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Despite the central role of IFN-γ in vitiligo pathogenesis, systemic IFN-γ neutralization is an impractical treatment option owing to strong immunosuppression. However, most patients with vitiligo present with20% affected body surface area, which provides an opportunity for localized treatments that avoid systemic side effects. After identifying keratinocytes as key cells that amplify IFN-γ signaling during vitiligo, we hypothesized that tethering an IFN-γ‒neutralizing antibody to keratinocytes would limit anti‒IFN-γ effects on the treated skin for the localized treatment. To that end, we developed a bispecific antibody capable of blocking IFN-γ signaling while binding to desmoglein expressed by keratinocytes. We characterized the effect of the bispecific antibody in vitro, ex vivo, and in a mouse model of vitiligo. Single-photon emission computed tomography/computed tomography biodistribution and serum assays after local footpad injection revealed that the bispecific antibody had improved skin retention, faster elimination from the blood, and less systemic IFN-γ inhibition than the nontethered version. Furthermore, the bispecific antibody conferred localized protection almost exclusively to the treated footpad during vitiligo, which was not possible by local injection of the nontethered anti‒IFN-γ antibody. Thus, keratinocyte tethering proved effective while significantly diminishing the off-tissue effects of IFN-γ blockade, offering a safer treatment strategy for localized skin diseases, including vitiligo.

Aberrant activation of interferon (IFN)-γ signaling plays a key role in several autoimmune skin diseases, including lupus erythematosus, alopecia areata, vitiligo, and lichen planus. Here, we identify fully chemically modified small interfering RNAs (siRNAs) that silence the ligand binding chain of the IFN-γ receptor (IFNGR1), for the modulation of IFN-γ signaling. Conjugating these siRNAs to docosanoic acid (DCA) enables productive delivery to all major skin cell types local to the injection site, with a single dose of injection supporting effective IFNGR1 protein reduction for at least 1 month in mice. In an ex vivo model of IFN-γ signaling, DCA-siRNA efficiently inhibits the induction of IFN-γ-inducible chemokines, CXCL9 and CXCL10, in skin biopsies from the injection site. Our data demonstrate that DCA-siRNAs can be engineered for functional gene silencing in skin and establish a path toward siRNA treatment of autoimmune skin diseases.

The accrual of cytosolic DNA leads to transcription of type I IFNs, proteolytic maturation of the IL-1 family of cytokines, and pyroptotic cell death. Caspase-1 cleaves pro-IL1β to generate mature bioactive cytokine and gasdermin D which facilitates IL-1 release and pyroptotic cell death. Absent in melanoma-2 ( AIM2 ) is a sensor of dsDNA leading to caspase-1 activation, although in human monocytes, cGAS-STING acting upstream of NLRP3 mediates the dsDNA-activated inflammasome response. In healthy human keratinocytes, AIM2 is not expressed yet caspase-1 is activated by the synthetic dsDNA mimetic poly(dA:dT). Here, we show that this response is not mediated by either AIM2 or the cGAS-STING-NLRP3 pathway and is instead dependent on NLRP1. Poly(dA:dT) is unique in its ability to activate NLRP1, as conventional linear dsDNAs fail to elicit NLRP1 activation. DsRNA was recently shown to activate NLRP1 and prior work has shown that poly(dA:dT) is transcribed into an RNA intermediate that stimulates the RNA sensor RIG-I. However, poly(dA:dT)-dependent RNA intermediates are insufficient to activate NLRP1. Instead, poly(dA:dT) results in oxidative nucleic acid damage and cellular stress, events which activate MAP3 kinases including ZAKα that converge on p38 to activate NLRP1. Collectively, this work defines a new activator of NLRP1, broadening our understanding of sensors that recognize poly(dA:dT) and advances the understanding of the immunostimulatory potential of this potent adjuvant.

Vitiligo is a chronic inflammatory autoimmune disease that targets melanocytes, causing skin de-pigmentation. A cream formulation of the Janus kinase (JAK) 1/JAK2 inhibitor, ruxolitinib demonstrated substantial re-pigmentation in a phase 2 study in adults with vitiligo. In two multinational, randomized, double-blind, vehicle-controlled phase 3 studies of adults and adolescents with vitiligo (TRuE-V1, NCT04052425; TRuE-V2, NCT04057573), ruxolitinib cream was superior to vehicle at Week 24 in the primary and all key secondary endpoints. Pooled results on achievement of ≥ 50% improvement in the Vitiligo Area Scoring Index (VASI50) by body region in TRuE-V1/TRuE-V2 were analysed and are reported herein. Patients ≥ 12 years old with nonsegmental vitiligo (NSV) with de-pigmentation covering ≤ 10% total body surface area, including a total VASI (T-VASI) score ≥ 3, were eligible for enrolment. Patients were randomized 2 : 1 to twice-daily 1·5% ruxolitinib cream or vehicle for 24 weeks, after which all patients could apply twice-daily 1·5% ruxolitinib cream through Week 52 (open-label extension). The percentage of patients achieving VASI50 was calculated for each body region [head and neck (not including face), hands, upper extremities, trunk (including genitals), lower extremities, feet] and total body (excluding face). In total, 674 patients were randomized in the TRuE-V studies (ruxolitinib cream, n = 450; vehicle, n = 224); 661 patients were included in the efficacy analysis (1 site excluded for data quality) and 569 continued in the open-label extension (ruxolitinib cream from Day 1, n = 385; crossover from vehicle, n = 184). At Week 12, more patients who applied 1·5% ruxolitinib cream vs. vehicle achieved VASI50 in the head and neck (28·3% vs. 19·8%), upper extremities (14·1% vs. 11·0%), trunk (15·5% vs. 12·9%) and lower extremities (15·1% vs. 10·9%). At Week 24, more patients who applied 1·5% ruxolitinib cream vs. vehicle achieved VASI50 regardless of body region [head and neck, 45·3% vs. 23·8%; hands, 24·9% vs. 14·4%; upper extremities, 33·2% vs. 8·2%; trunk, 26·4% vs. 12·3%; lower extremities, 29·5% vs. 12·2%; feet, 18·5% vs. 12·5%; total body (excluding face), 20·8% vs. 6·9%]. Similarly at Week 52 more patients who applied ruxolitinib cream from Day 1 achieved VASI50 than those who switched over from vehicle after Week 24 (head and neck, 68·1% vs. 51·0%; hands, 38·2% vs. 29·2%; upper extremities, 56·7% vs. 34·9%; trunk, 48·4% vs. 25·4%; lower extremities, 54·5% vs. 32·3%; feet, 29·3% vs. 22·5%; total body [excluding face], 47·7% vs. 23·3%). Attainment of VASI50 at Week 52 among crossover patients (i.e. after 28 weeks of ruxolitinib cream) was consistent with Week 24 data in patients who applied ruxolitinib cream from Day 1. Adolescents and adults with NSV applying ruxolitinib cream achieved VASI50 in higher percentages compared with vehicle at Week 12 in the head and neck, upper extremities, trunk and lower extremities and at Week 24, regardless of the body region involved. The percentage of patients who achieved VASI50 increased through Week 52, including among patients who switched over from vehicle to ruxolitinib cream after Week 24. In summary, ruxolitinib cream produced a clinically meaningful re-pigmentation of all body regions (including hands and feet that are notoriously difficult to re-pigment) in TRuE-V1/TruE-V2 through Week 52, including among patients who switched over to ruxolitinib cream from vehicle after Week 24.

Subacute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus are represented in the majority of cutaneous lupus subtypes, each of which has variable implications for systemic manifestations such as lupus nephritis. On dermatologic examination, subacute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus are distinct. However, it is often difficult to diagnose the subtype from histology alone. Our study utilized whole-genome microarray expression analysis on human skin samples of subacute cutaneous lupus erythematosus, on human skin samples of chronic cutaneous lupus erythematosus, and on healthy controls, along with analysis on human samples of lupus nephritis and normal kidney tissue to compare cutaneous lupus subtypes with each other as well as with lupus nephritis. The data revealed that cutaneous lupus subtypes were distinct from healthy control skin, with gene expression predominantly characterized by upregulation of IFN-1 and T-cell chemotactic genes. However, the cutaneous lupus subtypes were very similar to one another; comparative analyses revealed few statistically significant differences in gene expression. There were also distinct differences between the gene signatures of cutaneous lupus and lupus nephritis. Cutaneous lupus samples revealed gene signatures demonstrating a prominent inflammatory component that may suggest the skin as an early site of initiation of lupus pathogenesis, whereas lupus nephritis reflected the recruitment and activation of M2 macrophages and a wound healing signature.

BACKGROUND: Vitiligo is a chronic autoimmune disease that causes skin depigmentation. A cream formulation of ruxolitinib (an inhibitor of Janus kinase 1 and 2) resulted in repigmentation in a phase 2 trial involving adults with vitiligo. METHODS: We conducted two phase 3, double-blind, vehicle-controlled trials (Topical Ruxolitinib Evaluation in Vitiligo Study 1 [TRuE-V1] and 2 [TRuE-V2]) in North America and Europe that involved patients 12 years of age or older who had nonsegmental vitiligo with depigmentation covering 10% or less of total body-surface area. Patients were randomly assigned in a 2:1 ratio to apply 1.5% ruxolitinib cream or vehicle control twice daily for 24 weeks to all vitiligo areas on the face and body, after which all patients could apply 1.5% ruxolitinib cream through week 52. The primary end point was a decrease (improvement) of at least 75% from baseline in the facial Vitiligo Area Scoring Index (F-VASI; range, 0 to 3, with higher scores indicating a greater area of facial depigmentation), or F-VASI75 response, at week 24. There were five key secondary end points, including improved responses on the Vitiligo Noticeability Scale. RESULTS: A total of 674 patients were enrolled, 330 in TRuE-V1 and 344 in TRuE-V2. In TRuE-V1, the percentage of patients with an F-VASI75 response at week 24 was 29.8% in the ruxolitinib-cream group and 7.4% in the vehicle group (relative risk, 4.0; 95% confidence interval [CI], 1.9 to 8.4; P

Vitiligo is a chronic autoimmune disorder characterized by depigmented patches of the skin.To evaluate the efficacy and safety of ritlecitinib, an oral JAK3 (Janus kinase)/TEC (tyrosine kinase expressed in hepatocelluar carcinoma) inhibitor, in patients with active nonsegmental vitiligo in a phase 2b trial (NCT03715829).Patients were randomized to once-daily oral ritlecitinib ± 4-week loading dose (200/50 mg, 100/50 mg, 30 mg, or 10 mg) or placebo for 24 weeks (dose-ranging period). Patients subsequently received ritlecitinib 200/50 mg daily in a 24-week extension period. The primary efficacy endpoint was percent change from baseline in Facial-Vitiligo Area Scoring Index at week 24.A total of 364 patients were treated in the dose-ranging period. Significant differences from placebo in percent change from baseline in Facial-Vitiligo Area Scoring Index were observed for the ritlecitinib 50 mg groups with (-21.2 vs 2.1; P .001) or without (-18.5 vs 2.1; P .001) a loading dose and ritlecitinib 30 mg group (-14.6 vs 2.1; P = .01). Accelerated improvement was observed after treatment with ritlecitinib 200/50 mg in the extension period (n = 187). No dose-dependent trends in treatment-emergent or serious adverse events were observed across the 48-week treatment.Patients with stable vitiligo only were excluded.Oral ritlecitinib was effective and well tolerated over 48 weeks in patients with active nonsegmental vitiligo.

Despite the central role of IFNγ in vitiligo pathogenesis, systemic IFNγ neutralization is an impractical treatment option due to strong immunosuppression. However, most vitiligo patients present with less than 20% affected body surface area, which provides an opportunity for localized treatments that avoid systemic side effects. After identifying keratinocytes as key cells that amplify IFNγ signaling during vitiligo, we hypothesized that tethering an IFNγ neutralizing antibody to keratinocytes would limit anti-IFNγ effects to the treated skin for the localized treatment. To that end, we developed a bispecific antibody (BsAb) capable of blocking IFNγ signaling while binding to desmoglein expressed by keratinocytes. We characterized the effect of the BsAb in vitro, ex vivo, and in a mouse model of vitiligo. SPECT/CT biodistribution and serum assays after local footpad injection revealed that the BsAb had improved skin retention, faster elimination from the blood, and less systemic IFNγ inhibition than the non-tethered version. Furthermore, the BsAb conferred localized protection almost exclusively to the treated footpad during vitiligo that was not possible by local injection of the non-tethered anti-IFNγ antibody. Thus, keratinocyte-tethering proved effective while significantly diminishing off-tissue effects of IFNγ blockade, offering a new treatment strategy for localized skin diseases, including vitiligo.

Reduced graphene oxide/aramid nanofiber (rGO/ANF) supercapacitor electrodes have a good combination of energy storage and mechanical properties, but ion transport remains an issue toward achieving ...

Vitiligo is an autoimmune skin disease in which epidermal melanocytes are targeted for destruction by CD8+ T cells specific for melanocyte/melanoma-shared antigens. IFNγ is the central cytokine driving disease, but the role of type I IFN in vitiligo remains unclear. We investigated the functional role of type I IFN during vitiligo progression using two different mouse models: one induced with a vaccinia virus (VV) vaccine and one induced with dendritic cells to prime autoimmune T cells. Induction of vitiligo by VV in IFNaR-deficient mice led to the development of severe vitiligo compared with wild-type (WT) mice and was characterized by a significantly enhanced effector CD8+ T-cell response. Severe vitiligo in this model was a result of VV persistence, because exacerbation of disease in IFNaR-deficient mice was not observed when antigen-pulsed dendritic cells were used to induce vitiligo instead of virus. Treatment of B16F10 melanoma-inoculated mice with VV vaccine therapy also induced a significantly enhanced anti-tumor response in IFNaR-deficient mice compared with WT. These results not only help define the pathways responsible for vitiligo progression but also suggest that blockade of type I IFNs following administration of a VV vaccine may provide increased immunogenicity and efficacy for melanoma immunotherapy.

Summary Background Vitiligo is a chronic autoimmune disease resulting in skin depigmentation and reduced quality of life. There is no approved treatment for vitiligo repigmentation and current off-label therapies have limited efficacy, emphasising the need for improved treatment options. We investigated the therapeutic potential of ruxolitinib cream in patients with vitiligo and report the efficacy and safety results up to 52 weeks of double-blind treatment. Methods We did a multicentre, randomised, double-blind, phase 2 study for adult patients with vitiligo in 26 US hospitals and medical centres in 18 states. Patients with depigmentation of 0·5% or more of their facial body surface area (BSA) and 3% or more of their non-facial BSA were randomly assigned (1:1:1:1:1) by use of an interactive response technology system to receive ruxolitinib cream (1·5% twice daily, 1·5% once daily, 0·5% once daily, or 0·15% once daily) or vehicle (control group) twice daily on lesions constituting 20% or less of their total BSA for 24 weeks. Patients in the control group in addition to patients in the 0·15% once daily group who did not show a 25% or higher improvement from baseline in facial Vitiligo Area Scoring Index (F-VASI) at week 24 were re-randomised to one of three higher ruxolitinib cream doses (0·5% once daily, 1·5% once daily, 1·5% twice daily). Patients in the 0·5% once daily, 1·5% once daily, or 1·5% twice daily groups remained at their original dose up to week 52. Patients, investigators, and the study sponsor (except members of the interim analysis and primary endpoint analysis data monitoring teams) remained masked to treatment assignment throughout the study. The primary endpoint was the proportion of patients achieving a 50% or higher improvement from baseline in F-VASI (F-VASI50) at week 24, assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov , NCT03099304 . Findings Between June 7, 2017, and March 21, 2018, 205 patients were screened for eligibility, 48 were excluded and 157 patients (mean age, 48·3 years [SD 12·9]; 73 [46%] male and 84 [54%] female) were randomly assigned to either an intervention group or the control group. 32 (20%) of 157 were assigned to the control group, 31 (20%) to the 0·15% once daily group, 31 (20%) to the 0·5% once daily group, 30 (19%) to the 1·5% once daily group, and 33 (21%) to the 1·5% twice daily group. F-VASI50 at week 24 was reached by significantly more patients given ruxolitinib cream at 1·5% twice daily (15 [45%] of 33) and 1·5% once daily (15 [50%] of 30) than were treated with vehicle (one [3%] of 32). Four patients had serious treatment-emergent adverse events (one patient in the 1·5% twice daily group developed subdural haematoma; one patient in the 1·5% once daily group had a seizure; one patient in the 0·5% once daily group had coronary artery occlusion; and one patient in the 0·5% once daily group had oesophageal achalasia), all of which were unrelated to study treatment. Application site pruritus was the most common treatment-related adverse event among patients given ruxolitinib cream (one [3%] of 33 in the 1·5% twice daily group; three [10%] of 30 in the 1·5% once daily group; three [10%] of 31 in the 0·5% once daily group; and six [19%] of 31 in the 0·15% once daily group)with three [9%] of 32 patients showing application site pruritis in the control group. Acne was noted as a treatment-related adverse event in 13 (10%) of 125 patients who received ruxolitinib cream and one (3%) of 32 patients who received vehicle cream. All treatment-related adverse events were mild or moderate in severity and similar across treatment groups. Interpretation Treatment with ruxolitinib cream was associated with substantial repigmentation of vitiligo lesions up to 52 weeks of treatment, and all doses were well tolerated. These data suggest that ruxolitinib cream might be an effective treatment option for patients with vitiligo. Funding Incyte.

Vitiligo is an autoimmune disease of the skin that targets pigment-producing melanocytes and results in patches of depigmentation that are visible as white spots. Recent research studies have yielded a strong mechanistic understanding of this disease. Autoreactive cytotoxic CD8+ T cells engage melanocytes and promote disease progression through the local production of IFN-γ, and IFN-γ-induced chemokines are then secreted from surrounding keratinocytes to further recruit T cells to the skin through a positive-feedback loop. Both topical and systemic treatments that block IFN-γ signaling can effectively reverse vitiligo in humans; however, disease relapse is common after stopping treatments. Autoreactive resident memory T cells are responsible for relapse, and new treatment strategies focus on eliminating these cells to promote long-lasting benefit. Here, we discuss basic, translational, and clinical research studies that provide insight into the pathogenesis of vitiligo, and how this insight has been utilized to create new targeted treatment strategies.

Vitiligo is an autoimmune skin disease caused by melanocyte-targeting autoreactive CD8+ T cells. Regulatory T cells (Tregs) have been implicated in restraining vitiligo severity in both mouse models and human patients; however, whether they must be present in the skin for their suppressive function is still unclear. We observed uneven distribution of Tregs within different anatomical locations of mouse skin, which correlated with reduced depigmentation after vitiligo induction. We specifically depleted Tregs in our mouse model of vitiligo and observed increased disease. Next, we found that Tregs contact CD8+ T effector cells in vitiligo lesional skin and that Treg recruitment to the skin inversely correlated with disease severity, suggesting a critical role for Treg suppression within the skin. When we investigated the signals facilitating Treg migration to the skin, we found that although CXCR3 was dispensable for Treg migration and function in vitiligo, Tregs lacking CCR6 exhibited a reduced capacity to migrate to the skin and suppress depigmentation, despite normal systemic numbers in the skin-draining lymph nodes. Our observations highlight a key role for cutaneous Tregs in disease suppression during vitiligo and identify CCR6 as a chemokine receptor that contributes to Treg migration to the skin.

Vitiligo is an autoimmune skin disease characterized by the targeted destruction of melanocytes by T cells. Cytokine signaling between keratinocytes and T cells results in CD8+ T cell infiltration of vitiligo lesions, but the full scope of signals required to coordinate autoimmune responses is not completely understood. We performed single-cell RNA sequencing (scRNA-seq) on affected and unaffected skin from vitiligo patients, as well as healthy controls, to define the role of each cell type in coordinating autoimmunity during disease progression. We confirmed that type 1 cytokine signaling occupied a central role in disease, but we also discovered that this pathway was used by regulatory T cells (Tregs) to restrain disease progression in non-lesional skin. We determined that CCL5-CCR5 signaling served as a chemokine circuit between effector CD8+ T cells and Tregs, and mechanistic studies in a mouse model of vitiligo revealed that CCR5 expression on Tregs was required to suppress disease in vivo but not in vitro. CCR5 was not required for Treg recruitment to skin but appeared to facilitate Treg function by properly positioning these cells within the skin. Our data provides critical insights into the pathogenesis of vitiligo and uncovers potential opportunities for therapeutic interventions.

scRNA-seq of human vitiligo samples reveals complex autoimmune networks, including a role for CCR5 in T reg function.

Vitiligo is an autoimmune skin disease mediated by autoreactive CD8+ T cells that destroy the pigment-producing cells of the epidermis, melanocytes, leading to areas of depigmentation. Patients with vitiligo require lifelong treatment to regain and maintain their pigment. Clinical observations uncovered the importance of autoimmune memory in vitiligo because cessation of treatment frequently led to relapse of disease at the site of previous lesions. A subset of memory T cells known as CD8+ resident memory T cells (TRM) are long-lived, nonmigratory memory cells that persist in most nonlymphoid tissues, including the skin. Recent reports describe the presence of CD8+ TRM in lesional vitiligo patient skin and suggest their role as active players in disease maintenance. In this review, we will discuss the role of skin CD8+ TRM in maintaining disease in vitiligo and the opportunity to target this population to induce a long-lasting reversal of disease.

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.

Tissue resident memory T cells (TRM) are a critical component of the immune system, providing the body with an immediate and highly specific response against pathogens re-infecting peripheral tissues. More recently, however, it has been demonstrated that TRM cells also form during autoimmunity. TRM mediated autoimmune diseases are particularly destructive, because unlike foreign antigens, the self-antigens are never cleared, continuously activating self-reactive TRM T cells. In this article, we will focus on how TRMs mediate disease in autoimmune skin conditions, specifically vitiligo, psoriasis, cutaneous lupus erythematosus, alopecia areata and frontal fibrosing alopecia.

Summary Background Shared decision-making tools (SDMt) are visual tools developed to promote joint medical decisions between physicians and patients. There is a paucity of such tools in dermatology. Objectives To develop and validate a SDMt for use in specialized consultation for vitiligo. Methods A prospective cross-sectional study was carried out from March 2019 to March 2020. We first conducted a qualitative study of topics discussed by patients and clinicians during therapeutic decision-making in the setting of a specialized consultation for vitiligo using an anchored-theory method, which allowed conceptualization of the SDMt. The usefulness of the SDMt was evaluated by a working group of multidisciplinary health workers and patients with vitiligo. Consensus on the final tool was obtained through an e-Delphi method. Results We recruited 30 patients with vitiligo for the qualitative study, which identified 91 topics related to therapeutic decision-making. Hierarchical clustering analysis confirmed the distribution of these topics in two subgroups (general treatment goals and priorities, and topics specific to each treatment). The consensus of a multidisciplinary group was used to develop the SDMt. The tool was comprised of eight A5 cards, which addressed face repigmentation; body repigmentation (limited area); body repigmentation (extended area); partial or complete depigmentation; coping with the disease; stabilization of disease; maintaining repigmentation; and disease information. Cognitive interviews confirmed the satisfaction, readability and usefulness of the SDMt. The SDMt was then translated and culturally validated in English. Conclusions We developed a tool for shared decision-making in nonsegmental vitiligo, which we translated and cross-culturally validated in a US patient population with vitiligo to ensure its generalizability.

Several epidemiologic studies and GWASs have implicated genetic factors in the pathogenesis of vitiligo. The report by Kim et al. (2020) describes a prospective cohort study from Korea that has the greatest statistical power to date in addressing the epidemiology of vitiligo inheritance. The authors reported the incidence risk ratios in individuals whose first-degree relatives or spouses are affected, providing clear evidence that both genetic and nongenetic factors influence the pathogenesis of vitiligo.

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The STING and absent in melanoma 2 (AIM2) pathways are activated by the presence of cytosolic DNA, and STING agonists enhance immunotherapeutic responses. Here, we show that dendritic cell (DC) expression of AIM2 within human melanoma correlates with poor prognosis and, in contrast to STING, AIM2 exerts an immunosuppressive effect within the melanoma microenvironment. Vaccination with AIM2-deficient DCs improves the efficacy of both adoptive T cell therapy and anti–PD-1 immunotherapy for “cold tumors,” which exhibit poor therapeutic responses. This effect did not depend on prolonged survival of vaccinated DCs, but on tumor-derived DNA that activates STING-dependent type I IFN secretion and subsequent production of CXCL10 to recruit CD8+ T cells. Additionally, loss of AIM2-dependent IL-1β and IL-18 processing enhanced the treatment response further by limiting the recruitment of regulatory T cells. Finally, AIM2 siRNA-treated mouse DCs in vivo and human DCs in vitro enhanced similar anti-tumor immune responses. Thus, targeting AIM2 in tumor-infiltrating DCs is a promising new treatment strategy for melanoma.

BACKGROUND There is no cure or firm clinical recommendations for the treatment of vitiligo. One of the main issues is the heterogeneity of outcome measures used in randomized controlled trials for vitiligo. OBJECTIVES To define successful repigmentation from the patients' point of view and to propose how and when repigmentation should be evaluated in clinical trials in vitiligo. METHODS We conducted three workshops with patients with vitiligo and their parents or caregivers. Workshop 1 was held at World Vitiligo Day (Detroit, MI), workshop 2 at the University of Texas Southwestern Medical Center and workshop 3 at the Vitiligo and Pigmentation Institute of Southern California, University of California. RESULTS Seventy-three participants were recruited. Consensus on the following questions was achieved unanimously: (i) the definition of 'successful repigmentation' was 80-100% of repigmentation of a target lesion and (ii) both an objective and a subjective scale to measure repigmentation should be used. CONCLUSIONS This was the largest patients' outcomes workshop. We followed the guidance from the CSG-COUSIN and the Vitiligo Global Issues Consensus Group. Our recommendations to use percentage of repigmentation quartiles (0-25%, 26-50%, 51-79%, 80-100%) and the Vitiligo Noticeability Scale are based on the best available current evidence. A limitation of the research is that the workshops were conducted only in the U.S.A., due to pre-existing organisational support and the availability of funding.

Toll-like receptors TLR7 and TLR9 are both implicated in the activation of autoreactive B cells and other cell types associated with systemic lupus erythematosus (SLE) pathogenesis. However, Tlr9–/– autoimmune-prone strains paradoxically develop more severe disease. We have now leveraged the negative regulatory role of TLR9 to develop an inducible rapid-onset murine model of systemic autoimmunity that depends on T cell detection of a membrane-bound OVA fusion protein expressed by MHC class II+ cells, expression of TLR7, expression of the type I IFN receptor, and loss of expression of TLR9. These mice are distinguished by a high frequency of OVA-specific Tbet+, IFN-γ+, and FasL-expressing Th1 cells as well as autoantibody-producing B cells. Unexpectedly, contrary to what occurs in most models of SLE, they also developed skin lesions that are very similar to those of human cutaneous lupus erythematosus (CLE) as far as clinical appearance, histological changes, and gene expression. FasL was a key effector mechanism in the skin, as the transfer of FasL-deficient DO11gld T cells completely failed to elicit overt skin lesions. FasL was also upregulated in human CLE biopsies. Overall, our model provides a relevant system for exploring the pathophysiology of CLE as well as the negative regulatory role of TLR9.

Alopecia areata (AA) is a common autoimmune skin disease that results in the loss of hair on the scalp and elsewhere on the body and affects over 146 million people worldwide at some point in their lives. Founded in 1981, the National Alopecia Areata Foundation is a nonprofit organization that supports research to find a cure or acceptable treatment for AA, supports those with the disease, and educates the public about AA. The National Alopecia Areata Foundation conducts research summits every 2 years to review progress and create new directions in its funded and promoted research. The Foundation brings together scientists from all disciplines to get a broad and varied perspective. These AA research summits are part of the Foundation's main strategic initiative, the AA Treatment Development Program, to enhance the understanding of AA and accelerate progress toward a viable treatment.