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Alopecia areata (AA) is a prevalent autoimmune disease with 10 known susceptibility loci. Here we perform the first meta-analysis of research on AA by combining data from two genome-wide association studies (GWAS), and replication with supplemented ImmunoChip data for a total of 3,253 cases and 7,543 controls. The strongest region of association is the major histocompatibility complex, where we fine-map four independent effects, all implicating human leukocyte antigen-DR as a key aetiologic driver. Outside the major histocompatibility complex, we identify two novel loci that exceed the threshold of statistical significance, containing ​ACOXL/​BCL2L11(​BIM) (2q13); ​GARP (​LRRC32) (11q13.5), as well as a third nominally significant region ​SH2B3(​LNK)/​ATXN2 (12q24.12). Candidate susceptibility gene expression analysis in these regions demonstrates expression in relevant immune cells and the hair follicle. We integrate our results with data from seven other autoimmune diseases and provide insight into the alignment of AA within these disorders. Our findings uncover new molecular pathways disrupted in AA, including autophagy/apoptosis, transforming growth factor beta/Tregs and JAK kinase signalling, and support the causal role of aberrant immune processes in AA.

Primary cicatricial alopecia (PCA) is a group of inflammatory hair disorders that cause scarring and permanent hair loss. Previous studies have implicated PPARγ, a transcription factor that integrates lipogenic and inflammatory signals, in the pathogenesis of PCA. However, it is unknown what triggers the inflammatory response in these disorders, whether the inflammation is a primary or secondary event in disease pathogenesis, and whether the inflammatory reaction reflects an autoimmune process. In this paper, we show that the cholesterol biosynthetic pathway is impaired in the skin and hair follicles of PCA patients. Treatment of hair follicle cells with BM15766, a cholesterol biosynthesis inhibitor, or 7-dehydrocholesterol (7-DHC), a sterol precursor, stimulates the expression of pro-inflammatory chemokine genes. Painting of mouse skin with 7-DHC or BM15766 inhibits hair growth, causes follicular plugging and induces the infiltration of inflammatory cells into the interfollicular dermis. Our results demonstrate that cholesterologenic changes within hair follicle cells trigger an innate immune response that is associated with the induction of toll-like receptor (TLR) and interferon (IFN) gene expression, and the recruitment of macrophages that surround the hair follicles and initiate their destruction. These findings reveal a previously unsuspected role for cholesterol precursors in PCA pathogenesis and identify a novel link between sterols and inflammation that may prove transformative in the diagnosis and treatment of these disorders.

Background: Traction alopecia is hair loss due to prolonged or repetitive tension on the hair. Diagnostic challenges may be encountered if the clinical suspicion for traction is not high, or if the history of traction is remote or not obtained. Since pathologic features can vary dramatically with the stage of the disorder clinico-pathologic correlation is essential. We have made the observation that the presence of retained hairs along the frontal and/or temporal rim, which we termed the "fringe sign", is a finding that can be see in both early and late traction alopecia, and thus may be a useful clinical marker of the condition. Objective: To determine the frequency of the fringe sign in a series of patients with a diagnosis of traction alopecia. Methods: This was a retrospective single-center review. Results: Over a 3.5 year period the diagnosis of traction alopecia was made in 41women. Twelve of the 41 patients were Hispanic (29%). The average age of our cohort was 34. Thirty-five (85%) of all women and 100% of women who had traction involving the marginal hair line had the fringe sign. The majority of African American women (54%) compared to 17% of the Hispanic women had some clinical sign of scalp inflammation(most frequently scalp scaling). Fourteen biopsies(58%) were available for review. Histopathologic findings included retained sebaceous glands (100%) and an increase in vellus-sized hairs (50%), a decrease in terminal hairs (100%), fibrotic fibrous tracts (100%), and sparse lyphocytic inflammation (57%). Trichomalacia was only noted in only one of the biopsies. Limitations: Retrospective analysis, uncontrolled study. Conclusions: Hispanic women as well as African American women are at high risk for traction alopecia. The fringe sign was a sensitive and specific clinical feature of traction alopecia when it involved the marginal hair line. Retained sebaceous glands, decreased terminal hairs, and fibrotic fibrous tracts were noted in all histopathologic specimens.

We discuss a patient with central centrifugal cicatricial alopecia (CCCA) who developed severe scalp pruritus that was initially attributed to the cicatricial alopecia and ultimately diagnosed as tinea capitis. The rarity of severe pruritus in CCCA should prompt a search for a fungal infection in these patients.

Alopecia areata (AA) is an autoimmune disease typified by nonscarring hair loss with a variable clinical course. In this study, we conducted whole genome gene expression analysis of 96 human scalp skin biopsy specimens from AA or normal control subjects. Based on gene expression profiling, samples formed distinct clusters based on the presence or absence of disease as well as disease phenotype (patchy disease compared with alopecia totalis or universalis). Differential gene expression analysis allowed us to robustly demonstrate graded immune activity in samples of increasing phenotypic severity and generate a quantitative gene expression scoring system that classified samples based on interferon and cytotoxic T lymphocyte immune signatures critical for disease pathogenesis., Highlights • Gene expression analysis of 96 scalp biopsies from patients with alopecia areata (AA) and healthy controls was performed. • Samples from AA patchy, alopecia universalis/totalis and control patients formed distinct clusters by gene expression. • A set of gene expression biomarkers, the Alopecia Areata Disease Activity Index (ALADIN), was formulated. • ALADIN distinguished AA phenotypes and normal controls. • ALADIN may have utility in clinical trials of AA. Alopecia areata is a disease characterized by autoimmune attack of the hair follicle. A complete understanding of the signaling pathways involved in the disease is lacking. Based on gene expression profiling of skin samples from 96 patients and controls, a set of biomarkers, termed the Alopecia Areata Disease Activity Index, or ALADIN, was formulated. ALADIN was able to distinguish samples from patients with patchy disease from samples from patients with the more extensive forms of disease. The usefulness of this biomarker tool is ready to be assessed in clinical trials of therapeutics for alopecia areata.

Trichothiodystrophy (TTD), an autosomal recessive disorder characterized by sulfur-deficient brittle hair, identifies a group of genetic disorders with an altered synthesis of high-sulfur matrix proteins and a defect in excision repair of ultraviolet damage in fibroblasts of most TTD patients. In contrast to patients with xeroderma pigmentosum (XP), TTD patients do not have an increased frequency of skin cancers. TTD patients may be grouped into four categories: 1) those without photosensitivity and without a defect in excision repair of UV damage; 2) those without photosensitivity and with an excision-repair defect in the same gene as in XP-D (complementation group D); 3) those with photosensitivity and with the XP-D repair defect; 4) those with photosensitivity and with a repair defect distinct from that in XP-D. We present a brother and sister in the third category of TTD. Clinically, the patients have brittle hair, short stature, ichthyosis, photosensitivity, nail and dental dysplasias, cataracts, mental retardation, and pyramidal tract abnormalities. Diagnosis was made by hair mount, which shows the characteristic banding pattern with polarizing microscopy, and by hair amino acid analysis, which demonstrated decreased high-sulfur matrix proteins. Fibroblasts cultured from skin biopsies had a marked DNA excision repair defect similar to the repair defect seen in XP-D. We have documented a unique dysmyelinating disorder on magnetic resonance imaging of the brain that might explain their mental retardation, marked hyperactivity, and neurologic deficits. Following the discovery that the human excision repair cross complementing rodent ultraviolet group 2 (ERCC2) gene is able to correct the ultraviolet sensitivity of XP-D cell strains, the ERCC2 cDNA from previous TTD patients was sequenced and shows frameshifts, deletions and point mutations in the ERCC2 gene. Molecular analysis of our patients is in progress. Molecular analysis of the defects in ERCC2 in clinically distinct patients with XP, XP/Cockayne's syndrome, and TTD may provide insight into the molecular mechanisms of these genetically related but clinically distinct disorders. J Invest Dermatol 103:154S-158S, 1994

13 páginas, 7 figuras, 3 tablas., Alopecia areata (AA) is a genetically determined, immune-mediated disorder of the hair follicle that affects 1%-2% of the U.S. population. It is defined by a spectrum of severity that ranges from patchy localized hair loss on the scalp to the complete absence of hair everywhere on the body. In an effort to define the genetic basis of AA, we performed a genomewide search for linkage in 20 families with AA consisting of 102 affected and 118 unaffected individuals from the United States and Israel. Our analysis revealed evidence of at least four susceptibility loci on chromosomes 6, 10, 16 and 18, by use of several different statistical approaches. Fine-mapping analysis with additional families yielded a maximum multipoint LOD score of 3.93 on chromosome 18, a two-point affected sib pair (ASP) LOD score of 3.11 on chromosome 16, several ASP LOD scores >2.00 on chromosome 6q, and a haplotype-based relative risk LOD of 2.00 on chromosome 6p (in the major histocompatibility complex locus). Our findings confirm previous studies of association of the human leukocyte antigen locus with human AA, as well as the C3H-HeJ mouse model for AA. Interestingly, the major loci on chromosomes 16 and 18 coincide with loci for psoriasis reported elsewhere. These results suggest that these regions may harbor gene(s) involved in a number of different skin and hair disorders., This work was supported in part by grants from the NAAF (to A.M.C. and A.Z.), Israeli Alopecia Areata Fund (to A.Z.), Columbia University Clinical Trials Office Pilot Award (to A.M.-M.), the North American Hair Research Society Mentorship Award (to A.M.-M.), and the National Institutes of Health: National Institute of Arthritis and Musculoskeletal and Skin Diseases grants N01AR02249 (AA Registry [to M.D.]), R03AR050158 (to A.M-M. and J.M.), and R01AR52579 (to A.M.C.) and National Institute of Mental Health grant R01MH44292 (to J.O.).

Over the past decade, basic research has established alopecia areata as a T cell-mediated autoimmune disease and has clarified many of its genetic, cellular, and molecular aspects. Perifollicular and intrafollicular mononuclear cell infiltrates directed at anagen hair bulbs are characteristic and striking histologic features in early alopecia areata. The inflammatory infiltrate is composed predominantly of activated CD4+ and CD8+ T cells, together with macrophages and Langerhans cells. The initiation phase of alopecia areata is mediated by type 1 cytokines, including interleukin-2, interferon-gamma, and tumor necrosis factor-alpha. Like other diseases with a strong autoimmune component, alopecia areata has associated with it specific human leukocyte antigens, which determine susceptibility, severity, chronicity, and resistance. New topical immunomodulating drugs and biologic therapies that have been developed, or that are in development, for the treatment of other immune-mediated inflammatory skin diseases will likely be effective in alopecia areata as well. The present discussion addresses the treatment of alopecia areata within the framework of these new modalities.

The National Alopecia Areata Registry was awarded as a five-year contract by NIAMS to promote research on the genetic basis of alopecia areata. The registry is Web based and can be accessed online at http://www. AlopeciaAreata Registry.org. Samples of DNA, lymphoblast lines, and sera, as well as epidemiology and quality-of-life data, are being collected from well-characterized individuals, multiplex families, and sib pairs for future research studies and investigators.

The Workshop highlighted the current findings of several centers studying the immunologic and genetic aspects of alopecia areata (AA), including the resistance of interferon- (IFN-)-knockout mice to the development of AA, and results of an open pilot study using anti-INF- in the treatment of human AA.