Western diet reduces small intestinal intraepithelial lymphocytes via FXR-Interferon pathway.

The prevalence of obesity in the United States has continued to increase over the past several decades. Understanding how diet-induced obesity modulates mucosal immunity is of clinical relevance. We previously showed that consumption of a high fat, high sugar "Western" diet (WD) reduces the density and function of small intestinal Paneth cells, a small intestinal epithelial cell type with innate immune function. We hypothesized that obesity could also result in repressed gut adaptive immunity. Using small intestinal intraepithelial lymphocytes (IEL) as a readout, we found that in non-inflammatory bowel disease (IBD) subjects, high body mass index correlated with reduced IEL density. We recapitulated this in wild type (WT) mice fed with WD. A 4-week WD consumption was able to reduce IEL but not splenic, blood, or bone marrow lymphocytes, and the effect was reversible after another 2 weeks of standard diet (SD) washout. Importantly, WD-associated IEL reduction was not dependent on the presence of gut microbiota, as WD-fed germ-free mice also showed IEL reduction. We further found that WD-mediated Farnesoid X Receptor (FXR) activation in the gut triggered IEL reduction, and this was partially mediated by intestinal phagocytes. Activated FXR signaling stimulated phagocytes to secrete type I IFN, and inhibition of either FXR or type I IFN signaling within the phagocytes prevented WD-mediated IEL loss. Therefore, WD consumption represses both innate and adaptive immunity in the gut. These findings have significant clinical implications in the understanding of how diet modulates mucosal immunity.

Progenitors of distinct lineages shape the diversity of mature type 2 conventional dendritic cells.

Conventional dendritic cells (cDC) are antigen-presenting cells comprising cDC1 and cDC2, responsible for priming naive CD8+ and CD4+ T cells, respectively. Recent studies have unveiled cDC2 heterogeneity and identified various cDC2 progenitors beyond the common DC progenitor (CDP), hinting at distinct cDC2 lineages. By generating Cd300ciCre-hCD2R26tdTomato reporter mice, we identified a bone marrow pro-cDC2 progenitor exclusively generating cDC2 in vitro and in vivo. Single-cell analyses and multiparametric flow cytometry demonstrated that pro-cDC2 encompasses myeloid-derived pre-cDC2 and lymphoid-derived plasmacytoid DC (pDC)-like precursors differentiating into a transcriptionally convergent cDC2 phenotype. Cd300c-traced cDC2 had distinct transcriptomic profiles, phenotypes, and tissue distributions compared with Ms4a3CreR26tdTomato lineage-traced DC3, a monocyte-DC progenitor (MDP)-derived subset that bypasses CDP. Mice with reduced Cd300c-traced cDC2 showed impaired humoral responses to T cell-dependent antigens. We conclude that progenitors of distinct lineages shape the diversity of mature cDC2 across tissues. Thus, ontogenesis may impact tissue immune responses.

Repression of the aryl-hydrocarbon receptor prevents oxidative stress and ferroptosis of intestinal intraepithelial lymphocytes.

The aryl-hydrocarbon receptor (AHR) is a ligand-activated transcription factor that buoys intestinal immune responses. AHR induces its own negative regulator, the AHR repressor (AHRR). Here, we show that AHRR is vital to sustaining intestinal intraepithelial lymphocytes (IELs). AHRR deficiency reduced IEL representation in a cell-intrinsic fashion. Single-cell RNA sequencing revealed an oxidative stress profile in Ahrr-/- IELs. AHRR deficiency unleashed AHR-induced expression of CYP1A1, a monooxygenase that generates reactive oxygen species, increasing redox imbalance, lipid peroxidation, and ferroptosis in Ahrr-/- IELs. Dietary supplementation with selenium or vitamin E to restore redox homeostasis rescued Ahrr-/- IELs. Loss of IELs in Ahrr-/- mice caused susceptibility to Clostridium difficile infection and dextran sodium-sulfate-induced colitis. Inflamed tissue of inflammatory bowel disease patients showed reduced Ahrr expression that may contribute to disease. We conclude that AHR signaling must be tightly regulated to prevent oxidative stress and ferroptosis of IELs and to preserve intestinal immune responses.

SLC7A8 is a key amino acids supplier for the metabolic programs that sustain homeostasis and activation of type 2 innate lymphoid cells.

Group 2 innate lymphoid cells (ILC2) are innate counterparts of T helper 2 (Th2) cells that maintain tissue homeostasis and respond to injuries through rapid interleukin (IL)-5 and IL-13 secretion. ILC2s depend on availability of arginine and branched-chain amino acids for sustaining cellular fitness, proliferation, and cytokine secretion in both steady state and upon activation. However, the contribution of amino acid transporters to ILC2 functions is not known. Here, we found that ILC2s selectively express Slc7a8, encoding a transporter for arginine and large amino acids. Slc7a8 was expressed in ILC2s in a tissue-specific manner in steady state and was further increased upon activation. Genetic ablation of Slc7a8 in lymphocytes reduced the frequency of ILC2s, suppressed IL-5 and IL-13 production upon stimulation, and impaired type 2 immune responses to helminth infection. Consistent with this, Slc7a8-deficient ILC2s also failed to induce cytokine production and recruit eosinophils in a model of allergic lung inflammation. Mechanistically, reduced amino acid availability due to Slc7a8 deficiency led to compromised mitochondrial oxidative phosphorylation, as well as impaired activation of mammalian target of rapamycin and c-Myc signaling pathways. These findings identify Slc7a8 as a key supplier of amino acids for the metabolic programs underpinning fitness and activation of ILC2s.

The aryl hydrocarbon receptor instructs the immunomodulatory profile of a subset of Clec4a4+ eosinophils unique to the small intestine.

C-type lectin domain family 4, member a4 (Clec4a4) is a C-type lectin inhibitory receptor specific for glycans thought to be exclusively expressed on murine CD8α− conventional dendritic cells. Using newly generated Clec4a4-mCherry knock-in mice, we identify a subset of Clec4a4-expressing eosinophils uniquely localized in the small intestine lamina propria. Clec4a4+ eosinophils evinced an immunomodulatory signature, whereas Clec4a4− eosinophils manifested a proinflammatory profile. Clec4a4+ eosinophils expressed high levels of aryl hydrocarbon receptor (Ahr), which drove the expression of Clec4a4 as well as other immunomodulatory features, such as PD-L1. The abundance of Clec4a4+ eosinophils was dependent on dietary AHR ligands, increased with aging, and declined in inflammatory conditions. Mice lacking AHR in eosinophils expanded innate lymphoid cells of type 2 and cleared Nippostrongylus brasiliensis infection more effectively than did wild-type mice. These results highlight the heterogeneity of eosinophils in response to tissue cues and identify a unique AHR-dependent subset of eosinophils in the small intestine with an immunomodulatory profile.

Comparison of Hematological and Biochemical Parameters of SARS-CoV-2-Positive and -Negative Neonates of COVID-19 Mothers in a COVID-19 Hospital, Odisha State.

Introduction Data are scarce on the hematological and biochemical changes caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in neonates. This study aimed to compare hematological and biochemical parameters in SARS-CoV-2-positive neonates with healthy neonates born to mothers diagnosed with coronavirus disease 2019 (COVID-19) and assess disease severity in both groups. Methodology  This prospective observational study was conducted at a COVID-19 hospital at Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India, from May 1 to November 30, 2020. Forty-eight babies, including 39 inborn and nine outborn, were enrolled in the study after their parents provided written informed consent. Neonates were diagnosed with COVID-19 via nasopharyngeal real-time reverse transcription-polymerase chain reaction testing. The hematological and biochemical parameters of these 48 neonates were recorded and analyzed. Results  SARS-CoV-2-infected neonates had lower hemoglobin, neutrophil to lymphocyte ratio, total white blood cell count, and absolute neutrophil count compared to noninfected babies (p<0.05). All SARS-CoV-2-infected neonates had serum transaminase levels and renal function tests within reference ranges. We saw no significant differences in hematological and biochemical parameters among asymptomatic SARS-CoV-2-infected and noninfected neonates.  Conclusions Hematological and biochemical parameters between asymptomatic SARS-CoV-2-infected and non-infected neonates were similar. The blood count abnormalities found in SARS-CoV-2-infected neonates could be due to other associated neonatal comorbidities. According to our results, asymptomatic SARS-CoV-2-infected newborns need close monitoring rather than a battery of investigation.

Clinical Outcome of Neonates Born to SARS-CoV-2 Positive Mothers in India: A Systematic Review and Meta-Analysis.

During the SARS-CoV-2 pandemic, India accounted for 10-50% of cases reported across the world. Perinatal care from a developing country during this period has its own importance. This study was conducted to evaluate the health outcome of neonates born to SARS-CoV-2 positive mothers in India from the published literature by a systematic review and meta-analysis. Articles reporting neonates born from SARS-CoV-2 confirmed mothers in India, published in PubMed, Scopus®, and Embase® databases, were analyzed. After registration with the International Prospective Register of Systematic Reviews (PROSPERO), the study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The primary outcomes were the mode of delivery, perinatal asphyxia, preterm birth, breastfeeding, neonatal mortality, SARS-CoV-2 infectivity among neonates of SARS-CoV-2 mothers. The pooled rate was expressed with a 95% confidence interval. Heterogeneity and study level effect size were assessed using I² statistics and DerSimonian and Laird random effect method of meta-analysis. Data analysis was made by Stata 15.1 (StataCorp LLC, College Station, Texas, USA). Total 3,551 neonates born from 3,542 SARS-CoV-2 positive mothers were included from 14 studies (four prospective and 10 retrospective studies). The pooled rates of premature birth, Caesarean delivery, breastfeeding, and neonatal mortality were 18.89%, 55.89%, 67.79%, respectively, with 12.64/1000 live births. SARS-CoV-2 positivity rate was 5.28%; 11.76% were symptomatic, and five (1.7%) died from 281 SARS-CoV-2 positive neonates. There was an increase in the number of Caesarean delivery, premature birth, and lower mortality among neonates born to SARS-CoV-2 positive mothers compared to the Indian neonatal database. Around five percent of neonates delivered to SARS-CoV-2 positive mothers were infected, and the majority of them had good clinical outcomes.

Nonfermenting, Gram-Negative Bacilli Causing Neonatal Sepsis in Odisha, India: Four-Year Surveillance.

Introduction In India, blood culture-positive sepsis results in mortality in 33%-35% of affected neonates. Nonfermenting Gram-negative bacilli (NFGNB), particularly Acinetobacter baumannii  and Burkholderia   cepacia commonly cause hospital-acquired infection. Materials and methods We performed a subgroup analysis as part of a prospective study conducted in a neonatal intensive care unit in a tertiary care hospital in Odisha, India, between January 2017 and December 2020. Neonates with blood culture-positive sepsis caused by NFGNB were enrolled in this study. Demographic characteristics of the neonates, clinical features of sepsis, complications, need for supportive care, and blood culture sensitivity patterns were recorded and analyzed. Results A total of 168 organisms were isolated in blood cultures during our study period, of which 48 (29%) were NFGNB species. Among these 48 species, A.  baumannii  (37.5%) and B. cepacia (33.3%) were the most common NFGNB in our study. Neonates with sepsis commonly exhibited feeding intolerance (64.5%), circulatory insufficiency that necessitated vasopressor treatment (54.1%), disseminated intravascular coagulopathy (35.4%), seizures (33.3%), and the need for respiratory support (56.2%). NFGNB were multidrug-resistant (MDR) in 70.8% of cases, and 93.7% of B. cepacia and 55.5% of A.   baumanni i were MDR. Conclusions A. baumannii  and B. cepacia are NFGNB commonly isolated in neonatal cases of blood culture-positive sepsis. The prevalence of MDR NFGNB sepsis is gradually increasing, which poses a threat to neonates. Strict aseptic precautions and antibiotic stewardship are thus mandatory in perinatal practice.

A Comparison Between Transcutaneous Bilirubin and Total Serum Bilirubin Levels for the Management of Jaundice in Preterm Neonates by Bland-Altman Plot.

Objective To compare the bilirubin levels measured by transcutaneous bilirubinometer and serum samples for the management of jaundice in preterm neonates. Methods The study was a prospective comparative observational study conducted in a tertiary care neonatal unit of Odisha from January 2019 to June 2020. All inborn and outborn neonates with a gestational age of 280/7 weeks to 366/7 weeks with the clinical diagnosis of neonatal jaundice were included in the study. Transcutaneous bilirubin (TcB) was estimated by Dragger jaundice meter JM-105 and simultaneously venous blood and total serum bilirubin levels (TSB) were measured by diazonium method. The comparison between TcB and TSB values was analyzed by direct linear correlation in scatter plot and Bland-Altman plot. Results A total of 167 preterm neonates (66, 28-336/7 and 111, 34-366/7), with a mean gestational age 33.55 ±2.36 weeks and a mean birth weight of 1960 ± 613 grams, were analyzed. The mean TSB and TcB levels were 12.99 ± 3.47 mg/dl (min-max 4.9-18.3 mg/dl) and 14.156 ± 4.71 mg/dl (min-max 4-20.1 mg/dL), respectively. The TcB is excellently correlated with TSB with a correlation coefficient of r =0.948, p ≤0.001. The bias difference between TcB and TSB is -1.16 (95% CI: 2.35, -4.6) mg/dl. The correlation coefficients between 28-336/7 weeks gestational age groups (r = 0.944) and 34-366/7gestational age (r = 0.950) were similar. Conclusion TcB is well correlated with TSB level in preterm neonates. Hence, TcB can be used for the guidance of management in these neonates.

The Utility of the Neutrophil-Lymphocyte Ratio as an Early Diagnostic Marker in Neonatal Sepsis.

Aim To find the diagnostic utility of the neutrophil to lymphocyte ratio (NLR) in the early diagnosis of neonatal sepsis. Methodology The case records of all blood culture-positive septic neonates admitted from January 2018 to December 2018 were reviewed. Total leucocyte count, absolute neutrophil count, absolute lymphocyte counts, NLR, and C-reactive protein (CRP) of septic neonates were compared with gestational age-matched nonseptic neonates by an unpaired t-test. The diagnostic performance of NLR and CRP was analyzed by receiver operating characteristic (ROC) analysis. Result A total of 41 blood culture-positive neonates and 52 nonseptic neonates were enrolled in this study. There was no significant difference in the total leucocyte count and absolute neutrophil counts of septic and nonseptic neonates. The mean absolute lymphocyte count of septic neonates (2795±1424/cumm) was significantly lower than that of nonseptic neonates (4449±1794/cumm; p=<0.001). The mean NLR of septic neonates (3.88±1.78) was significantly higher as compared to nonseptic (2.3404 ±1.98) neonates (p=0.045). For the diagnosis of sepsis, NLR at cutoff >1.7 had a sensitivity and specificity of 68.3% and 46.2%, respectively; CRP at cutoff >6 mg/dl had sensitivity and specificity of 78.05% and 92.31%, respectively. In the ROC analysis, the area under the curve (AUC) for CRP and NLR for the diagnosis of neonatal sepsis was 0.918 (p=<0.001) and 0.623 (p=0.042), respectively. Conclusion Blood culture-positive septic neonates had significantly higher NLR as compared to nonseptic neonates. However, when compared to CRP, NLR was not found to be a better predictor of sepsis in our study.

TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy.

Checkpoint immunotherapy unleashes T cell control of tumors, but is undermined by immunosuppressive myeloid cells. TREM2 is a myeloid receptor that transmits intracellular signals that sustain microglial responses during Alzheimer's disease. TREM2 is also expressed by tumor-infiltrating macrophages. Here, we found that Trem2-/- mice are more resistant to growth of various cancers than wild-type mice and are more responsive to anti-PD-1 immunotherapy. Furthermore, treatment with anti-TREM2 mAb curbed tumor growth and fostered regression when combined with anti-PD-1. scRNA-seq revealed that both TREM2 deletion and anti-TREM2 are associated with scant MRC1+ and CX3CR1+ macrophages in the tumor infiltrate, paralleled by expansion of myeloid subsets expressing immunostimulatory molecules that promote improved T cell responses. TREM2 was expressed in tumor macrophages in over 200 human cancer cases and inversely correlated with prolonged survival for two types of cancer. Thus, TREM2 might be targeted to modify tumor myeloid infiltrates and augment checkpoint immunotherapy.

Innate Lymphoid Cells in Mucosal Immunity.

Innate lymphoid cells (ILCs) are innate counterparts of T cells that contribute to immune responses by secreting effector cytokines and regulating the functions of other innate and adaptive immune cells. ILCs carry out some unique functions but share some tasks with T cells. ILCs are present in lymphoid and non-lymphoid organs and are particularly abundant at the mucosal barriers, where they are exposed to allergens, commensal microbes, and pathogens. The impact of ILCs in mucosal immune responses has been extensively investigated in the gastrointestinal and respiratory tracts, as well as in the oral cavity. Here we review the state-of-the-art knowledge of ILC functions in infections, allergy and autoimmune disorders of the mucosal barriers.

Self-reactive IgG4 antibodies are associated with blocking of pathology in human lymphatic filariasis.

Lymphatic filariasis, a chronic disfiguring disease exhibits complex pathology. Based on different clinical manifestations, infected individuals are categorized into asymptomatic-carriers and chronic-patients. The mechanism behind differential clinical outcomes remains unclear. Roles of filaria-specific B cell responses in filariasis have been documented, whereas the contribution of B1 cell response and poly-specific IgG and IgA in the context of clinical filariasis is not deciphered. In this study, we measured the poly-specific IgG and IgA levels in different clinical categories of filariasis. Asymptomatic-carriers exhibited increased IgG4 antibodies against both filarial-antigens as well as auto-antigens compared to other clinical categories, although IgG against these auto-antigens remained lower. IgA levels against both filarial and auto-antigens were decreased in asymptomatic-carriers. A positive correlation between anti-filarial IgG4 and IgG4 against auto-antigens were observed, suggesting the synergistic role of poly-specific natural IgG4 with anti-filarial IgG4 in blocking the pathogenesis in asymptomatic microfilarial cases.

Novel Chitohexaose Analog Protects Young and Aged mice from CLP Induced Polymicrobial Sepsis.

In Gram-negative bacterial sepsis, production of excess pro-inflammatory cytokines results in hyperinflammation and tissue injury. Anti-inflammatory cytokines such as IL-10 inhibit inflammation and enhance tissue healing. Here, we report a novel approach to treat septicemia associated with intra-abdominal infection in a murine model by delicately balancing pro- and anti-inflammatory cytokines. A novel oligosaccharide compound AVR-25 selectively binds to the TLR4 protein (IC50 = 0.15 µM) in human peripheral blood monocytes and stimulates IL-10 production. Following the cecal ligation and puncture (CLP) procedure, intravenous dosing of AVR-25 (10 mg/kg, 6-12 h post-CLP) alone and in combination with antibiotic imipenem protected both young adult (10-12 week old) and aged (16-18 month old) mice against polymicrobial infection, organ dysfunction, and death. Proinflammatory cytokines (TNF-α, MIP-1, i-NOS) were decreased significantly and restoration of tissue damage was observed in all organs. A decrease in serum C-reactive protein (CRP) and bacterial colony forming unit (CFU) confirmed improved bacterial clearance. Together, these findings demonstrate the therapeutic ability of AVR-25 to mitigate the storm of inflammation and minimize tissue injury with high potential for adjunctive therapy in intra-abdominal sepsis.

Innate lymphoid cells: A potential link between microbiota and immune responses against cancer.

The adaptive immune system plays a crucial role in anti-tumor surveillance. Enhancement of T cell responses through checkpoint blockade has become a major therapeutic avenue of intervention for several tumors. Because it shapes immune responses and regulates their amplitude and duration, the microbiota has a substantial impact on anti-tumor immunity. Innate lymphoid cells (ILCs) comprise a heterogeneous population of lymphocytes devoid of antigen-specific receptors that mirror T helper cells in their ability to secrete cytokines that activate immune responses. Ongoing studies suggest that ILCs contribute to anti-tumor responses. Moreover, since ILCs are present at barrier surfaces, they are stimulated by the microbiota and, reciprocally, influence the composition of the microbiota by regulating the surface barrier microenvironment. Thus, ILC-microbiota cross-talk may in part underpin the effects of the microbiota on anti-tumor responses. In this article, we review current evidence linking ILCs to cancer and discuss the potential impact of ILC-microbiota cross-talk in anti-tumor immune responses.

Anti-filarial immunity blocks parasite development and plays a protective role.

Lymphatic filariasis is a complex parasitic disease having a spectrum of clinical parameters which are critical in deciding the severity of the pathogenesis. Individuals residing in the endemic areas are categorized into different clinical groups such as: EC (endemic controls-free of disease and infection), AS (asymptomatic carriers- free of disease but carries both antigens and microfilaria (Mf) in circulation), CR (cryptic-free of disease and Mf but having circulatory antigen) and CH (chronic-having manifestations of elephantiasis and hydrocele). The immune response to the parasitic infection is well studied, whereas the protective mechanism explaining the fate of antigenemia and filaremia between AS and CR group remains unexplained. Increased anti-Mf antibodies have been implicated for Mf clearance in experimental infection models whereas its role in clinical filariasis is not known. Here, we followed up two groups of 24 and 33 CR cases for 18 and 36 months respectively and analyzed both the clinical parameters and the anti-filarial antibody response. The humoral response to both whole filarial antigen and Mf antigens as well as recombinant active parasitic antigens was significantly higher in CR cases than AS individuals, whereas the clinical parameters remain unchanged. This study made insights into the protective immune mechanism responsible for the clearance of Mf from circulation in CR individuals.

Galectin-9 inhibits TLR7-mediated autoimmunity in murine lupus models.

Uncontrolled secretion of type I IFN, as the result of endosomal TLR (i.e., TLR7 and TLR9) signaling in plasmacytoid DCs (pDCs), and abnormal production of autoantibodies by B cells are critical for systemic lupus erythematosus (SLE) pathogenesis. The importance of galectin-9 (Gal-9) in regulating various autoimmune diseases, including lupus, has been demonstrated. However, the precise mechanism by which Gal-9 mediates this effect remains unclear. Here, using spontaneous murine models of lupus (i.e., BXSB/MpJ and NZB/W F1 mice), we demonstrate that administration of Gal-9 results in reduced TLR7-mediated autoimmune manifestations. While investigating the mechanism underlying this phenomenon, we observed that Gal-9 inhibits the phenotypic maturation of pDCs and B cells and abrogates their ability to mount cytokine responses to TLR7/TLR9 ligands. Importantly, immunocomplex-mediated (IC-mediated) and neutrophil extracellular trap-mediated (NET-mediated) pDC activation was inhibited by Gal-9. Additionally, the mTOR/p70S6K pathway, which is recruited by both pDCs and B cells for TLR-mediated IFN secretion and autoantibody generation, respectively, was attenuated. Gal-9 was found to exert its inhibitory effect on both the cells by interacting with CD44.

Pathogenic mechanisms of IgE-mediated inflammation in self-destructive autoimmune responses.

Autoantibodies of the IgG subclass are pathogenic in a number of autoimmune disorders such as systemic lupus erythomatosus. The presence of circulating IgE autoantibodies in autoimmune patients has also been known for almost 40 years. Despite their role in allergies, IgE autoantibodies are not associated with a higher rate of atopy in these patients. However, recently they have been recognized as active drivers of autoimmunity through mechanisms involving the secretion of Type I interferons by plasmacytoid dendritic cells (pDC), the recruitment of basophils to lymph nodes, and the activation of adaptive immune responses through B and T cells. Here, we will review the formation, prevalence, affinity, and roles of the IgE autoantibodies that have been described in autoimmunity. We also present novel evidence supporting that triggering of IgE receptors in pDC induces LC3-associated phagocytosis, a cellular process also known as LAP that is associated with interferon responses. The activation of pDC with immune complexes formed by DNA-specific IgE antibodies also induce potent B-cell differentiation and plasma cell formation, which further define IgE's role in autoimmune humoral responses.

Plasmacytoid dendritic cells in autoimmunity.

Plasmacytoid dendritic cells (pDC) is a unique cell population that produces large amounts of type I interferon upon recognition of nucleic acids placing them at the crossroad of both innate and adaptive immunity. Their ability to produce interferon makes them central to anti-viral responses. They are also responsive to circulating autoantibodies bound to nuclear antigens and in that scenario the release of interferons initiate self-directed immune responses. There are now a growing number of autoimmune disorders where unabated activation of pDC is suspected to be pathogenic. Here, we discuss the different mechanisms responsible for breaking tolerance to self-nucleic acids by pDC, including the novel role of IgE autoantibodies in systemic lupus erythematosus. We also summarized the recent progress on therapies undergoing clinical testing that target either pDC or type I interferons.

Chitohexaose activates macrophages by alternate pathway through TLR4 and blocks endotoxemia.

Sepsis is a consequence of systemic bacterial infections leading to hyper activation of immune cells by bacterial products resulting in enhanced release of mediators of inflammation. Endotoxin (LPS) is a major component of the outer membrane of Gram negative bacteria and a critical factor in pathogenesis of sepsis. Development of antagonists that inhibit the storm of inflammatory molecules by blocking Toll like receptors (TLR) has been the main stay of research efforts. We report here that a filarial glycoprotein binds to murine macrophages and human monocytes through TLR4 and activates them through alternate pathway and in the process inhibits LPS mediated classical activation which leads to inflammation associated with endotoxemia. The active component of the nematode glycoprotein mediating alternate activation of macrophages was found to be a carbohydrate residue, Chitohexaose. Murine macrophages and human monocytes up regulated Arginase-1 and released high levels of IL-10 when incubated with chitohexaose. Macrophages of C3H/HeJ mice (non-responsive to LPS) failed to get activated by chitohexaose suggesting that a functional TLR4 is critical for alternate activation of macrophages also. Chitohexaose inhibited LPS induced production of inflammatory molecules TNF-α, IL-1ß and IL-6 by macropahges in vitro and in vivo in mice. Intraperitoneal injection of chitohexaose completely protected mice against endotoxemia when challenged with a lethal dose of LPS. Furthermore, Chitohexaose was found to reverse LPS induced endotoxemia in mice even 6/24/48 hrs after its onset. Monocytes of subjects with active filarial infection displayed characteristic alternate activation markers and were refractory to LPS mediated inflammatory activation suggesting an interesting possibility of subjects with filarial infections being less prone to develop of endotoxemia. These observations that innate activation of alternate pathway of macrophages by chtx through TLR4 has offered novel opportunities to cell biologists to study two mutually exclusive activation pathways of macrophages being mediated through a single receptor.