Cytoplasmic RNA quality control failure engages mTORC1-mediated autoinflammatory disease.

Inborn errors of nucleic acid metabolism often cause aberrant activation of nucleic acid sensing pathways, leading to autoimmune or autoinflammatory diseases. The SKIV2L RNA exosome is cytoplasmic RNA degradation machinery that was thought to be essential for preventing the self-RNA-mediated interferon (IFN) response. Here, we demonstrate the physiological function of SKIV2L in mammals. We found that Skiv2l deficiency in mice disrupted epidermal and T cell homeostasis in a cell-intrinsic manner independently of IFN. Skiv2l-deficient mice developed skin inflammation and hair abnormality, which were also observed in a SKIV2L-deficient patient. Epidermis-specific deletion of Skiv2l caused hyperproliferation of keratinocytes and disrupted epidermal stratification, leading to impaired skin barrier with no appreciable IFN activation. Moreover, Skiv2l-deficient T cells were chronically hyperactivated and these T cells attacked lesional skin as well as hair follicles. Mechanistically, SKIV2L loss activated the mTORC1 pathway in both keratinocytes and T cells. Both systemic and topical rapamycin treatment of Skiv2l-deficient mice ameliorated epidermal hyperplasia and skin inflammation. Together, we demonstrate that mTORC1, a classical nutrient sensor, also senses cytoplasmic RNA quality control failure and drives autoinflammatory disease. We also propose SKIV2L-associated trichohepatoenteric syndrome (THES) as a new mTORopathy for which sirolimus may be a promising therapy.

Combined Immunodeficiency in Patients With Trichohepatoenteric Syndrome.

The syndromic diarrhea/trichohepatoenteric syndrome (SD/THE) is a rare and multi-system genetic disorder caused by mutation in SKIV2L or in TTC37, two genes encoding subunits of the putative human SKI complex involved in RNA degradation. The main features are intractable diarrhea of infancy, hair abnormalities, facial dysmorphism, and intrauterine growth restriction. Immunologically this syndrome is associated with a hypogammaglobulinemia leading to an immunoglobulin supplementation. Our immune evaluation of a large French cohort of SD/THE patient revealed several immunological defects. First, switched memory B lymphocytes count is very low. Second, IFN-γ production by T and NK cells is impaired and associated with a reduced degranulation of NK cells. Third, T cell proliferation was abnormal in 3/6 TTC37-mutated patients. These three patients present with severe EBV infection and a transient hemophagocytosis which may be related to these immunological defects. Moreover, an immunological screening of patients with clinical features of SD/THE could facilitate both diagnosis and therapeutic management of these patients.

Basal-Cell Carcinoma With Matrical Differentiation: Report of a New Case in a Renal-Transplant Recipient and Literature Review.

Basal-cell carcinoma with matrical differentiation (BCC-MD) is one of the rarest pathologic variants of basal-cell carcinoma, of which 41 cases have been so far reported in detail. One of them developed in a heart-transplant recipient. We report a new case of BCC-MD occurring in a renal-transplant recipient and review the relevant literature. A 75-year-old white man who had received a renal allograft 7 years ago developed a tumor on the left temple clinically suggestive of basal-cell carcinoma. Microscopically, the tumor associated features typical of basal-cell carcinoma (basaloid lobules with peripheral palisading and clefting) and pilomatricoma (presence of shadow/ghost cells). The 2 tumor components expressed variably beta-catenin, HEA/Ber-EP4, CD10, PHLDA-1, MIB-1/Ki67, calretinin, and bcl-2. BCC-MD has no distinctive clinical features. It affects predominantly male patients with a mean age of 69 years. More than half of cases appear on the head/neck area. Some cases harbor CTNNB1 mutations. Differential diagnosis includes tumors with matrical differentiation, namely pilomatrix carcinoma. The outcome is usually favorable after surgical excision, although regional lymph node metastases developed in 2 patients.

Detection of Beta-Human Papillomavirus in a Child With Polyomavirus-Associated Trichodysplasia Spinulosa.

Viral associated trichodysplasia spinulosa (VATS) is a rare cutaneous eruption characterized by folliculocentric papules, keratin spicules, and alopecia associated with trichodysplasia spinulosa-associated polyomavirus (TSPyV) infection. We report a case of a 6-year-old male child who presented with a generalized papular eruption during chemotherapy for acute lymphoblastic leukemia. The papules were tested for human papillomavirus (HPV) DNA by nested polymerase chain reaction (PCR) and TSPyV using PCR and gene sequencing studies. The lesions were positive for TSPyV by PCR combined with sequencing and showed high copy number with real-time PCR, and beta-papillomavirus was identified by PCR and sequencing. Immunohistochemistry revealed inner root sheath keratinocytes expressing nuclear HPV L1 capsid antigen. To our knowledge, this is the first case of concomitant productive HPV and TSPyV infection in a VATS-affected patient. The presence of HPV may be coincidental, however, further studies are needed to establish whether specific HPV genotypes influence the development of abnormal inner root sheath trichohyalin granules found in VATS.

The role of enterocyte defects in the pathogenesis of congenital diarrheal disorders.

Congenital diarrheal disorders are rare, often fatal, diseases that are difficult to diagnose (often requiring biopsies) and that manifest in the first few weeks of life as chronic diarrhea and the malabsorption of nutrients. The etiology of congenital diarrheal disorders is diverse, but several are associated with defects in the predominant intestinal epithelial cell type, enterocytes. These particular congenital diarrheal disorders (CDD(ENT)) include microvillus inclusion disease and congenital tufting enteropathy, and can feature in other diseases, such as hemophagocytic lymphohistiocytosis type 5 and trichohepatoenteric syndrome. Treatment options for most of these disorders are limited and an improved understanding of their molecular bases could help to drive the development of better therapies. Recently, mutations in genes that are involved in normal intestinal epithelial physiology have been associated with different CDD(ENT). Here, we review recent progress in understanding the cellular mechanisms of CDD(ENT). We highlight the potential of animal models and patient-specific stem-cell-based organoid cultures, as well as patient registries, to integrate basic and clinical research, with the aim of clarifying the pathogenesis of CDD(ENT) and expediting the discovery of novel therapeutic strategies.

The SKIV2L RNA exosome limits activation of the RIG-I-like receptors.

Sensors of the innate immune system that detect intracellular nucleic acids must be regulated to prevent inappropriate activation by endogenous DNA and RNA. The exonuclease Trex1 regulates the DNA-sensing pathway by metabolizing potential DNA ligands that trigger it. However, an analogous mechanism for regulating the RIG-I-like receptors (RLRs) that detect RNA remains unknown. We found here that the SKIV2L RNA exosome potently limited the activation of RLRs. The unfolded protein response (UPR), which generated endogenous RLR ligands through the cleavage of cellular RNA by the endonuclease IRE-1, triggered the production of type I interferons in cells depleted of SKIV2L. Humans with deficiency in SKIV2L had a type I interferon signature in their peripheral blood. Our findings reveal a mechanism for the intracellular metabolism of immunostimulatory RNA, with implications for specific autoimmune disorders.

Viral-associated trichodysplasia secondary to antineoplastic treatment in a patient with lymphoblastic leukemia.

Viral-associated trichodysplasia spinulosa is an unusual condition with distinctive clinical and histopathological features. Initially described in patients immunosupressed as a result of solid organ transplantation, it has also been reported in patients treated with immunosuppressive drugs other than cyclosporine or being treated for hematological malignancies. Patients presented with disseminated follicular, hyperkeratotic papules, and variable degrees of alopecia. Histopathological examination revealed shaftless bulbous and dilated hair follicles with keratotic plugging of the infundibulum. The authors reported a case of viral-associated trichodysplasia in a 5-year-old boy treated for a lymphoblastic leukemia. Eruption persisted, although treated with emollients and keratolytics, but resolved spontaneously after completing the antineoplastic medication.

Frequency, pattern, and extent of skin diseases in relation to CD4+ cell count among adults with human immunodeficiency virus infection or acquired immunodeficiency syndrome in Osogbo, southwestern Nigeria.

BACKGROUND: Skin diseases characterize all stages of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) and contribute significantly to associated morbidity and mortality. OBJECTIVES: The aim of this study was to document the prevalences, patterns, and extents (severity) of skin diseases and their relationships with immunologic status in HIV/AIDS patients. METHODS: A total of 140 HIV/AIDS patients in different stages of HIV infection and 140 controls were recruited. Skin diseases were documented and CD4+ cell counts determined in all subjects. Severity was assessed according to the body surface area affected (using the Wallace rule of nines and the rule of palm) for lesions that tended to be widespread. The number of digits involved was counted for lesions involving the nails. Intensity of pain was graded for specific conditions such as herpes zoster. Chi-squared statistics and Pearson correlations were determined. RESULTS: Mean±standard deviation age was 35.04±8.83 years in the patient group and 32.21±8.30 years in the control group. The prevalences and patterns of skin diseases in HIV/AIDS patients were similar to those reported in previous studies. Most commonly found dermatoses were oral candidiasis (n=28, 20.0%), pruritic papular eruption (n=27, 19.3%), xeroderma (n=23, 16.4%), dermatophytosis (n=22, 15.7%), and fluffy hair (n=19, 13.6%). The presence of specific skin lesions represented a better correlate with immunosuppression than cutaneous extents. However, the extents of viral warts and multiple blue­black nails correlated significantly with CD4+ cell count. The presence of a lighter hair color phenotype signifies a lower CD4+ cell count than a softer hair phenotype. CONCLUSIONS: The presence of specific skin lesions correlates more strongly with a low CD4+ cell count than does the extent of their distribution, except in cases of viral warts. The presence of and higher numbers of nails affected with blue­black nail hyperpigmentation suggest severe immunosuppression.

Hair loss in autoimmune systemic diseases.

Hair loss is commonly seen in autoimmune diseases. In pemphigus, although scalp involvement is common, hair loss is rarely reported. In classical bullous pemphigoid, alopecia is not reported while it is described in the Brusting-Perry variant of bullous pemphigoid and in epidermolysis bullosa acquisita. In these two diseases alopecia is cicatricial. In connective tissue diseases, in lupus erythematosus (LE) hair loss is frequent; in particular in LE there are two types of alopecia: non scarring and scarring alopecia. The non scarring form is a finding of acute systemic LE and the scarring form develops when a typical discoid lesion is located on the scalp. In dermatomyositis alopecia is usually non scarring and generalized. In scleroderma, alopecia is associated with en coupe de sabre morphea.

Syndromic (phenotypic) diarrhoea of infancy/tricho-hepato-enteric syndrome.

OBJECTIVES: Syndromic diarrhoea/tricho-hepato-enteric syndrome (SD/THE) is a rare congenital syndrome. The main features are intractable diarrhoea of infancy, hair abnormalities, facial dysmorphism, intrauterine growth restriction and immune system abnormalities. It has been linked to abnormalities in two components of the putative human ski complex: SKIV2L and TTC37. The long-term outcome of this syndrome is still unknown. We aim to describe the long-term outcome, in the French cohort of patients born since 1992. DESIGN: Review of the clinical and biological features of the 15 patients with SD/THE, followed in France and born between 1992 and 2010. RESULTS: All patients presented typical SD/THE syndrome features, of intractable diarrhoea in infancy requiring parenteral nutrition, a facial dysmorphism with hair abnormalities, and immunological disorders. Half of them also had liver and skin abnormalities. Five children died, among which 3 died due to infections. Probabilities of survival according to the Kaplan-Meier method were 93.3%, 86.7%, 74.3 and 61.9%, respectively at 1 year, 5 years, 10 years and 15 years of age. 3/15 were weaned from parenteral nutrition (PN) with likelihood of weaning being 10% at 5 years and 40% at 10 years. At birth 80% were small for gestational age and the short stature persisted in 60%. Haemophagocytic syndrome was noted in 60% and mild mental retardation was present in 60%. CONCLUSIONS: SD/THE is a rare disease with high morbidity and mortality. Management should be focused on nutrition and immunological defects.

[Immunohistochemical evaluation of inflammatory reaction in a case of pilomatrixoma]. / Evaluarea prin imunohistochimie a reactiei inflamatorii intr-un caz de pilomatricom.

OBJECTIVES: To identify the types of the cells in a case of pilomatricoma and to evaluate the lesion's stage, the cells' proliferating rate and the associated inflammatory reaction. MATERIAL AND METHODS: The paraffin-embedded tissue was investigated by histological examination and by immunohistochemistry for the expression of some markers such as: cytokeratins, CD3, CD20, CD68, PCNA, CD34 II. RESULTS: The lesion presented the characteristic epithelial cells of a classical pilomatricoma: bazaloid cells, ghost cells and transitional cells. 10-15% of the bazaloid cells were PCNA+. The MNF 116 antibody labeled only some of the transitional and of the ghost cells. We found no CD3-positive cells and few CD20-positive cells. A marked inflammatory reaction was noticed, dominated by giant multinucleated cells, positive for CD68 and PCNA and a rich network of blood vessels with a high vascular density. CONCLUSION: The histological pilomatricoma diagnosis was straightforward on the basis of the bazaloid and ghost cells presence. Immunohistochemistry brought additional data regarding the cells proliferation rate, the stage of the lesion and the intensity of the associated inflammation.

Restriction in T-cell receptor repertoire in a patient affected by trichothiodystrophy and CD4+ lymphopenia.

Molecular analysis of T-cell receptor (TCR) repertoire, by measuring the CDR3 heterogeneity length of beta-variable regions (spectratyping), is useful for acquiring novel information on the status of immune system in primary immunodeficiency. Here, we evaluate TCR repertoire in a child with trichothiodystrophy (TTD) and combined immunodeficiency (CID). Spectratyping revealed marked alterations of TCR repertoire distribution: 21 and 10 out of 27 TCR Vbeta (TCRBV) families and subfamilies were skewed in CD8+ and CD4+ subsets, respectively. These findings revealed, for the first time in a TTD patient with CID, a marked reduction in the TCR repertoire complexity, which may reflect alterations in the mechanisms regulating the generation and homeostasis of T cells.