Tapinarof validates the aryl hydrocarbon receptor as a therapeutic target: A clinical review.

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that has wide-ranging roles, including regulation of inflammation and homeostasis. AhR is not a cell surface receptor; rather, it exists in a cytoplasmic complex that responds to a wide variety of structurally dissimilar endogenous, microbial, and environmental ligands. The ubiquitous expression of AhR, its ability to be activated by a wide range of ligands, and its capacity to act as a master regulator for gene expression and homeostasis make it a promising new therapeutic target. Clinical trials of tapinarof cream have now validated AhR agonism as a therapeutic approach that can deliver significant efficacy for treating inflammatory skin diseases, including psoriasis and atopic dermatitis. Tapinarof 1% cream is a first-in-class, nonsteroidal, topical, AhR agonist with a pharmacokinetic profile that results in localized exposure at sites of disease, avoiding systemic safety concerns, drug interactions, or off-target effects. Psoriasis and atopic dermatitis both involve epidermal inflammation, cellular immune responses, dysregulation of skin barrier protein expression, and oxidative stress. On the basis of the clinical effectiveness of tapinarof cream for treating inflammatory skin diseases, we review how targeting AhR may offer a significant opportunity in other conditions that share key aspects of pathogenesis, including asthma, inflammatory bowel disease, eosinophilic esophagitis, ophthalmic, and nervous system diseases.

CD1a and bound lipids drive T-cell responses in human skin disease.

In addition to serving as the main physical barrier with the outside world, human skin is abundantly infiltrated with resident αß T cells that respond differently to self, infectious, microbiome, and noxious stimuli.  To study skin T cells during infection and inflammation, experimental biologists track T-cell surface phenotypes and effector functions, which are often interpreted with the untested assumption that MHC proteins and peptide antigens drive measured responses.  However, a broader perspective is that CD1 proteins also activate human T cells, and in skin, Langerhans cells (LCs) are abundant antigen presenting cells that express extremely high levels of CD1a.  The emergence of new experimental tools, including CD1a tetramers carrying endogenous lipids, now show that CD1a-reactive T cells comprise a large population of resident T cells in human skin.  Here, we review studies showing that skin-derived αß T cells directly recognize CD1a proteins, and certain bound lipids, such as contact dermatitis allergens, trigger T-cell responses. Other natural skin lipids inhibit CD1a-mediated T-cell responses, providing an entry point for the development of therapeutic lipids that block T-cell responses. Increasing evidence points to a distinct role of CD1a in type 2 and 22 T-cell responses, providing new insights into psoriasis, contact dermatitis, and other T-cell-mediated skin diseases.

Management of breakthrough bleeding in transgender and gender diverse individuals on testosterone.

BACKGROUND: While many transgender and gender diverse individuals rapidly achieve amenorrhea on testosterone, emerging data have identified that breakthrough bleeding can occur in up to one-third of individuals with long-term use. Breakthrough bleeding can worsen dysphoria and patients may seek management to reattain amenorrhea. Because of this, there is a need to assess efficacy of management approaches. OBJECTIVE: The primary aim of the study was to evaluate methods used by patients and their providers to manage breakthrough bleeding which arises after 1 year of testosterone use. Secondary aims included describing the diagnostic approaches to breakthrough bleeding, and proposing an algorithm for classification and management of breakthrough bleeding in this patient population. STUDY DESIGN: This was an institutional review board-approved single tertiary center, retrospective chart review of transgender and gender diverse individuals on testosterone gender affirming hormone therapy who experienced breakthrough bleeding after 1 year of use. Charts were reviewed to determine patient characteristics, testosterone use, and breakthrough bleeding management approaches. RESULTS: Of the 96 individuals who had been on testosterone for 1 year and experienced breakthrough bleeding, 97% (n=93) engaged in at least 1 approach to management. The mean age at initiation of testosterone was 21.9 (standard deviation 5.4) and the median duration of time on testosterone was 54.5 months (interquartile range 33.5, 82). Only 16% (n=15) were using menstrual suppression at the time of their breakthrough bleeding episode. Breakthrough bleeding was successfully managed in 77 (79%), following between 1 and 4 attempted approaches. More than half of management attempts (63%) were successful on the first try. When management approaches were analyzed independently, the range of success associated with any particular approach was between 33% and 100%. Other than hysterectomy, which was fully successful at managing breakthrough bleeding, no approach was significantly better than no intervention. This was true both for individuals who did and did not bleed with missed testosterone doses. Regardless of what approach was used, after a failed attempt, the next attempt was successful in more than half of individuals. Of the 16 who underwent hysterectomy, 1 did so in part as a first line approach to manage breakthrough bleeding. CONCLUSION: In this study, use of medical management methods was not found to be superior to observation alone in the management of breakthrough bleeding. In the absence of data supporting superiority of any method, we recommend tailoring method attempts to patients' goals.

Incidence of breakthrough bleeding in transgender and gender-diverse individuals on long-term testosterone.

BACKGROUND: Little is known about the maintenance of amenorrhea among transgender and gender-diverse individuals with uteri who are using long-term testosterone gender-affirming hormone therapy. Emerging data describe breakthrough bleeding among adolescents on long-term testosterone therapy and among adults who are seeking a gender-affirming hysterectomy. More studies are needed to better understand breakthrough bleeding patterns among transgender and gender-diverse individuals with uteri who are using testosterone, including the frequency, timing, and etiology of bleeding and how these patterns may differ between adults and younger populations. OBJECTIVE: The primary aim of this study was to characterize the incidence and patterns of breakthrough bleeding in a cohort of transgender and gender-diverse individuals who had been on testosterone for longer than 12 months and who had uteri in situ. Secondary aims included identifying the time to first bleed for those who experienced breakthrough bleeding and the risk factors associated with breakthrough bleeding while on testosterone therapy. STUDY DESIGN: This was an institutional review board-approved, single tertiary center, retrospective chart review of transgender and gender diverse individuals who had been on testosterone for at least 1 year. A primary survival analysis that evaluated the incidence of bleeding was combined with descriptive analyses and an evaluation of the factors associated with bleeding. RESULTS: Of the 279 patients included in the analysis, the median age of testosterone initiation was 22 years (interquartile range, 19-41), and the median follow-up time was 34 months (range, 12-278). The absolute proportion of individuals who ever experienced breakthrough bleeding on testosterone was 34% (n=96; 95% confidence interval, 29-40). Patients who experienced breakthrough bleeding initiated testosterone at a younger age (20.5 vs 22.0 years; P=.04), had lower mean serum testosterone levels (389.14 vs 512.7 ng/dL; P=.001), were more likely to have a mean testosterone level <320 ng/dL (52% vs 48%; P=.001), and had higher mean estradiol levels (62% vs 49%; P=.003). Survival analyses estimated a breakthrough bleeding incidence rate of 0.09 per year (95% confidence interval, 0.07-1.0). Although 58 people underwent a hysterectomy during the follow-up period, 64% of the cohort who maintained a uterus eventually experienced breakthrough bleeding. The median time to the initial bleeding episode was 22 months (interquartile range, 12-201) after testosterone initiation. CONCLUSION: These results suggest that a substantial fraction of transgender and gender-diverse individuals who are using testosterone will experience at least 1 episode of breakthrough bleeding even after their initial year of testosterone use. We recommend that clinicians inform all patients that breakthrough bleeding is a common occurrence even after the first year on testosterone therapy.

Bacterial culture and susceptibility test results for clinical mastitis samples from Australia's subtropical dairy region.

This study aimed to identify the pathogens isolated from the milk of cows with clinical mastitis in the subtropical region of Australia and to determine the antimicrobial susceptibility of these bacteria. Thirty dairy herds in the subtropical dairy region were asked to submit milk samples for the first 5 cases of clinical mastitis each month for 12 mo. Samples underwent aerobic culture, and isolates were identified via MALDI-TOF mass spectrometry. Antimicrobial susceptibility was determined for Escherichia coli, Enterococcus spp., Streptococcus agalactiae, Streptococcus uberis, Streptococcus dysgalactiae, Staphylococcus aureus, and non-aureus staphylococci and mammaliicocci (NASM). Between March 2021 and July 2022, 1,230 milk samples were collected. A positive culture result was recorded for 812 (66%) of the milk samples; from these samples, 909 isolates were obtained, including 49 isolates where no identification was possible. The remaining samples were classified as having no growth (16.8%) or as being contaminated (17.2%). The most common isolates with a MALDI-TOF diagnosis (n = 909) were Strep. uberis (23.6%), followed by the NASM group (15.0%). Farms enrolled in the study were in 3 distinct locations within the subtropical dairy region: North Queensland, Southeast Queensland, and Northern New South Wales. Some variation in isolate prevalence occurred between these 3 locations. We found lower odds of a sample being positive for E. coli in North Queensland (odds ratio [OR]: 0.25; 95% confidence interval [CI]: 0.07-0.87) and higher odds in Southeast Queensland (OR: 4.01; 95% CI: 1.96-8.20) compared with the reference, Northern New South Wales. We further found higher odds of Strep. dysgalactiae in North Queensland (OR: 5.69; 95% CI: 1.85-17.54) and Southeast Queensland compared with Northern New South Wales (OR: 3.99; 95% CI: 1.73-9.22). Although some seasonal patterns were observed, season was not significant for any of the analyzed isolates. Farm-level differences in pathogen profiles were obvious. Overall, clinical mastitis pathogens had low levels of resistance to the antimicrobials tested. This research demonstrates that Strep. uberis and the NASM bacterial group are the most common pathogens causing clinical mastitis in the subtropical dairy region. It highlights the importance of understanding pathogenic causes of mastitis at the farm and regional level for targeted control and therapy.

A Description of IVIG Use in Term Neonates with ABO Incompatibility.

OBJECTIVE: This study aimed to determine if treatment with IVIG of neonates with ABO incompatibility (without Rh incompatibility) results in decreased number of packed red blood cell (pRBC) transfusions and phototherapy use. STUDY DESIGN: An Institutional Review Board (IRB)-approved, single-institution retrospective study was conducted. Neonates ≥38 weeks' gestational age born between January 1, 2007, and December 31, 2016, with ABO incompatibility were included. The comparison among groups was performed using chi-square and Fisher's exact tests for categorical variables; continuous variables were assessed by Kruskal-Wallis test. RESULTS: Six hundred and sixty-eight neonates with ABO incompatibility met inclusion criteria, 579 were included in the analyses. From these, 431 (74%) neonates had positive Direct Antiglobulin Test (DAT); 98 (17%) received IVIG and 352 (61%) received phototherapy. Thirty-six (6%) neonates received pRBC and 6 (1%) required exchange transfusions. Only 3 (0.5%) infants received pRBC transfusions postdischarge, by 3 months of age. Neonates requiring IVIG had lower initial hemoglobin (13.6 vs. 16.0 g/dL, p ≤ 0.0001) and higher bilirubin at start of phototherapy (9.1 vs. 8.1 mg/dL, p = 0.0064). From the 42 (7%) neonates who received simple and exchange transfusions, IVIG use was not associated with decreased use or number of transfusions (p = 0.5148 and 0.3333, respectively). Newborns with A+ and B+ blood types had comparable initial hemoglobin, DAT positivity, APGAR, and bilirubin. However, infants with B+ blood group were more likely (than A + ) to require phototherapy (p < 0.001), receive IVIG (p = 0.003), and need phototherapy for a longer duration (p = 0.001). CONCLUSION: The results of this large retrospective study reveal that giving IVIG to neonates with ABO incompatibility was associated with increased simple or exchange transfusions. Newborns with B+ blood type required more phototherapy and IVIG. Further studies are needed to better stratify neonates who would benefit from IVIG use in order to optimize treatment strategies and avoid unnecessary risks and adverse events. KEY POINTS: · IVIG use not associated with decreased use of pRBC or exchanges.. · Phototherapy duration associated with increased IVIG and pRBC use.. · Newborns with B+ blood type had worse hemolytic anemia..

Low-dose interleukin-2 promotes immune regulation in face transplantation: A pilot study.

Face transplantation is a life-changing procedure for patients with severe composite facial defects. However, it is hampered by high acute rejection rates due to the immunogenicity of skin allograft and toxicity linked to high doses of immunosuppression. To reduce immunosuppression-associated complications, we, for the first time in face transplant recipients, used low-dose interleukin 2 (IL-2) therapy to expand regulatory T cells (Tregs) in vivo and to enhance immune modulation, under close immunological monitoring of peripheral blood and skin allograft. Low-dose IL-2 achieved a sustained expansion (∼4-fold to 5-fold) of circulating Tregs and a reduction (∼3.5-fold) of B cells. Post-IL-2 Tregs exhibited greater suppressive function, characterized by higher expression of TIM-3 and LAG3co-inhibitory molecules. In the skin allograft, Tregs increased after low-dose IL-2 therapy. IL-2 induced a distinct molecular signature in the allograft with reduced cytotoxicity-associated genes (granzyme B and perforin). Two complications were observed during the trial: one rejection event and an episode of autoimmune hemolytic anemia. In summary, this initial experience demonstrated that low-dose IL-2 therapy was not only able to promote immune regulation in face transplant recipients but also highlighted challenges related to its narrow therapeutic window. More specific targeted Treg expansion strategies are needed to translate this approach to the clinic.

Prevalence of pelvic pain in transgender individuals on testosterone.

BACKGROUND: Pelvic pain has been reported in transmasculine individuals taking testosterone. There is a need for further investigation to increase understanding of the prevalence and risk factors of this pain. AIM: We sought to determine the prevalence of pelvic pain reported by transmasculine individuals who had both a uterus and ovaries and were taking testosterone. METHODS: We conducted an institutional review board-approved retrospective study of all transmasculine individuals who had been taking testosterone for at least 1 year and had a uterus and ovaries at the time of testosterone initiation. Charts of participating patients were reviewed to determine patient characteristics, testosterone use, and pelvic pain symptoms both before and after initiation of testosterone. OUTCOMES: Patients reported experiences of pelvic pain while on testosterone. RESULTS: Of 280 individuals who had been on testosterone for at least 1 year, 100 (36%) experienced pelvic pain while on testosterone. Of those patients, 71% (n = 71) had not experienced pelvic pain prior to starting testosterone. There were 42 patients (15%) who had pelvic pain prior to starting testosterone, 13 (31%) of whom no longer experienced pain once starting testosterone. The median (IQR) age at initiation of testosterone was 22 (19-41) years and duration of testosterone treatment was 48 (27-251) months.Those patients who experienced pelvic pain while on testosterone were significantly more likely to have also reported pelvic pain prior to starting testosterone (29% vs 7%, P < .001). These patients were also more likely to have a pre-existing diagnosis of dysmenorrhea (27% vs 7%, P < .001), endometriosis (6% vs 2%, P = .049), or ovarian cysts and/or masses (12% vs 2% P < .001). Patients with pelvic pain were also more likely to have been on a menstrual suppression agent prior to and overlapping testosterone initiation (22% vs 12%, P = .03) and to have used menstrual suppression for longer durations (median [IQR] 18 [6-44] vs 8 [4-15] months, P = .04). CLINICAL IMPLICATIONS: Pelvic pain is common in transmasculine individuals who are initiating testosterone treatment, although testosterone has both positive and negative effects on pelvic pain in different individuals. STRENGTHS AND LIMITATIONS: The major strengths of this study included large numbers of patients, ability to assess for documentation of pelvic pain prior to testosterone, and ability to determine an actual prevalence of pelvic pain. Major limitations included the study being a retrospective analysis in a single tertiary care center, the limitations of clinical documentation, and the lack of a standard pelvic pain evaluation process. CONCLUSION: More than one-third of transmasculine patients with a uterus and ovaries had pelvic pain while on testosterone, with the majority reporting onset of pain after initiating testosterone.

Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism.

Tissue-resident memory T (TRM) cells persist indefinitely in epithelial barrier tissues and protect the host against pathogens. However, the biological pathways that enable the long-term survival of TRM cells are obscure. Here we show that mouse CD8+ TRM cells generated by viral infection of the skin differentially express high levels of several molecules that mediate lipid uptake and intracellular transport, including fatty-acid-binding proteins 4 and 5 (FABP4 and FABP5). We further show that T-cell-specific deficiency of Fabp4 and Fabp5 (Fabp4/Fabp5) impairs exogenous free fatty acid (FFA) uptake by CD8+ TRM cells and greatly reduces their long-term survival in vivo, while having no effect on the survival of central memory T (TCM) cells in lymph nodes. In vitro, CD8+ TRM cells, but not CD8+ TCM cells, demonstrated increased mitochondrial oxidative metabolism in the presence of exogenous FFAs; this increase was not seen in Fabp4/Fabp5 double-knockout CD8+ TRM cells. The persistence of CD8+ TRM cells in the skin was strongly diminished by inhibition of mitochondrial FFA ß-oxidation in vivo. Moreover, skin CD8+ TRM cells that lacked Fabp4/Fabp5 were less effective at protecting mice from cutaneous viral infection, and lung Fabp4/Fabp5 double-knockout CD8+ TRM cells generated by skin vaccinia virus (VACV) infection were less effective at protecting mice from a lethal pulmonary challenge with VACV. Consistent with the mouse data, increased FABP4 and FABP5 expression and enhanced extracellular FFA uptake were also demonstrated in human CD8+ TRM cells in normal and psoriatic skin. These results suggest that FABP4 and FABP5 have a critical role in the maintenance, longevity and function of CD8+ TRM cells, and suggest that CD8+ TRM cells use exogenous FFAs and their oxidative metabolism to persist in tissue and to mediate protective immunity.

CD1a-autoreactive T cells are a normal component of the human αß T cell repertoire.

CD1 activates T cells, but the function and size of the possible human T cell repertoires that recognize each of the CD1 antigen-presenting molecules remain unknown. Using an experimental system that bypasses major histocompatibility complex (MHC) restriction and the requirement for defined antigens, we show that polyclonal T cells responded at higher rates to cells expressing CD1a than to those expressing CD1b, CD1c or CD1d. Unlike the repertoire of invariant natural killer T (NKT) cells, the CD1a-autoreactive repertoire contained diverse T cell antigen receptors (TCRs). Functionally, many CD1a-autoreactive T cells homed to skin, where they produced interleukin 22 (IL-22) in response to CD1a on Langerhans cells. The strong and frequent responses among genetically diverse donors define CD1a-autoreactive cells as a normal part of the human T cell repertoire and CD1a as a target of the T(H)22 subset of helper T cells.

Management of relapsed cutaneous T-Cell lymphoma following allogeneic hematopoietic stem cell transplantation: Review with representative patient case.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for patients with refractory cutaneous T-cell lymphoma (CTCL) through replacement of the bone marrow responsible for lymphoma cells and possibly induction of a graft-versus-lymphoma effect. However, allo-HSCT is not always curative; relapse of CTCL occurs in about half of patients post-transplant. Treatment of relapsed CTCL after allo-HSCT is challenging because post-transplant patients are at high risk of graft-versus-host disease, and this condition may be precipitated or exacerbated by standard CTCL therapies. The benefit of each potential therapy must therefore be weighed against its risk of graft versus host disease (GVHD). In this article, we review the management of relapsed CTCL after allo-HSCT. We begin with an exemplative patient whose relapsed Sezary syndrome was successfully treated without development of GVHD. We also report high-throughput T-cell receptor sequencing data obtained during the patient's disease relapse and remission. We then review general guidelines for management of relapsed CTCL and summarize all reported cases and outcomes of relapsed CTCL after transplant. We conclude by reviewing the current CTCL therapies and their risk of GVHD.

Self-Care Capacity and Its Relationship to Age, Disability, and Perceived Well-Being in Medicare Beneficiaries.

BACKGROUND: Self-care is a multicomponent set of capacities that influence beliefs about health and well-being. OBJECTIVES: We examined the relationship between self-care capacity, age, and disability status with two perceptions of well-being in a cohort of Medicare beneficiaries. METHODS: The current study is part of a multisite research project to determine factors associated with cross-sectional and longitudinal morbidity and mortality trajectories observed in Medicare beneficiaries. Variable selection was informed by the health disparities and outcomes model. Using data from the 2013 Medicare Current Beneficiary Survey and logistic regression models, we determined associations between self-care capacity, including indicators of self-care ability and self-care agency and two perceptions of well-being. Participants were divided into four groups based on how they qualified for Medicare: (a) over 65 years of age, and below 65 years of age and disabled because of (b) physical or (c) mental disorder, or (d) disabled and could not be classified as physically or mentally disabled as the primary cause of eligibility. RESULTS: Self-care ability limitations in activities of daily living (ADL), instrumental activities of living (IADL), and social activity participation were associated with both health perceptions. Those with physical disabilities reported more ADL and IADL limitations when compared with the other eligibility groups and were significantly more likely to have negative health perceptions. Those with serious mental illness were most likely to report the most severe IADL limitations. The over 65 years of age group reported less self-care incapacity than the other three eligibility types. Other components of self-care, including health literacy, agency, and health behaviors, significantly influenced perceptions of health. Women and people identifying as non-Whites were more likely to have negative health perceptions. DISCUSSION: Self-care capacity is a complex construct, and its varied elements have differential relationships with perceptions of well-being. Those with physical disabilities reported more self-care limitations, poorer perceived health, and more health worries than the other groups. Still, there were different patterns of self-care capacities in the serious mental illness type-especially in IADL limitations. The study adds empirical evidence to previous research documenting inequities in health outcomes for women and non-Whites. Findings provide empirical support for the health disparities and outcomes model.

Preoperative spinal angiography decreases risk of spinal ischemia in pediatric posterior thoracic tumor resection.

PURPOSE: Resection of pediatric posterior thoracic tumors (PTTs) can be complicated by Artery of Adamkiewicz (AKA) injury. Post-op spinal ischemia occurs in approx. 3.2% of patients, typically due to iatrogenic vascular injury. Pre-op angiography (PSA) may help to avoid this complication. Herein, we aim to evaluate outcomes after initiation of routine PSA prior to PTT resection. METHODS: A single-institution retrospective review identified 25 children (< 18 years) treated for PTTs from 2009 to 2021. PTTs included: posterior mediastinum, paraspinal thorax and posterior chest wall tumors. PSA patients were compared to those without pre-operative angiography (NA). Demographics, perioperative and long-term outcomes and event-free survival (EFS) were assessed. RESULTS: Prior to 2012, eleven patients were treated without PSA. However, the last developed post-operative paraplegia secondary to spinal ischemia. Since this event, PSA has become routine for all PTTs (n = 14) identifying six AKAs and nine accessory spinal arteries. Resection was performed in ten (90.1%) NA patients and eight (57.1%) PSA patients. Based on PSA findings, resection was not offered to six patients and planned partial resection was performed in three patients. Five PSA patients required radiation therapy for local control vs two NA patients. There were no differences in recurrence or overall EFS. CONCLUSION: PSA aids in identifying patients with high-risk thoracic vascular anatomy and may prevent risk of post-operative paraplegia associated with PTT resection.

Skin-resident natural killer T cells participate in cutaneous allergic inflammation in atopic dermatitis.

BACKGROUND: Natural killer T (NKT) cells are unconventional T cells that bridge innate and adaptive immunity. NKT cells have been implicated in the development of atopic dermatitis (AD). OBJECTIVE: We aimed to investigate the role of NKT cells in AD development, especially in skin. METHODS: Global proteomic and transcriptomic analyses were performed by using skin and blood from human healthy-controls and patients with AD. Levels of CXCR4 and CXCL12 expression in skin NKT cells were analyzed in human AD and mouse AD models. By using parabiosis and intravital imaging, the role of skin CXCR4+ NKT cells was further evaluated in models of mice with AD by using CXCR4-conditionally deficient or CXCL12 transgenic mice. RESULTS: CXCR4 and its cognate ligand CXCL12 were significantly upregulated in the skin of humans with AD by global transcriptomic and proteomic analyses. CXCR4+ NKT cells were enriched in AD skin, and their levels were consistently elevated in our models of mice with AD. Allergen-induced NKT cells participate in cutaneous allergic inflammation. Similar to tissue-resident memory T cells, the predominant skin NKT cells were CXCR4+ and CD69+. Skin-resident NKT cells uniquely expressed CXCR4, unlike NKT cells in the liver, spleen, and lymph nodes. Skin fibroblasts were the main source of CXCL12. CXCR4+ NKT cells preferentially trafficked to CXCL12-rich areas, forming an enriched CXCR4+ tissue-resident NKT cells/CXCL12+ cell cluster that developed in acute and chronic allergic inflammation in our models of mice with AD. CONCLUSIONS: CXCR4+ tissue-resident NKT cells may form a niche that contributes to AD, in which CXCL12 is highly expressed.

Induction of IL-1ß and antimicrobial peptides as a potential mechanism for topical dithranol.

Topical dithranol is effective in autoimmune conditions like alopecia areata, inducing hair regrowth in a high percentage of cases. Exact mechanisms of dithranol in alopecia areata, with seemingly healthy epidermis besides altered hair follicles, are not well understood. To better understand dithranol's mechanisms on healthy skin, we analysed its effect on normal murine as well as xenografted human skin. We found a strong increase in mRNA expression of anti-microbial peptides (AMPs) (eg Lcn2, Defb1, Defb3, S100a8, S100a9), keratinocyte differentiation markers (eg Serpinb3a, Flg, Krt16, Lce3e) and inflammatory cytokines (eg Il1b and Il17) in healthy murine skin. This effect was paralleled by inflammation and disturbed skin barrier, as well as an injury response resulting in epidermal hyperproliferation, as observed in murine and xenografted adult human skin. This contact response and disturbed barrier induced by dithranol might lead via a vicious loop between AMPs such as S100a8/a9 (that led to skin swelling itself after topical application) and cytokines such as IL-1ß to an immune suppressive environment in the skin. A better understanding of the skin's physiologic response to dithranol may open up new avenues for the establishment of novel therapeutics (including AMP-related/interfering molecules) for certain skin conditions, such as alopecia areata.

Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells.

Recent studies have demonstrated that the skin of a normal adult human contains 10-20 billion resident memory T cells, including various helper, cytotoxic, and regulatory T cell subsets, that are poised to respond to environmental antigens. Using only autologous human tissues, we report that both in vitro and in vivo, resting epidermal Langerhan cells (LCs) selectively and specifically induced the activation and proliferation of skin resident regulatory T (Treg) cells, a minor subset of skin resident memory T cells. In the presence of foreign pathogen, however, the same LCs activated and induced proliferation of effector memory T (Tem) cells and limited Treg cells' activation. These underappreciated properties of LCs, namely maintenance of tolerance in normal skin, and activation of protective skin resident memory T cells upon infectious challenge, help clarify the role of LCs in skin.

"I had hope. I loved this city once.": A mixed methods study of hope within the context of poverty.

The purpose of this emergent mixed methods study was to measure hope in individuals living in poverty and to explore potential contextual influences on hope. We used a sequential mixed methods study in which the quantitative phase was administered first followed by a qualitative phase. Participants in impoverished areas scored higher in hope than a comparison group of university students. In a follow-up qualitative phase, participants named contributors to and detractors from hope that included experiences driven by environmental factors. Findings were organized according to Ecological Systems Theory (EST). Participants named factors from all levels of EST, and interactions between levels were evident. These results and findings support the inclusion of relevant contextual factors in psychological inquiry, and we suggest deliberate inclusion of individuals from all socioeconomic groups in future positive psychological research.

Staged development of long-lived T-cell receptor αß TH17 resident memory T-cell population to Candida albicans after skin infection.

BACKGROUND: Candida albicans is a dimorphic fungus to which human subjects are exposed early in life, and by adulthood, it is part of the mycobiome of skin and other tissues. Neonatal skin lacks resident memory T (TRM) cells, but in adults the C albicans skin test is a surrogate for immunocompetence. Young adult mice raised under specific pathogen-free conditions are naive to C albicans and have been shown recently to have an immune system resembling that of neonatal human subjects. OBJECTIVE: We studied the evolution of the adaptive cutaneous immune response to Candida species. METHODS: We examined both human skin T cells and the de novo and memory immune responses in a mouse model of C albicans skin infection. RESULTS: In mice the initial IL-17-producing cells after C albicans infection were dermal γδ T cells, but by day 7, αß TH17 effector T cells were predominant. By day 30, the majority of C albicans-reactive IL-17-producing T cells were CD4 TRM cells. Intravital microscopy showed that CD4 effector T cells were recruited to the site of primary infection and were highly motile 10 days after infection. Between 30 and 90 days after infection, these CD4 T cells became increasingly sessile, acquired expression of CD69 and CD103, and localized to the papillary dermis. These established TRM cells produced IL-17 on challenge, whereas motile migratory memory T cells did not. TRM cells rapidly clear an infectious challenge with C albicans more effectively than recirculating T cells, although both populations participate. We found that in normal human skin IL-17-producing CD4+ TRM cells that responded to C albicans in an MHC class II-restricted fashion could be identified readily. CONCLUSIONS: These studies demonstrate that C albicans infection of skin preferentially generates CD4+ IL-17-producing TRM cells, which mediate durable protective immunity.

Modeling Health Disparities and Outcomes in Disenfranchised Populations.

The Health Disparities and Outcomes (HDO) model originally created to explain the complexity of obtaining healthcare in rural settings has been revised and updated using emerging theoretical models of adversity and inequity and two decades of empirical work by the authors. With a strong orientation to explaining population-based health inequities, the HDO is applied to individuals with Serious Mental Illness (SMI), to explain their high rates of morbidity and mortality compared to the general population. Individual-, community-, and system-level factors that reflect an understanding of life-long risk, accrued hazards associated with multiple and intersecting disadvantages, and difficulty obtaining healthcare that meets accepted standards are described. The revised HDO can be applied to populations with disproportionate health challenges to identify multi-level factors that affect illness trajectory and overall health outcomes.

Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity.

Protective T-cell memory has long been thought to reside in blood and lymph nodes, but recently the concept of immune memory in peripheral tissues mediated by resident memory T (T(RM)) cells has been proposed. Here we show in mice that localized vaccinia virus (VACV) skin infection generates long-lived non-recirculating CD8(+) skin T(RM) cells that reside within the entire skin. These skin T(RM) cells are potent effector cells, and are superior to circulating central memory T (T(CM)) cells at providing rapid long-term protection against cutaneous re-infection. We find that CD8(+) T cells are rapidly recruited to skin after acute VACV infection. CD8(+) T-cell recruitment to skin is independent of CD4(+) T cells and interferon-γ, but requires the expression of E- and P-selectin ligands by CD8(+) T cells. Using parabiotic mice, we further show that circulating CD8(+) T(CM) and CD8(+) skin T(RM) cells are both generated after skin infection; however, CD8(+) T(CM) cells recirculate between blood and lymph nodes whereas T(RM) cells remain in the skin. Cutaneous CD8(+) T(RM) cells produce effector cytokines and persist for at least 6 months after infection. Mice with CD8(+) skin T(RM) cells rapidly cleared a subsequent re-infection with VACV whereas mice with circulating T(CM) but no skin T(RM) cells showed greatly impaired viral clearance, indicating that T(RM) cells provide superior protection. Finally, we show that T(RM) cells generated as a result of localized VACV skin infection reside not only in the site of infection, but also populate the entire skin surface and remain present for many months. Repeated re-infections lead to progressive accumulation of highly protective T(RM) cells in non-involved skin. These findings have important implications for our understanding of protective immune memory at epithelial interfaces with the environment, and suggest novel strategies for vaccines that protect against tissue tropic organisms.