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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.

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 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.