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.

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.

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.

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.

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.

Eritema discrómico perstans (dermatosis cenicienta) / Erythema dyschromicum perstans (ashy dermatosis)

El Eritema Discrómico Perstans (EDP) o Dermatosis Cenicienta es una condición poco común y se caracteriza por máculas grisáceas bien definidas y de contornos policíclicos. En la histopatología los hallazgos son característicos, pero no patognomónicos, y corresponden a una dermatitis liquenoide. La causa del EDP continúa siendo un misterio; se han propuesto causas infecciosas, alteraciones del sistema inmune, e incluso, factores ambientales. Para el diagnóstico, la mayoría de las veces el cuadro clínico es muy típico. Aún no existe un tratamiento efectivo probado para el EDP, sin embargo, la clofazimina parece ser la mejor alternativa.

Purpura annularis telangiectodes of Majocchi.

A case is presented of a man with a 3-year history of ulcers in the setting of pigmented, annular and purpuric lesions of the lower extremities. A skin biopsy suggested a diagnosis of purpura annularis telangiectodes of Majocchi. First described in 1896 by Majocchi [1], purpura annularis telangiectodes is an uncommon pigmented purpuric eruption, which is characterized by symmetrical, purpuric, telangiectatic, and atrophic patches with a predilection for the lower extremities and buttocks. Histopathology and immunopathogenesis of this disease are similar to the other subtypes of pigmented purpuric dermatoses.

[Hemophagocytic syndromes and primary immunodeficiencies]. / Syndromes hémophagocytaires et déficits immunitaires primitifs.

Lymphohistiocytic activation syndromes are characterized by activation and proliferation of T cells and macrophages usually reflecting an inappropriate response of the host to an infection. The clinical manifestations are often alarming symptoms suggestive of severe sepsis. Most patients have a known underlying disease (hemopathy, lupus, Still's disease, HIV infection, bone marrow or organ transplantation). In the few cases that occur apparently without any risk factors, investigations should be done to look for a predisposing inherited disease such as familial lymphohistiocytosis or Purtilo syndrome in boys. The treatment relies on immunosuppressive agents followed by bone marrow transplantation, which can provide a definitive cure in genetics forms.

Monoclonal rearrangement of the T cell receptor gamma-chain in lichenoid pigmented purpuric dermatitis of gougerot-blum responding to topical corticosteroid therapy.

Lichenoid pigmented purpuric dermatitis of Gougerot-Blum belongs to a group of closely related disorders which are termed pigmented purpuric dermatoses. It clinically manifests itself with grouped lichenoid papules in association with purpuric lesions. We report a case of lichenoid pigmented purpuric dermatitis of Gougerot-Blum with a heavy band-like CD4-positive lymphocytic infiltrate and clonal rearrangements of the gamma-chain of the T cell receptors as detected by polymerase chain reaction/denaturing gradient gel electrophoresis. Monoclonal expansion of T cells in combination with certain histological features of mycosis fungoides (MF) might support a biological relationship between lichenoid pigmented purpuric dermatitis of Gougerot-Blum and MF. However, prompt clinical response to topical steroid therapy supports the benign clinical nature of our case.

Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome.

Griscelli syndrome (GS, MIM 214450), a rare, autosomal recessive disorder, results in pigmentary dilution of the skin and the hair, the presence of large clumps of pigment in hair shafts and an accumulation of melanosomes in melanocytes. Most patients also develop an uncontrolled T-lymphocyte and macrophage activation syndrome (known as haemophagocytic syndrome, HS), leading to death in the absence of bone-marrow transplantation. In contrast, early in life some GS patients show a severe neurological impairment without apparent immune abnormalities. We previously mapped the GS locus to chromosome 15q21 and found a mutation in a gene (MYO5A) encoding a molecular motor in two patients. Further linkage analysis suggested a second gene associated with GS was in the same chromosomal region. Homozygosity mapping in additional families narrowed the candidate region to a 3.1-cM interval between D15S1003 and D15S962. We detected mutations in RAB27A, which lies within this interval, in 16 patients with GS. Unlike MYO5A, the GTP-binding protein RAB27A appears to be involved in the control of the immune system, as all patients with RAB27A mutations, but none with the MYO5A mutation, developed HS. In addition, RAB27A-deficient T cells exhibited reduced cytotoxicity and cytolytic granule exocytosis, whereas MYO5A-defective T cells did not. RAB27A appears to be a key effector of cytotoxic granule exocytosis, a pathway essential for immune homeostasis.

Doença de Schamberg: capilarite linfocítica pigmentar purpúrica / Schamberg's disease: lymphocitic pigmentar purpuric capilaritis

Objetivos: Revisäo da doença de Schamberg enfocando os aspectos imunológicos e terapêuticos. Métodos: A doença de Schamberg, o líquen aureus, e as purpúras de Majocchi, Gougerot-Blum, e ectematosa de Doucas-Kapetanakis, pertencem ao espectro das chamads púrpuras simples. As lesöes purpúricas pigmentadas säo geralmente assintomáticas e näo têm etiopatogenia estabelecida. Resultados: A púrpura de Schamberg apresenta um quadro histopatológico de inflamaçäo com hemorragia, sem necrose fibrinóide (capilarite ou pervasculite). A agressäo vascular, com estravazamentode hemácias e conseqüente deposiçäo de hemossiderina, é secundária a reaçöes imunológicas mediadas por linfócitos T na regiäo capilar dérmica. As citocinas e oa umento da expressäo das moléculas de adesäo endoteliais promovem a aderência células T -queratinócitos. A ativaçäo precoce destes receptores de adesäo endoteliais, determina a organizaçäo do infiltrado inflamatório pericapilar. Alteraçöes sutis no sistema coagulaçäo-fibrinólise foram descritas. Näo há terapia definida. A pentoxifilina, diminuindo a adesäo de células T às células endoteliais e aos queratinócitos, foi útil no controle das lesöes de alguns casos. Há um potencial futuro para a utilizaçäo de outras estratégias terapêuticas antiinflamatórias. Conclusöes: A púrpura de Schamberg é uma capilarite com a participaçäo de linfócitos T, queratinócitos, citocinas e moléculas de adesäo. Requer terapia antiinflamatória potente.

Involvement of cell adhesion and activation molecules in the pathogenesis of erythema dyschromicum perstans (ashy dermatitis). The effect of clofazimine therapy.

OBJECTIVES: To assess the expression of several cell adhesion and lymphocyte activation molecules in erythema dyschromicum perstans lesions, and to evaluate the effect of clofazimine therapy on the expression of these molecules. DESIGN AND METHODS: A prospective study. Skin biopsy samples were obtained from patients before and after 3 months of clofazimine therapy, and the expression of cell adhesion and activation molecules was assessed by an immunohistochemical technique. SETTING: This study was performed in a clinical referral center and an immunology research laboratory. PATIENTS: We studied 6 patients with erythema dyschromicum perstans. A diagnosis was made on the basis of clinical and histological criteria. Two patients discontinued participation in the study: one because of adverse effects and the other for unknown reasons. INTERVENTIONS: Patients were treated with clofazimine, 100 mg/d, for 3 months. MAIN OUTCOME MEASURES: Expression of cell adhesion and lymphocyte activation molecules in skin biopsy specimens before and after clofazimine therapy. RESULTS: Before clofazimine therapy, we detected a noticeable expression of intercellular adhesion molecule 1 and major histocompatibility complex class II molecules (HLA-DR) in the keratinocyte basal cell layer. In addition, CD36, a thrombospondin receptor that is not expressed by normal skin, was detected in the strata spinosum and granulosum. The dermal cell infiltrate expressed the activation molecule AIM/CD69 and the cytotoxic cell marker CD94. After clofazimine therapy, the expression of intercellular adhesion molecule 1 and HLA-DR disappeared, as well as the mononuclear cell infiltrate. CONCLUSIONS: Our results suggest that some cell adhesion and activation molecules are involved in the pathogenesis of erythema dyschromicum perstans. Clofazimine appears to have an important effect on the inflammatory phenomenon of erythema dyschromicum perstans.

Subpopulations of T lymphocytes in the peripheral blood, dermal lesions and lymph nodes of post kala-azar dermal leishmaniasis patients.

Distribution of different subpopulations of T cells in the dermal lesions, lymph nodes and peripheral blood of post kala-azar dermal lesihmaniasis (PKADL) patients was studied by using appropriate phenotypic markers for CD2+, CD4+ and CD8+ cells. Histopathological studies of skin lesions showed marginal to massive infiltration of mononuclear cells depending upon the duration of illness and type of lesions. Thus, while the hypopigmented patches were represented by small focal collections of lymphocytes with scanty parasites in the dermis, these were replaced at the nodular stage with massive granulomas consisting of lymphocytes, plasma cells and histiocytes with numerous amastigotes. The involvement of CD4+ and CD8+ cell types in these lesions also showed a gradual change from the appearance of a few cells of both the phenotypes in early hypopigmented type to massive accumulation of cells, primarily of CD8+ phenotype, in the granuloma of nodular type. However, the observed preponderance of CD8+ cells at the lesion site of chronic PKADL patients is in contrast to their peripheral blood CD4+/CD8+ cell ratio (1.9:1) which remained within the normal limits. Similar studies of lymph nodes from PKADL patients with lymphadenopathy revealed infiltration of the cortical areas by T cells which were more of CD8+ than CD4+ phenotypes. All these results document the involvement of CD8+ cells in leishmanoid lesions. Thus, it is likely that these cells, in association with appropriate subpopulations of CD4+ cells, play a profound role in the evolution of dermal pathology in PKADL.

Vitiligo- and melanoma-associated hypopigmentation: a similar appearance but a different mechanism.

The significance of the association between the appearance of hypopigmentation in patients with melanoma and the prognosis is still not clear. It was postulated that, in melanoma, an immune response is responsible for the destruction of the malignant as well as the normal pigmented cells, and that the eventual development of vitiligo-like patches in melanoma patients improves their prognosis. We studied the level of anti-melanoma antibodies in the sera of patients with melanoma with hypopigmentation and compared it to the titer in patients with melanoma only, to the titer of patients with vitiligo, and to that of healthy subjects. Only IgG-type antibodies were found in the sera of patients with vitiligo, with melanoma, or with melanoma with hypopigmentation. No significant differences in the titer of anti-melanoma antibodies could be found between the patients with melanoma when subgrouped according to the initial stage and the status of the disease at the time when the test was carried out. Statistically significantly (P < 0.001) higher titers of antibodies were detected in the sera of patients with vitiligo in comparison to the lower titers in the other groups. Our results point to a similar immunobiological status, which probably does not give any advantage to patients with melanoma with hypopigmentation compared to patients without it. The appearance of hypopigmentary plaques in melanoma patients should be regarded, in our opinion, as a concomitant immunological phenomenon of the disease.