Human Regulatory T Cells: Understanding the Role of Tregs in Select Autoimmune Skin Diseases and Post-Transplant Nonmelanoma Skin Cancers.

Regulatory T cells (Tregs) play an important role in maintaining immune tolerance and homeostasis by modulating how the immune system is activated. Several studies have documented the critical role of Tregs in suppressing the functions of effector T cells and antigen-presenting cells. Under certain conditions, Tregs can lose their suppressive capability, leading to a compromised immune system. For example, mutations in the Treg transcription factor, Forkhead box P3 (FOXP3), can drive the development of autoimmune diseases in multiple organs within the body. Furthermore, mutations leading to a reduction in the numbers of Tregs or a change in their function facilitate autoimmunity, whereas an overabundance can inhibit anti-tumor and anti-pathogen immunity. This review discusses the characteristics of Tregs and their mechanism of action in select autoimmune skin diseases, transplantation, and skin cancer. We also examine the potential of Tregs-based cellular therapies in autoimmunity.

A protocol to detect human CD4+ T cell extracellular traps using scanning electron microscopy.

We present a protocol to detect extracellular traps (ETs) induced by Cutibacterium acnes in cultured TH17 clones. We first describe the isolation of C. acnes-specific TH17 clones by sterile cell sorting. We then detail the in vitro induction of ETs in TH17 clones stimulated by C. acnes and the imaging of released ETs using scanning electron microscopy. This protocol can be applied to the study of other ETs released by other T cell subsets. For complete details on the use and execution of this protocol, please refer to Agak et al. (2021).1.

T-Cell Mediated Immunity in Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is a rare and frequently lethal skin cancer with neuroendocrine characteristics. MCC can originate from either the presence of MCC polyomavirus (MCPyV) DNA or chronic ultraviolet (UV) exposure that can cause DNA mutations. MCC is predominant in sun-exposed regions of the body and can metastasize to regional lymph nodes, liver, lungs, bone, and brain. Older, light-skinned individuals with a history of significant sun exposure are at the highest risk. Previous studies have shown that tumors containing a high number of tumor-infiltrating T-cells have favorable survival, even in the absence of MCPyV DNA, suggesting that MCPyV infection enhances T-cell infiltration. However, other factors may also play a role in the host antitumor response. Herein, we review the impact of tumor infiltrating lymphocytes (TILs), mainly the CD4+, CD8+, and regulatory T-cell (Tregs) responses on the course of MCC, including their role in initiating MCPyV-specific immune responses. Furthermore, potential research avenues related to T-cell biology in MCC, as well as relevant immunotherapies are discussed.

T Cell Extracellular Traps: Tipping the Balance Between Skin Health and Disease.

The role of extracellular traps (ETs) in the innate immune response against pathogens is well established. ETs were first identified in neutrophils and have since been identified in several other immune cells. Although the mechanistic details are not yet fully understood, recent reports have described antigen-specific T cells producing T cell extracellular traps (TETs). Depending on their location within the cutaneous environment, TETs may be beneficial to the host by their ability to limit the spread of pathogens and provide protection against damage to body tissues, and promote early wound healing and degradation of inflammatory mediators, leading to the resolution of inflammatory responses within the skin. However, ETs have also been associated with worse disease outcomes. Here, we consider host-microbe ET interactions by highlighting how cutaneous T cell-derived ETs aid in orchestrating host immune responses against Cutibacterium acnes (C. acnes), a commensal skin bacterium that contributes to skin health, but is also associated with acne vulgaris and surgical infections following joint-replacement procedures. Insights on the role of the skin microbes in regulating T cell ET formation have broad implications not only in novel probiotic design for acne treatment, but also in the treatment for other chronic inflammatory skin disorders and autoimmune diseases.

Persistence of Gender Bias Over Four Decades of Surgical Training.

OBJECTIVE: Female surgeons face gender-specific obstacles during residency training, yet longitudinal data on gender bias experienced by female surgery residents are lacking. We aimed to investigate the evolution of gender bias, identify obstacles experienced by female general surgery residents, and discuss approaches to supporting female surgeons during residency training. METHODS: Between August 2019 and January 2021, we conducted a retrospective cohort study using structured telephone interviews of female graduates of the UCLA General Surgery Residency training program. Responses of early graduates (1981-2009) were compared with those of recent graduates (2010-2020). Quantitative data were compared with Fisher's exact tests and Chi-squared tests. Interview responses were reviewed to catalog gender bias, obstacles experienced by female surgeons, and advice offered to training programs to address women's concerns. RESULTS: Of 61 female surgery residency graduates, 37 (61%) participated. Compared to early graduates (N = 20), recent graduates (N = 17) were significantly more likely to pursue fellowship training (100% vs. 65%, p < 0.01) and have children before or during residency (65% vs. 25%, p = 0.02). A substantial proportion in each cohort experienced some form of gender bias (71% vs. 85%, p = 0.43). Compared to early graduates, recent graduates were significantly less likely to report experiencing explicit gender bias (12% vs. 50%, p = 0.02) but equally likely to report implicit gender bias (71% vs. 55%, p = 0.50). Female graduates across the decades advocated for specific measures to champion work-life balance in residency (51%), strengthen female mentorship (49%), increase childcare support (41%), and promote women into leadership positions (32%). CONCLUSIONS: While having children during residency has become more common and accepted over the decades, female surgery residents continue to experience implicit gender bias in the workplace. Female surgeons advocate for targeted interventions to establish systems for parental leave, address gender bias, and strengthen female mentorship.

Multiple Cytokines Elevated in Patients with Keloids: Is It an Indication of Auto-Inflammatory Disease?

BACKGROUND: Inflammation seems to play a major role in the pathophysiology of keloids. However, the role of cytokines in keloid pathophysiology has not been fully evaluated with only a few cytokines studied. We undertook this study to compare various cytokines in patients with keloids and a control group of patients without keloids nor family history of keloids so as to determine which cytokines are elevated and could thus be critical in keloid formation. METHODS: This was a cross-sectional study of patients with keloids and a control group of those without. Patients in both groups were matched for age, sex and body mass index. Their plasma was analyzed for both inflammatory and anti-inflammatory cytokines using the Bio-flex ElisaTM method. Comparisons of cytokines means in both groups were done using Student's t-test. RESULTS: A total of 84 participants with 42 participants in each group were followed during the study. Male to female ratio was 1:2. Age ranges were similar with a mean of 29.6 years. A total of 28 cytokines were assayed. Statistically significant differences were noted in 15 of the 28 cytokines assayed with 11 being elevated more in keloid patients with only four in the non-keloid forming group. Among elevated cytokines in keloid patients were granulocyte colony-stimulating factors, granulocyte-monocyte-colony-stimulating factors, interleukins 4, 6 and 13. CONCLUSION: Patients with keloids have significantly higher cytokines compared with non-keloid forming patients. This finding suggests that keloid formation could be influenced by multiple inflammatory cytokines, an indication that the patient's immune system could play a role in keloid formation akin to auto-inflammatory disease.

Does Keloid Histology Influence Recurrence?

ABSTRACT: Keloids are fibroproliferative disorders characterized by high recurrence rates, with few factors known to influence the same. We conducted a study to determine whether keloid histology influences recurrence. This was a prospective longitudinal study to determine whether histopathological parameters of keloid influence recurrence. Patients with keloids managed by surgical excision were followed up at Kenyatta National Hospital between August 2018 and July 2020. The excised keloids were processed for histology using hematoxylin,/eosin, Masson, and trichrome stains. The slides were analyzed for inflammatory cells, fibroblasts, and capillary density using the hot spot technique and correlated to keloid recurrence. Postoperative follow-up was for a minimum of 1 year. A total of 90 patients with 104 keloids were recruited in the study. Overall keloid recurrence rate was 28.6%. There was a correlation between the absolute count of more than 50 per High power field of lymphocytes, fibroblasts, and macrophages with recurrence of the disease. The sensitivity and specificity for the above parameters were lymphocytes 48% and 81%, macrophages 57% and 83%, mast cells 32% and 33%, and fibroblasts 41% and 91%, respectively. There was no correlation between mast cells and vascularity status with recurrence. Routine histology should, therefore, be performed to determine these parameters. Close monitoring and second-line therapy should be considered for patients with elevated macrophages and/or lymphocytes so as to reduce the risk of recurrence.

Phenotype and Antimicrobial Activity of Th17 Cells Induced by Propionibacterium acnes Strains Associated with Healthy and Acne Skin.

Studies of the human skin microbiome suggest that Propionibacterium acnes strains may contribute differently to skin health and disease. However, the immune phenotype and functions of T helper type 17 (Th17) cells induced by healthy (PH) versus acne (PA) skin-associated P. acnes strains are currently unknown. We stimulated peripheral blood mononuclear cells from healthy donors and observed that PA strains induce higher IL-17 levels than PH strains. We next generated PH and PA strain-specific Th17 clones and show that P. acnes strains induce Th17 cells of varied phenotype and function that are stable in the presence of IL-2 and IL-23. Although PH- and PA-specific clones expressed similar levels of LL-37 and DEFB4, only PH-specific clones secreted molecules sufficient to kill P. acnes. Furthermore, electron microscopic studies showed that supernatants derived from activated PH and not PA-specific clones exhibited robust bactericidal activity against P. acnes, and complete breaches in the bacterial cell envelope were observed. This antimicrobial activity was independent of IL-26, because both natural IL-26 released by Th17 clones and rhIL-26 lacked antimicrobial potency against P. acnes. Overall, our data suggest that P. acnes strains may differentially modulate the CD4+ T-cell responses, leading to the generation of Th17 cells that may contribute to either homeostasis or acne pathogenesis.