An Oral Interleukin-23-Receptor Antagonist Peptide for Plaque Psoriasis.

BACKGROUND: The use of monoclonal antibodies has changed the treatment of several immune-mediated inflammatory diseases, including psoriasis. However, these large proteins must be administered by injection. JNJ-77242113 is a novel, orally administered interleukin-23-receptor antagonist peptide that selectively blocks interleukin-23 signaling and downstream cytokine production. METHODS: In this phase 2 dose-finding trial, we randomly assigned patients with moderate-to-severe plaque psoriasis to receive JNJ-77242113 at a dose of 25 mg once daily, 25 mg twice daily, 50 mg once daily, 100 mg once daily, or 100 mg twice daily or placebo for 16 weeks. The primary end point was a reduction from baseline of at least 75% in the Psoriasis Area and Severity Index (PASI) score (PASI 75 response; PASI scores range from 0 to 72, with higher scores indicating greater extent or severity of psoriasis) at week 16. RESULTS: A total of 255 patients underwent randomization. The mean PASI score at baseline was 19.1. The mean duration of psoriasis was 18.2 years, and 78% of the patients across all the trial groups had previously received systemic treatments. At week 16, the percentages of patients with a PASI 75 response were higher among those in the JNJ-77242113 groups (37%, 51%, 58%, 65%, and 79% in the 25-mg once-daily, 25-mg twice-daily, 50-mg once-daily, 100-mg once-daily, and 100-mg twice-daily groups, respectively) than among those in the placebo group (9%), a finding that showed a significant dose-response relationship (P<0.001). The most common adverse events included coronavirus disease 2019 (in 12% of the patients in the placebo group and in 11% of those across the JNJ-77242113 dose groups) and nasopharyngitis (in 5% and 7%, respectively). The percentages of patients who had at least one adverse event were similar in the combined JNJ-77242113 dose group (52%) and the placebo group (51%). There was no evidence of a dose-related increase in adverse events across the JNJ-77242113 dose groups. CONCLUSIONS: After 16 weeks of once- or twice-daily oral administration, treatment with the interleukin-23-receptor antagonist peptide JNJ-77242113 showed greater efficacy than placebo in patients with moderate-to-severe plaque psoriasis. (Funded by Janssen Research and Development; FRONTIER 1 ClinicalTrials.gov number, NCT05223868.).

Evaluation of dual potentiality of 2,4,5-trisubstituted oxazole derivatives as aquaporin-4 inhibitors and anti-inflammatory agents in lung cells.

Inflammation is a multifaceted "second-line" adaptive defense mechanism triggered by exo/endogenous threating stimuli and inter-communicated by various inflammatory key players. Unresolved or dysregulated inflammation in lungs results in manifestation of diseases and leads to irreparable damage. Aquaporins (AQPs) are a ubiquitously expressed superfamily of intrinsic transmembrane water channel proteins that modulate the fluid homeostasis. In addition to their conventional functions, AQPs have clinical relevance to inflammation prevailing under the infectious conditions of various lung diseases and this proclaims them as appropriate biomarkers to be targeted. Hence an endeavor was undertaken to identify potential ligands to target AQP4 for the treatment of lung diseases. Oxazole being a versatile bio-potent core, a series of 2,4,5-trisubstituted oxazoles 3a-j were synthesized by a Lewis acid mediated reaction of aroylmethylidene malonates with nitriles. In silico studies conducted using the protein data bank (PDB) structure 3gd8 for AQP4 revealed that compound 3a would serve as a suitable candidate to inhibit AQP4 in human lung cells (NCI-H460). Further, in vitro studies demonstrated that compound 3a could effectively inhibit AQP4 and inflammatory cytokines in lung cells and hence it may be considered as a viable drug candidate for the treatment of various lung diseases.

Importance of PLD2 in an IL-23 driven psoriasiform dermatitis model and potential link to human psoriasis.

Phospholipase D2 (PLD2), a major isoform of the PLD family, has been reported to regulate inflammatory responses. Thus far, the relevance of PLD2 in psoriasis, an inflammatory skin disease, has not been explored. In the current study, we examined PLD2 expression in the skin of psoriasis patients and the role of PLD2 in an interleukin (IL)-23-induced mouse model of psoriasiform dermatitis. Both in situ hybridization and bulk RNA sequencing showed PLD2 gene expression is significantly higher in lesional relative to non-lesional skin of psoriasis patients or the skin of healthy subjects. PLD2 expression is also enriched in residual lesions from patients on biologic therapies. Murine in vivo studies showed that PLD2 deficiency significantly reduced psoriasiform inflammation in IL-23-injected ears, as reflected by decreases in ear thickness, expression of defensin beta 4A and the S100 calcium binding protein A7A, macrophage infiltrate, and expression of CXCL10 and IL-6. However, the expression of type 17 cytokines, IL-17A and IL-17F, were not reduced. Dual knockout of PLD1 and PLD2 offered little additional protection compared to PLD2 knockout alone in the IL-23 model. In addition, pharmacological inhibition with a pan-PLD1/PLD2 inhibitor also suppressed IL-23-induced psoriasiform dermatitis. Bone-marrow-derived macrophages from wild type (WT) and PLD2 knockout (KO) mice exhibited little difference in viability and sensitivity to lipopolysaccharide and/or interferon gamma, or resiquimod (R848). PLD2 deficiency did not alter the differentiation and function of Th17 cells in an ex vivo study with splenocytes isolated from WT and PLD2 KO mice. Overall, these data suggest that PLD2 may play a role in the pathophysiology of psoriasis. Reducing macrophage infiltrate and cytokine/chemokine production might contribute to an anti-inflammatory effect observed in PLD2 knockout mice. Further studies are required to better understand the mechanisms by which PLD2 contributes to skin lesions in psoriasis patients and psoriasiform dermatitis models.

Does total hip arthroplasty with high hip centre in dysplasia compromise acetabular bone stock?

BACKGROUND: The placement of uncemented acetabular components during total hip arthroplasty (THA) in Crowe II and Crowe III dysplasia can be at the anatomic or high hip centre position. PURPOSES: Using computerised tomography data, we simulated acetabular cup placement at the anatomic hip centre and the high hip centre positions to assess whether there is a difference between the 2 in terms of bone loss from acetabular reaming and in acetabular coverage by host bone. METHODS: The study population included a consecutive cohort of 19 patients (22 hips) with Crowe II or III dysplasia. 3-dimensional models of the pelvis were created for each patient and digital templating was used to determine the anatomic and high hip centre positions. The coordinates of the digitally templated cup positions were fed into an image processing software to estimate the amount of bone reamed, the cup coverage by host bone and the elevation from tear drop. RESULTS: The mean volume of bone reamed was greater in the high hip centre position as compared to the anatomic position (27.3 ± 11. 4 cm3 vs. 19.4 ± 12.2 cm3, p < 0.0001). The coverage of the acetabular cup by host bone was greater in the high hip centre position (87.3 ± 5.9% vs. 68.3 ± 10%). The mean elevation in the high hip centre group was 13 mm with 3 hips having a breach of the medial wall. CONCLUSIONS: In Crowe II and III dysplasia, placement of acetabular cups at the anatomic hip centre better preserves bone stock as compared to high hip centre placement and should be preferred in young patients requiring THA.

Aquaporin 9 regulates Leydig cell steroidogenesis in diabetes.

Diabetes mellitus induced hyperglycemia increases oxidative stress, which contributes to impairment of male reproductive function. Aquaporins (AQPs) belong to a transmembrane protein superfamily containing 13 isoforms (AQP0-12), differentially expressed in various organs, and play a pivotal role in male reproductive function. In the current study, we investigated the relationship between AQPs and testicular steroidogenesis under hyperglycemia in vivo and in vitro. The effect of high glucose on the role of AQPs in Leydig cell steroidogenesis was analyzed in diabetic rats (in-vivo) and LC540 rat Leydig cells (in vitro) via enzyme assays, quantitative RT-PCR, siRNA knock down and western blotting. AQP 9 was significantly up-regulated in STZ-induced diabetic rat testis and high glucose treated LC540 cells. Further, oxidative stress marker nuclear factor erythroid 2-related factor 2 (Nrf2) expression was decreased with impaired testicular steroidogenesis under hyperglycemia. Knock-down of AQP 9 resulted in increased Nrf2 expression and thus increased testicular steroidogenesis in hyperglycemia. Diabetes-associated hyperglycemia induced oxidative stress is a widely proven cause for diabetes-related male infertility. Our results collectively suggest that AQP 9 impairs testicular steroidogenesis via the regulation of oxidative stress in diabetes.

HLA-DRB1 genes and the expression dynamics of HLA CIITA determine the susceptibility to T2DM.

Type 2 diabetes mellitus (T2DM) is a disease with polygenic inheritance. The expression of major histocompatibility complex class II genes are regulated by several trans-activators. We have studied the expression of HLA-DRB1, RFX, CIITA-P1, PIV transactivators, immunophenotyping of cells, SNPs in CIITA-168 (A/G) and IFN-γ + 874 (T/A) in T2DM patients and controls (n = 201 each). We observed increased frequencies of DRB1*03, DRB1*04 and DRB1*07 and decreased frequencies of DRB1*10, DRB1*14, and DRB1*15 alleles among patients. Significant up-regulations of HLA-DRB1 genes were observed in patients (p < 0.0001). Down-regulated expressions were documented in DRB1*03-homo (p < 0.002) and DRB1*04-homo (p < 0.009) patients. No significant differences were observed for CIITA-P1 expression except DRB1*04-pooled (p < 0.0113). The CIITA-PIV was up-regulated in overall (p < 0.0001), DRB1*03-pooled (p < 0.0006), DRB1*03-hetero (p < 0.0006) and DRB1*03-homo (p < 0.001) T2DM patients. However, significant down-regulations were documented for DRB1*04-pooled (p < 0.040), DRB1*04-hetero (p < 0.060), and DRB1*04-homo (p < 0.027) combinations. Further, significant down-regulations of RFX5 were observed in overall (p < 0.0006), DRB1*04-pooled (p < 0.0022), and DRB1*04-hetero (p < 0.0004) combinations. Immunophenotyping studies revealed significant increase of CD45+ CD14-, CD19+, CD14- and CD8 cells and elevated level of expression of IFN-γ (p < 0.0001) in patients. A significant increase of TT (p < 3.35 × 10-6) and decrease of TA (p < 4.57 × 10-4) genotypes of IFN-γ + 874 (T/A) and an increase of GG (p < 0.001) and decrease of AG (p < 8.24 × 10-5) genotypes of CIITA-168 A/G SNPs were observed. The combinatorial analysis revealed susceptible associations for DRB1*03 + AA, *03 + AG, *03 + GG and *04 + GG and protective associations for DRB1*10 + AG, *10 + GG, *15 + AG, and *14 + GG combinations. Thus, the present study corroborated the effect of differential expressions of promoters of risk alleles in the pathogenesis of T2DM.

Do Fixed or Mobile Bearing Implants Have Better Survivorship in Medial Unicompartmental Knee Arthroplasty? A Study From the Australian Orthopaedic Association National Joint Replacement Registry.

BACKGROUND: During the last 5 years, there has been an increase in the use of unicompartmental knee arthroplasty (UKA) to treat knee osteoarthritis in Australia, and these account for almost 6% of annual knee replacement procedures. However, there is debate as to whether a fixed bearing or a mobile bearing design is best for decreasing revision for loosening and disease progression as well as improving survivorship. Small sample sizes and possible confounding in the studies on the topic may have masked differences between fixed and mobile bearing designs. QUESTIONS/PURPOSES: Using data from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR), we selected the four contemporary designs of medial compartment UKA: mobile bearing, fixed modular, all-polyethylene, and fixed molded metal-backed used for the treatment of osteoarthritis to ask: (1) How do the different designs of unicompartmental knees compare with survivorship as measured by cumulative percentage revision (CPR)? (2) Is there a difference in the revision rate between designs as a function of patient sex or age? (3) Do the reasons for revision differ, and what types of revision procedures are performed when these UKA are revised? METHODS: The AOANJRR longitudinally maintains data on all primary and revision joint arthroplasties, with nearly 100% capture. The study population included all UKA procedures undertaken for osteoarthritis between September 1999 and December 2018. Of 56,628 unicompartmental knees recorded during the study period, 50,380 medial UKA procedures undertaken for osteoarthritis were included in the analysis after exclusion of procedures with unknown bearing types (31 of 56,628), lateral or patellofemoral compartment UKA procedures (5657 of 56,628), and those performed for a primary diagnosis other than osteoarthritis (560 of 56,628). There were 50,380 UKA procedures available for analysis. The study group consisted of 40% (20,208 of 50,380) mobile bearing UKA, 35% (17,822 of 50,380) fixed modular UKA, 23% (11,461 of 50,380) all-polyethylene UKA, and 2% (889 of 50,380) fixed molded metal-backed UKA. There were similar sex proportions and age distributions for each bearing group. The overall mean age of patients was 65 ± 9.4 years, and 55% (27,496 of 50,380) of patients were males. The outcome measure was the CPR, which was defined using Kaplan-Meier estimates of survivorship to describe the time to the first revision. Hazard ratios from Cox proportional hazards models, adjusted for sex and age, were performed to compare the revision rates among groups. The cohort was stratified into age groups of younger than 65 years and 65 years and older to compare revision rates as a function of age. Differences among bearing groups for the major causes and modes of revision were assessed using hazard ratios. RESULTS: At 15 years, fixed modular UKA had a CPR of 16% (95% CI 15% to 17%). In comparison, the CPR was 23% (95% CI 22% to 24%) for mobile bearing UKA, 26% (95% CI 24% to 27%) for all-polyethylene UKA, and 20% (95% CI 16% to 24%) for fixed molded metal-backed UKA. The lower revision rate for fixed modular UKA was seen through the entire period compared with mobile bearing UKA (hazard ratio 1.5 [95% CI 1.4 to 1.6]; p < 0.001) and fixed molded metal-backed UKA (HR 1.3 [95% CI 1.1 to 1.6]; p = 0.003), but it varied with time compared with all-polyethylene UKA. The findings were consistent when stratified by sex or age. Although all-polyethylene UKA had the highest revision rate overall and for patients younger than 65 years, for patients aged 65 years and older, there was no difference between all-polyethylene and mobile bearing UKA. When compared with fixed modular UKA, a higher revision risk for loosening was shown in both mobile bearing UKA (HR 1.7 [95% CI 1.5 to 1.9]; p < 0.001) and all-polyethylene UKA (HR 2.4 [95% CI 2.1 to 2.7]; p < 0.001). The revision risk for disease progression was higher for all-polyethylene UKA at all time points (HR 1.4 [95% CI 1.3 to 1.6]; p < 0.001) and for mobile bearing UKA after 8 years when each were compared with fixed modular UKA (8 to 12 years: HR 1.4 [95% CI 1.2 to 1.7]; p < 0.001; 12 or more years: HR 1.9 [95% CI 1.5 to 2.3]; p < 0.001). The risk of revision to TKA was higher for mobile bearing UKA compared with fixed modular UKA (HR 1.4 [95% CI 1.3 to 1.5]; p < 0.001). CONCLUSION: If UKA is to be considered for the treatment of isolated medial compartment osteoarthritis, the fixed modular UKA bearing has the best survivorship of the current UKA designs. LEVEL OF EVIDENCE: Level III, therapeutic study.

The possible role of sirtuins in male reproduction.

Global influence of male infertility is increasing in recent decades. Proper understanding of genetics, anatomy, physiology and the intricate interrelation of male reproductive system are much needed for explaining the etiology of male infertility; and a detailed study on the epigenetics, indeed, will reveal the molecular mechanism behind its etiology. Sirtuins, the molecular sensors, are NAD+ dependent histone deacetylases and ADP- ribosyl transferases, participate in the chief events of epigenetics. In mammals, sirtuin family comprises seven members (SIRT1-SIRT7), and they all possess a conserved NAD+ binding catalytic domain, termed the sirtuin core domain which is imperative for their activity. Sirtuins exert a pivotal role in cellular homeostasis, energy metabolism, apoptosis, age-related disorders and male reproductive system. However, their exact role in male reproduction is still obscure. This article specifically reviews the role of mammalian sirtuins in male reproductive function, thereby, prompting further research to discover the restorative methods and its implementation in reproductive medicine.

Could aquaporin modulators be employed as prospective drugs for COVID-19 related pulmonary comorbidity?

COVID-19 initially an epidemic caused by SARS-CoV-2 has turned out to be a life- threatening global pandemic with increased morbidity and mortality. The presence of cytokine storm has been linked with the pathogenesis of severe lung injury as evinced in COVID-19. Aquaporins (AQPs) are molecular water channels, facilitating water transport across the cell membrane in response to osmotic gradients. Impairment in alveolar fluid clearance due to altered functional expression of respiratory AQPs highlight their pathophysiological significance in pulmonary edema associated respiratory illness. Therefore, we hypothesize that targeted modulation of AQPs in lungs in the intervening period of time, could diminish the dreadful effects of inflammation- induced comorbidity in COVID-19.

Characterization of Lead Adherence Using Intravascular Ultrasound to Assess Difficulty of Transvenous Lead Extraction.

BACKGROUND: Clinical factors associated with development of intravascular lead adherence (ILA) are unreliable predictors. Because vascular injury in the superior vena cava-right atrium during transvenous lead extraction is more likely to occur in segments with higher degrees of ILA, reliable and accurate assessment of ILA is warranted. We hypothesized that intravascular ultrasound (IVUS) could accurately visualize and quantify ILA and degree of ILA correlates with transvenous lead extraction difficulty. METHODS: Serial imaging of leads occurred before transvenous lead extraction using IVUS. ILA areas were classified as high or low grade. Degree of extraction difficulty was assessed using 2 metrics and correlated with ILA grade. Lead extraction difficulty was calculated for each patient and compared with IVUS findings. RESULTS: One hundred fifty-eight vascular segments in 60 patients were analyzed: 141 (89%) low grade versus 17 (11%) high grade. Median extraction time (low=0 versus high grade=97 seconds, P<0.001) and median laser pulsations delivered (low=0 versus high grade=5852, P<0.001) were significantly higher in high-grade segments. Most patients with low lead extraction difficulty score had low ILA grades. Eighty-six percentage of patients with high lead extraction difficulty score had low IVUS grade, and the degree of transvenous lead extraction difficulty was similar to patients with low IVUS grades and lead extraction difficulty scores. CONCLUSIONS: IVUS is a feasible imaging modality that may be useful in characterizing ILA in the superior vena cava-right atrium region. An ILA grading system using imaging correlates with extraction difficulty. Most patients with clinical factors associated with higher extraction difficulty may exhibit lower ILA and extraction difficulty based on IVUS imaging. Graphic Abstract: A graphic abstract is available for this article.

Role of Aquaporins in Inflammation-a Scientific Curation.

Inflammation is a universal response mechanism existing as inter-communicator of biological systems. Uncontrolled or dysregulated inflammation addresses chronic low-grade effects eventually resulting in multimorbidity. Active solute transport across the membrane establishes varying osmotic gradients. Aquaporins (AQPs) are a class of critical ubiquitously expressed transmembrane proteins that aid in fluid and small solute transport via facilitated diffusion over established osmotic gradients. Numerous significant data features the biological functions of AQPs rendering them as an appropriate biomarker of health and diseases. Besides their physiological role in well-balanced inflammatory responses, it is worth noting the dysregulation of AQPs during any undesirable inflammatory event. Most literature to date clearly sets out AQPs as potential drug targets instigating AQP-based therapies. In light of this conception, the current review provides a compendious overview on the propitious and portentous out-turns of AQPs under inflammation.

Role of Aquaporins in Spermatogenesis and Testicular Steroidogenesis.

The transport of water and several other small molecules across cell membranes is vital in many of the processes underlying reproduction. Fluid transport in cells and tissues inclusive of male reproductive organs are regulated by disparate isoforms of aquaporins (AQPs) in living organisms. Alteration in the expression, function and/or regulation of AQPs leads to some forms of male subfertility and infertility. The emerging role of AQPs in male and female reproductive function has been revealed in recent times. However, the role of AQPs with reference to male reproductive system needs to be explored in greater detail. This review emphasizes the distribution of AQPs and their physiological and pathophysiological role in spermatogenesis and steroidogenesis; and understanding the molecular mechanisms behind AQPs mediated regulation of spermatogenesis and steroidogenesis will help us in developing treatment strategies towards improved reproductive health.

Reentrant para-Hisian ventricular tachycardia eliminated from the noncoronary cusp: Importance of regional anatomy for vantage-point ablation.

We present a rare case of reentrant ventricular tachycardia proven by entrainment maneuvers that was successfully ablated from the noncoronary cusp. The case highlights regional anatomy, pacing maneuvers with multi-modality images from fluoroscopy, intracardiac echo, and electroanatomical mapping.

Persistence of Inflammatory Phenotype in Residual Psoriatic Plaques in Patients on Effective Biologic Therapy.

Many psoriasis patients treated with biologics do not achieve total skin clearance. These patients possess residual plaques despite ongoing biologic treatment. To elucidate mechanisms of plaque persistence despite overall good drug response, we studied 50 subjects: psoriasis patients with residual plaques treated with one of three different biologics, untreated patients, and healthy controls. Skin biopsies from all subjects were characterized using three methods: mRNA expression, histology, and FACS of hematopoietic skin cells. Although all three methods provided evidence of drug effect, gene expression analysis revealed the persistence of key psoriasis pathways in treated plaques, including granulocyte adhesion and diapedesis, T helper type17 activation pathway, and interferon signaling with no novel pathways emerging. Focal decreases in parakeratosis and keratinocyte proliferation and differential reduction in IL-17 producing CD103- T cells, but no change in CD103+ tissue-resident memory T cells were observed. Of note, antitumor necrosis factor increased the interferon signaling pathway already present. Interestingly mast cells were the dominant source of IL-22 in all psoriasis subjects. These data suggest that while subtle differences can be observed in drug-treated plaques, underlying biologic mechanisms are similar to those present in untreated psoriatic lesions.

IL-23 induces regulatory T cell plasticity with implications for inflammatory skin diseases.

Foxp3+ regulatory T cells (Tregs) represent a major fraction of skin resident T cells. Although normally protective, Tregs have been shown to produce pro-inflammatory cytokines in human diseases, including psoriasis. A significant hurdle in the Treg field has been the identification, or development, of model systems to study this Treg plasticity. To overcome this gap, we analyzed skin resident Tregs in a mouse model of IL-23 mediated psoriasiform dermatitis. Our results demonstrate that IL-23 drove the accumulation of Tregs; including a subpopulation that co-expressed RORγt and produced IL-17A. Genesis of this population was attenuated by a RORγt inverse agonist compound and clinically relevant therapeutics. In vitro, IL-23 drove the generation of CD4+Foxp3+RORγt+IL-17A+ cells from Treg cells. Collectively, our data shows that IL-23 drives Treg plasticity by inducing a population of CD4+Foxp3+RORγt+IL-17A+ cells that could play a role in the disease pathogenesis. Through this work, we define an in vitro system and a pre-clinical in vivo mouse model that can be used to further study Treg homeostasis and plasticity in the context of psoriasis.

PAX proteins and their role in pancreas.

Gene regulatory factors that govern the expression of heritable information come in an array of flavors, chiefly with transcription factors, the proteins which bind to regions of specific genes and modulate gene transcription, subsequently altering cellular function. PAX transcription factors are sequence-specific DNA-binding proteins exerting its regulatory activity in many tissues. Notably, three members of the PAX family namely PAX2, PAX4 and PAX6 have emerged as crucial players at multiple steps of pancreatic development and differentiation and also play a pivotal role in the regulation of pancreatic islet hormones synthesis and secretion. Providing a comprehensive outline of these transcription factors and their primordial and divergent roles in the pancreas is far-reaching in contemporary diabetes research. Accordingly, this review furnishes an outline of the role of pancreatic specific PAX regulators in the development of the pancreas and its associated disorders.

Diversity and association of HLA/KIR receptors with type 2 diabetes in South India.

The present study was undertaken to delineate the association(s) of KIR-HLA combination in South Indian Type 2 diabetes mellitus (T2DM) patients. The T2DM patients (n = 343) and healthy controls (n = 309) were genotyped for KIR/HLA ligands by PCR-SSP method. The increased frequency of activatory KIR (aKIR) 2DS2 (OR = 1.91; p < 2.91 × 10-4 ) was observed in patients suggesting a susceptible association. The frequencies of iKIR 2DL2 (OR = 0.38; p < 1.55 × 10-5 ) and aKIRs 2DS1 (OR = 0.60; p < 0.001) and 3DS1 (OR = 0.52; p < 5.83 × 10-5 ) were decreased in patients suggesting protective associations. The C1/C2 combinatorial analysis has revealed an increased frequency of C1+ /C2- in T2DM patients (OR = 1.62; p < 0.014). The KIR "AB" genotype (OR = 2.41; p < 3.87 × 10-5 ) was observed to be higher in patients. However, the "BB" genotype (OR = 0.32; p < 4.71 × 10-7 ) was increased in controls. The KIR motifs, "Tel-B/B" (OR = 1.84; p < 0.007), were observed higher among patients. However, the frequency of "Tel-A/B" motif genotype was decreased in patients (OR = 0.56; p < 3.13 × 10-4 ). The iKIR/HLA combinations such as 2DL2/3 +C1 and 3DL2+A3/A11 were increased in patients (OR = 3.90; p < 7.5 × 10-5 ) suggesting susceptible associations. On the contrary, the aKIR+HLA combinations such as 2DS2+C1, 2DS1+C2 and 3DS1+Bw4 were less frequent in patients (OR = 0.32; p < 4.2 × 10-4 ) suggesting protective associations. Thus, the present study clearly establishes the positive and negative associations of different KIR-HLA receptor combinations with T2DM in South India.

IL-36 receptor antagonistic antibodies inhibit inflammatory responses in preclinical models of psoriasiform dermatitis.

Psoriasis vulgaris (PV) results from activation of IL-23/Th17 immune pathway and is further amplified by cytokines/chemokines from skin cells. Among skin-derived pro-inflammatory cytokines, IL-36 family members are highly upregulated in PV patients and play a critical role in general pustular psoriasis. However, there is limited data showing crosstalk between the IL-23 and IL-36 pathways in PV. Herein, potential attenuation of skin inflammation in the IL-23-induced mouse model of psoriasiform dermatitis by functional inhibition of IL-36 receptor (IL-36R) was interrogated. Anti-mouse IL-36R monoclonal antibodies (mAbs) were generated and validated in vitro by inhibiting IL-36α-induced secretion of CXCL1 from NIH 3T3 cells. Antibody target engagement was demonstrated by inhibition of CXCL1 production in a novel acute model of IL-36α systemic injection in mice. In addition, anti-IL-36R mAbs inhibited tissue inflammation and inflammatory gene expression in an IL-36α ear injection model of psoriasiform dermatitis demonstrating engagement of the target in the ear skin. To elucidate the possible role of IL-36 signalling in IL-23/Th17 pathway, the ability of anti-IL-36R mAbs to inhibit skin inflammation in an IL-23 ear injection model was assessed. Inhibiting the IL-36 pathway resulted in significant attenuation of skin thickening and psoriasis-relevant gene expression. Taken together, these data suggest a role for IL-36 signalling in the IL-23/Th17 signalling axis in PV.