosis Factor-alpha (TNF-α), and Interleukin (IL-10). Also, stereological assessments evaluated the spinal cord, central cavity volumes, and numerical density of the glial and neural cells in the traumatic area. The open-field test, rotarod test, Narrow Beam Test (NBT), Electromyography recording (EMG) test and the Basso-Beattie-Bresnehan (BBB) evaluated the neurological functions. Our results showed that the stereological parameters, biochemical profiles (except MDA), and neurological functions were markedly greater in the SCI-PBM group in comparison with SCI group. The transcript for the IL-10 gene was seriously upregulated in the SCI-PBM group compared to the SCI group. This is while gene expression of TNF-α and IL-1ß, also density of apoptosis cells in Caspase-3 evaluation decreased significantly more in the SCI-PBM group compared to the SCI group. Overall, using PBM treatment immediately after SCI has neuroprotective effects by controlling oxidative stress and inflammation and preventing the spread of damage.

Thalidomide alleviates neuropathic pain through microglial IL-10/ß-endorphin signaling pathway.

Thalidomide is an antiinflammatory, antiangiogenic and immunomodulatory agent which has been used for the treatment of erythema nodosum leprosum and multiple myeloma. It has also been employed in treating complex regional pain syndromes. The current study aimed to reveal the molecular mechanisms underlying thalidomide-induced pain antihypersensitive effects in neuropathic pain. Thalidomide gavage, but not its more potent analogs lenalidomide and pomalidomide, inhibited mechanical allodynia and thermal hyperalgesia in neuropathic pain rats induced by tight ligation of spinal nerves, with ED50 values of 44.9 and 23.5 mg/kg, and Emax values of 74% and 84% MPE respectively. Intrathecal injection of thalidomide also inhibited mechanical allodynia and thermal hyperalgesia in neuropathic pain. Treatment with thalidomide, lenalidomide and pomalidomide reduced peripheral nerve injury-induced proinflammatory cytokines (TNFα, IL-1ß and IL-6) in the ipsilateral spinal cords of neuropathic rats and LPS-treated primary microglial cells. In contrast, treatment with thalidomide, but not lenalidomide or pomalidomide, stimulated spinal expressions of IL-10 and ß-endorphin in neuropathic rats. Particularly, thalidomide specifically stimulated IL-10 and ß-endorphin expressions in microglia but not astrocytes or neurons. Furthermore, pretreatment with the IL-10 antibody blocked upregulation of ß-endorphin in neuropathic rats and cultured microglial cells, whereas it did not restore thalidomide-induced downregulation of proinflammatory cytokine expression. Importantly, pretreatment with intrathecal injection of the microglial metabolic inhibitor minocycline, IL-10 antibody, ß-endorphin antiserum, and preferred or selective µ-opioid receptor antagonist naloxone or CTAP entirely blocked thalidomide gavage-induced mechanical antiallodynia. Our results demonstrate that thalidomide, but not lenalidomide or pomalidomide, alleviates neuropathic pain, which is mediated by upregulation of spinal microglial IL-10/ß-endorphin expression, rather than downregulation of TNFα expression.

C-Terminal Fragment of Vitellogenin II, a Potential Yolkin Polypeptide Complex Precursor Protein-Heterologous Expression, Purification, and Immunoregulatory Activity.

The aim of this research was to analyze the heterologous expression, purification, and immunoregulatory activity of recombinant YGP40 (rYGP40), the potential precursor of the yolkin peptide complex. The ygp40 coding sequence was codon optimized, successfully expressed in the E. coli system, and purified from inclusion bodies with a yield of about 1.1 mg/L of culture. This study showed that the protein exhibits immunomodulatory activity, expressed by the stimulation of TNF-α and IL-10 production and nitric oxide induction at a level comparable to that of the natural yolkin peptide complex obtained by other authors from hen egg yolk. At the highest dose of 100 µg/mL, rYGP40 also caused the up-regulation of iNOS expression in murine bone marrow-derived macrophages (BMDM). Moreover, no cytotoxic effects of rYGP40 on the BMDM cell line were observed.

Myxomavirus serpin alters macrophage function and prevents diffuse alveolar hemorrhage in pristane-induced lupus.

C57BL/6 mice with pristane-induced lupus develop macrophage-dependent diffuse alveolar hemorrhage (DAH), which is blocked by treatment with liver X receptor (LXR) agonists and is exacerbated by low IL-10 levels. Serp-1, a myxomavirus-encoded serpin that impairs macrophage activation and plasminogen activation, blocks DAH caused by MHV68 infection. We investigated whether Serp-1 also could block DAH in pristane-induced lupus. Pristane-induced DAH was prevented by treatment with recombinant Serp-1 and macrophages from Serp1-treated mice exhibited an anti-inflammatory M2-like phenotype. Therapy activated LXR, promoting M2 polarization and expression of Kruppel-like factor-4 (KLH4), which upregulates IL-10. In contrast, deficiency of tissue plasminogen activator or plasminogen activator inhibitor had little effect on DAH. We conclude that Serp-1 blocks pristane-induced lung hemorrhage by enhancing LXR-regulated M2 macrophage polarization and KLH4-regulated IL-10 production. In view of the similarities between DAH in pristane-treated mice and SLE patients, Serp-1 may represent a potential new therapy for this severe complication of SLE.

Th17 Cells in Viral Infections-Friend or Foe?

Th17 cells are recognized as indispensable in inducing protective immunity against bacteria and fungi, as they promote the integrity of mucosal epithelial barriers. It is believed that Th17 cells also play a central role in the induction of autoimmune diseases. Recent advances have evaluated Th17 effector functions during viral infections, including their critical role in the production and induction of pro-inflammatory cytokines and in the recruitment and activation of other immune cells. Thus, Th17 is involved in the induction both of pathogenicity and immunoprotective mechanisms seen in the host's immune response against viruses. However, certain Th17 cells can also modulate immune responses, since they can secrete immunosuppressive factors, such as IL-10; these cells are called non-pathogenic Th17 cells. Here, we present a brief review of Th17 cells and highlight their involvement in some virus infections. We cover these notions by highlighting the role of Th17 cells in regulating the protective and pathogenic immune response in the context of viral infections. In addition, we will be describing myocarditis and multiple sclerosis as examples of immune diseases triggered by viral infections, in which we will discuss further the roles of Th17 cells in the induction of tissue damage.

Vagal Nerve Stimulation-Modulation of the Anti-Inflammatory Response and Clinical Outcome in Psoriatic Arthritis or Ankylosing Spondylitis.

OBJECTIVES: The vagal nerve exerts an essential pathway in controlling the cholinergic anti-inflammatory reflex. Thus, the study is aimed at investigating the acute effect of a noninvasive transcutaneous vagus nerve stimulation on clinical disease activity and systemic levels of inflammation in patients with psoriatic arthritis or ankylosing spondylitis. METHODS: Twenty patients with psoriatic arthritis (PsA) and 20 patients with ankylosing spondylitis (AS) were included and stimulated bilaterally with a handheld vagal nerve stimulator for 120 seconds 3 times a day for 5 consecutive days. All patients were in remission. Cardiac vagal tone, clinical scores, CRP, and cytokine levels were assessed. RESULTS: In PsA and AS, decreased heart rate was observed, confirming compliance. Furthermore, in PsA, a clear reduction of clinical disease activity associated with a 20% reduction in CRP was shown. In AS, a reduction in interferon-γ, interleukin- (IL-) 8, and 10 was shown. No side effects were described. CONCLUSION: This open-label study provides support for an anti-inflammatory effect of transcutaneous vagus nerve stimulation in patients with psoriatic arthritis and ankylosing spondylitis. The modulated immune response and reduced disease activity and CRP-levels raise the fascinating possibility of using neuromodulation as an add-on to existing pharmacological treatments.

Sensory neuron-derived TAFA4 promotes macrophage tissue repair functions.

Inflammation is a defence response to tissue damage that requires tight regulation in order to prevent impaired healing. Tissue-resident macrophages have a key role in tissue repair1, but the precise molecular mechanisms that regulate the balance between inflammatory and pro-repair macrophage responses during healing remain poorly understood. Here we demonstrate a major role for sensory neurons in promoting the tissue-repair function of macrophages. In a sunburn-like model of skin damage in mice, the conditional ablation of sensory neurons expressing the Gαi-interacting protein (GINIP) results in defective tissue regeneration and in dermal fibrosis. Elucidation of the underlying molecular mechanisms revealed a crucial role for the neuropeptide TAFA4, which is produced in the skin by C-low threshold mechanoreceptors-a subset of GINIP+ neurons. TAFA4 modulates the inflammatory profile of macrophages directly in vitro. In vivo studies in Tafa4-deficient mice revealed that TAFA4 promotes the production of IL-10 by dermal macrophages after UV-induced skin damage. This TAFA4-IL-10 axis also ensures the survival and maintenance of IL-10+TIM4+ dermal macrophages, reducing skin inflammation and promoting tissue regeneration. These results reveal a neuroimmune regulatory pathway driven by the neuropeptide TAFA4 that promotes the anti-inflammatory functions of macrophages and prevents fibrosis after tissue damage, and could lead to new therapeutic perspectives for inflammatory diseases.

IL-10 producing B cells regulated 1,3-ß-glucan induced Th responses in coordinated with Treg.

Repeated exposure to fungi-contaminated dust can lead to multiple adverse effects on the lung, such as hypersensitivity pneumonitis, granuloma even irreversible fibrosis. 1,3-ß-glucan, a major cell wall component of fungi, is considered as its exposure biomarker. Existing studies showed that a series of Th responses were involved in 1,3-ß-glucan induced hypersensitivity pneumonitis, in which macrophages, Treg, and IL-10 producing B cells were reported to participate. The reciprocal interaction among those critical immune cells in 1,3-ß-glucan induced inflammation was not investigated yet. To clarify the regulatory mechanism of IL-10 producing B cells on Th and Treg, the current study set up a primary cell co-culture system. The anti-CD22 antibody was injected intraperitoneally to generate IL-10 producing B cells deficiency mouse model. Cells were isolated and purified from C57BL∖6 mice in different groups. Flow cytometry was used to check the phenotype of different cell subtypes. CBA assay and real-time PCR were used to examine the levels of multiple cytokines. Our results indicated that IL-10 producing B cells could modulate the 1,3-ß-glucan induced inflammatory response. The modulation of IL-10 producing B cells on Th response after 1,3-ß-glucan treatment was cell contact independent. What's more, the modulation pattern of IL-10 producing B cells might be impaired without Treg response. IL-10-producing B cells regulated 1,3-ß-glucan induced Th responses in co-ordination with Treg cells.