Enkephalin-mediated modulation of basal somatic sensitivity by regulatory T cells in mice.

CD4CD25Foxp3 regulatory T cells (Treg) have been implicated in pain modulation in various inflammatory conditions. However, whether Treg cells hamper pain at steady state and by which mechanism is still unclear. From a meta-analysis of the transcriptomes of murine Treg and conventional T cells (Tconv), we observe that the proenkephalin gene (), encoding the precursor of analgesic opioid peptides, ranks among the top 25 genes most enriched in Treg cells.

Absence of sympathetic innervation hampers the generation of tertiary lymphoid structures upon acute lung inflammation.

Tertiary lymphoid structures (TLS) are lymphoid organs present in inflammatory non-lymphoid tissues. Studies have linked TLS to favorable outcomes for patients with cancers or infectious diseases, but the mechanisms underlying their formation are not fully understood. In particular, secondary lymphoid organs innervation raises the question of sympathetic nerve fibers involvement in TLS organogenesis.

Defects in mucosal immunity and nasopharyngeal dysbiosis in HSC-transplanted SCID patients with IL2RG/JAK3 deficiency.

Both innate and adaptive lymphocytes have critical roles in mucosal defense that contain commensal microbial communities and protect against pathogen invasion. Here we characterize mucosal immunity in patients with severe combined immunodeficiency (SCID) receiving hematopoietic stem cell transplantation (HSCT) with or without myeloablation. We confirmed that pretransplant conditioning had an impact on innate (natural killer and innate lymphoid cells) and adaptive (B and T cells) lymphocyte reconstitution in these patients with SCID and now show that this further extends to generation of T helper 2 and type 2 cytotoxic T cells.

Tissue-restricted control of established central nervous system autoimmunity by TNF receptor 2-expressing Treg cells.

CD4Foxp3 regulatory T (Treg) cells are central modulators of autoimmune diseases. However, the timing and location of Treg cell-mediated suppression of tissue-specific autoimmunity remain undefined. Here, we addressed these questions by investigating the role of tumor necrosis factor (TNF) receptor 2 (TNFR2) signaling in Treg cells during experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis.

Lymphocytes are a major source of circulating soluble dipeptidyl peptidase 4.

Dipeptidyl peptidase 4 (DPP4, CD26) is a serine protease that is expressed constitutively by many haematopoietic and non-haematopoietic tissues. It exists as a membrane-associated protein, as well as in an active, soluble form (herein called sDPP4), present at high concentrations in bodily fluids. Despite the proposed use of sDPP4 as a biomarker for multiple diseases, its cellular sources are not well defined.

Interplay of DDP4 and IP-10 as a Potential Mechanism for Cell Recruitment to Tuberculosis Lesions.

Introduction: is one of the world's most successful pathogens equipped to establish itself within the human host as a subclinical infection without overt disease. Unable to eradicate the bacteria, the immune system contains the infection in a granuloma structure. Th1 cells that are essential for infection control are recruited to the site of infection directed by chemokines, predominantly CXCL10.

Systemic DPP4 activity is reduced during primary HIV-1 infection and is associated with intestinal RORC CD4 cell levels: a surrogate marker candidate of HIV-induced intestinal damage.

Introduction: Combined anti-retroviral therapy (cART) transformed HIV-1 from a deadly disease into a chronic infection, but does not cure HIV infection. It also does not fully restore HIV-induced gut damage unless administered extremely early after infection. Additional biomarkers are needed to evaluate the capacity of therapies aimed at HIV remission/cure to restore HIV-induced intestinal immune damage and limit chronic inflammation.

Multimarker risk stratification approach at multiple sclerosis onset.

Delay in the diagnosis of multiple sclerosis (MS) stems from the lack of specific clinical and analytical markers to assist in the early diagnosis and prediction of progressive course. We propose a decision-tree model that better defines early at onset MS patients and those with the progressive form by analysing a 12-biomarkers panel in serum and CSF samples of patients with MS, other neurological diseases (OND) and healthy contols. Thus, patients at onset of neurological disease were first classified by serum IL-7 levels <141pg/ml (OR=6.

Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation.

Innate lymphoid cells (ILCs) represent innate versions of T helper and cytotoxic T cells that differentiate from committed ILC precursors (ILCPs). How ILCPs give rise to mature tissue-resident ILCs remains unclear. Here, we identify circulating and tissue ILCPs in humans that fail to express the transcription factors and cytokine outputs of mature ILCs but have these signature loci in an epigenetically poised configuration.

Elevated Basal Pre-infection CXCL10 in Plasma and in the Small Intestine after Infection Are Associated with More Rapid HIV/SIV Disease Onset.

Elevated blood CXCL10/IP-10 levels during primary HIV-1 infection (PHI) were described as an independent marker of rapid disease onset, more robust than peak viremia or CD4 cell nadir. IP-10 enhances the recruitment of CXCR3+ cells, which include major HIV-target cells, raising the question if it promotes the establishment of viral reservoirs. We analyzed data from four cohorts of HIV+ patients, allowing us to study IP-10 levels before infection (Amsterdam cohort), as well as during controlled and uncontrolled viremia (ANRS cohorts).

Dynamic Changes of Post-Translationally Modified Forms of CXCL10 and Soluble DPP4 in HCV Subjects Receiving Interferon-Free Therapy.

Serum levels of the interferon (IFN)-stimulated chemokine CXCL10 are increased during chronic HCV infection and associate with outcome of IFN-based therapy. Elevated levels of NH2-terminal truncated CXCL10 (3-77aa), produced by DPP4 cleavage, negatively associate with spontaneous clearance of acute HCV infection and sustained virological response (SVR) with IFN-based therapy for chronic infection. The association of different CXCL10 forms and DPP4 with outcome during IFN-free HCV therapy has not been examined.

Plasma biomarkers discriminate clinical forms of multiple sclerosis.

Multiple sclerosis, the most common cause of neurological disability in young population after trauma, represents a significant public health burden. Current challenges associated with management of multiple sclerosis (MS) patients stem from the lack of biomarkers that might enable stratification of the different clinical forms of MS and thus prompt treatment for those patients with progressive MS, for whom there is currently no therapy available. In the present work we analyzed a set of thirty different plasma cytokines, chemokines and growth factors present in circulation of 129 MS patients with different clinical forms (relapsing remitting, secondary progressive and primary progressive MS) and 53 healthy controls, across two independent cohorts.

Plasma apolipoprotein H limits HCV replication and associates with response to NS3 protease inhibitors-based therapy.

Background & Aims: Chronic infection with HCV remains a public health problem with approximately 150 million people infected worldwide. HCV intersects with lipid metabolism for replication and entry; and plasma concentrations of apolipoproteins have been identified as predictors for response to therapy. Herein, we conducted a screen of plasma proteins, including all apolipoproteins, to identify correlates of response to pegylated-interferon/ribavirin (PR) and HCV non-structural protein 3 (NS3) inhibitors (i.

Baseline sensitivity of T cells to alpha-IFN correlates with sustained virological response to IFN-based triple therapy in HCV infection.

Chronic infection with HCV is a public health problem with approximately 170 million people infected worldwide. Interferon alpha (IFNα) sensitivity in liver and IL28B genotype has been identified as important determinants of HCV clearance in the setting of pegylated interferon/ribavirin treatment. Herein, we explored IFNα sensitivity in PBMC from 21 healthy donors and 21 HCV-infected patients treated with pegylated interferon/ribavirin and HCV nonstructural protein-3 inhibitors (i.

Apolipoprotein H expression is associated with IL28B genotype and viral clearance in hepatitis C virus infection.

Background & Aims: HCV requires host lipid metabolism for replication, and apolipoproteins have been implicated in the response to treatment.

Methods: We examined plasma apolipoprotein concentrations in three cohorts of patients: mono-infected patients with symptomatic acute hepatitis C (aHCV); those undergoing treatment for chronic hepatitis C (cHCV); and HIV/HCV co-infected patients being treated for their chronic hepatitis C. We also evaluated associations between apolipoproteins and IL28B polymorphisms, a defined genetic determinant of viral clearance.

Truncated CXCL10 is associated with failure to achieve spontaneous clearance of acute hepatitis C infection.

Unlabelled: The pathogenesis of hepatitis C virus (HCV) infection is strongly influenced by the nature of the host's antiviral immunity. Counterintuitively, elevated serum concentrations of C-X-C chemokine 10 (CXCL10), a potent chemoattractant for antiviral T-cells and NK-cells, are associated with poor treatment outcomes in patients with chronic HCV. It has been reported that an N-terminal truncated form of CXCL10, generated by the protease dipeptidylpeptidase 4 (DPP4), can act as chemokine antagonist.

The ABCs of viral hepatitis that define biomarker signatures of acute viral hepatitis.

Unlabelled: Viral hepatitis is the leading cause of liver disease worldwide and can be caused by several agents, including hepatitis A (HAV), B (HBV), and C (HCV) virus. We employed multiplexed protein immune assays to identify biomarker signatures of viral hepatitis in order to define unique and common responses for three different acute viral infections of the liver. We performed multianalyte profiling, measuring the concentrations of 182 serum proteins obtained from acute HAV- (18), HBV- (18), and HCV-infected (28) individuals, recruited as part of a hospital-based surveillance program in Cairo, Egypt.

Low DPP4 expression and activity in multiple sclerosis.

Multiple sclerosis (MS) is a prototypic Th1/Th17 chronic autoimmune disease of the central nervous system. Dipeptidyl peptidase 4 (DPP4 or CD26) is a multifunctional molecule involved in autoimmune diseases' pathophysiology. We sought to integrate disparate pieces of data and analyze the plasma levels of sDPP4, DPP activity and DPP4 surface expression on T-cells in 129 MS patients with different clinical forms and 53 healthy controls, across two independent cohorts.

CXCL10 antagonism and plasma sDPPIV correlate with increasing liver disease in chronic HCV genotype 4 infected patients.

Egypt has the highest prevalence of hepatitis C virus infection worldwide. CXCL10 is a potent chemoattractant that directs effector lymphocytes to sites of inflammation. It has been reported that plasma CXCL10 is processed by dipeptidylpeptidase IV (DPPIV) thus leading to the generation of an antagonist form.

Discrimination of agonist and antagonist forms of CXCL10 in biological samples.

The ready access to commercially available multiplex assays and the importance of inflammation in disease pathogenesis has resulted in an abundance of studies aimed at identifying surrogate biomarkers for different clinically important questions. Establishing a link between a biomarker and disease pathogenesis, however, is quite complex, and in some instances this complexity is compounded by post-translational modifications and the use of immunoassays that do not always discriminate between the different forms of the same protein. Herein, we provide a detailed description of an assay system that has been established to discriminate the agonist form of CXCL10 from the NH(2) -terminal truncated form of the molecule generated by dipeptidylpeptidase IV (DPP4) cleavage.

Evidence for an antagonist form of the chemokine CXCL10 in patients chronically infected with HCV.

Chronic infection with hepatitis C virus (HCV) is a major public health problem, with nearly 170 million infected individuals worldwide. Current treatment for chronic infection is a combination of pegylated IFN-α2 and ribavirin (RBV); however, this treatment is effective in fewer than 50% of patients infected with HCV genotype 1 or 4. Recent studies identified the chemokine CXCL10 (also known as IP-10) as an important negative prognostic biomarker.

Circulating plasmacytoid dendritic cells in acutely infected patients with hepatitis C virus genotype 4 are normal in number and phenotype.

The incidence of hepatitis C virus (HCV) genotype 4 infection in Egypt provides a unique opportunity to study the innate immune response to symptomatic acute HCV infection. We investigated whether plasmacytoid dendritic cells (pDCs) are activated as a result of HCV infection. We demonstrate that, even during symptomatic acute infection, circulating pDCs maintained a similar precursor frequency and resting phenotype, compared with pDCs in healthy individuals.

TLR3 deficiency in patients with herpes simplex encephalitis.

Some Toll and Toll-like receptors (TLRs) provide immunity to experimental infections in animal models, but their contribution to host defense in natural ecosystems is unknown. We report a dominant-negative TLR3 allele in otherwise healthy children with herpes simplex virus 1 (HSV-1) encephalitis. TLR3 is expressed in the central nervous system (CNS), where it is required to control HSV-1, which spreads from the epithelium to the CNS via cranial nerves.