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Immune check point inhibitor-induced bullous pemphigoid (ICI-BP) is a clinically debilitating immune related adverse event in need of novel therapeutic approaches, as conventional therapy treatment can counteract intended tumor immunity. Here we demonstrate that IL4 and IL13 cytokine expression is elevated in ICI-BP similar to conventional autoimmune bullous pemphigoid and further demonstrate partial and complete disease clearance in four ICI-BP patients with dupilumab. These data indicate that IL-4Ralpha inhibition may be a promising new therapy for ICI-BP.

Photosensitivity in lupus and subsequent systemic disease flares contribute to disease burden and is incompletely understood. Skin communicates with lymphoid tissues via lymphatics and reduced lymphatic flow in murine models results in skin inflammation and autoimmunity. Here, we demonstrate that the skin of lupus patients and multiple murine lupus models are characterized by lymphatic flow dysfunction. Improving lymphatic flow in murine lupus models via manual lymphatic drainage or by utilizing a transgenic model with increased lymphatics ameliorated cutaneous photosensitivity and diminished draining lymph node germinal center B cell and plasmablast responses. Improved lymphatic flow limited B cell responses via acting on a stromal-immune circuit previously described by our lab. Increased lymphatic flow increases stromal CCL2, which modulates monocyte function and limits B cell responses. This work provides a link between cutaneous photosensitivity and systemic disease in lupus and suggests that improving lymphatic flow or targeting the lymph node microenvironment could be potential therapeutic targets.

ObjectiveIn antiphospholipid antibody (aPL) nephropathy, activation of the mammalian target of rapamycin (mTOR) contributes to endothelial cell proliferation, a key finding of aPL microvascular disease. Here, we examined mTOR activation in the skin of aPL-positive patients with livedo.MethodsThree patient groups with livedo were studied: (1) persistently aPL-positive with systemic lupus erythematosus (SLE); (2) persistently aPL-positive without SLE; and (3) aPL-negative SLE (control). After collecting aPL-related medical history, two 5-mm skin biopsies of livedo were performed on each patient: (1) peripheral (erythematous-violaceous lesion); and (2) central (nonviolaceous area). We stained specimens for phosphorylated protein kinase B (p-AKT) and phosphorylated S6 ribosomal protein (p-S6RP) as mTOR activity markers, CD31 to identify endothelial cells, and Ki-67 to show cellular proliferation. We counted cells in the epidermis and compared mTOR-positive cell counts between peripheral and central samples, and between patient groups, using Freidman test and Wilcoxon signed-rank test.ResultsTen patients with livedo reticularis were enrolled: 4 aPL-positive without SLE (antiphospholipid syndrome [APS] classification met, n = 3), 4 aPL-positive SLE (APS classification met, n = 3), and 2 aPL-negative SLE (control). In all aPL-positive patients, epidermal p-AKT and p-S6RP staining were significantly increased in both peripheral and central skin samples when compared to aPL-negative SLE controls; both were more pronounced in the lower basal layers of epidermis.ConclusionOur study demonstrates increased mTOR activity in livedoid lesions of aPL-positive patients with or without SLE compared to aPL-negative patients with SLE, with more prominent activity in the lower basal layers of the epidermis. These findings may serve as a basis for further investigating the mTOR pathway in aPL-positive patients.

The recent advent of single-cell technologies has fast-tracked the discovery of multiple fibroblast subsets in tissues affected by autoimmune disease. In recent years, interest in lymph node fibroblasts that support and regulate immune cells has also grown, leading to an expanding framework of stromal cell subsets with distinct spatial, transcriptional, and functional characteristics. Inflammation can drive tissue fibroblasts to adopt a lymphoid tissue stromal cell phenotype, suggesting that fibroblasts in diseased tissues can have counterparts in lymphoid tissues. Here, we examine fibroblast subsets in tissues affected by autoimmunity in the context of knowledge gained from studies on lymph node fibroblasts, with the ultimate aim to better understand stromal cell heterogeneity in these immunologically reactive tissues.

Hidradenitis suppurativa (HS), also known as acne inversa, is a debilitating inflammatory skin disorder that is characterized by nodules that lead to the development of connected tunnels and scars as it progresses from Hurley stages I to III. HS has been associated with several autoimmune diseases, including inflammatory bowel disease and spondyloarthritis. We previously reported dysregulation of humoral immune responses in HS, characterized by elevated serum total IgG, B-cell activation, and antibodies recognizing citrullinated proteins. In this study, we characterized IgG autoreactivity in HS sera and lesional skin compared with those in normal healthy controls using an array-based high-throughput autoantibody screening. The Cy3-labeled anti–human assay showed the presence of autoantibodies against nuclear antigens, cytokines, cytoplasmic proteins, extracellular matrix proteins, neutrophil proteins, and citrullinated antigens. Most of these autoantibodies were significantly elevated in stages II‒III in HS sera and stage III in HS skin lesions compared with those of healthy controls. Furthermore, immune complexes containing both native and citrullinated versions of antigens can activate M1 and M2 macrophages to release proinflammatory cytokines such as TNF-α, IL-8, IL-6, and IL-12. Taken together, the identification of specific IgG autoantibodies that recognize circulating and tissue antigens in HS suggests an autoimmune mechanism and uncovers putative therapeutic targets.

BackgroundThe autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure inflames skin. Beneficial effects of anifrolumab (anti-interferon α/breceptor (anti-IFNAR)) on lupus skin disease support a pathogenic role for IFN-I, but mechanistic understanding is limited. We have shown that Langerhans cell (LC) dysfunction contributes to photosensitivity. Healthy LCs act via a disintegrin and metalloprotease 17 (ADAM17) to release epidermal growth factor receptor (EGFR) ligands that limit UVR-induced keratinocyte apoptosis and photosensitivity. However, LC ADAM17 activity is reduced in non-lesional lupus model skin, and data point to reduced LC-mediated protection in human lupus. Here, we asked about the role of the IFN-rich lupus skin environment in LC dysfunction and the implications of this regulation for photosensitivity.MethodsGene expression patterns in non-lesional skin from human lupus and multiple murine models were examined. We used MRL/lpr, B6.Sle1yaa, and imiquimod models of lupus inin vivostudies to assess the role of IFN-I in LC ADAM17 dysfunction and photosensitivity.ResultsWe show a shared IFN-rich environment in non-lesional skin across human and murine model systems, that IFN-I inhibits LC ADAM17 activity, and that anti-IFNAR in lupus models restores LC ADAM17 function and reduces photosensitivity in EGFR and LC ADAM17-dependent manners. Reactive oxygen species (ROS) can mediate ADAM17 activity, and we show reduced LC ROS expression in lupus models that is restored by anti-IFNAR.ConclusionsOur findings suggest that IFN-I promotes photosensitivity by causing LC ADAM17 dysfunction and that anifrolumab ameliorates lupus skin disease at least in part by restoring LC function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a mechanism of action for anifrolumab in lupus.

Hidradenitis suppurativa (HS) is a chronic inflammatory disorder characterized by painful nodules, sinus tracts, and scars occurring predominantly in intertriginous regions. The prevalence of HS is currently 0.053–4%, with a predominance in African-American women and has been linked to low socioeconomic status. The majority of the reported literature is retrospective, population based, epidemiologic studies. In this regard, there is a need to establish a repository of biospecimens, which represent appropriate gender and racial demographics amongst HS patients. These efforts will diminish knowledge gaps in understanding the disease pathophysiology. Hence, we sought to outline a step-by-step protocol detailing how we established our HS biobank to facilitate the formation of other HS tissue banks. Equipping researchers with carefully detailed processes for collection of HS specimens would accelerate the accumulation of well-organized human biological material. Over time, the scientific community will have access to a broad range of HS tissue biospecimens, ultimately leading to more rigorous basic and translational research. Moreover, an improved understanding of the pathophysiology is necessary for the discovery of novel therapies for this debilitating disease. We aim to provide high impact translational research methodology for cutaneous biology research and foster multidisciplinary collaboration and advancement of our understanding of cutaneous diseases.

Background Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by systemic disease flares, renal complications, photosensitivity, and other clinical manifestations. A research area of particular interest to our lab is photosensitivity, an immune system reaction precipitated by ultraviolet radiation (UVR) exposure that results in epidermal keratinocyte apoptosis and contributes to overall skin inflammation. Importantly, many SLE patients attribute a decrease in quality of life due to photosensitivity. Our lab has recently identified a mechanism in which a disintegrin and metalloprotease 17 (ADAM17) located on Langerhans cells (LCs) limits UVR-induced keratinocyte apoptosis and skin injury via keratinocyte epidermal growth factor receptor (EGFR) stimulation in mice and humans. While we have delineated the downstream effects of UVR-induced ADAM17 activity and expression in healthy and SLE skin, factors that regulate ADAM17 remain poorly understood. Previous studies have shown that elevated levels of type I interferon (IFN) are characteristic of SLE patients. Here, we hypothesize that type I interferon may regulate ADAM17 in LCs in lupus models. Methods To quantify ADAM17 activity, we developed an assay that uses flow cytometry and co-culture systems. We use this assay in in vitro models and in vivo mouse models. To quantify the relative ratio of IFN-inducible genes, we use quantitative polymerase chain reaction (qPCR). To apply IFN-k to mice, we solubilize the protein and paint it on murine back skin. Results In vitro methods showed that type I IFN was sufficient to reduce LC ADAM17 activity, and in vivo models showed that type I IFN receptor blockade corrected the LC ADAM17 defect in photosensitive lupus mouse models. We are analyzing qPCR data. Conclusions We show that type I interferon (IFN) can reduce ADAM17 activity on epidermal cells. We also show that type I interferon receptor blockade in lupus mouse models rescues ADAM17 activity. Our data together suggest that type I IFN in lupus may contribute to Langerhans cell dysfunction and propensity to photosensitivity in SLE. Funding Source(s): None

Background Proper function of lymphatic vessels is needed to limit the magnitude and duration of tissue inflammation, and in direct regulation of immune cell activity. Inflammatory states such as rheumatoid arthritis and psoriasis are associated with lymphatic dysfunction, but lymphatics in lupus models have not been well characterized. SLE patients are photosensitive, developing inflammatory skin lesions upon exposure to even ambient ultraviolet radiation (UVR). We hypothesized that lymphatic dysfunction may contribute to photosensitivity in lupus. Methods MRL/MpJ-Faslpr/lpr (lpr) mice and age-/sex-matched MRL controls were evaluated at baseline, 1 day, 1 week and 1 month after exposure to 2000–2500 J/m2 of UVB radiation. Lymphatic function was assessed with an intradermal injection of 1 µL of 2% evans blue (EB) to the ear, followed by measurement of EB concentration in the draining lymph node (dLN) 1 min later. Flow cytometry of ears and dLN allowed quantification of resident cell populations. Kruskal-Wallis test, followed by Dunns test for multiple comparisons were used to compare the groups; data is presented as mean ±SE, with a two-tailed p-value of Results At baseline, the effective flow of EB, calculated as EB concentration in the dLN, per ear lymphatic endothelial cell (LEC) number, is comparable between the 2 groups. Following UVR, in both lpr and control mice, there is an increase in the effective flow of EB to the dLN, that starts as early as 1 day, and continues to increase at 1 week, in similar levels between the 2 groups. At 1 month post-UVR, however, the flow continues to improve in the MRL control mice, but there is no similar improvement in the lpr mice. In fact, while at baseline, 1 day and 1 week the mean relative lymphatic flow in the lpr mice ranges from 1.6-, 2.5- and 0.9- fold of controls, respectively, at 1 month the effective flow in the lpr mice is only 5% that of controls (p=0.007). Conclusions Dermal lymphatic network of lupus models have never been characterized, despite evidence for a major role of lymphatics in the regulation of chronic inflammation and autoimmunity. Here we provide indications to impaired long-term response of lymphatic drainage in the lpr lupus strain, which can lead to reduced lymphatic regulation of the immune response, contributing to the unchecked skin inflammation known to occur in SLE. Funding Source(s): NIH T32AR071302-01 (NS) NIH R01AI079178 (TTL) Lupus Research Alliance (TTL)

Background Hydroxychloroquine is widely used for the treatment of cutaneous lupus erythematosus (CLE). Although new recommendations exist for hydroxychloroquine dosing, there is still uncertainty about the dosage that will elicit a satisfactory response in CLE while limiting adverse effects, specifically retinopathy. Objective To summarize hydroxychloroquine dosages, outcomes, and adverse effects in the treatment of CLE, focusing on retinopathy. Methods A comprehensive literature search from inception to December 2018 was performed in Ovid MEDLINE, Ovid Embase, and The Cochrane Library (Wiley). Studies were screened against predefined inclusion and exclusion criteria. Results Twelve studies were selected and included 5 retrospective studies, 3 prospective studies, 2 case series, and 2 randomized controlled trials. These studies show that a hydroxychloroquine dosage up to 400 mg/d is effective for most CLE patients (range of effectiveness, 50%-97%), with few adverse effects. One incidence of retinopathy, after a very high cumulative dose, was reported across all 12 studies (852 total patients). Limitations Because retinopathy and other serious adverse effects may not appear until much later, many of these studies are limited by short follow-up time. Conclusions This evidence suggests that hydroxychloroquine for CLE is effective at 400 mg/d, with an exceedingly low incidence of retinopathy and other adverse effects.

Lymphatic vessels are critical for clearing fluid and inflammatory cells from inflamed tissues and also have roles in immune tolerance. Given the functional association of the lymphatics with the immune system, lymphatic dysfunction may contribute to the pathophysiology of rheumatic autoimmune diseases. Here we review the current understanding of the role of lymphatics in the autoimmune diseases rheumatoid arthritis, scleroderma, lupus, and dermatomyositis and consider the possibility that manual therapies such as massage and acupuncture may be useful in improving lymphatic function in autoimmune diseases.

Photosensitivity, or skin sensitivity to ultraviolet radiation (UVR), is a feature of lupus erythematosus and other autoimmune and dermatologic conditions, but the mechanistic underpinnings are poorly understood. We identify a Langerhans cell (LC)–keratinocyte axis that limits UVR-induced keratinocyte apoptosis and skin injury via keratinocyte epidermal growth factor receptor (EGFR) stimulation. We show that the absence of LCs in Langerin–diphtheria toxin subunit A (DTA) mice leads to photosensitivity and that, in vitro, mouse and human LCs can directly protect keratinocytes from UVR-induced apoptosis. LCs express EGFR ligands and a disintegrin and metalloprotease 17 (ADAM17), the metalloprotease that activates EGFR ligands. Deletion of ADAM17 from LCs leads to photosensitivity, and UVR induces LC ADAM17 activation and generation of soluble active EGFR ligands, suggesting that LCs protect by providing activated EGFR ligands to keratinocytes. Photosensitive systemic lupus erythematosus (SLE) models and human SLE skin show reduced epidermal EGFR phosphorylation and LC defects, and a topical EGFR ligand reduces photosensitivity. Together, our data establish a direct tissue-protective function for LCs, reveal a mechanistic basis for photosensitivity, and suggest EGFR stimulation as a treatment for photosensitivity in lupus erythematosus and potentially other autoimmune and dermatologic conditions.

During normal and pathologic immune responses, lymph nodes can swell considerably. The lymph node vascular–stromal compartment supports and regulates the developing immune responses and undergoes dynamic expansion and remodeling. Recent studies have shown that dendritic cells (DCs), best known for their antigen presentation roles, can directly regulate the vascular–stromal compartment, pointing to a new perspective on DCs as facilitators of lymphoid tissue function. Here, we review the phases of lymph node vascular–stromal growth and remodeling during immune responses, discuss the roles of DCs, and discuss how this understanding can potentially be used for developing novel therapeutic approaches.

Tertiary lymphoid organs are found at sites of chronic inflammation in autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. These organized accumulations of T and B cells resemble secondary lymphoid organs and generate autoreactive effector cells. However, whether they contribute to disease pathogenesis or have protective functions is unclear. Here, we discuss how tertiary lymphoid organs can generate potentially pathogenic cells but may also limit the extent of the response and damage in autoimmune disease.

THE next five to ten years will see nuclear power come of age in several parts of the United States. New England, because of its high fossil fuel costs, will probably be the first region to take full advantage of the new source of power generation, although California and the Middle Atlantic Seaboard are also strong contenders. With economically competitive nuclear power a near-term probability in these areas, it should be instructive to see exactly what effects can be expected to accrue from the new power source. This paper explores some possibilities in the case of New England. The summer of I96I ushered in the era of nuclear power in this region. The Yankee Atomic Electric plant at Rowe, Massachusetts, began operating on a commercial basis in July of that year. By the end of I963 this plant, which is owned jointly by ten of the area's utilities, had contributed something like 2 1 billion kilowatt-hours to the New England electrical network. Initial cost of the new I85,000 kilowatt station was just under $235 per kilowatt, including the Atomic Energy Commission's share of preliminary research and development expenses. Operating costs on the second nuclear core were approximately 4.2 mills, including fuel, resulting in a total I963 generating cost of 8.9 mills per kilowatt-hour (Table I). Later cores may lower total cost to 8.5 mills or less, depending primarily on the amount of time the reactor is shut down during future refuelings.' For the sake of comparison, the conventional I36,000 kilowatt Mt. Tom station at Holyoke, Massachusetts, built about the same time, went in for $ I 74 per kilowatt (one unit). If the actual I963 plant factor of go per cent is adjusted downward to 8o per cent and a fixed rate of I4 per cent assigned for purposes of comparison, total cost of production was approximately 7.2 mills.2 Hence, the Yankee plant produced energy at a cost approximately I .7 mills, or 24 per cent higher than its contemporary alternative. This differential