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Guard proteins initiate defense mechanisms upon sensing pathogen-encoded virulence factors. Successful viral pathogens likely inhibit guard protein activity, but these interactions have been largely undefined. Here, we demonstrate that the human pathogen herpes simplex virus 1 (HSV-1) stimulates and inhibits an antiviral pathway initiated by NLRP1, a guard protein that induces inflammasome formation and pyroptotic cell death when activated. Notably, HSV-1 infection of human keratinocytes promotes posttranslational modifications to NLRP1, consistent with MAPK-dependent NLRP1 activation, but does not result in downstream inflammasome formation. We identify infected cell protein 0 (ICP0) as the critical HSV-1 protein that is necessary and sufficient for inhibition of the NLRP1 pathway. Mechanistically, ICP0's cytoplasmic localization and function as an E3 ubiquitin ligase prevents proteasomal degradation of the auto-inhibitory NT-NLRP1 fragment, thereby preventing inflammasome formation. Further, we demonstrate that inhibiting this inflammasome is important for promoting HSV-1 replication. Thus, we have established a mechanism by which HSV-1 overcomes a guard-mediated antiviral defense strategy in humans., (© 2024 Parameswaran et al.)

The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure can lead to development of inflammatory skin lesions. We have previously shown that Langerhans cells (LCs) limit keratinocyte apoptosis and photosensitivity via a disintegrin and metalloprotease 17 (ADAM17)-mediated release of epidermal growth factor receptor (EGFR) ligands and that LC ADAM17 sheddase activity is reduced in lupus. Here, we sought to understand how the lupus skin environment contributes to LC ADAM17 dysfunction and, in the process, differentiate between effects on LC ADAM17 sheddase function, LC ADAM17 expression, and LC numbers. We show through transcriptomic analysis a shared IFN-rich environment in non-lesional skin across human lupus and three murine models: MRL/lpr, B6.Sle1yaa, and imiquimod (IMQ) mice. IFN-I inhibits LC ADAM17 sheddase activity in murine and human LCs, and IFNAR blockade in lupus model mice restores LC ADAM17 sheddase activity, all without consistent effects on LC ADAM17 protein expression or LC numbers. Anti-IFNAR-mediated LC ADAM17 sheddase function restoration is associated with reduced photosensitive responses that are dependent on EGFR signaling and LC ADAM17. Reactive oxygen species (ROS) is a known mediator of ADAM17 activity; we show that UVR-induced LC ROS production is reduced in lupus model mice, restored by anti-IFNAR, and is cytoplasmic in origin. Our findings suggest that IFN-I promotes photosensitivity at least in part by inhibiting UVR-induced LC ADAM17 sheddase function and raise the possibility that anifrolumab ameliorates lupus skin disease in part by restoring this function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a potential mechanism of action for anifrolumab in lupus., Competing Interests: TL, VZ, ES, MD, YC, KV, DO, PC, YL, WS, ST, KO, MR, IR No competing interests declared, AD, PL is an employee of AMPEL BioSolutions, but has no financial conflicts of interest to report, NS was awarded the Lupus Therapeutics: The Clinical Trial Network Infrastructure Grant, received by The Albert Einstein College of Medicine. The author received payment for lectures at the Congress of Clinical Rheumatology East and the Congress of Clinical Rheumatology West. The author has no other competing interests to declare, JL has received the grants F31 NIH GM136144 and T32 NIH GM008539. The author has received stock or stock options from NASDAQ/NYSE Ticker: FULC, ABCL, AVXL, VOR, MRNA, BNTX, SAVA, OCGN, CTMX, BCEL, GE. The author has no other competing interests to declare, WA received support for travel and attending Lupus 21st century meeting in 2021. The author has no other competing interests to declare, JZ received a grant from NIH NIAMS, and consulting fees from Hoth Therapeutics and Pfizer. The author received payment for participation on a Data Safety Monitoring Board/ Advisory Board for Hoth Therapeutics and acts as President elect for PASPCR. The author holds stock options from Hoth Therapeutics, FoxWayne Inc and YouV labs. The author has no other competing interests to declare, JK has received grant support from AbbVie, Akros, Allergan, Amgen, Avillion, Biogen, Botanix, Boehringer Ingelheim, Bristol-Myers Squibb, Exicure, Innovaderm, Incyte, Janssen, Kyowa Kirin, Lilly, Nimbus Lackshmi, Novan, Novartis, PAREXEL, Pfizer, Regeneron, UCB, Vitae Pharmaceuticals. The author received consulting fees from AbbVie, Aclaris, Allergan, Almirall, Amgen, Artax Biopharma, Arena, Aristea, Asana, Aurigene, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Escalier, Galapagos, Janssen, Kyowa Kirin, Lilly, MoonLake Immunotherapeutics, Nimbus, Novartis, Pfizer, Sanofi, Sienna Biopharmaceuticals, Sun Pharma, Target-Derm, UCB, Valeant, Ventyx. The author has no other competing interests to declare, NA has received the following grants: NIAMS AR080436-01, NIAMS R56AR078686-01 and NIH NIAMS 5R01 GRANT AR070234-05. The author received consulting fees from Immunitas, Shennon Bio and Janssen. The author received payment as a lecturer from 23 and me, Cellino and Bristol Meyer Squibb Genomics. They are also a board member of the Society of Investigative Dermatology. The author has no other competing interests to declare, AJ has received grants from the NIH and the VA and consulting fees from Pfizer. The author has no other competing interests to declare, CB The patent number is US10024844B2 and the title of the patent is "Identification of an inhibitor of iRhom1 or an inhibitor of iRhom2", which is also what the patent relates to. Carl Blobel and the Hospital for Special Surgery have identified iRhom2 inhibitors and have co-founded the start-up company SciRhom in Munich to commercialize these inhibitors, TL has received the following grants: NIH R01AI079178, NIH R21 AR081493, Department of Defense W81XWH-21-LRP-IPA, Lupus Research Alliance Lupus Innovation Award grant, Barbara Volcker Center for Women and Rheumatic Diseases grant. She has also received funding support from the St. Giles Foundation and A Lasting Mark Foundation. She has received consulting fees from Pfizer, and has a received payment from Bristol Meyers Squibb for giving a lecture. The author has received payment for attending Lupus 21st Century meeting. The author has no other competing interests to declare, (© 2024, Li, Zyulina, Seltzer et al.)

Inhibition of Janus kinase (JAK) family enzymes is a popular strategy for treating inflammatory and autoimmune skin diseases. In the clinic, small molecule JAK inhibitors show distinct efficacy and safety profiles, likely reflecting variable selectivity for JAK subtypes. Absolute JAK subtype selectivity has not yet been achieved. Here, we rationally design small interfering RNAs (siRNAs) that offer sequence-specific gene silencing of JAK1, narrowing the spectrum of action on JAK-dependent cytokine signaling to maintain efficacy and improve safety. Our fully chemically modified siRNA supports efficient silencing of JAK1 expression in human skin explant and modulation of JAK1-dependent inflammatory signaling. A single injection into mouse skin enables five weeks of duration of effect. In a mouse model of vitiligo, local administration of the JAK1 siRNA significantly reduces skin infiltration of autoreactive CD8 + T cells and prevents epidermal depigmentation. This work establishes a path toward siRNA treatments as a new class of therapeutic modality for inflammatory and autoimmune skin diseases., (© 2023. The Author(s).)

The melanocyte-keratinocyte transplantation procedure (MKTP) treats stable and recalcitrant vitiligo. Despite careful selection of candidates based on clinical stability, the success of the procedure is unpredictable. The aim of our study was to define the immunological profile of stable vitiligo lesions undergoing MKTP and correlate them with clinical outcomes. We included 20 MKTP candidates with vitiligo and a patient with piebaldism as a control. Prior to MKTP, T-cell subsets and chemokines in the recipient skin were measured by flow cytometry and ELISA. During MKTP, melanocytes in the donor skin were quantified by flow cytometry. After MKTP, patients were followed for 12 months and repigmentation was assessed clinically and by ImageJ analysis of clinical photographs. Baseline immunologic biomarkers, duration of clinical stability, and transplanted melanocyte number were correlated to postsurgical repigmentation scores. CD8+ T cells were elevated in 43% of the clinically stable vitiligo lesions. CD8+ T-cell number negatively correlated with postsurgical repigmentation scores (r = -0.635, P = 0.002). Duration of clinical stability, skin chemokines, and transplanted melanocyte number did not influence postsurgical repigmentation. This study demonstrates that CD8+ T-cell number correlates negatively with success of postsurgical repigmentation and can be a biomarker to identify ideal surgical candidates., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Connective tissue diseases (CTDs) are a category of conditions that affect tissues that support and provide structure to the body. These diseases include rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, and sclerosing diseases. CTDs can be caused by dysregulation of inflammatory pathways, specifically an upregulation of interferons and JAK/STAT pathway activation., Areas Covered: While CTDs have historically been treated with broadly immunosuppressant medications such as corticosteroids and disease-modifying antirheumatic drugs (DMARDS), newer and more targeted immunomodulating medications called Janus kinase inhibitors (JAKi) have emerged as potential treatments., Expert Opinion: While most studies regarding JAKi for CTDs have focused on adult populations, pediatric patients with CTDs may also benefit from JAKi therapy. Moreover, the JAK/STAT inhibitor tofacitinib has been approved by the FDA for the treatment of active polyarticular course juvenile idiopathic arthritis. In this review, we have summarized what has been published on the use of JAKi for various pediatric CTDs.

Morphea (localized scleroderma) is a rare autoimmune connective tissue disease with variable clinical presentations, with an annual incidence of 0.4-2.7 cases per 100,000. Morphea occurs most frequently in children aged 2-14 years, and the disease exhibits a female predominance. Insights into morphea pathogenesis are often extrapolated from studies of systemic sclerosis due to their similar skin histopathologic features; however, clinically they are two distinct diseases as evidenced by different demographics, clinical features, disease course and prognosis. An interplay between genetic factors, epigenetic modifications, immune and vascular dysfunction, along with environmental hits are considered as the main contributors to morphea pathogenesis. In this review, we describe potential new therapies for morphea based on both preclinical evidence and ongoing clinical trials. We focus on different classes of therapeutics, including antifibrotic, anti-inflammatory, cellular and gene therapy, and antisenolytic approaches, and how these target different aspects of disease pathogenesis., (© 2021 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

A unique and sudden need for virtual medical visits created by the coronavirus disease 2019 (COVID-19) pandemic has led to an unprecedented expansion of telemedicine across nearly all medical specialties in the United States. In addition to providing essential medical services during the pandemic, telemedicine has the potential to expand health care access to underserved populations by eliminating traditional barriers to care such as transportation needs, distance from specialty providers, and approved time off from work. However, the literature regarding telehealth accessibility for low-income, non-English-speaking, and minority patients remains limited. Through a cross-sectional analysis comparing 2019 clinic visits with 2020 telehealth visits at the UMass Memorial Medical Center, we demonstrate specialty-specific changes in patient demographics, including a younger population, fewer non-English-speaking patients, and a relative preservation of minority, Medicaid, and Medicare patients among telehealth visits in comparison to clinic visits. We also demonstrate that nonsurgical specialties had significantly lower no-show rates and the greatest number of telehealth visits. Overall, our findings highlight the potential shortcomings of telemedicine in servicing non-English-speaking patients, while maintaining that it is an important tool with the potential to improve access to health care, particularly in nonprocedural specialties.

Competing Interests: Competing interests: None declared.

Progressive Macular Hypomelanosis (PMH) is a common but often misdiagnosed disorder of acquired hypopigmentation. An adolescent female presented with irregular, hypopigmented patches ultimately diagnosed as PMH. Complete repigmentation was achieved with narrowband UVB phototherapy, benzoyl peroxide wash, and clindamycin lotion., Competing Interests: Conflict of interest: the authors declare no potential conflict of interests., (©Copyright: the Author(s).)

Cutaneous Lupus Erythematosus (CLE) is a clinically diverse group of autoimmune skin diseases with shared histological features of interface dermatitis and autoantibodies deposited at the dermal-epidermal junction. Various genetic and environmental triggers of CLE promote infiltration of T cells, B cells, neutrophils, antigen presenting cells, and NK cells into lesional skin. In this mini-review, we will discuss the clinical features of CLE, insights into CLE immunopathogenesis, and novel treatment approaches., (Copyright © 2020 Garelli, Refat, Nanaware, Ramirez-Ortiz, Rashighi and Richmond.)

Tissue resident memory T cells (Trm) form in the skin in vitiligo and persist to maintain disease, as white spots often recur rapidly after discontinuing therapy. We and others have recently described melanocyte-specific autoreactive Trm in vitiligo lesions. Here, we characterize the functional relationship between Trm and recirculating memory T cells (Tcm) in our vitiligo mouse model. We found that both Trm and Tcm sensed autoantigen in the skin long after stabilization of disease, producing IFN-γ, CXCL9, and CXCL10. Blockade of Tcm recruitment to the skin with FTY720 or depletion of Tcm with low-dose Thy1.1 antibody reversed disease, indicating that Trm cooperate with Tcm to maintain disease. Taken together, our data provide characterization of skin memory T cells in vitiligo, demonstrate that Trm and Tcm work together during disease, and indicate that targeting their survival or function may provide novel, durable treatment options for patients., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Vitiligo is an autoimmune disease of the skin with limited treatment options; there is an urgent need to identify and validate biomarkers of disease activity to support vitiligo clinical studies., Objective: To investigate potential biomarkers of disease activity directly in the skin of vitiligo subjects and healthy subjects., Methods: Patient skin was sampled via a modified suction-blister technique, allowing for minimally invasive, objective assessment of cytokines and T-cell infiltrates in the interstitial skin fluid. Potential biomarkers were first defined and later validated in separate study groups., Results: In screening and validation, CD8 + T-cell number and C-X-C motif chemokine ligand (CXCL) 9 protein concentration were significantly elevated in active lesional compared to nonlesional skin. CXCL9 protein concentration achieved greater sensitivity and specificity by receiver operating characteristic analysis. Suction blistering also allowed for phenotyping of the T-cell infiltrate, which overwhelmingly expresses C-X-C motif chemokine receptor 3., Limitations: A small number of patients were enrolled for the study, and only a single patient was used to define the treatment response., Conclusion: Measuring CXCL9 directly in the skin might be effective in clinical trials as an early marker of treatment response. Additionally, use of the modified suction-blister technique supports investigation of inflammatory skin diseases using powerful tools like flow cytometry and protein quantification., (Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

The pathogenesis of vitiligo involves interplay between intrinsic and extrinsic melanocyte defects, innate immune inflammation, and T-cell-mediated melanocyte destruction. The goal of treatment is to not only halt disease progression but also promote repigmentation through melanocyte regeneration, proliferation, and migration. Treatment strategies that address all aspects of disease pathogenesis and repigmentation are likely to have greatest efficacy, a strategy that may require combination therapies. Current treatments generally involve nontargeted suppression of autoimmunity, whereas emerging treatments are likely to use a more targeted approach based on in-depth understanding of disease pathogenesis, which may provide higher efficacy with a good safety profile., (Copyright © 2016 Elsevier Inc. All rights reserved.)