Innate Lymphoid Cells in Autoimmune Diseases

Innate lymphoid cells (ILC) are a heterogeneous group of immune cells characterized by lymphoid morphology and cytokine profile similar to T cells but which do not express clonally distributed diverse antigen receptors. These particular cells express transcription factors and cytokines reflecting their similarities to T helper (Th)1, Th2, and Th17 cells and are therefore referred to as ILC1, ILC2, and ILC3. Other members of the ILC subsets include lymphoid tissue inducer (LTi) and regulatory ILC (ILCreg). Natural killer (NK) cells share a common progenitor with ILC and also exhibit a lymphoid phenotype without antigen specificity. ILC are found in low numbers in peripheral blood but are much more abundant at barrier sites such as the skin, liver, airways, lymph nodes, and the gastrointestinal tract. They play an important role in innate immunity due to their capacity to respond rapidly to pathogens through the production of cytokines. Recent evidence has shown that ILC also play a key role in autoimmunity, as alterations in their number or function have been identified in systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Here, we review recent advances in the understanding of the role of ILC in the pathogenesis of autoimmune diseases, with particular emphasis on their role as a potential diagnostic biomarker and as therapeutic targets.

Genome-wide DNA methylome and transcriptome changes induced by inorganic nanoparticles in human kidney cells after chronic exposure

The unique physicochemical properties make inorganic nanoparticles (INPs) an exciting tool in diagnosis and disease management. However, as INPs are relatively difficult to fully degrade and excrete, their unintended accumulation in the tissue might result in adverse health effects. Herein, we provide a methylome–transcriptome framework for chronic effects of INPs, commonly used in biomedical applications, in human kidney TH-1 cells. Renal clearance is one of the most important routes of nanoparticle excretion; therefore, a detailed evaluation of nanoparticle-mediated nephrotoxicity is an important task. Integrated analysis of methylome and transcriptome changes induced by INPs (PEG-AuNPs, Fe3O4NPs, SiO2NPs, and TiO2NPs) revealed significantly deregulated genes with functional classification in immune response, DNA damage, and cancer-related pathways. Although most deregulated genes were unique to individual INPs, a relatively high proportion of them encoded the transcription factors. Interestingly, FOS hypermethylation inversely correlating with gene expression was associated with all INPs exposures. Our study emphasizes the need for a more comprehensive investigation of INPs’ biological safety, especially after chronic exposure. Graphical abstract

GPR120 induces regulatory dendritic cells by inhibiting HK2-dependent glycolysis to alleviate fulminant hepatic failure

Fulminant hepatic failure (FHF) is a potentially fatal liver disease that is associated with intrahepatic infiltration of inflammatory cells. As the receptor of polyunsaturated long chain fatty acids, GPR120 can regulate cell differentiation, proliferation, metabolism, and immune response. However, whether GPR120 is involved in FHF remains unknown. Using Propionibacterium acnes (P. acnes)-primed, LPS-induced FHF in mice, we found that interference with GPR120 activity using pharmacological agonist attenuated the severity of the liver injury and mortality of FHF in mice, while a lack of GPR120 exacerbated the disease. GPR120 activation potently alleviated FHF and led to decreased T helper (Th) 1 cell response and expansion of regulatory T cells (Tregs). Interestingly, GPR120 agonist didn’t directly target T cells, but dramatically induced a distinct population of CD11c+MHC IIlowCD80lowCD86low regulatory DCs in the livers of FHF mice. GPR120 was found to restrict HIF-1α-dependent glycolysis. The augmented HIF-1α stabilization caused by GPR120 antagonism or deletion could be attenuated by the inhibition of ERK or by the activation of AMPK. Through the analysis of the clinical FHF, we further confirmed the activation of GPR120 was negatively associated with the severity in patients. Our findings indicated that GPR120 activation has therapeutic potential in FHF. Strategies to target GPR120 using agonists or free fatty acids (FFAs) may represent a novel approach to FHF treatment.

A COMPARATIVE PROSPECTIVE STUDY OF EFFICACY AND VISUAL OUTCOME OF PHACOEMULSIFICATION AND SICS IN NORTH INDIAN POPULATION IN AND AROUND LUCKNOW.

PURPOSE: To evaluate efcacy and visual outcome of manual small incision cataract surgery (SICS) and phacoemulsication. METHODS: A prospective, interventional, observational, follow up study was conducted on 120 patients with clinically signicant senile cataract undergoing cataract surgery by either SICS or phacoemulsication, at a tertiary eye care centre in Lucknow. The follow up evaluations were carried out at post-operative day st rd th 1, 1 week, 3 week and 6 week. RESULTS: On rst postoperative day, there was signicantly better visual outcome with phacoemulsication than SICS (p = 0.005) with 80% patients in SICS group and 90% patients in phacoemulsication group, th had best corrected visual acuity (BCVA) better than equal to 6/18. However at 6 week, nal visual recovery was similar in both the groups (BCVA 6/18 in 96.7% in SICS group and 100% in phacoemulsication group) with no statistically signicant difference. There was no signicant difference in overall per operative and post operative complications between SICS and phacoemulsication. SICS and phacoemulsication did not show signicant difference in surgery induced astigmatism (SIA) with SIA of 0.733D and 0.775D in SICS and phacoemulsication group respectively. CONCLUSIONS: Phacoemulsication is superior to SICS in terms of early visual rehabilitation. But there is no signicant difference in nal visual outcome and complication rates between the two techniques.

Erythromycin reduces nasal inflammation by inhibiting immunoglobulin production, attenuating mucus secretion, and modulating cytokine expression

Allergic rhinitis (AR) and chronic rhinosinusitis (CRS) share some similar pathological mechanisms. In current study, we intend to investigate the impact of AR on CRS. In addition, we explored the efficacy of erythromycin (EM) treatment on CRS mice with or without AR (CRSwoAR, CRSwAR). Study subjects were divided into control, CRSwoAR, and CRSwAR groups. Experimental mice were divided similarly into control, CRSwoAR, and CRSwAR groups. In addition, CRS mice were treated with EM at 0.75, 7.5, or 75 mg/kg or with dexamethasone (Dex) at 1 mg/kg. In our results, allergy exacerbates inflammation that was evident in nasal histology and cytokine expression both in patients and in mice with CRS. Dex 1 mg/kg, EM 7.5 or 75 mg/kg treatments significantly inhibited serum IgE and IgG2a in CRS mice. EM-treated CRS mice had significantly elevated IL-10 levels and had a reversal of Th-1/Th-2 cytokine expression in nasal-associated lymphoid tissue. MUC5AC expressions were significantly reduced in the 7.5 or 75 mg/kg EM-treated mice compared with untreated mice. EM showed inhibitions on immunoglobulin production and mucus secretion stronger than Dex. We concluded that comorbid AR enhanced inflammation of CRS. EM and Dex treatments showed similar anti-inflammatory effects on CRS but through partly different mechanisms.

887 Repolarization of T cells by AMV564 in patients progressing on checkpoint blockade

BackgroundMDSC produce numerous immune-suppressive factors and are associated with poor outcomes across different cancers. They are frequently elevated in patients experiencing inadequate benefit from checkpoint blockade and there is a crucial need for therapies for this patient population. MDSC are recruited from bone marrow in response to both tumor signaling and T cell activation, and their accumulation in tumors and lymphatics can limit the potential benefits of immunostimulatory therapies. AMV564 is a bivalent T cell engager that selectively depletes MDSC. In a phase 1 study, pharmacodynamic analyses revealed significant depletion of MDSC, T cell activation, expansion of the T cell repertoire and an IFN-gamma-dominant cytokine profile with comparatively limited IL6 induction.1 Monotherapy activity including a confirmed RECIST complete response was observed. The clinical and pharmacodynamic profiles of AMV564 are being further evaluated in specific patient cohorts, including patients progressing on checkpoint blockade.MethodsIn a phase 1b expansion study (NCT04128423), patient cohorts with cancers more likely to include actionable tumor antigens were selected for treatment with AMV564, with most patients representing checkpoint treatment failures. An additional cohort of patients included heterogeneous tumor types stratified by tumor mutation burden (TMB) score from circulating tumor DNA. Pharmacodynamic analyses including direct immunophenotyping (flow cytometry) of T and myeloid cell compartments in peripheral blood were performed on patients treated with AMV564 (15 µg daily for 10 of 21 days by subcutaneous injection).ResultsChanges in myeloid and T cell profiles consistent with the pharmacodynamic signature of AMV564 were observed in patients receiving AMV564 despite one or more prior lines of checkpoint blockade therapy. Notably, both high baseline MDSC and elevated induction of MDSC after T cell activation were apparent (figure 1). Control of MDSC by AMV564 was associated with increases in both effector CD8 and CD4 T cells (figure 2). Extremely elevated levels of regulatory T cells were often observed: after treatment with AMV564, a Th-1-like repolarization of these cells was apparent, often associated with reduction in CD25 (figure 3).Abstract 887 Figure 1Significantly higher induction of M-MDSC is apparent in patients previously receiving checkpoint blockade (CPB) after T cell activation by AMV564.Abstract 887 Figure 2Treatment with AMV564 promotes increases in effector CD8 and CD4 T cells in patients previously treated with CPB (examples shown are Merkel cell carcinoma (MCC) and head and neck squamous cell carcinoma (HNSCC)).Abstract 887 Figure 3Th-1 like repolarization of Treg is apparent in patients previously treated with CPB (MCC, HNSCC examples) after treatment with AMV564 (a). Example CD25 low and T-Bet high cells in HNSCC patient (arrow, b).ConclusionsTreatment with AMV564 yielded substantial reductions in MDSC and favorable polarization of CD8 and CD4 T cells, including Th1-like polarization of Treg. This signature was apparent in patients previously treated with checkpoint inhibitors, despite strong induction of MDSC in response to T cell activation, and high baseline levels (>20%) of Treg.Trial RegistrationNCT04128423ReferencesSmith V, Eckard S, Rettig MP, et al. AMV564, a bivalent, bispecific T-cell engager, depletes myeloid derived suppressor cells and activates T cells in cancer patients. Cancer Res 2020;80(16 Supplement):5699.Ethics ApprovalThis study was approved by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) at each participating institution (including Ohio State University, MD Anderson Cancer Center, Duke University, University of California Los Angeles, Advent Health, Christ Hospital). All participants gave informed consent for samples used to generate pharmacodynamic data. No sensitive of identifiable information is included.

Janus Kinase Inhibitors for the Treatment of Atopic Dermatitis: Focus on Abrocitinib, Baricitinib, and Upadacitinib

Atopic dermatitis (AD) is a clinically heterogenous, inflammatory skin condition with a high impact on patients’ daily activities that remains difficult to treat. The knowledge acquired over the last decade on AD pathophysiology and disease burden led to the development of new targeted therapeutic options that enable clinicians to better manage AD patients. The JAK/STAT signaling pathway modulates several immune pathways (T helper (Th)1, Th2, Th17, and Th22 cells) that have been found to be involved in AD pathogenesis. For this reason, JAK inhibitors emerged as a possible therapy for AD. Baricitinib, upadacitinib, and abrocitinib are the three oral JAK inhibitors already approved or in advanced clinical development for this purpose. The results showed that this drug class is highly effective achieving symptomatic relief (itch control) in the short term, as well as improving disease severity in the short and medium term. However, their efficacy should be balanced with possible side effects, that have been reported in clinical trials. More data on the long-term efficacy and safety, as well as from head-to-head comparisons and from real-world setting will be crucial to position oral JAK inhibitors in the AD therapeutic armamentarium.

Dysregulated expression of miRNAs in immune thrombocytopenia

In recent years the critical role of miRNAs has been established in many diseases, including autoimmune disorders. Immune thrombocytopenia purpura (ITP) is a predominant autoimmune disease, in which aberrant expression of miRNAs has been observed, suggesting that miRNAs are involved in its development. miRNAs could induce an imbalance in the T helper (Th)1/Th2 cell and Th17/Treg cell-related responses. Moreover, they could also cause alterations in Th9 and Th22 cell responses, and activate Tfh (T follicular helper) cell-dependent auto-reactive B cells, thus influencing megakaryogenesis. Herein, we summarize the role of immune-related miRNAs in ITP pathogenesis, and look forward to clinical applications.

Vulvar Lichen Sclerosus from Pathophysiology to Therapeutic Approaches: Evidence and Prospects

Vulvar lichen sclerosus (VLS) is a chronic, distressing, inflammatory disease with an enormous impact on quality of life. Treatment goals are relieving symptoms, reversing signs and preventing anatomical changes. Despite the availability of numerous therapeutic options, treatment outcome may not be entirely satisfactory and a definitive cure does not exist. This may be due to the fact that the exact VLS etiopathogenesis remains unknown. The objectives of this paper were to review the most up-to-date knowledge on VLS etiopathogenesis and to consider the available therapies through the lens of a plausible pathogenetic model. An electronic search on both VLS etiopathogenesis and its treatment was performed using the National Library of Medicine PubMed database. Based on current knowledge, it is conceivable that various, heterogeneous environmental factors acting on a genetic background trigger an autoimmune, Th-1 response, which leads to a chronic inflammatory state. This, in turn, can determine both tissue and micro-vascular injury and activation of signaling pathways involved in fibroblast and collagen metabolism. This pathogenetic sequence may explain the effectiveness of anti-inflammatory treatments, mostly topical corticosteroids, in improving VLS clinical-pathological changes. Further deepening of the disease pathways will presumably allow key mediators to become new therapeutic targets and optimize the available treatments.