[Show abstract][Hide abstract] ABSTRACT: Caspase Recruitment Family Member 14 (CARD14, also known as CARMA2) is a scaffold protein that mediates NF-κB signal transduction in skin keratinocytes. Gain-of-function CARD14 mutations have been documented in familial forms of psoriasis vulgaris (PV) and pityriasis rubra pilaris (PRP). More recent investigations have also implicated CARD14 in the pathogenesis of pustular psoriasis. Follow-up studies, however, have been limited, so that it is not clear to what extent CARD14 alleles account for the above conditions. Here, we sought to address this question by carrying out a systematic CARD14 analysis in an extended patient cohort (n=416). We observed no disease alleles in subjects with familial PV (n=159), erythrodermic psoriasis (n=23), acral pustular psoriasis (n=105) or sporadic pityriasis rubra pilaris (n=29). Conversely, our analysis of 100 individuals with generalised pustular psoriasis (GPP) identified a low-frequency variant (p.Asp176His) which causes constitutive CARD14 oligomerization and shows significant association with GPP in Asian populations (P=8.4 × 10(-5); OR=6.4). These data indicate that the analysis of CARD14 mutations could help to stratify pustular psoriasis cohorts but would be mostly uninformative in the context of psoriasis and sporadic pityriasis rubra pilaris.Journal of Investigative Dermatology accepted article preview online, 23 July 2015. doi:10.1038/jid.2015.288.
No preview · Article · Jul 2015 · Journal of Investigative Dermatology
[Show abstract][Hide abstract] ABSTRACT: Epidermolytic ichthyosis (EI) due to keratin-10 (KRT10) mutations is a rare, typically autosomal dominant, disorder characterized by generalized erythema and cutaneous blistering at birth followed by hyperkeratosis and less frequent blistering later in life. We identified two KRT10 mutations p.Q434del and p.R441P in subjects presenting with a mild EI phenotype. Both occur within the mutational "hot spot" of the keratin 10 (K10) 2B rod domain, adjacent to severe EI-associated mutations. p.Q434del and p.R441P formed collapsed K10 fibers rather than aggregates characteristic of severe EI KRT10 mutations such as p.R156C. Upon differentiation, keratinocytes from p.Q434del showed significantly lower apoptosis (p-value <0.01) compared to p.R156C as assessed by TUNEL assay. Conversely, the mitotic index of the p.Q434del epidermis was significantly higher than that of p.R156C (p-value <0.01) as estimated by Ki67 assay. Structural basis of EI phenotype variation was investigated by homology-based modeling of WT and mutant K1-K10 dimers. Both mild EI mutations were found to affect surface exposed residues of the K10 alpha helix coiled-coil and caused localized disorganization of the K1-K10 heterodimer. In contrast adjacent severe EI mutations disrupt key inter-molecular dimer interactions. Our findings provide structural insights into phenotypic variation in EI due to KRT10 mutations.Journal of Investigative Dermatology accepted article preview online, 15 July 2015. doi:10.1038/jid.2015.284.
No preview · Article · Jul 2015 · Journal of Investigative Dermatology
[Show abstract][Hide abstract] ABSTRACT: Background & aims:
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autoimmune disorder characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency, but patients also develop intestinal disorders. APECED is an autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE, which regulates immune tolerance) that allow self-reactive T cells to enter the periphery. Enteric α-defensins are antimicrobial peptides secreted by Paneth cells. Patients with APECED frequently have gastrointestinal symptoms and seroreactivity against secretory granules of Paneth cells. We investigated whether enteric α-defensins are autoantigens in humans and mice with AIRE deficiency.
We analyzed clinical data, along with serum and stool samples and available duodenal biopsies from 50 patients with APECED collected from multiple centers in Europe. Samples were assessed for expression of defensins and other molecules by quantitative reverse transcription polymerase chain reaction and flow cytometry; levels of antibodies and other proteins were measured by immunohistochemical and immunoblot analyses. Histologic analyses were performed on biopsy samples. We used Aire(-/-) mice as a model of APECED, and studied the effects of transferring immune cells from these mice to athymic mice.
Enteric defensins were detected in extraintestinal tissues of patients with APECED, especially in medullary thymic epithelial cells. Some patients with APECED lacked Paneth cells and were seropositive for defensin-specific autoantibodies; the presence of autoantibodies correlated with frequent diarrhea. Aire(-/-) mice developed defensin-specific T cells. Adoptive transfer of these T cells to athymic mice resulted in T-cell infiltration of the gut, loss of Paneth cells, microbial dysbiosis, and the induction of T-helper 17 cell-mediated autoimmune responses resembling those observed in patients with APECED.
In patients with APECED, loss of AIRE appears to cause an autoimmune response against enteric defensins and loss of Paneth cells. Aire(-/-) mice developed defensin-specific T cells that cause intestinal defects similar to those observed in patients with APECED. These findings provide a mechanism by which loss of AIRE-mediated immune tolerance leads to intestinal disorders in patients with APECED.
No preview · Article · May 2015 · Gastroenterology
[Show abstract][Hide abstract] ABSTRACT: Cutaneous lupus erythematosus (CLE) is a chronic autoimmune disease of the skin with typical clinical manifestations. Here, we genotyped 906,600 single nucleotide polymorphisms (SNPs) in 183 CLE cases and 1288 controls of Central European ancestry. Replication was performed for 13 SNPs in 219 case subjects and 262 controls from Finland. Association was particularly pronounced at 4 loci, all with genome-wide significance (P ≤ 5 x 10(-8) ): rs2187668 (PGWAS = 1.4 x 10(-12) ); rs9267531 (PGWAS = 4.7 x 10(-10) ); rs4410767 (PGWAS = 1.0 x 10(-9) ); rs3094084 (PGWAS = 1.1 x 10(-9) ). All mentioned SNPs are located within the major histocompatibility complex (MHC) region of chromosome 6 and near genes of known immune functions or associations with other autoimmune diseases such as HLA-DQ alpha chain 1 (HLADQA1), MICA, MICB, MSH5, TRIM39, and RPP21. E.g., TRIM39-RPP21 read through transcript is known mediator of the interferon response, a central pathway involved in the pathogenesis of CLE and systemic lupus erythematosus (SLE). Taken together, this genome-wide analysis of disease-association of CLE identified candidate genes and genomic regions that may contribute to pathogenic mechanisms in CLE via dysregulated antigen presentation (HLADQA1), apoptosis regulation, RNA processing and interferon response (MICA, MICB, MSH5, TRIM39, RPP21). This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
No preview · Article · Apr 2015 · Experimental Dermatology
[Show abstract][Hide abstract] ABSTRACT: Subcutaneous panniculitis-like T cell lymphomas represent a rare and difficult to diagnose entity of cutaneous T cell lymphomas. SPTL affects predominantly young adults and presents with multifocal subcutaneous nodules and frequently associated autoimmune features. The pathogenesis of SPTL is not completely understood.
The aim of this study was to unravel molecular pathways critical to the SPTL pathogenesis. Therefore, we analyzed 23 skin samples from 20 newly diagnosed SPTL patients and relevant control samples of adipose and non-malignant panniculitis tissue by using gene expression microarray, quantitative PCR, and two-colour immunohistochemistry.
Interestingly, indoleamine 2,3-dioxygenase (IDO-1), an immunotolerance-inducing enzyme, was among the most highly overexpressed genes in all comparisons. The expression of Th1-specific cytokines, known to be associated with autoimmune inflammation (i.e. IFNG, CXCR3, CXCL9, CXCL10, CXCL11, and CCL5), were also significantly increased. Confirmed using immunohistochemistry, the morphologically malignant lymphocytes expressed CXCR3 and CXCL9. IDO-1 expression was found both in some morphologically malignant lymphocytes rimming the adipocytes and in surrounding CD11c(-) CD68(-) cells but not in CD11c(+) dendritic cells in the microenvironment. The proportion of FoxP3+ cells in SPTL exceeded that in the benign panniculitis samples.
Our results indicate that the up regulation of the tolerogenic IDO-1 together with the up regulation of IFNG, CXCR3 ligands, and CCL5 are features of SPTL lesions. We anticipate that the IFNG-inducible IDO-1 expression contributes to the formation of an immunosuppressive microenvironment, favorable for the malignant T cells. This study provides a relevant molecular basis for further studies exploring novel therapeutic means for subcutaneous T cell lymphoma.
Full-text · Article · Dec 2014 · Orphanet Journal of Rare Diseases
[Show abstract][Hide abstract] ABSTRACT: Lentigo maligna (LM) is an in situ form of melanoma which can progress into invasive lentigo maligna melanoma (LMM). Variations in the pigmentation and thus visibility of the tumour make assessment of lesion borders challenging. We tested hyperspectral imaging system (HIS) in in vivo preoperative delineation of LM and LMM margins. We compared lesion margins delineated by HIS with those estimated clinically, and confirmed histologically. A total of 14 LMs and 5 LMMs in 19 patients were included. HIS analysis matched the histo-pathological analysis in 18/19 (94.7%) cases while in 1/19 (5.3%) cases HIS showed lesion extension not confirmed by histopathology (false positives). Compared to clinical examination, HIS defined lesion borders more accurately in 10/19 (52.6%) of cases (wider, n = 7 or smaller, n = 3) while in 8/19 (42.1%) cases lesion borders were the same as delineated clinically as confirmed histologically. Thus, HIS is useful for the detection of subclinical LM/LMM borders.
Full-text · Article · Nov 2014 · British Journal of Dermatology
[Show abstract][Hide abstract] ABSTRACT: Abstract Autoimmune polyendocrinopathy - candidiasis - ectodermal dystrophy (APECED) is caused by mutations in the Autoimmune regulator (AIRE) gene and is associated with neutralizing anti-cytokine autoantibodies. We have used an in vivo challenge model to analyze antigen-specific CD4(+) T cell responses. Bacille Calmette-Guérin (BCG)-vaccinated patients and controls were injected tuberculin intradermally, skin blisters were induced by suction on the indurations and on unexposed skin, and the infiltrating cells harvested. The patients had a quantitatively normal CD4(+) T cell response and no significant abnormalities in the expression of T helper type (Th) 1- or Th2-related genes. The expression of interleukin (IL)-22, in contrast, was lower in the patients. Two patients, both with a pre-existing ocular keratopathy, experienced a relapse of keratoconjunctivitis, suggesting a possible immunological basis for this APECED component. Our in vivo data are compatible with a selective IL-22 defect in the activated CD4(+) T cells of APECED patients, affecting also unexposed skin in steady-state conditions.
[Show abstract][Hide abstract] ABSTRACT: Objective
Patients with Addison's disease (AD) on conventional replacement therapy have impaired health-related quality of life (HRQoL). It is possible that lower hydrocortisone (HC) doses recommended by current guidelines could restore HRQoL. We compared HRQoL in AD patients treated according to current HC recommendations to that of the age- and gender-standardized general population.Subjects, design and measurementWe assessed HRQoL in a cross-sectional setting with the 15D instrument in a Finnish AD cohort (n=107) and compared the results with those of a large sample of general population (n= 5671).We examined possible predictors of HRQoL in AD. Within the patient group, HRQoL was also assessed by SF-36.ResultsMean HC dose was 22 mg/d, corresponding to 12 ± 4mg/m2. HRQoL was impaired in AD compared to the general population (15D score; 0.853 vs. 0.918, p<0.001). Within single 15D dimensions, discomfort and symptoms, vitality and sexual activity were most affected. Stepwise regression analysis demonstrated that Patient's Association membership (p = 0.02), female gender (p<0.01), presence of other autoimmune or inflammatory co-morbidity (p <0.02), lower education (p < 0.02), and longer disease duration (p <0.05), independently predicted impaired HRQoL. Replacement regimens, autoimmune-related co-morbidities, total number of co-morbidities or level of healthcare follow-up did not. In AD, HRQoL was impaired also as assessed by SF-36.ConclusionsHRQoL is significantly impaired in AD compared to the general population despite use of recommended HC doses. Patient's Association membership was the most significant predictor of impaired HRQoL. This finding should be explored in more detail in the future.This article is protected by copyright. All rights reserved.
No preview · Article · May 2014 · Clinical Endocrinology
[Show abstract][Hide abstract] ABSTRACT: Autoimmune tubulo-interstitial nephritis (TIN) is a rare complication of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Previous data on TIN and other renal or urologic manifestations of APECED are sparse.
We performed a retrospective study on the urinary and renal tract diseases in a cohort of 30 Finnish patients with APECED (mean age 40 years), with special emphasis on the clinical presentation and the immunologic characteristics of TIN. Clinical and laboratory findings, specific anticytokine and kidney-specific antibodies were analysed.
Five of the 30 (17%) patients had moderate-to-severe renal failure, including 3 (10%) with TIN, leading to either transplantation, haemodialysis or immunosuppressive treatment. No other cause other than APECED was found for the TIN. All three patients with TIN had circulating antibodies against the distal part of the nephron, as did 30% of all cohort cases. Two had nephrocalcinosis, and two had renal tubular acidosis type 1. Immunosuppressive therapy with mycophenolate mofetil or rituximab in one pediatric case did not revert the TIN, however.
Renal failure should raise concern for TIN in APECED. It discloses some specific features: no uveitis, no glycosuria and inconstant urinalysis anomalies. Regular renal monitoring for any APECED patient should be performed. Circulating antibodies against the distal part of the nephron are frequent and present in all TIN patients, but their pathologic significance is not yet known. Future studies will be needed to understand the triggers leading to overt clinical disease in these patients.
[Show abstract][Hide abstract] ABSTRACT: Sezary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma. Recurrent chromosomal aberrations have been found in SS, but the whole genetic mutation spectrum is unknown. To better understand the molecular pathogenesis of SS, we performed exome sequencing, copy number variation (CNV) and gene expression analysis of primary SS cells. In our index patient with typical SS, we found novel somatic missense mutations in TBL1XR1, EPHA7 and SLFN12 genes in addition to larger chromosomal changes. The mutations are located in biologically relevant genes affecting apoptosis and T-cell maturation. They may play a role in the pathobiology of the disease, but no recurrent mutations were discovered in nine additional SS patients studied. Thus, screening of larger patient cohorts are needed to confirm their prevalence and biological significance in SS. This article is protected by copyright. All rights reserved.