Maria K. Hordinsky

Genome-wide association study in alopecia areata implicates both innate and adaptive immunity

Alopecia areata (AA) is among the most highly prevalent human autoimmune diseases, leading to disfiguring hair loss due to the collapse of immune privilege of the hair follicle and subsequent autoimmune attack. The genetic basis of AA is largely unknown. We undertook a genome-wide association study (GWAS) in a sample of 1,054 cases and 3,278 controls and identified 139 single nucleotide polymorphisms that are significantly associated with AA (Pu2009≤u20095u2009×u200910−7). Here we show an association with genomic regions containing several genes controlling the activation and proliferation of regulatory T cells (Treg cells), cytotoxic T lymphocyte-associated antigen 4 (CTLA4), interleukin (IL)-2/IL-21, IL-2 receptor A (IL-2RA; CD25) and Eos (also known as Ikaros family zinc finger 4; IKZF4), as well as the human leukocyte antigen (HLA) region. We also find association evidence for regions containing genes expressed in the hair follicle itself (PRDX5 and STX17). A region of strong association resides within the ULBP (cytomegalovirus UL16-binding protein) gene cluster on chromosome 6q25.1, encoding activating ligands of the natural killer cell receptor NKG2D that have not previously been implicated in an autoimmune disease. By probing the role of ULBP3 in disease pathogenesis, we also show that its expression in lesional scalp from patients with AA is markedly upregulated in the hair follicle dermal sheath during active disease. This study provides evidence for the involvement of both innate and acquired immunity in the pathogenesis of AA. We have defined the genetic underpinnings of AA, placing it within the context of shared pathways among autoimmune diseases, and implicating a novel disease mechanism, the upregulation of ULBP ligands, in triggering autoimmunity.

Bone Marrow Transplantation for Recessive Dystrophic Epidermolysis Bullosa

BACKGROUNDnRecessive dystrophic epidermolysis bullosa is an incurable, often fatal mucocutaneous blistering disease caused by mutations in COL7A1, the gene encoding type VII collagen (C7). On the basis of preclinical data showing biochemical correction and prolonged survival in col7 −/− mice, we hypothesized that allogeneic marrow contains stem cells capable of ameliorating the manifestations of recessive dystrophic epidermolysis bullosa in humans.nnnMETHODSnBetween October 2007 and August 2009, we treated seven children who had recessive dystrophic epidermolysis bullosa with immunomyeloablative chemotherapy and allogeneic stem-cell transplantation. We assessed C7 expression by means of immunofluorescence staining and used transmission electron microscopy to visualize anchoring fibrils. We measured chimerism by means of competitive polymerase-chain-reaction assay, and documented blister formation and wound healing with the use of digital photography.nnnRESULTSnOne patient died of cardiomyopathy before transplantation. Of the remaining six patients, one had severe regimen-related cutaneous toxicity, with all having improved wound healing and a reduction in blister formation between 30 and 130 days after transplantation. We observed increased C7 deposition at the dermal-epidermal junction in five of the six recipients, albeit without normalization of anchoring fibrils. Five recipients were alive 130 to 799 days after transplantation; one died at 183 days as a consequence of graft rejection and infection. The six recipients had substantial proportions of donor cells in the skin, and none had detectable anti-C7 antibodies.nnnCONCLUSIONSnIncreased C7 deposition and a sustained presence of donor cells were found in the skin of children with recessive dystrophic epidermolysis bullosa after allogeneic bone marrow transplantation. Further studies are needed to assess the long-term risks and benefits of such therapy in patients with this disorder. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00478244.)

Genomewide Scan for Linkage Reveals Evidence of Several Susceptibility Loci for Alopecia Areata

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.

Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci

Alopecia areata (AA) is a prevalent autoimmune disease with ten known susceptibility loci. Here we perform the first meta-analysis in 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 MHC, where we fine-map 4 independent effects, all implicating HLA-DR as a key etiologic driver. Outside the MHC, we identify two novel loci that exceed 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, TGFß/Tregs and JAK kinase signaling, and support the causal role of aberrant immune processes in AA.

Efficacy and safety of a low-level laser device in the treatment of male and female pattern hair loss: a multicenter, randomized, sham device-controlled, double-blind study.

SignificanceMale and female pattern hair loss are common, chronic dermatologic disorders with limited therapeutic options. In recent years, a number of commercial devices using low-level laser therapy have been promoted, but there have been little peer-reviewed data on their efficacy.ObjectiveTo determine whether treatment with a low-level laser device, the US FDA-cleared HairMax Lasercomb®, increases terminal hair density in both men and women with pattern hair loss.MethodsRandomized, sham device-controlled, double-blind clinical trials were conducted at multiple institutional and private practices. A total of 146 male and 188 female subjects with pattern hair loss were screened. A total of 128 male and 141 female subjects were randomized to receive either a lasercomb (one of three models) or a sham device in concealed sealed packets, and were treated on the whole scalp three times a week for 26xa0weeks. Terminal hair density of the target area was evaluated at baseline and at 16- and 26-week follow-ups, and analyzed to determine whether the hypothesis formulated prior to data collection, that lasercomb treatment would increase terminal hair density, was correct. The site investigators and the subjects remained blinded to the type of device they dispensed/received throughout the study. The evaluator of masked digital photographs was blinded to which trial arm the subject belonged.ResultsSeventy-eight, 63, 49, and 79 subjects were randomized in four trials of 9-beam lasercomb treatment in female subjects, 12-beam lasercomb treatment in female subjects, 7-beam lasercomb treatment in male subjects, and 9- and 12-beam lasercomb treatment in male subjects, compared with the sham device, respectively. Nineteen female and 25 male subjects were lost to follow-up. Among the remaining 122 female and 103 male subjects in the efficacy analysis, the mean terminal hair count at 26xa0weeks increased from baseline by 20.2, 20.6, 18.4, 20.9, and 25.7 per cm2 in 9-beam lasercomb-treated female subjects, 12-beam lasercomb-treated female subjects, 7-beam lasercomb-treated male subjects, and 9- and 12-beam lasercomb-treated male subjects, respectively, compared with 2.8 (pxa0<xa00.0001), 3.0 (pxa0<xa00.0001), 1.6 (pxa0=xa00.0017), 9.4 (pxa0=xa00.0249), and 9.4 (pxa0=xa00.0028) in sham-treated subjects (95xa0% confidence interval). The increase in terminal hair density was independent of the age and sex of the subject and the lasercomb model. Additionally, a higher percentage of lasercomb-treated subjects reported overall improvement of hair loss condition and thickness and fullness of hair in self-assessment, compared with sham-treated subjects. No serious adverse events were reported in any subject receiving the lasercomb in any of the four trials.Conclusions and relevanceWe observed a statistically significant difference in the increase in terminal hair density between lasercomb- and sham-treated subjects. No serious adverse events were reported. Our results suggest that low-level laser treatment may be an effective option to treat pattern hair loss in both men and women. Additional studies should be considered to determine the long-term effects of low-level laser treatment on hair growth and maintenance, and to optimize laser modality.

Subcutaneous efalizumab is not effective in the treatment of alopecia areata

BACKGROUNDnAlopecia areata (AA) is a T-cell-mediated autoimmune disease. Efalizumab is a T-cell-targeted therapy approved for the treatment of psoriasis.nnnOBJECTIVEnTo assess the efficacy and safety of efalizumab in the treatment of moderate-to-severe AA.nnnMETHODSnSixty-two patients were enrolled into this phase II, placebo-controlled trial. The trial consisted of three 12-week periods-a double-blind treatment period, an open-label efalizumab treatment period, and a safety follow-up.nnnRESULTSnThere were no statistical differences between treatment groups in percent hair regrowth, quality-of-life measures, or changes in biologic markers of disease severity after 12 or 24 weeks. In both groups, there was an approximately 8% response rate for hair regrowth (at 12 weeks). Efalizumab was well tolerated.nnnLIMITATIONSnNumbers were too small for certain analyses.nnnCONCLUSIONnA 3- to 6-month trial of efalizumab was not effective in promoting hair regrowth in this small cohort of patients with moderate-to-severe AA.

Germline melanoma susceptibility and prognostic genes: A review of the literature

In recent years, there have been increasing efforts to identify germline genetic variants that may alter melanoma susceptibility and prognosis. The findings of these studies have indicated the presence of rare, high-penetrance alleles with large effects, such as CDKN2A and CDK4, more common, moderately penetrant genes like MC1R, and very common, low-penetrance polymorphisms with small effects that are related to pigmentation, nevus count, immune responses, DNA repair, metabolism, and the vitamin D receptor. The study of these low-penetrance single nucleotide polymorphisms is relatively new; thus many of them are termed candidate melanoma susceptibility or prognostic genes. This review summarizes the research on germline polymorphisms that have been implicated in melanoma susceptibility and prognosis in order to provide a framework for additional studies to meet the ultimate goal of predicting a patients risk of, and prognosis in, cutaneous malignant melanoma.

Cicatricial alopecia: discoid lupus erythematosus

ABSTRACT:u2003 Chronic cutaneous lupus erythematosus consists of three major dermatologic diseases: discoid lupus erythematosus (DLE), lupus panniculitis/lupus profundus, and lupus tumidus ( Table 1 ). DLE is estimated to be responsible for 50–85% of patients with chronic cutaneous lupus erythematosus. Scalp involvement is most often the presenting symptom. The clinical features and diagnosis of DLE, its pathophysiology and treatment, are reviewed.

Overview of alopecia areata.

Alopecia areata is a complex genetic, immune-mediated disease that targets anagen hair follicles. The disease affects children and adults and is characterized by round or oval patches of hair loss, loss of all scalp hair (alopecia totalis), body hair (alopecia universalis), or ophiasis pattern hair loss. Patients may also present with patchy loss in multiple hair-bearing areas. Commonly associated diseases include asthma, allergic rhinitis, atopic dermatitis, thyroid disease, and automimmune diseases, such as thyroiditis and vitiligo. Nail abnormalities may precede, follow, or occur concurrently with hair loss activity. Alopecia areata has no known age, race, or ethnic preponderance and in contrast to other autoimmune diseases such as thyroiditis or lupus, the hair follicle does not usually sustain permanent injury and maintains its potential to regrow hair. It is estimated that alopecia areata affects between six and seven million individuals in the United States. Genes, the immune and nervous systems have all been implicated in the pathogenesis of alopecia areata. Although many treatments are available, there is still no cure. Bolstered by new scientific and translational opportunities from recently published genome-wide association studies, an ambitious treatment development program has recently been initiated by the National Alopecia Areata Foundation.

A Comprehensive Pathophysiology of Dandruff and Seborrheic Dermatitis: Towards a More Precise Definition of Scalp Health

Despite an increasing knowledge of dandruff and seborrheic dermatitis (D/SD), the pathophysiological understanding is still incomplete but suggests a role of Malassezia yeasts in triggering inflammatory and hyper-proliferative epidermal responses. The objective of this report is to review published literature from in vivo studies of D/SD populations to provide a more complete description of overall scalp health. New biomolecular capabilities establish a depth of pathophysiological understanding not previously achievable with traditional means of investigation. Biomarkers representing inflammation, hyper-proliferation and barrier function are all perturbed by the D/SD condition and robustly respond to therapeutic resolution. These biomarkers can be sampled noninvasively, enabling their use in routine clinical evaluations as either surrogate endpoints or complementary ones to classical signs/symptoms to broaden the etiological learning.