Myron Gordon Award paper: Microbes, T-cell diversity and pigmentation.

Melanocytes are static, minimally proliferative cells. This leaves them vulnerable in vitiligo. Yet upon malignant transformation, they form vicious tumors. This profound switch in physiology is accompanied by genetic change and is driven by environmental factors. If UV exposure in younger years supports malignant transformation and melanoma formation, it can likewise impart mutations on melanocytes that reduce their viability, to initiate vitiligo. A wide variety of microbes can influence these diametrically opposed outcomes before either disease takes hold. These microbes are vehicles of change that we are only beginning to study. Once a genetic modification occurs, there is a wide variety of immune cells ready to respond. Though it does not act alone, the T cell is among the most decisive responders in this process. The same biochemical process that offered the skin protection by producing melanin can become an Achilles heel for the cell when the T cells target melanosomal enzymes or, on occasion, neoantigens. T cells are precise, determined, and consequential when they strike. Here, we probe the relationship between the microbiome and its metabolites, epithelial integrity, and the activation of T cells that target benign and malignant melanocytes in vitiligo and melanoma.

Roles of inflammation factors in melanogenesis (Review).

The occurrence of hyperpigmentation or hypopigmentation after inflammation is a common condition in dermatology and cosmetology. Since the exact mechanism of its occurrence is not yet known, prevention and treatment are troublesome. Previous studies have confirmed that α­melanocyte­stimulating hormone, stem cell factor and other factors can promote melanogenesis­related gene expression through the activation of signaling pathways. Recent studies have revealed that a variety of inflammatory mediators can also participate in the regulation of melanogenesis in melanocytes. In this review, we summarized that interleukin­18, interleukin­33, granulocyte­macrophage colony stimulating factor, interferon­Î³, prostaglandin E2 have the effect of promoting melanogenesis, while interleukin­1, interleukin­4, interleukin­6, interleukin­17 and tumor necrosis factor can inhibit melanogenesis. Further studies have found that these inflammatory factors may activate or inhibit melanogenesis­related signaling pathways (such as protein kinase A and mitogen activated protein kinase) by binding to corresponding receptors, thereby promoting or inhibiting the expression of melanogenesis­related genes and regulating skin pigmentation processes. This suggests that the development of drugs or treatment methods from the perspective of regulating inflammation can provide new ideas and new targets for the treatment of pigmented dermatosis. This review outlines the current understanding of the inflammation factors' roles in melanogenesis.

Case Series: Gene Expression Analysis in Canine Vogt-Koyanagi-Harada/Uveodermatologic Syndrome and Vitiligo Reveals Conserved Immunopathogenesis Pathways Between Dog and Human Autoimmune Pigmentary Disorders.

Vogt-Koyanagi-Harada syndrome (VKH) and vitiligo are autoimmune diseases that target melanocytes. VKH affects several organs such as the skin, hair follicle, eyes, ears, and meninges, whereas vitiligo is often limited to the skin and mucosa. Many studies have identified immune genes, pathways and cells that drive the pathogeneses of VKH and vitiligo, including interleukins, chemokines, cytotoxic T-cells, and other leukocytes. Here, we present case studies of 2 canines with VKH and 1 with vitiligo, which occurred spontaneously in client-owned companion dogs. We performed comparative transcriptomics and immunohistochemistry studies on lesional skin biopsies from these cases in order to determine if the immunopathogenesis of autoimmune responses against melanocytes are conserved. In dogs, we found enrichment of T cell gene signatures, with upregulation of IFNG, TNF, PRF1, IL15, CTSW, CXCL10, and CCL5 in both VKH and vitiligo in dogs compared to healthy controls. Similar findings were reported in humans, suggesting that these genes play a role in the pathogenesis of spontaneous VKH and vitiligo. T cell-associated genes, including FOXP3 and TBX21, were enriched, while IGFBP5, FOXO1, and PECAM1 were decreased compared to healthy controls. Further, we identified TGFB3, SFRP2, and CXCL7 as additional potential drivers of autoimmune pigmentary disorders. Future studies exploring the immunopathogenesis of spontaneous autoimmunity will expand our understanding of these disorders, and will be useful in developing targeted therapies, repurposing drugs for veterinary and human medicine, and predicting disease prognosis and treatment response.

Cutaneous sequelae in neonatal lupus: A retrospective cohort study.

BACKGROUND: Cutaneous eruptions in neonatal lupus erythematosus (NLE) are thought to be self-resolving. Limited literature suggests cutaneous changes may persist. OBJECTIVE: To characterize cutaneous residua in NLE and identify predictors for their development. METHODS: A retrospective cohort study of patients with cutaneous NLE born between January 1980 and May 2017 was performed. Primary outcome was the proportion of patients with cutaneous residua. Secondary outcomes included associations/predictors of sequelae. RESULTS: At the last follow-up, at a mean age of 4 years (range, 0.5-18.7 years), 34% of 106 patients had cutaneous sequelae, 13% had telangiectasia, 17% had dyspigmentation, and 9% had atrophic scarring. Scarring at the last follow-up was significantly associated with the presence of skin lesions at birth (P < .001). LIMITATIONS: This study was limited by the retrospective design, short follow-up duration in a subset of patients, and small sample size. CONCLUSION: Cutaneous NLE can exhibit long-term cutaneous residua. These findings underlie the importance of accurate diagnosis, long-term monitoring, and appropriate counseling.

NK cell defects in X-linked pigmentary reticulate disorder.

X-linked reticulate pigmentary disorder (XLPDR, Mendelian Inheritance in Man #301220) is a rare syndrome characterized by recurrent infections and sterile multiorgan inflammation. The syndrome is caused by an intronic mutation in POLA1, the gene encoding the catalytic subunit of DNA polymerase-α (Pol-α), which is responsible for Okazaki fragment synthesis during DNA replication. Reduced POLA1 expression in this condition triggers spontaneous type I interferon expression, which can be linked to the autoinflammatory manifestations of the disease. However, the history of recurrent infections in this syndrome is as yet unexplained. Here we report that patients with XLPDR have reduced NK cell cytotoxic activity and decreased numbers of NK cells, particularly differentiated, stage V, cells (CD3-CD56dim). This phenotype is reminiscent of hypomorphic mutations in MCM4, which encodes a component of the minichromosome maintenance (MCM) helicase complex that is functionally linked to Pol-α during the DNA replication process. We find that POLA1 deficiency leads to MCM4 depletion and that both can impair NK cell natural cytotoxicity and show that this is due to a defect in lytic granule polarization. Altogether, our study provides mechanistic connections between Pol-α and the MCM complex and demonstrates their relevance in NK cell function.

Congenital Hypopigmentary Disorders with Multiorgan Impairment: A Case Report and an Overview on Gray Hair Syndromes.

The term congenital hypopigmentary disorders refers to a wide group of heterogeneous hereditary diseases, clinically characterized by inborn pigmentary defects of the iris, hair, and/or skin. They include Gray Hair Syndromes (GHSs), a rare group of autosomal recessive genodermatosis hallmarked by inborn silvery gray hair. GHSs encompass Griscelli, Chediak⁻Higashi, Elejalde, and Cross syndromes, which are all characterized by a broad spectrum of severe multisystem disorders, including neurological, ocular, skeletal, and immune system impairment. In this manuscript, we describe in detail the clinical, trichoscopic, and genetic features of a rare case of Griscelli syndrome; moreover, we provide an overview of all the GHSs known to date. Our report highlights how an accurate clinical examination with noninvasive methods, like trichoscopy, may play a crucial rule in diagnosis of rare and potentially lethal genetic syndromes such as Griscelli syndrome, in which timely diagnosis and therapy may modify the clinical course, quality of life, and likelihood of survival.

Acquired diffuse slate-grey facial dyspigmentation due to henna: an unrecognized cause of pigment contact dermatitis in Korean patients.

Henna is a vegetable hair dye that can be used by individuals who are sensitized to oxidative dyes due to low allergenicity. The reported incidence of slate-grey facial dyspigmentation following the use of henna hair dye is extremely rare. This study aimed to identify the clinical, dermoscopic, and histopathological features of slate-grey facial dyspigmentation following the use of henna hair dye in Korean patients. We identified all patients who presented with slate-grey facial dyspigmentation following usage of henna hair dye. Patients were further evaluated for clinical, dermoscopic, and histopathological findings along with their patch test results. All 11 patients were females with Fitzpatrick's skin phototype III or IV. Prominent slate-grey-coloured dyspigmentation on the lateral side of the face and neck was most common in eight (72%) patients. Under dermoscopic examination, a pseudo-network with grey dots was observed in all patients. Histopathological examination revealed liquefaction degeneration of the epidermal basal layer and pigmentary incontinence in the papillary dermis in all patients. The diagnosis of pigmented contact dermatitis following usage of henna was made based on the clinical, dermoscopic, and histopathological findings in all patients. Pigmented contact dermatitis associated with henna occurs mostly in middle-aged women and requires long-term treatment. Therefore, careful attention should be paid when henna is used to dye hair in this age group.

Three cases of pigmented cosmetic dermatitis-like eruptions associated with primary Sjögren's syndrome or anti-SSA antibody.

Pigmented cosmetic dermatitis-like (Riehl's melanosis-like) pigmentation was reported in three of 27 patients with primary Sjögren's syndrome. But case reports of such eruptions are rare. We describe three cases of such eruptions associated with primary Sjögren's syndrome or anti-SSA antibody and possible associations with specific types of human leukocyte antigen (HLA) and infiltrating lymphocytes. These middle-aged Japanese women had reticular facial pigmentation and histopathological examination revealed interface dermatitis, melanophages, and dense lymphocytic infiltration around hair follicles and sweat ducts. HLA typing revealed common antigenic equivalents or genetic typing of HLA-A2, DR52, DPA1(02:02) and DPB1(05:01). Immunohistochemical staining revealed major subsets of T cells to be CD8 and CD45RO. Some Foxp3- and few IL17-positive cells were found in strong contrast to the major CD4 subset of infiltrated T cells in annular erythema associated with Sjögren's syndrome. Apparently, our patients' pigmentation represented a specific etiology associated with primary Sjögren's syndrome or anti-SSA antibody.

Immunotherapy-induced leukoderma from treatment of melanoma with IL-2: a case report and a review of the literature.

Melanoma-associated leukoderma (MAL) is a relatively uncommon phenomenon in the literature that can present (1) before melanoma detection, (2) after detection and before treatment, and (3) after treatment with immunotherapeutic agents. We report a case of MAL in an 83-year-old man after treatment with high dose IL-2 for metastatic melanoma and further describe the literature of the underlying mechanisms behind it that involve the immune system. Cytotoxic CD8+ T cells are thought the mediate the process at a cellular level. Self-antigens (e.g. MART-1/2, gp100, tyrosinase) have been presented on the surface of both normal and malignant melanocytes and mediate the development of MAL after cytotoxic CD8+ T cells attack both cell types. Autoimmune manifestations have a positive effect on tumor immunity, with patients at stage III and stage IV melanoma showing a better prognosis after leukoderma development. In addition, immunotherapy induced leukoderma has been associated with a higher therapeutic response rate. Recently, newer immuno-therapeutic drugs, such as vemurafenib and ipilimumab, have been associated with leukoderma as a side effect.

Melanocyte-specific CD8+ T cells are associated with epidermal depigmentation in a novel mouse model of vitiligo.

In the present study, we established a novel murine model of vitiligo by sequential prime/boost immunizations into the hind footpad and tail dermis with tyrosinase-related protein 2 (TRP2)-180 (SVYDFFVWL) peptide, lipopolysaccharides and cytosine-phosphate-guanosine (CpG) oligodeoxynucleotides. Immunized mice developed epidermal depigmentation in the tail skin without hair depigmentation, thereby differentiating this approach from established models of vitiligo. Following intradermal tail immunization, activated CD8(+) interferon (IFN)-γ(+) T cells were recruited locally to the tail skin. In-vivo cytotoxicity assays demonstrated specific lysis of TRP2-180-presenting cells in immunized mice. Furthermore, the extent of skin depigmentation correlated with the frequency of TRP2-180-specific splenic CD8(+) T cells, as determined by IFN-γ and tumour necrosis factor (TNF)-α production, and cytotoxic degranulation evidenced by CD107a staining. These findings suggest a correlation between the presence of TRP2-180-specific CD8(+) effector T cells and the development of depigmented skin lesions in our vitiligo model. This new model of vitiligo, characterized by skin depigmentation without hair depigmentation, is more similar to human disease than previous murine models. Therefore, this model is well suited to future studies on the pathogenesis of vitiligo and the development of novel therapeutics for vitiligo.

Lateral line depigmentation (LLD) in channel catfish, Ictalurus punctatus (Rafinesque).

Head and lateral line erosion (HLLE) is a chronic dermatopathy affecting a number of fish that presents as depigmented skin along the lateral line system of the trunk and head. We present microbiological, immunological and histopathological features of this lesion in channel catfish, Ictalurus punctatus (Rafinesque), that developed after exposure to a chronic nutritional stress. Depigmention was limited to skin that was adjacent to the lateral line. The epidermis of affected fish was thin and reduced to a one-cell-thick layer over the lateral line. Melanocytes were depleted at the dermo-epidermal junction and formed aggregates in the epidermis. Innate immunity was weaker in affected fish than that previously measured in well-fed channel catfish. Because the pathology and apparent aetiology of HLLE described in various fish species are highly variable, HLLE appears to be a clinical sign, rather than a disease or syndrome. Thus, we propose that this clinical sign be referred to as lateral line depigmentation (LLD), because this description more accurately encompasses all cases of this presentation reported in fish. As nutritional requirements of channel catfish and lateral line neuroanatomy are well-known, the ability to reproducibly induce LLD in this species could provide a useful model for understanding its pathogenesis.

Pigmented purpuric dermatosis: classification by phenotypic and molecular profiles.

The categorization of pigmented purpuric dermatosis (PPD) as a form of cutaneous lymphoid dyscrasia has been suggested. Phenotypic and molecular studies were done on 43 patients with PPD. The molecular studies used a capillary gel electrophoresis T-cell receptor beta multiplex polymerase chain reaction assay. There were 2 principal categories: polyclonal PPD represented by 22 cases and monoclonal variants comprising 21 cases. Monoclonal cases had extensive skin lesions. An identical restricted T-cell repertoire independent of time and location was observed. Approximately 40% of the monoclonal cases had clinical and pathologic features of mycosis fungoides (MF). In the polyclonal variant, disease outside the lower extremities was uncommon; there were no patients with MF. Striking reductions in CD7 and CD62L were seen in both groups. PPD is a form of cutaneous T-cell lymphoid dyscrasia, based on the frequency of monoclonality, the preservation of persistent T-cell clonotypes, and extent of pan-T-cell marker loss. Stratification of lesions of PPD according to the molecular profile may be of significant value prognostically and influence therapeutic intervention.

Metallic pigmentation of human teeth and gingiva: morphological and immunological aspects.

The composition of metallic pigmentations in gingiva and dental roots was determined by means of transmission electron microscopy with energy dispersive x-ray microanalysis. The systemic immune response to the metals found in the oral cavity was evaluated in 10 patients by using a modified lymphocyte proliferation test. Immunological results were compared with a group of five controls without metallic materials and pigmentation. Dense particles of various shapes and sizes, as well as of diverse extracellular and intracellular localization patterns, were detected in the pigmented lamina propria gingivae. Metallic deposits consisted predominantly of silver accompanied by selenium or sulfur or both. Besides, Ag, Au, Cr, Ni, Fe, Hg, Cu, and Ti were identified in dentinal tubules of teeth reconstructed with dental alloys. Nine patients with metallic pigmentations had a positive lymphocyte proliferative response to one or more metals present in their own metal reconstructions. Results of this study thus indicated that dental alloys-by virtue of their corrosion process-might pose a significant risk to immunologically susceptible patients.

Immunopathologic study of erythema dyschromicum perstans (ashy dermatosis).

Erythema dyschromicum perstans (EDP) is a pigmentary disease of unknown etiology in which damage to basal cells is thought to be mediated by adhesion molecules. The aim of this study was to characterize the histopathology and immunopathology of EDP. Forty-three patients from Medellín, Colombia, with the diagnosis of EDP were evaluated. Skin biopsy specimens were obtained for histopathology and immunohistochemistry, using monoclonal antibodies directed against the following markers: CD4, CD8, CD56, CD1a, CD68, CLA, HLA-DR, ICAM-1 and LFA-1alpha. A dermal lymphocytic infiltrate was observed in all cases, with a perivascular location in 86%. Other histologic features included melanophages in all specimens, vacuolization of the basement membrane zone (BMZ) 58% and exocytosis of lymphocytes (53.5%). The mean number of total leukocytes was 1510 cells mm-2 of tissue. There was a predominance of CD8+ T lymphocytes in the dermis and HLA-DR+, ICAM-1+ keratinocytes in the epidermis. Exocytosis of cutaneous lymphocyte antigen (CLA)+cells was observed in areas of BMZ damage, suggesting that response to antigenic stimulation may play a role in the development of EDP.

Cutaneous plasmacytosis: A report of five cases with immunohistochemical evaluation for HHV-8 expression.

Cutaneous plasmacytosis is a rare disorder that typically affects middle-aged to older individuals of Asian, particularly Japanese, descent. Clinically, it is characterized by multiple asymptomatic red-brown plaques and nodules on the trunk. Lymphadenopathy and hypergammaglobulinemia may be present. Histologically, the lesions show a moderately dense superficial and deep perivascular infiltrate composed predominantly of mature plasma cells without atypia or light chain restriction. We report our experience with five additional cases, including results of immunohistochemical studies for human herpes virus 8.