bromochloroacetic-acid and Alopecia-Areata

Topics: Alopecia Areata; Child; Collagen Diseases; DNA; Genetic Counseling; Humans; Keratins; Male; Nevus; Pharmaceutical Preparations; Pharmacogenetics; Research; Skin Abnormalities; Skin Diseases; Skin Diseases, Vesiculobullous; Skin Neoplasms; Syndrome

Topics: Adolescent; Adult; Alopecia; Alopecia Areata; Anemia, Sickle Cell; Animals; Autoradiography; Child; Child, Preschool; Down Syndrome; Female; Hair; Humans; Infant; Infant, Newborn; Keratins; Male; Pregnancy; Puerperal Disorders; Rats; Stress, Physiological; Zinc

Alopecia areata (AA) is considered a highly heritable, T-cell-mediated autoimmune disease of the hair follicle. However, no convincing susceptibility gene has yet been pinpointed in the major histocompatibility complex (MHC), a genome region known to be associated with AA as compared to other regions.. We engineered mice carrying AA risk allele identified by haplotype sequencing for the MHC region using allele-specific genome editing with the CRISPR/Cas9 system. Finally, we performed functional evaluations in the mice and AA patients with and without the risk allele.. We identified a variant (rs142986308, p.Arg587Trp) in the coiled-coil alpha-helical rod protein 1 (CCHCR1) gene as the only non-synonymous variant in the AA risk haplotype. Furthermore, mice engineered to carry the risk allele displayed a hair loss phenotype. Transcriptomics further identified CCHCR1 as a novel component interacting with hair cortex keratin in hair shafts. Both, these alopecic mice and AA patients with the risk allele displayed morphologically impaired hair and comparable differential expression of hair-related genes, including hair keratin and keratin-associated proteins (KRTAPs).. Our results implicate CCHCR1 with the risk allele in a previously unidentified subtype of AA based on aberrant keratinization in addition to autoimmune events.. This work was supported by JSPS KAKENHI (JP16K10177) and the NIHR UCLH Biomedical Research center (BRC84/CN/SB/5984).

Topics: Alleles; Alopecia Areata; Animals; Autoimmune Diseases; Carrier Proteins; Disease Models, Animal; Genetic Predisposition to Disease; Genome; Hair; Hair Follicle; Haplotypes; Humans; Intracellular Signaling Peptides and Proteins; Keratins; Keratins, Hair-Specific; Major Histocompatibility Complex; Mice; T-Lymphocytes

Alopecia areata (AA) has been recently shown to also include T-helper cell type 2/IL-23 activation, in addition to T-helper cell type 1/IFN-skewing. The success of Jak inhibition together with IL-4Rα antagonism and limited response to IL-17A and PDE4 (protein) inhibition in AA are increasing our understanding of the complex immune interplay in AA. Trials testing targeted therapeutics are needed to further elucidate the pathogenic contribution of various cytokines.

Topics: Alopecia Areata; Autoimmune Diseases; Cytokines; Gene Expression; Humans; Keratins; Molecular Targeted Therapy; Transcriptome

Alopecia areata (AA) is a common inflammatory disease targeting the anagen-stage hair follicle. Different cytokines have been implicated in the disease profile, but their pathogenic role is not yet fully determined. We studied biopsies of pretreatment lesional and non-lesional (NL) scalp and post-treatment (intra-lesional steroid injection) lesional scalp of 6 patchy patients with AA using immunohistochemistry and gene expression analysis. Immunohistochemistry showed increases in CD3(+) , CD8(+) T cells, CD11c(+) dendritic cells and CD1a(+) Langerhans cells within and around hair follicles of pretreatment lesional scalp, which decreased upon treatment. qRT-PCR showed in pretreatment lesional scalp (compared to NL) significant increases (P < 0.05) in expression of inflammatory markers (IL-2, IL-2RA, JAK3, IL-15), Th1 (CXCL10 and CXCL9), Th2 (IL-13, CCL17 and CCL18), IL-12/IL-23p40 and IL-32. Among these, we observed significant downregulation with treatment in IL-12/IL-23p40, CCL18 and IL-32. We also observed significant downregulation of several hair keratins in lesional scalp, with significant upregulation of KRT35, KRT75 and KRT86 in post-treatment lesional scalp. This study shows concurrent activation of Th1 and Th2 immune axes as well as IL-23 and IL-32 cytokine pathways in lesional AA scalp and defined a series of response biomarkers to corticosteroid injection. Clinical trials with selective antagonists coupled with cytokine-pathway biomarkers will be necessary to further dissect pathogenic immunity.

Topics: Adrenal Cortex Hormones; Alopecia Areata; Biomarkers; Biopsy; Cytokines; Female; Gene Expression Profiling; Gene Expression Regulation; Hair Follicle; Humans; Immunohistochemistry; Inflammation; Interleukins; Keratins; Langerhans Cells; Male; Scalp; Th1 Cells; Th2 Cells

We have previously described spontaneous but reversible hair loss that clinically and histologically resembles human alopecia areata in a colony of C3H/HeJ mice. Alopecia areata in humans is associated with antibodies to hair follicles. This study was conducted to determine whether C3H/HeJ mice with hair loss have a similar abnormal antibody response to hair follicles. Eighteen C3H/HeJ mice with alopecia, 12 unaffected littermates, and 15 control mice were examined for circulating antibodies to C3H/HeJ anagen hair follicles by indirect immunofluorescence and against extracts of isolated C3H/HeJ and human anagen hair follicles by immunoblotting. Using both procedures, antibodies to anagen hair follicles were present in all C3H/HeJ mice with alopecia but in none of the control mice. The antibodies were also present in some unaffected C3H/HeJ littermates but were absent in mice of an unrelated strain with inflammatory skin disease and alopecia, indicating that their appearance did not result from the hair loss. These antibodies reacted to hair follicle-specific antigens of 40-60 kDa present in murine and human anagen hair follicles. These antigens were also reactive with human alopecia areata antibodies. Some of the antibodies in both C3H/HeJ mice and humans with alopecia areata reacted to antigens of 44 and 46 kDa, which were identified as hair follicle-specific keratins. This study indicates that C3H/HeJ mice with hair loss have circulating antibodies to hair follicles similar to those present in humans with alopecia areata. These findings confirm that these mice are an appropriate model for human alopecia areata and support the hypothesis that alopecia areata results from an abnormal autoimmune response to hair follicles.

Topics: Alopecia Areata; Animals; Antibody Specificity; Autoantibodies; Autoantigens; Disease Models, Animal; Female; Fluorescent Antibody Technique, Indirect; Hair Follicle; Humans; Immunoblotting; Keratins; Male; Mice; Tissue Distribution

Alopecia areata is a human hair disease of unknown etiology. Immunological mechanisms, alterations in the extracellular matrix and follicular growth abnormalities have been suggested as a possible cause. Here we compare the expression of cytokeratins in normal hair follicles to that of alopecia areata using immunohistology with monoclonal antibodies. A number of cytokeratins were specifically expressed in defined anatomical parts of the follicle; however, no gross qualitative or quantitative differences were found between normal and diseased scalp. Interestingly, the expression of cytokeratin 16, which is modulated by conditions that affect the rate of keratinocyte proliferation, was found to be unchanged in the outer root sheet of alopecia areata follicles. This is in contrast with earlier observations of a decrease in the expression of the proliferation-associated, Ki-67 nuclear antigen.

Topics: Alopecia Areata; Antibodies, Monoclonal; Hair; Humans; Keratins

There is evidence suggesting that alopecia areata (AA) may have an autoimmune pathogenesis, and it was recently reported that keratinocytes in the bulb of some hair follicles affected by this condition express class II HLA (HLA-DR) antigens, which are not present on the same cells in normal tissue. Since it has been proposed that an analogous ectopic HLA-DR expression by epithelial cells in other organs might be an early event leading to organ-specific autoimmunity, we have investigated the sequence in which perifollicular mononuclear cell (MNC) infiltration and ectopic HLA-DR expression on keratinocytes appear in recent-onset and long-standing cases of AA by immunostainings of affected and unaffected areas with monoclonal antibodies against leukocyte and HLA-DR antigens. In recent-onset AA lesions, ectopic HLA-DR expression on hair follicle keratinocytes was found only occasionally (in 3 out of 247 follicles examined) and was restricted to biopsies from the affected areas. This prevalence was significantly lower than the prevalence of hair follicles showing perifollicular MNC infiltrates in the same biopsies, and was also significantly lower than the prevalence of hair follicles showing ectopic HLA-DR expression on keratinocytes in the affected areas of longstanding cases. These findings suggest that in AA lesions the perifollicular MNC infiltration precedes the ectopic HLA-DR expression on hair follicle keratinocytes, and therefore argue against the notion of a primary role for that ectopic HLA-DR expression on epithelial cells in triggering the putative autoimmune response in AA.

Topics: Adolescent; Adult; Alopecia Areata; Autoantibodies; Epidermis; Female; Hair; HLA-D Antigens; HLA-DQ Antigens; HLA-DR Antigens; Humans; Keratins; Leukocytes, Mononuclear; Male

Fragments of nail keratin removed with tweezers from patients suffering from alopecia areata were examined using light microscopy and electron microscopy. The results obtained from these two techniques show nail changes which are slits, cupuliform dips of the upper edge and parakeratosis, under light microscopy; vacuoles, depletion of keratin fibers, and electron-dense fibrillary deposits, under electron microscopy. These changes predominate in the nail plate with a maximum in the upper part while the subungual keratin is preserved. A serious disorder of the matrix keratinization is probably the source of this preferential localization. To determine whether it is a disorder of the keratin fibers themselves or rather of the interfilamentary matrix and especially of the filaggrin system will require further biochemical and immunological studies.

Topics: Alopecia Areata; Filaggrin Proteins; Humans; Keratins; Microscopy, Electron; Nails; Parakeratosis

Topics: Alopecia; Alopecia Areata; Dermatitis; Dermatitis, Atopic; Dermatitis, Seborrheic; Dermatology; Humans; Keratins; Mercury; Nails; Ointments; Pigmentation; Psoriasis