Autoimmune Skin Condition Research Articles

A psoriasis target in Langerhans cells

Immunology Psoriasis is an autoimmune skin condition that is linked to the proinflammatory cytokine interleukin-17 (IL-17), which is produced by T cells in the skin. Zheng et al. found that p38α signaling in skin-resident dendritic cells (Langerhans cells) was important for the pathogenesis of

A study of prevalence of autoantibodies in patients with lichen planus from Mumbai, India.

Lichen planus is a common chronically relapsing autoimmune skin condition with poorly understood etiology. Apart from cellular immunity, presence of various antibodies has been hypothesized. Various studies have found the presence of serum anti-nuclear antibody, anti-mitochondrial antibody, anti-desmoglein 1 and 3 antibodies, anti-keratinocyte antibody and anti-thyroglobulin antibody in patients of cutaneous and oral lichen planus. To study the prevalence of autoantibodies and the clinical spectrum of disease in an Indian patient subpopulation with lichen planus. A cross-sectional epidemiological study comprising 100 lichen planus patients was conducted in the dermatology outpatient department of Seth G.S Medical College and King Edward Memorial Hospital, Mumbai, Maharashtra, India. Serum concentrations of circulating anti-nuclear antibodies, anti-desmoglein 1 antibody, anti-desmoglein 3 antibody, anti-keratinocyte antibodies, anti-mitochondrial antibodies and anti-thyroglobulin antibodies were determined by indirect immunofluorescence. Pairs of groups were compared using "Student's t-test" for normally distributed continuous data. The "χ2-test" was used for the categorical variables as needed. Statistical significance was set at P < 0.05. It was found that 65 (65%) patients showed the presence of at least one of the six autoantibodies that we studied, while 35 (35%) tested negative for all six of them. Positivity of anti-keratinocyte antibody in 26 (26%), anti-nuclear antibody in 22 (22%), anti-desmoglein 1 antibody in 19 (19%), anti-desmoglein 3 antibody in 16 (16%), anti-mitochondrial antibody in 9 (9%) and anti-thyroglobulin antibody in 6 (6%) patients was detected. It was observed that 55 (71.4%) patients of cutaneous lichen planus, 6 (46.1%) patients of mucosal lichen planus and 4 (40%) patients of cutaneous and mucosal lichen planus overlap showed presence of at least one autoantibody. This study provides the serological parameters of a population of lichen planus from western India. Presence of autoantibodies in lichen planus suggests the possible role of humoral immunity in lichen planus. Identifying antibodies linked to lichen planus may help in identifying suitable diagnostic tests and therapeutic targets. Well-controlled studies with larger sample size are the need of the hour to confirm the role of humoral immunity in lichen planus. Studies with a larger number of patients as well as controls should be undertaken to further evaluate the role of autoantibodies in lichen planus.

Correlation between IL36α and IL17 and Activity of the Disease in Selected Autoimmune Blistering Diseases.

Dermatitis herpetiformis (DH), bullous pemphigoid (BP), and pemphigus vulgaris (PV) are autoimmune bullous skin conditions with eosinophilic and neutrophilic infiltrations. While cytokines are crucial for the affinity and activation of different leukocyte cells in the inflammation and blister formation, there are no studies concerning a role of IL-36. The goal of the study was to analyze whether interleukin 36 is involved in pathogenesis of DH, BP, and PV. And the second aim of the study was the estimation of correlation between Il-36 and IL-17 and titers of specific antibodies in these diseases. Expression of IL-36 and IL-17 was detected in serum in all DH, BP, and PV samples. Serum levels of IL-36 and IL-17α were statistically higher in DH, BP, and PV groups as compared to the control group. IL-36α levels were statistically higher in DH patients, as compared to patients with PV and BP. Our results showed that IL-36 may be helpful in the diagnostic and monitoring of the activity of the disease. IL 36 may play a relevant role of enrolling eosinophils and neutrophils in DH, BP, and PV and finally provoke tissue injury.

Mesenchymal stromal cells: properties and role in management of cutaneous diseases.

This review describes the current understanding and the potential use of mesenchymal stromal cells (MSCs) in cell-based therapies for clinical management of difficult wounds and other dermatoses. MSCs have been shown to possess many advantageous properties that make them a promising therapeutic modality in dermatology still under investigation. In fact, MSCs' ability to promote wound healing through its paracrine function and pro-angiogenic properties have generated increasing interest for treating acute and chronic wounds. There is also great interest in utilizing MSCs' immunological characteristics for therapeutic use especially for patients with debilitating systemic autoimmune and inflammatory skin conditions who have failed other therapies. Its role in aesthetics has also been explored with clinical data showing improvement of acne scars and wrinkles from photoaging. Clinical trials are underway investigating the safety and efficacy of MSCs in the treatment of different skin conditions such as acute burns, diabetic and venous stasis ulcers, epidermolysis bullosa and systemic sclerosis, among others. We anticipate that as our understanding of the characteristics and function of MSCs grow, so will its role in cell-based treatments of dermatological conditions.

A 3′UTR polymorphism marks differential KLRG1 mRNA levels through disruption of a miR-584-5p binding site and associates with pemphigus foliaceus susceptibility

Genetic variations mapping to 3′ untranslated regions (3′UTRs) may overlap with microRNA (miRNA) binding sites, therefore potentially interfering with translation inhibition or messenger RNA (mRNA) degradation. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) located within the 3′UTRs of six candidate genes and predicted to interfere with miRNA ligation could account for disease-relevant differential mRNA levels. Focusing on pemphigus foliaceus (PF) – an autoimmune blistering skin condition with unique endemic patterns – we investigated whether nine 3′UTR SNPs from the CD1D, CTLA4, KLRD1, KLRG1, NKG7, and TNFSF13B genes differentially expressed in PF were disease-associated. The heterozygous genotype of the KLRG1 rs1805672 polymorphism was associated with increased predisposition to PF (A/G vs. A/A: P=0.038; OR=1.60), and a trend for augmented susceptibility was observed for carriers of the G allele (P=0.094; OR=1.44). In silico analyses suggested that rs1805672 G allele could disrupt binding of miR-584-5p, and indicated rs1805672 as an expression Quantitative Trait Locus (eQTL), with an effect on KLRG1 gene expression. Dual-luciferase assay showed that miR-584-5p mediated approximately 50% downregulation of the reporter gene's activity through the 3′UTR of KLRG1 harboring rs1805672 A allele (vs. miRNA-negative condition, P=0.006). This silencing relationship was lost after site-directed mutation to G allele (vs. miRNA-negative condition, P=0.391; vs. rs1805672 A allele, P=0.005). Collectively, these results suggest that a disease-associated SNP located within the 3′UTR of KLRG1 directly interferes with miR-584-5p binding, allowing for KLRG1 mRNA differential accumulation, which in turn may contribute to pathogenesis of autoimmune diseases, such as pemphigus.

Granzyme B Disrupts Epithelial Barrier Function

The epithelium functions as a barrier to the external environment, which is maintained in large part by cell junctions. Age‐related and chronic inflammatory conditions of the skin result in a loss of epithelial barrier integrity through the degradation of cell adhesion proteins. Granzyme B (GzmB) is a serine protease that accumulates in the extracellular milieu in a number of autoimmune skin conditions. As such, GzmB may contribute to the progressive loss of epithelial barrier function. We hypothesized that GzmB disrupts epithelial barrier function through the proteolytic cleavage of cell junction proteins. Human keratinocytes were treated with exogenous GzmB, in the presence or absence of a GzmB inhibitor. Subsequently, epithelial barrier function was assessed by Electric Cell‐substrate Impedance Sensing (ECIS) and immunofluorescence (confocal) microscopy was used to visualize E‐cadherin. GzmB treatment resulted in a loss of E‐cadherin staining on the cell membrane which was further supported by western blot analysis of cell supernatants and biochemical cleavage assays, where we observed a dose‐dependent increase in E‐cadherin fragmentation. E‐cadherin cleavage was markedly decreased when treated with a GzmB inhibitor. Moreover, ECIS analysis showed a noticeable decline in barrier function after GzmB treatment. In summary, GzmB contributes to a decline in epithelial barrier function in part through the proteolytic cleavage of E‐cadherin.Support or Funding InformationBC Lung Association

Multiple Autoimmune Skin Manifestations in a Patient with Crohn's Disease Treated with a Tumor Necrosis Factor-Alpha Blocker.

Dear Editor: Tumor necrosis factor (TNF)-alpha is an important mediator of chronic inflammation. TNF-alpha inhibitors have been shown to be effective in the treatment of several chronic inflammatory diseases. However, various immune-mediated disorders are reportedly induced by anti-TNF-alpha therapies, including autoimmune skin conditions such as psoriasis, granuloma annulare, vasculitis, alopecia areata (AA), lupus erythematosus, skin sarcoidosis, lichenoid eruption, and vitiligo. Here, we report a case of concomitant multiple autoimmune dermatoses in a patient with Crohn's disease (CD) treated with infliximab. A 51-year-old man presented to our unit for a few non-scarring patchy hair loss areas on the scalp. Circular areas of alopecia with otherwise normal skin were evident (Fig. 1A). Black dots and a few exclamation mark-like hairs were appreciable in addition to leucotrichia. He was diagnosed with AA. The patient had been affected by CD for approximately 20 years and had been treated with infliximab for the previous 3 months. A mild form of rheumatoid arthritis involving the proximal interphalangeal and metacarpophalangeal joints was also present. The patient had been previously treated, with unsatisfactory response, with several immunomodulatory agents, notably cyclosporin, azathioprin, adalimumab, and etanercept. The patient continued anti-TNF-alpha therapy with infliximab despite the diagnosis of AA. Topical steroids were recommended for the hair loss. One year later, the patient presented again to our unit for a cutaneous rash that had been present for approximately 2 months. Skin examination revealed numerous circular, raised, 2~3-cm weals surrounded by inflammatory rings and involving the entire body surface. A clinical diagnosis of chronic urticaria was made (Fig. 1B). Skin examination also revealed the presence of whitish circular maculae replacing the previous nevi, which were consistent with the clinical diagnosis of multiple halo nevi (Fig. 2A). Moreover, the previously observed AA had evolved into the universalis form (Fig. 2B). Despite the skin autoimmune manifestations, infliximab therapy was maintained because of the aggressiveness of the CD. Fig. 1 (A) Circular areas of alopecia areata, (B) a circular, raised, 2~3-cm weal, surrounded by an inflammatory ring. Fig. 2 (A) Multiple halo nevi on the back, (B) alopecia areata universalis. AA has been reported to appear during anti-TNF-alpha treatment1. It is believed that multiple cytokines, such as TNF-alpha, interleukin-1, and interferons, might be relevant to the autoimmune pathogenesis of AA because peribulbar inflammation is believed to inhibit hair growth. AA usually appears within the first 3 months of treatment, either de novo or as a relapse of a previous, usually inactive AA, and may be partial or universalis. Discontinuation of the treatment may result in rapid hair regrowth. Direct involvement of the anti-TNF-alpha molecule seems very likely owing to chronological data and the long-evoked autoimmune hypothesis regarding AA pathogenesis, although no specific immunological disturbance has ever been revealed in this peculiar setting. Chronic refractory urticaria has been treated with anti-TNF-alpha drugs2. Cases of urticaria induced by anti-TNF-alpha treatment have also been reported. These reactions suggest that potential immunogenic sites may appear either when a human monoclonal (adalimumab) or a chimeric human-mouse TNF-alpha antibody (infliximab) complexes with TNF-alpha. Halo nevi have been reported to appear during infliximab therapy together with the worsening of AA1. In the literature, no other cases of halo nevi onset during anti-TNF-alpha treatment have been described. However, several cases of vitiligo onset in patients receiving infliximab3 have been reported. In contrast, several cases of vitiligo improvement have been described in patients receiving infliximab4. The present patient with CD is an example of how infliximab use can cause the onset of concomitant autoimmune pathologies with different clinical presentations. Even if biotechnological drugs are considered to be the most innovative cure for several inflammatory diseases, these rare side effects should also be considered. These unwanted effects of TNF-alpha blockers are not predictable because the immune pathways involved in the autoimmune conditions that we described in the preceding paragraphs are not yet understood.

Nanorobotic investigation identifies novel visual, structural and functional correlates of autoimmune pathology in a blistering skin disease model.

There remain major gaps in our knowledge regarding the detailed mechanisms by which autoantibodies mediate damage at the tissue level. We have undertaken novel strategies at the interface of engineering and clinical medicine to integrate nanoscale visual and structural data using nanorobotic atomic force microscopy with cell functional analyses to reveal previously unattainable details of autoimmune processes in real-time. Pemphigus vulgaris is a life-threatening autoimmune blistering skin condition in which there is disruption of desmosomal cell-cell adhesion structures that are associated with the presence of antibodies directed against specific epithelial proteins including Desmoglein (Dsg) 3. We demonstrate that pathogenic (blister-forming) anti-Dsg3 antibodies, distinct from non-pathogenic (non-blister forming) anti-Dsg3 antibodies, alter the structural and functional properties of keratinocytes in two sequential steps - an initial loss of cell adhesion and a later induction of apoptosis-related signaling pathways, but not full apoptotic cell death. We propose a “2-Hit” model for autoimmune disruption associated with skin-specific pathogenic autoantibodies. These data provide unprecedented details of autoimmune processes at the tissue level and offer a novel conceptual framework for understanding the action of self-reactive antibodies.

Helicobacter pyloriand autoimmune disease: Cause or bystander

Helicobacter pylori (H. pylori) is the main cause of chronic gastritis and a major risk factor for gastric cancer. This pathogen has also been considered a potential trigger of gastric autoimmunity, and in particular of autoimmune gastritis. However, a considerable number of reports have attempted to link H. pylori infection with the development of extra-gastrointestinal autoimmune disorders, affecting organs not immediately relevant to the stomach. This review discusses the current evidence in support or against the role of H. pylori as a potential trigger of autoimmune rheumatic and skin diseases, as well as organ specific autoimmune diseases. We discuss epidemiological, serological, immunological and experimental evidence associating this pathogen with autoimmune diseases. Although over one hundred autoimmune diseases have been investigated in relation to H. pylori, we discuss a select number of papers with a larger literature base, and include Sjögrens syndrome, rheumatoid arthritis, systemic lupus erythematosus, vasculitides, autoimmune skin conditions, idiopathic thrombocytopenic purpura, autoimmune thyroid disease, multiple sclerosis, neuromyelitis optica and autoimmune liver diseases. Specific mention is given to those studies reporting an association of anti-H. pylori antibodies with the presence of autoimmune disease-specific clinical parameters, as well as those failing to find such associations. We also provide helpful hints for future research.

Disease facts: pemphigus foliaceus in the dog and cat

Pemphigus foliaceus is one of the most frequently occuring auto-immune skin conditions in the dog and cat. It is characterised by a pustular, crusting dermatosis and affects mainly middle-aged-to-older dogs. In this article, veterinary dermatologist Mark Craig presents key ‘disease facts’ for the practicing veterinarian on the most common condition of the pemphigus complex in the dog and cat. Clinical features, diagnostic steps, treatment options and prognosis will be discussed.

Cutaneous sarcoidosis and infliximab: evidence for efficacy in refractory disease

Biological therapy with tumour necrosis factor alpha antibodies continues to offer a life-changing option for a range of autoimmune and inflammatory skin conditions. We present three cases of sarcoidosis, with refractory cutaneous disease successfully treated with infliximab. A review of the literature shows increased numbers of cases of refractory cutaneous sarcoidosis successfully cleared with infliximab therapy.

Exploring the link between herpes viruses and pemphigus vulgaris: literature review and commentary

Pemphigus vulgaris (PV) is an autoimmune skin condition characterized by the presence of circulating autoantibodies specific for a subset of cellular adhesion proteins within mucosal and/or non-mucosal epidermal surfaces. Although the presence of self-directed antibodies is well established, the exact etiology of PV is still uncertain. Environmental factors have been linked to a variety of autoimmune disorders. Specifically, viral infection has been considered to act as one contributory component in disease pathogenesis. Perhaps the most studied group of pathogens is that of herpes viruses, with considerable evidence linking the herpes simplex virus and PV. These viruses have been reported to influence the course of disease and have been associated with PV flares and clinical exacerbations. However, there are significant inconsistencies amongst published data; additional analysis is required to solidify the proposed relationship. In the following article, we critically review the literature regarding the impact of the herpes viruses on PV, providing a framework for clinical application, mechanistic pathways, and future investigation.

Bullous pemphigoid: guide to diagnosis and treatment

Bullous pemphigoid is a rare autoimmune skin condition with a high mortality rate. Here, Dr Bower explains the characteristic features of this distressing disease and discusses how it should best be managed. Copyright © 2006 Wiley Interface Ltd

Development of novel cellular model for affinity studies of histamine H(4) receptor ligands.

The G protein-coupled histamine H4 receptor (H4R) is the last member of histamine receptors family discovered so far. Its expression pattern, together with postulated involvement in a wide variety of immunological and inflammatory processes make histamine H4 receptor an interesting target for drug development. Potential H4R ligands may provide an innovative therapies for different immuno-based diseases, including allergy, asthma, pruritus associated with allergy or autoimmune skin conditions, rheumatoid arthritis and pain. However, none of successfully developed selective and potent histamine H4 receptor ligands have been introduced to the market up to date. For that reason there is still a strong demand for pharmacological models to be used in studies on potent H4R ligands. In current work we present the development of novel mammalian cell line, stably expressing human histamine H4 receptor, with use of retroviral transduction approach. Obtained cell line was pharmacologically characterized in radioligand binding studies and its utility for affinity testing of potent receptor ligands was confirmed in comparative studies with the use of relevant insect cells expression model. Obtained results allow for statement that developed cellular model may be successfully employed in search for new compounds active at histamine H4 receptor.