bromochloroacetic-acid and Hidradenitis-Suppurativa

Hidradenitis suppurativa (HS) is characterized by deep-seated, highly inflamed, and painful lumps/abscesses, fistulae, and sinus tracts that grow extensively deep in the dermis and are highly immunogenic in nature. In about one-third of the HS patients there is strong evidence for the role of γ-secretase mutations along with dysregulated Notch signaling. However, the contribution of dysregulated Notch signaling in HS pathogenesis in relation to hair follicle alterations and hyper-activation of the immune system remains undefined. A genome-wide association study (GWAS), proteomic data and functional investigations of identified sequence variants in HS pathology are not fully revealing. The disease initiation or progression may involve bacterial infection besides intrinsic functional defects in keratinocytes, which may be key to further exacerbate immune cell infiltration and cytokine production in and around the lesional tissue. The absence of a suitable animal model that could fully recapitulate the pathogenesis of HS is a major impediment for proper understanding the underlying mechanisms and development of effective treatments. The presence of extracellular matrix (ECM) degradation products along with dysregulation in keratinocytes and, dermal fibroblasts ultimately affect immune regulation and are various components of HS pathogenesis. Bacterial infection further exacerbates the complexity of the disease progression. While anti-TNFα therapy shows partial efficacy, treatment to cure HS is absent. Multiple clinical trials targeting various cytokines, complement C5a and ECM products are in progress. This review provides state-of-the-art information on these aspects with a focus on dysregulated keratinocyte and immune cells; and role of ECM, and Keratin functions in this regard.

Topics: Animals; Cytoskeletal Proteins; Genome-Wide Association Study; Hidradenitis Suppurativa; Humans; Keratins; Proteomics; Signal Transduction

Hidradenitis suppurativa (HS) is an inflammatory, debilitating follicular skin disease with recurring flare-ups. The painful, deep-seated, inflamed lesions in the inverse areas of the body cause severe discomfort, and hence, serious psycho-social and economic costs. HS is common, but often misdiagnosed and mechanistically poorly understood. Furthermore, HS is notoriously difficult to treat resulting in a high unmet medical need. To provoke debate, rational experimentation and initiate strategic studies, we here present a concise viewpoint on seven topics: the diagnosis of HS, the role of mechanical friction, the critical importance of accurate clinical subgrouping, smoking and obesity, the role of bacteria, and our comprehensive view on HS pathogenesis with a central role for keratin clearance, and novel treatment approaches.

Topics: Diagnostic Errors; Friction; Hidradenitis Suppurativa; Humans; Immunologic Factors; Inflammation Mediators; Keratins; Metagenome; Models, Biological; Obesity; Risk Factors; Smoking; Stress, Mechanical; Sweat Glands

Hidradenitis suppurativa (HS)/acne inversa is an intractable skin disease that is characterized by destructive lesions - primarily on the flexural areas. Although its etiology is unknown, genetics is considered to be a factor of its pathology - mutations in γ-secretase genes have been identified in certain familial HS patients, and follicular occlusion is widely accepted as the primary cause of HS. But, no relationship between these mutations and the components of hair follicles has been reported. Thus, we examined changes in these components in mice with a mutation in NCSTN (a γ-secretase gene).. We generated C57BL/6 mice with an NCSTN mutation and examined their expression of hair cortex cytokeratin and trichohyalin by Western blot and immunohistochemistry, in addition to nicastrin, the product of NCSTN, and NICD compared with wild-type mice. The structure of hair follicles was analyzed by hematoxylin-eosin staining and transmission electron microscopy.. In mice with an NCSTN mutation, HS-like skin lesions appeared after age 6 months, the pathological manifestations of which were consistent with the features of human HS. The structure of hair follicles was abnormal in mice with an NCSTN mutation versus wild-type mice, and hair cortex cytokeratin, trichohyalin, nicastrin, and NICD were downregulated in these mice.. This NCSTN mutant mouse model could be an improved model to study early lesion development aspects of human HS pathogenesis and could perhaps be a better alternative for evaluating early-acting and preventive therapeutics for HS experimentally before clinical trials in HS patients. NCSTN mutations disrupt the development of hair follicles, leading to abnormal hair follicle structures, perhaps resulting in the onset of HS.

Topics: Amyloid Precursor Protein Secretases; Animals; Hair Follicle; Hidradenitis Suppurativa; Humans; Infant; Keratins; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mutation

Topics: Cytoskeletal Proteins; Hidradenitis Suppurativa; Humans; Keratin-16; Keratin-17; Keratin-6; Keratins; Pachyonychia Congenita; Pedigree

To test the capability of 70-MHz ultrasound for detecting initial ultrasound signs of hidradenitis suppurativa (HS) linked to severity.. A cross-sectional study of the ultrasound images of patients with HS was conducted and compared with a healthy control group. Detection and identification of early subclinical ultrasound signs in the lesional and perilesional areas of the HS cases in comparison with the control group were performed. Statistical analyses included mean, dispersion measures, the Kruskal-Wallis test, and bivariate and multivariate ordered logistic regression studies. Significance was assessed at P < .05.. A total of 139 patients with HS met the criteria and showed abnormalities of the hair follicles such as a curved shape, ballooning, and protrusion into pseudocysts, collections, or tunnels (donor of keratin sign). Significant increases in the sizes of the hair follicles and hair shafts were found in HS cases. The following ultrasound signs were significantly linked to severity: a connecting band between the base of adjacent hair follicles (bridge sign), a fragment of the hair shaft extruding through a dilated hair follicle (sword sign), and retained cylindrical fragments of keratin in the dermis. Two patterns of fragmentation of the keratin were detected: multifragment and cylindrical.. Ultrasound can detect early HS signs that are significantly linked to severity and 2 types of fragmentation of the keratin, which could support the generation and perpetuation of the fluid collections and tunnels. These ultrasound signs can help prompt diagnosis and management, the development and testing of medications, and the measure of treatment outcomes in HS.

Topics: Adolescent; Adult; Child; Cross-Sectional Studies; Female; Hair Follicle; Hidradenitis Suppurativa; Humans; Keratins; Male; Middle Aged; Retrospective Studies; Severity of Illness Index; Ultrasonography; Young Adult

Topics: Hidradenitis Suppurativa; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Inflammation; Keratinocytes; Keratins

Current insight into the histopathological course of events during disease progression in hidradenitis suppurativa (HS) is fragmentary.. To identify histological alterations and leucocyte subsets in normal-appearing perilesional skin, and early and chronic HS lesions.. In this observational study we examined eight perilesional skin samples, and six early and 10 chronic prototypic HS lesions, as well as skin samples from four healthy donors using in situ immunostaining.. Perilesional skin showed mild psoriasiform hyperplasia and follicular plugging as well as a low-grade influx of tryptase-positive mast cells, CD3+ T cells, CD138+ plasma cells and factor XIIIa+ dendritic cells. In early HS lesions, neutrophilic abscess formation and influx of mainly macrophages, monocytes and dendritic cells predominated. In chronic disease, the infiltrate expanded with markedly increased frequencies of CD20+ and CD79a+ B cells and CD138+ plasma cells. As in early lesions, free keratin fibres were detected in the dermis and within giant cells. Single detached keratinocytes and strands of follicular epithelium were observed in the dermis, the latter frequently expressing Ki67, indicative of active proliferation.. Psoriasiform hyperplasia, follicular plugging and low-grade leucocytic infiltration are already present in normal-appearing perilesional skin. Keratin fibres in the dermis are associated with clinical disease. Early lesions are characterized by neutrophilic abscess formation and influx of mainly histiocytes, and chronic lesions mainly by expansion of B cells and plasma cells in 'pseudo' follicles. Proliferating strands of follicular epithelium may initiate fistula formation. Mast cells are increased in all stages of HS including perilesional skin.

Topics: Acute Disease; Cell Proliferation; Chronic Disease; Epidermis; Hidradenitis Suppurativa; Humans; Hyperplasia; Immunohistochemistry; Immunophenotyping; Keratins; Leukocytes; Skin

Clear-cell acanthoma (CCA) has been reported to be a benign epidermal neoplasm; however, several authors have suggested alternative differentiation as well as other nosologic categories, including a reactive dermatosis. Fourteen CCAs, ten tricholemmomas, and seven cases of psoriasis were reviewed with conventional microscopy, periodic acid-Schiff stains, and immunohistochemical stains. Twelve of fourteen (86%) CCAs were associated with underlying or adjacent conditions. The CCAs stained immunohistochemically in a pattern similar to normal epidermis and psoriasis. Tricholemmomas stained in a distinctly different pattern with MNF116 and NGFR/p75. These cases demonstrate CCA in settings that reflect chronic inflammation, primarily scars and stasis dermatitis, and with an immunophenotype that parallels psoriasis. These findings support the contention that CCA does not show outer follicular sheath (tricholemmal) differentiation. Furthermore, these cases lend additional support to the contention that CCA represents a psoriasiform reaction pattern, which, in appropriately taken biopsies, usually has a demonstrable associated condition. Nonetheless, the precise nosology of this phenomenon has yet to be elucidated completely.

Topics: Acanthoma; Adult; Aged; Aged, 80 and over; Cicatrix; Dermatitis; Epidermis; Female; Hair Follicle; Hidradenitis Suppurativa; Humans; Hyperplasia; Keratins; Keratosis, Seborrheic; Male; Middle Aged; Molecular Weight; Neoplasms, Basal Cell; Nerve Tissue Proteins; Psoriasis; Receptors, Nerve Growth Factor; Skin; Skin Neoplasms

We have studied cytokeratin (CK) expression in two cases of well-differentiated and poorly differentiated squamous cell carcinoma (SCC) arising from hidradenitis suppurativa (HS) (acne inversa). In both cases, type A (infundibular-like keratinized) epithelia were observed. In type A epithelia, CK 1 and 10 expressions were decreased, and CK 14 and 17 were detectable in the whole layers. CK 7, 8, 15, 16 and 18 were not detected in type A epithelia. In tumor nests of well-differentiated SCC, CK 1 and 10 expressions were downregulated, and CK 14 expression was upregulated. In tumor nests of poorly differentiated SCC, CK 1 and 10 were not expressed, but simple epithelial keratins (CK 8, 18 and 19) were expressed. These changes of CK expression are related to malignant transformation from the sinus tract (type A epithelium) in HS to SCC.

Topics: Aged; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Fatal Outcome; Hidradenitis Suppurativa; Humans; Immunoenzyme Techniques; Keratins; Male; Middle Aged; Skin Neoplasms

Pilonidal sinus (PS) is considered to belong in the category of follicular occlusion diseases (acne triad).. The aim of our study was to elucidate the pathogenesis of PS by evaluating its cytokeratin (CK) expression.. CK expression in nine cases of PS was studied immunohistochemically using six antikeratin antibodies.. Infundibular-like epithelium contained CK1, 10 and 14 similar to normal infundibulum, but it did not contain CK17. In non-infundibular-like epithelium, CK14, 16 and 17 were detected similar to that in normal outer root sheath. CK expression in PS was similar to that in hidradenitis suppurativa, suggesting that sinus epithelium may be fragile, hyperproliferative and undifferentiated.. PS can be classified in the same entity as follicular occlusion diseases based on CK expression.

Topics: Adult; Buttocks; Epithelium; Hidradenitis Suppurativa; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Pilonidal Sinus; Skin

The draining sinus is a late complication of several forms of severe acne, leading to extensive, periodically inflamed lesions that are undermined by a system of fistulas, supposed to be of follicular origin. We investigated the expression of various cytokeratins (CKs) and desmosomal proteins in the draining sinus of acne inversa (hidradenitis suppurativa) using monoclonal antibodies in immunohistochemistry on paraffin-embedded sections. We were able to define three different phenotypes of stratified squamous epithelia covering the sinus tracts. Type I epithelium was cornifying and characterized by the presence of CK 10, desmogleins 1-3 and desmocollins 1-3 in an epidermis-like pattern. Type II epithelium was non-cornifying, negative for CK 10 and positive for CK 13. It was negative for desmocollin 1 but strongly immunopositive for desmoglein 1 suprabasally and for desmoglein 2 in the basal cells. Type III epithelium was non-cornifying and strongly inflamed. It was marked by the presence of CK 7, CK 19 and desmoglein 2 and the absence of CK 10, desmoglein 1 and desmocollin 1. In both type II and III epithelium, desmoglein 3, desmocollin 2 and desmocollin 3 showed an inverted staining pattern as compared with normal epidermis and type I epithelium. Desmoglein 2 and CK 5/14 always remained restricted to the basal cell layer. Antibodies against CK 6 and CK 13/15/16 were immunopositive in all three phenotypes and CK 17 was predominantly immunolocalized to suprabasal layers of type II and III epithelium. The three phenotypes are characterized as pathological stratified squamous epithelia reflecting the dynamic process of inflammation, proliferation and stratification taking place in acne inversa.

Topics: Antibodies, Monoclonal; Cell Differentiation; Cutaneous Fistula; Cytoskeletal Proteins; Desmocollins; Desmoglein 1; Desmoglein 2; Desmoglein 3; Desmogleins; Desmoplakins; Epithelium; Hidradenitis Suppurativa; Humans; Immunohistochemistry; Keratins