Breg-Mediated Immunoregulation in the Skin.

Wound healing is a complex process involving a coordinated series of events aimed at restoring tissue integrity and function. Regulatory B cells (Bregs) are a subset of B lymphocytes that play an essential role in fine-tuning immune responses and maintaining immune homeostasis. Recent studies have suggested that Bregs are important players in cutaneous immunity. This review summarizes the current understanding of the role of Bregs in skin immunity in health and pathology, such as diabetes, psoriasis, systemic sclerosis, cutaneous lupus erythematosus, cutaneous hypersensitivity, pemphigus, and dermatomyositis. We discuss the mechanisms by which Bregs maintain tissue homeostasis in the wound microenvironment through the promotion of angiogenesis, suppression of effector cells, and induction of regulatory immune cells. We also mention the potential clinical applications of Bregs in promoting wound healing, such as the use of adoptive Breg transfer.

Clinical and pathology characterization of small nerve fiber neuro(no)pathy in cerebellar ataxia with neuropathy and vestibular areflexia syndrome.

BACKGROUND AND PURPOSE: Biallelic mutation/expansion of the gene RFC1 has been described in association with a spectrum of manifestations ranging from isolated sensory neuro(no)pathy to a complex presentation as cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). Our aim was to define the frequency and characteristics of small fiber neuropathy (SFN) in RFC1 disease at different stages. METHODS: RFC1 cases were screened for SFN using the Neuropathic Pain Symptom Inventory and Composite Autonomic Symptom Score 31 questionnaires. Clinical data were retrospectively collected. If available, lower limb skin biopsy samples were evaluated for somatic epidermal and autonomic subepidermal structure innervation and compared to healthy controls (HCs). RESULTS: Forty patients, median age at onset 54 years (interquartile range [IQR] 49-61) and disease duration 10 years (IQR 6-16), were enrolled. Mild-to-moderate positive symptoms (median Neuropathic Pain Symptom Inventory score 12.1/50, IQR 5.5-22.3) and relevant autonomic disturbances (median Composite Autonomic Symptom Score 31 37.0/100, IQR 17.7-44.3) were frequently reported and showed scarce correlation with disease duration. A non-length-dependent impairment in nociception was evident in both clinical and paraclinical investigations. An extreme somatic denervation was observed in all patients at both proximal (fibers/mm, RFC1 cases 0.0 vs. HCs 20.5, p < 0.0001) and distal sites (fibers/mm, RFC1 cases 0.0 vs. HCs 13.1, p < 0.0001); instead only a slight decrease was observed in cholinergic and adrenergic innervation of autonomic structures. CONCLUSIONS: RFC1 disease is characterized by a severe and widespread somatic SFN. Skin denervation may potentially represent the earliest feature and drive towards the suspicion of this disorder.

Tenacibaculosis in Norwegian Atlantic salmon (Salmo salar) cage-farmed in cold sea water is primarily associated with Tenacibaculum finnmarkense genomovar finnmarkense.

Skin conditions associated with Tenacibaculum spp. constitute a significant threat to the health and welfare of sea-farmed Atlantic salmon (Salmo salar L.) in Norway. Fifteen presumptive tenacibaculosis outbreaks distributed along the Norwegian coast during the late winter and spring of 2018 were investigated. Bacteriological culture confirmed the presence of Tenacibaculum spp. Seventy-six isolates cultured from individual fish were selected and subjected to whole-genome sequencing and MALDI-TOF MS analysis. Average nucleotide identity and MALDI-TOF analyses confirmed the presence of T. finnmarkense and T. dicentrarchi, with further division of T. finnmarkense into genomovars (gv.) finnmarkense and ulcerans. Core genome multilocus sequence typing (cgMLST) and single-nucleotide polymorphism (SNP) analyses identified the presence of a genetically conserved cluster of gv. finnmarkense isolates against a background of relatively genetically diverse gv. finnmarkense and gv. ulcerans isolates in 13 of the 15 studied cases. This clustering strongly suggests a link between T. finnmarkense gv. finnmarkense and development of clinical tenacibaculosis in sea-farmed Norwegian salmon in the late winter and spring. Analysis of 25 Tenacibaculum isolates collected during the spring of 2019 from similar cases identified a similar distribution of genotypes. Low water temperatures were common to all cases, and most incidences involved relatively small fish shortly after sea transfer, suggesting that these fish are particularly predisposed to Tenacibaculum infection.

Cd34+ Stromal Cells/Telocytes in Normal and Pathological Skin.

We studied CD34+ stromal cells/telocytes (CD34+SCs/TCs) in pathologic skin, after briefly examining them in normal conditions. We confirm previous studies by other authors in the normal dermis regarding CD34+SC/TC characteristics and distribution around vessels, nerves and cutaneous annexes, highlighting their practical absence in the papillary dermis and presence in the bulge region of perifollicular groups of very small CD34+ stromal cells. In non-tumoral skin pathology, we studied examples of the principal histologic patterns in which CD34+SCs/TCs have (1) a fundamental pathophysiological role, including (a) fibrosing/sclerosing diseases, such as systemic sclerosis, with loss of CD34+SCs/TCs and presence of stromal cells co-expressing CD34 and αSMA, and (b) metabolic degenerative processes, including basophilic degeneration of collagen, with stromal cells/telocytes in close association with degenerative fibrils, and cutaneous myxoid cysts with spindle-shaped, stellate and bulky vacuolated CD34+ stromal cells, and (2) a secondary reactive role, encompassing dermatitis-e.g., interface (erythema multiforme), acantholytic (pemphigus, Hailey-Hailey disease), lichenoid (lichen planus), subepidermal vesicular (bullous pemphigoid), psoriasiform (psoriasis), granulomatous (granuloma annulare)-vasculitis (leukocytoclastic and lymphocytic vasculitis), folliculitis, perifolliculitis and inflammation of the sweat and sebaceous glands (perifolliculitis and rosacea) and infectious dermatitis (verruca vulgaris). In skin tumor and tumor-like conditions, we studied examples of those in which CD34+ stromal cells are (1) the neoplastic component (dermatofibrosarcoma protuberans, sclerotic fibroma and solitary fibrous tumor), (2) a neoplastic component with varying presentation (fibroepithelial polyp and superficial myxofibrosarcoma) and (3) a reactive component in other tumor/tumor-like cell lines, such as those deriving from vessel periendothelial cells (myopericytoma), epithelial cells (trichoepithelioma, nevus sebaceous of Jadassohn and seborrheic keratosis), Merkel cells (Merkel cell carcinoma), melanocytes (dermal melanocytic nevi) and Schwann cells (neurofibroma and granular cell tumor).

Revisiting the role of B cells in skin immune surveillance.

Whereas our understanding of the skin immune system has increased exponentially in recent years, the role of B cells in cutaneous immunity remains poorly defined. Recent studies have revealed the presence of B cells within lymphocytic infiltrates in chronic inflammatory skin diseases and cutaneous malignancies including melanoma, and have examined their functional significance in these settings. We review these findings and discuss them in the context of the current understanding of the role of B cells in normal skin physiology, as well as in both animal and human models of skin pathology. We integrate these findings into a model of cutaneous immunity wherein crosstalk between B cells and other skin-resident immune cells plays a central role in skin immune homeostasis.

Deciphering the molecular events during arsenic induced transcription signal cascade activation in cellular milieu.

Anthropogenic sources of arsenic poses and creates unintentional toxico-pathological concerns to humans in many parts of the world. The understanding of toxicity of this metalloid, which shares properties of both metal and non-metal is principally structured on speciation types and holy grail of toxicity prevention. Visible symptoms of arsenic toxicity include nausea, vomiting, diarrhea and abdominal pain. In this review, we focused on the dermal cell stress caused by trivalent arsenic trioxide and pentavalent arsanilic acid. Deciphering the molecular events involved during arsenic toxicity and signaling cascade interaction is key in arsenicosis prevention. FoxO1 and FoxO2 transcription factors, members of the Forkhead/Fox family, play important roles in this aspect. Like Foxo family proteins, ATM/CHK signaling junction also plays important role in DNA nuclear factor guided cellular development. This review will summarize and discuss current knowledge about the interplay of these pathways in arsenic induced dermal pathogenesis.

3D imaging of cleared human skin biopsies using light-sheet microscopy: A new way to visualize in-depth skin structure.

BACKGROUND: Human skin is composed of the superimposition of tissue layers of various thicknesses and components. Histological staining of skin sections is the benchmark approach to analyse the organization and integrity of human skin biopsies; however, this approach does not allow 3D tissue visualization. Alternatively, confocal or two-photon microscopy is an effective approach to perform fluorescent-based 3D imaging. However, owing to light scattering, these methods display limited light penetration in depth. The objectives of this study were therefore to combine optical clearing and light-sheet fluorescence microscopy (LSFM) to perform in-depth optical sectioning of 5 mm-thick human skin biopsies and generate 3D images of entire human skin biopsies. MATERIALS AND METHODS: A benzyl alcohol and benzyl benzoate solution was used to successfully optically clear entire formalin fixed human skin biopsies, making them transparent. In-depth optical sectioning was performed with LSFM on the basis of tissue-autofluorescence observations. 3D image analysis of optical sections generated with LSFM was performed by using the Amira® software. RESULTS: This new approach allowed us to observe in situ the different layers and compartments of human skin, such as the stratum corneum, the dermis and epidermal appendages. With this approach, we easily performed 3D reconstruction to visualise an entire human skin biopsy. Finally, we demonstrated that this method is useful to visualise and quantify histological anomalies, such as epidermal hyperplasia. CONCLUSION: The combination of optical clearing and LSFM has new applications in dermatology and dermatological research by allowing 3D visualization and analysis of whole human skin biopsies.

The relationship between skin symptoms and the scleroderma modification of the health assessment questionnaire, the modified Rodnan skin score, and skin pathology in patients with systemic sclerosis.

OBJECTIVE: To determine how well skin symptoms considered specific to SSc are captured by patient reported outcomes currently used for assessing patients with SSc, the SHAQ, or skin disease, the Skindex-29; and how well these symptoms correlate with the extent of skin disease on physical exam and skin pathology. METHODS: SSc patients completed the scleroderma modification of the Health Assessment Questionnaire (SHAQ), Skindex-29 and a Skin Symptom Assessment questionnaire developed for this study. Correlations were assessed between the Skin Symptom Assessment and SHAQ, Skindex-29, modified Rodnan skin score, and skin pathological features including myofibroblast staining completed on the same date. RESULTS: Tight, hard and rigid/stiff skin symptoms correlated moderately highly with the modified Rodnan skin score (r = 0.445, P = 0.0008; r = 0.486, P = 0.0002; and r = 0.488, P = 0.0002, respectively). Tight skin symptoms correlated moderately with myofibroblast infiltration (r = 0.544, P = 0.0023) and hyalinized collagen (r = 0.442, P = 0.0164), while both hard and rigid/stiff skin correlated moderately with inflammation (r = 0.401, P = 0.0310 and r = 0.513, P = 0.0045), myofibroblast infiltration(r = 0.480, P = 0.0084 and r = 0.527, P = 0.0033) and hyalinized collagen (r = 0.453, P = 0.0137 and r = 0.478, P = 0.0087), while the SHAQ was not found to correlate with any of these pathological changes. In contrast, painful skin symptoms correlated moderately with the SHAQ (r = 0.413, P = 0.0073), and with the three domains of Skindex-29: Symptoms, Emotions and Functioning. Skindex-29 indicates that dcSSc patient skin symptoms are nearly as severe as those of patients with psoriasis or atopic dermatitis. CONCLUSION: Patient reported skin symptoms correlate with clinical and pathological measures in the skin. A validated patient reported skin symptom instrument might considerably improve evaluation of SSc skin disease.

Cutaneous manifestations in inflammatory bowel disease: a single institutional study of non-neoplastic biopsies over 13 years.

BACKGROUND: Skin is commonly affected by extraintestinal manifestations of inflammatory bowel disease (IBD), but a controlled, systematic histopathologic analysis of cutaneous lesions is lacking. METHODS: A total of 4147 classified IBD [Crohn disease (CD) or ulcerative colitis (UC); 2000-2013] resections were cross referenced with skin biopsies. Associated non-neoplastic skin biopsies were categorized by basic reaction pattern and neutrophilic vs. granulomatous. RESULTS: Of 4147 patients, 133 had non-neoplastic skin biopsies (106/2772, 3.7% CD; 27/1375, 2% UC). Overall, miscellaneous > nodular and diffuse dermal > spongiotic dermatitides were most common (31.6, 21.8 and 15%, respectively). Spongiotic dermatitis, vasculitis, panniculitis and infections showed CD bias. Psoriasiform, perivascular, nodular/diffuse dermal and bullous categories, as well as neutrophilic processes, showed UC bias. Leukocytoclastic vasculitis, panniculitis and pyoderma gangrenosum were exclusive to CD and psoriasis vulgaris to UC. One CD patient had inverse psoriasis. CONCLUSIONS: Our findings show the majority of dermatopathologic manifestations of IBD to have overlapping histology or pathophysiology to intestinal disease; with a wider spectrum of histologic patterns than typically discussed. Diseases 'classically' associated with IBD are relatively rare biopsy specimens. Cutaneous manifestations of IBD are more common in CD than UC and should be considered when reviewing an unexplained skin lesion in an IBD patient.

Dermatologic Conditions Following Limb Loss.

The use of prostheses in individuals with limb loss increases the risk of maceration, friction, and pressure-induced skin injuries due to the vulnerability of the residual limb and the close contact with the socket. Poorly fitting prostheses exacerbate these issues, especially for those with immunosuppression or vascular conditions. Skin pathologies disrupt daily prosthetic limb use and impact the independence of those with limb loss. Preventive measures, including proper prosthesis socket fitting and meticulous skin care, are crucial. This review explores residual limb-site skin pathologies and details current mitigation and management strategies.

Cutaneous Sarcoidosis Induced by Laser Therapy: Case Report and Review of the Literature.

BACKGROUND: Sarcoidosis, characterized by non-caseating epithelioid granulomas, presents diagnostic and therapeutic challenges. METHOD: Here we present a 38-year-old woman who exhibited erythematous and infiltrated skin lesions on her facial region following fractional laser treatment. RESULTS: Histological analysis confirmed cutaneous sarcoidosis. Initial interventions with topical clobetasol and oral chloroquine provided transient relief. Subsequent outpatient management comprised topical tacrolimus and clobetasol, as well as systemic methotrexate, later substituted with prednisone. Gradual tapering resulted in lesion reduction. CONCLUSIONS: This case underscores the intricate nature of cutaneous sarcoidosis and the necessity for personalized therapeutic approaches. The association with cosmetic procedures highlights the importance of understanding potential triggers. The presented case highlights and reminds the medical community that lasers are not only used for therapeutic purposes but can also induce specific responses through laser therapy. Notably, while laser therapy is frequently employed in treating cutaneous sarcoidosis, its role in inducing sarcoidosis warrants further investigation.

What factors influence cellular pathologists' confidence in case reporting?

Histopathology is a challenging interpretive discipline, and the level of confidence a pathologist has in their diagnosis is known to vary, which is conveyed descriptively in pathology reports. There has been little study to accurately quantify pathologists' diagnostic confidence or the factors that influence it. In this study involving sixteen pathologists from six NHS trusts, we assessed diagnostic confidence across multiple variables and four specialties. Each case was reported by four pathologists, with each pathologist reporting each case twice (on light microscopy (LM) and digital pathology (DP)). For each diagnosis, pathologists recorded their confidence on a 7-point Likert scale. This provided 16,187 diagnoses and associated confidence scores for analysis. All variables investigated were found to be significantly predictive of diagnostic confidence, except level of pathologist experience. Confidence was lower for difficult to report cases, cases where there was inter- and intra-pathologist variation in the diagnosis, and cases where the pathologist made an incorrect diagnosis. Confidence was higher, although nominally, for LM diagnoses than DP (rate ratio 1.09 (95% CI 1.01-1.18), p = 0.035), although results indicate pathologists are confident to report on DP. Lowest confidence scores were seen in areas of known diagnostic complexity and cases with quality issues. High confidence in incorrect diagnoses were almost invariably attributed to interpretive diagnostic differences which occurred across both rare and common lesions. The results highlight the value of external quality control schemes and the benefits of selective peer review when reporting.

Mapping epidermal and dermal cellular senescence in human skin aging.

Single-cell RNA sequencing and spatial transcriptomics enable unprecedented insight into cellular and molecular pathways implicated in human skin aging and regeneration. Senescent cells are individual cells that are irreversibly cell cycle arrested and can accumulate across the human lifespan due to cell-intrinsic and -extrinsic stressors. With an atlas of single-cell RNA-sequencing and spatial transcriptomics, epidermal and dermal senescence and its effects were investigated, with a focus on melanocytes and fibroblasts. Photoaging due to ultraviolet light exposure was associated with higher burdens of senescent cells, a sign of biological aging, compared to chronological aging. A skin-specific cellular senescence gene set, termed SenSkin™, was curated and confirmed to be elevated in the context of photoaging, chronological aging, and non-replicating CDKN1A+ (p21) cells. In the epidermis, senescent melanocytes were associated with elevated melanin synthesis, suggesting haphazard pigmentation, while in the dermis, senescent reticular dermal fibroblasts were associated with decreased collagen and elastic fiber synthesis. Spatial analysis revealed the tendency for senescent cells to cluster, particularly in photoaged skin. This work proposes a strategy for characterizing age-related skin dysfunction through the lens of cellular senescence and suggests a role for senescent epidermal cells (i.e., melanocytes) and senescent dermal cells (i.e., reticular dermal fibroblasts) in age-related skin sequelae.

Podiatric Skin and Nail Involvement and Biomechanical Pathology in Renal Transplant Recipients: Assessment of the Foot as a Contributing Factor to Their Health.

Although several studies show the prevalence of podiatric conditions in people with end-stage renal disease or renal replacement therapy with hemodialysis, there is little scientific literature on this when subjects are undergoing kidney transplantation. The aim of this study is to determine the prevalence of podiatric skin and nail pathology in renal transplant recipients. A descriptive, observational, prevalence study was conducted at the Nephrology Department of the University Hospital of A Coruña. A total of 371 subjects were studied. The variables studied were sociodemographic (age, sex), anthropometric (Body Mass Index), comorbidity (Charlson Comorbidity Index), and podological (skin and nail alterations). A high presence of skin (83.1%) and nail pathology (85.4%) was observed, with hyperkeratosis (68.8%), onychogryphosis (39.4%), and onychocryptosis (36.9%) being the most predominant alterations. Although it was not significant, patients with a higher risk of presenting podiatric pathology were of female sex and had a high BMI, and both age and the Charlson comorbidity index were significantly associated with this risk. There was an increased risk of both skin and nail pathology at older age and in the presence of diabetes mellitus.

Case Report: Acquired collagenoma on the dorsum of the foot.

Collagenoma is a rare benign skin lesion classified as a hamartomatous proliferation of normal collagen fibres and varying amounts of elastic fibres. They most frequently occur on the arms or trunk and may present as solitary or multiple lesions, as part of a syndrome (such as Cowden Syndrome, Tuberous Sclerosis, or MEN1) or sporadic and of varying sizes. Herein, we report on a case of large acquired collagenomas found in an unusual location on the dorsum of both feet.

Linear Cutaneous Lupus Erythematosus Following Blaschko's Lines on the Scalp: Additional Cases and Review of the Literature.

Description Alopecia of the scalp has various causes and presentations. However, linear alopecia is unusual and lupus erythematosus presenting as linear alopecia is exceedingly rare. To date, there have been 16 documented cases of linear alopecia diagnosed as chronic cutaneous lupus erythematosus occurring in a linear configuration following Blaschko's lines. We report 2 additional cases and review the clinical and histologic features along with treatment. This Blaschkoid linear variant of cutaneous lupus erythematosus has distinct clinical and histologic characteristics that set it apart from other causes of alopecia and from classic forms of cutaneous lupus. These distinct features include a linear configuration, a younger age of presentation, a disproportionate number of Asians affected, and a paucity of cases with systemic involvement. Histologically, the lesions are characterized by prominent mucin in the dermis and subcutaneous tissues. Blaschkoid linear lupus of the scalp is sufficiently distinctive to suggest the diagnosis on histology alone, in the appropriate clinical context. The most common and successful treatments included systemic and/or combination treatment with oral hydroxychloroquine, oral steroids, and/or intralesional steroids.

Does the development and implementation of a procedure-specific proforma for skin lesion surgery improve quality of operation notes?

BACKGROUND: Operation notes often have omissions and are difficult to locate in patients notes despite clear guidance from the Royal College of Surgeons (RCS) 'Good Surgical Practice' 2014 outlining what should be included in operation notes. Procedure-specific proformas are rarely used by Plastic surgeons despite being utilised by other specialities. With an alarming rise of incidence of skin malignancies there has been an increase in the number of skin lesions referred to Plastic surgeons for excision. The need for reliable, reproducible, accurate and easily accessible operating notes for skin lesion excision is pivotal for continuity of care and treatment planning. This study aimed at comparing the quality of skin lesion operation notes prior-to and after implementation of a procedure-specific proforma in relation to RCS recommendations. METHODS: Fourteen parameters from the recommendations by the RCS 'Good Surgical Practice' 2014 guidelines were used to audit skin lesion operation notes. The study consisted of a retrospective audit of 80 operation notes and a prospective audit of 80 operation notes following the development and implementation of a skin lesion procedure-specific proforma. We assessed and compared the operation notes overall compliance with the RCS guidelines. Statistical analysis highlighting the difference between both groups was performed using the independent sample t-test. RESULTS: After implementation of the skin lesion procedure-specific proforma, the average compliance with the RCS recommendations increased significantly from 87.5% retrospectively to 98.8% prospectively (p-value 0.0414). In 6 of the 14 parameters assessed significant improvements with regards compliance to the guidelines was demonstrated. CONCLUSION: The development and implementation of a skin lesion procedure-specific proforma has demonstrated a significant improvement in the quality of operation notes within a Plastic surgery department which has the potential to minimise omissions and improve continuity of surgical patient care.

Necrobiosis lipoidica-like lesions in a nondiabetic patient with systemic sarcoidosis: A case report and review of the literature.

Necrobiosis lipoidica-like lesions, in known cases of sarcoidosis, can be considered as a member of the broad spectrum of histologic changes in sarcoidosis.

Extracellular Vesicles in Trypanosomatids: Host Cell Communication.

Trypanosoma cruzi, Trypanosoma brucei and Leishmania (Trypanosomatidae: Kinetoplastida) are parasitic protozoan causing Chagas disease, African Trypanosomiasis and Leishmaniases worldwide. They are vector borne diseases transmitted by triatomine bugs, Tsetse fly, and sand flies, respectively. Those diseases cause enormous economic losses and morbidity affecting not only rural and poverty areas but are also spreading to urban areas. During the parasite-host interaction, those organisms release extracellular vesicles (EVs) that are crucial for the immunomodulatory events triggered by the parasites. EVs are involved in cell-cell communication and can act as important pro-inflammatory mediators. Therefore, interface between EVs and host immune responses are crucial for the immunopathological events that those diseases exhibit. Additionally, EVs from these organisms have a role in the invertebrate hosts digestive tracts prior to parasite transmission. This review summarizes the available data on how EVs from those medically important trypanosomatids affect their interaction with vertebrate and invertebrate hosts.