Treatment Of Autoimmune Skin Diseases Research Articles

Heterogeneity and plasticity of tissue-resident memory T cells in skin diseases and homeostasis: a review.

Skin tissue-resident memory T (Trm) cells are produced by antigenic stimulation and remain in the skin for a long time without entering the peripheral circulation. In the healthy state Trm cells can play a patrolling and surveillance role, but in the disease state Trm cells differentiate into various phenotypes associated with different diseases, exhibit different localizations, and consequently have local protective or pathogenic roles, such as disease recurrence in vitiligo and maintenance of immune homeostasis in melanoma. The most common surface marker of Trm cells is CD69/CD103. However, the plasticity of tissue-resident memory T cells after colonization remains somewhat uncertain. This ambiguity is largely due to the variation in the functionality and ultimate destination of Trm cells produced from memory cells differentiated from diverse precursors. Notably, the presence of Trm cells is not stationary across numerous non-lymphoid tissues, most notably in the skin. These cells may reenter the blood and distant tissue sites during the recall response, revealing the recycling and migration potential of the Trm cell progeny. This review focuses on the origin and function of skin Trm cells, and provides new insights into the role of skin Trm cells in the treatment of autoimmune skin diseases, infectious skin diseases, and tumors.

Plant exosomes fused with engineered mesenchymal stem cell-derived nanovesicles for synergistic therapy of autoimmune skin disorders.

Existing therapeutics for autoimmune diseases remain problematic due to low efficacy, severe side effects, and difficulties to reach target tissues. Herein, we design multifunctional fusion nanovesicles that can target lesions for the treatment of autoimmune skin diseases. The grapefruit-derived exosome-like nanovesicles (GEVs) with anti-inflammatory and antioxidant effects are first encapsulated with CX5461, an immunosuppressant with anti-proliferative properties to form GEV@CX5461. In order to enhance therapeutic efficiency and safety, GEV@CX5461 are then fused with CCR6+ nanovesicles derived from membranes of engineered gingiva-derived mesenchymal stem cells (GMSCs). The resulting FV@CX5461 not only maintain the bioactivity of GEVs, CX5461, and GMSC membranes but also home to inflamed tissues rich in chemokine CCL20 through the chemotaxis function of CCR6 on FVs. Moreover, FV@CX5461 reduce the secretion of inflammatory factors, calm down Th17 cell activation, and induce Treg cell infiltration. Finally, impressive therapeutic efficiency in both psoriasis and atopic dermatitis disease models is demonstrated using FV@CX5461 to reshape the unbalanced immune microenvironment. A nanotherapeutic drug delivery strategy is developed using fusion nanovesicles derived from plant and animal cells with high clinical potential.

1099 Rational development of JAK1-selective siRNA therapeutics for the treatment of autoimmune skin diseases

1099 Rational development of JAK1-selective siRNA therapeutics for the treatment of autoimmune skin diseases

Heat Shock Protein 90 (Hsp90) and Hsp70 as Potential Therapeutic Targets in Autoimmune Skin Diseases.

Over a hundred different autoimmune diseases have been described to date, which can affect every organ in the body, including the largest one, the skin. In fact, up to one-fifth of the world’s population suffers from chronic, noninfectious inflammatory skin diseases, the development of which is significantly influenced by an autoimmune response. One of the hallmarks of autoimmune diseases is the loss of immune tolerance, which leads to the formation of autoreactive lymphocytes or autoantibodies and, consequently, to chronic inflammation and tissue damage. The treatment of autoimmune skin diseases mainly focuses on immunosuppression (using, e.g., corticosteroids) but almost never leads to the development of permanent mechanisms of immune tolerance. In addition, current therapies and their long-term administration may cause serious adverse effects. Hence, safer and more effective therapies that bring sustained balance between pro- and anti-inflammatory responses are still desired. Both intra- and extracellular heat shock proteins (Hsps), specifically well-characterized inducible Hsp90 and Hsp70 chaperones, have been highlighted as therapeutic targets for autoimmune diseases. This review presents preclinical data on the involvement of Hsp90 and Hsp70 in modulating the immune response, specifically in the context of the treatment of selected autoimmune skin diseases with emphasis on autoimmune bullous skin diseases and psoriasis.

Potential shared therapeutic and hepatotoxic mechanisms of Tripterygium wilfordii polyglycosides treating three kinds of autoimmune skin diseases by regulating IL-17 signaling pathway and Th17 cell differentiation

Ethnopharmacological relevanceTripterygium wilfordii polyglycosides (TWP) are extracted from Tripterygium wilfordii Hook. f., which has the significant effects of anti-inflammation and immunosuppression and has been widely used to treat autoimmune diseases in traditional Chinese medicine. Aim of studyIn Chinese clinical dermatology, TWP was generally used for the treatment of autoimmune skin diseases including psoriasis (PSO), systemic lupus erythematosus (SLE) and pemphigus (PEM). However, the potential hepatotoxicity (HPT) induced by TWP was also existing with the long-term use of TWP. This study aims to explore the potential shared therapeutic mechanism of TWP treating PSO, SLE, PEM and the possible hepatotoxic mechanism induced by TWP. Materials and methodsNetwork pharmacology was used to predict the potential targets and pathways in this study. The main bioactive compounds in TWP was screened according to TCMSP, PubChem, ChEMBL databases and Lipinski's Rule of Five. The potential targets of these chemical constituents were obtained from PharmMapper, SEA and SIB databases. The related targets of PSO, SLE, PEM and HPT were collected from GeneCards, DrugBank, DisGeNET and CTD databases. The target network construction was performed through STRING database and Cytoscape. GO enrichment, KEGG enrichment and molecular docking were then performed, respectively. In particular, imiquimod (IMQ)-induced PSO model was selected as the representative for the experimental verification of effects and shared therapeutic mechanisms of TWP. Results41 targets were considered as the potential shared targets of TWP treating PSO, SLE and PEM. KEGG enrichment indicated that IL-17 signaling pathway and Th17 cell differentiation were significant in the potential shared therapeutic mechanism of TWP. The animal experimental verification demonstrated that TWP could notably ameliorate skin lesions (P˂0.001), decrease inflammatory response (P˂0.05, P˂0.01, P˂0.001) and inhibit the differentiation of Th1/Th17 cells (P˂0.05, P˂0.01) compared to PSO model group. The molecular docking and qPCR validation then showed that TWP could effectively act on MAPK14, IL-2, IL-6 and suppress Th17 cell differentiation and IL-17 signaling pathway. The possible hepatotoxic mechanism of TWP indicated that there were 145 hepatotoxic targets and it was also associated with IL-17 signaling pathway and Th17 cell differentiation, especially for the key role of ALB, CASP3 and HSP90AA1. Meanwhile, the potential correlations between efficacy and hepatotoxicity of TWP showed that 28 targets were shared by therapeutic and hepatotoxic mechanisms such as IL-6, IL-2, MAPK14, MMP9, ALB, CASP3 and HSP90AA1. These significant relevant targets were also involved in IL-17 signaling pathway and Th17 cell differentiation. ConclusionsThere were shared disease targets in PSO, SLE and PEM, and TWP could treat them by potential shared therapeutic mechanisms of suppressing IL-17 signaling pathway and Th17 cell differentiation. The possible hepatotoxicity induced by TWP was also significantly associated with the regulation of IL-17 signaling pathway and Th17 cell differentiation. Meanwhile, the potential correlations between efficacy and hepatotoxicity of TWP also mainly focused on IL-17 signaling pathway and Th17 cell differentiation, which provided a potential direction for the study of the mechanism of “You Gu Wu Yun” theory of TWP treating autoimmune skin diseases in the future.

RNAi-based modulation of IFN-γ signaling in skin

Aberrant activation of interferon (IFN)-γ signaling plays a key role in several autoimmune skin diseases, including lupus erythematosus, alopecia areata, vitiligo, and lichen planus. Here, we identify fully chemically modified small interfering RNAs (siRNAs) that silence the ligand binding chain of the IFN-γ receptor (IFNGR1), for the modulation of IFN-γ signaling. Conjugating these siRNAs to docosanoic acid (DCA) enables productive delivery to all major skin cell types local to the injection site, with a single dose of injection supporting effective IFNGR1 protein reduction for at least 1month in mice. In an exvivo model of IFN-γ signaling, DCA-siRNA efficiently inhibits the induction of IFN-γ-inducible chemokines, CXCL9 and CXCL10, in skin biopsies from the injection site.Our data demonstrate that DCA-siRNAs can be engineered for functional gene silencing in skin and establish a path toward siRNA treatment of autoimmune skin diseases.

Application of Hyperbaric Oxygen Therapy in the Skin Diseases Treatment

The hyperbaric oxygen therapy (HBOT) involves the use of 100% pure oxygen in conditions of increased pressure, exceeding atmospheric pressure. This allows the supply of several times more oxygen to internal organs and blood serum than when using standard pressure. HBOT has proven to support the treatment of autoimmune skin diseases, complications of metabolic diseases and burns, as confirmed by clinical studies. In addition, this therapy can also be used to improve the physiological condition of the skin after cosmetology procedures. The aim of this work is to review information on the therapeutic effects of hyperbaric oxygen therapy in the treatment of skin diseases, especially atopic dermatitis, psoriasis, diabetic foot, second degree burns and complications after cosmetic procedures. The review was based on the works published in the last twenty years (1999-2019), available in the following databases: PubMed, GoogleSchoolar, PEDro. The use of HBOT is becoming more common in the treatment of skin complications of diabetes, as well as burn wounds. It is estimated that HBOT reduces the risk of foot ulcers and amputation in diabetic foot syndrome. In addition, HBOT promotes faster healing of burn wounds, also with the use of allogenic skin grafts. By increasing the level of reactive oxygen species (ROS), hyperbaric oxygen therapy significantly supports the treatment of psoriasis and atopic dermatitis. Despite this, the exact mechanisms of hyperbaric oxygen are still poorly understood, and the use of HBOT in the treatment of skin diseases has not yet been included in treatment protocols.

Skin-Associated B Cells in the Pathogenesis of Cutaneous Autoimmune Diseases-Implications for Therapeutic Approaches.

B lymphocytes are crucial mediators of systemic immune responses and are known to be substantial in the pathogenesis of autoimmune diseases with cutaneous manifestations. Amongst them are lupus erythematosus, dermatomyositis, systemic sclerosis and psoriasis, and particularly those driven by autoantibodies such as pemphigus and pemphigoid. However, the concept of autoreactive skin-associated B cells, which may reside in the skin and locally contribute to chronic inflammation, is gradually evolving. These cells are believed to differ from B cells of primary and secondary lymphoid organs and may provide additional features besides autoantibody production, including cytokine expression and crosstalk to autoreactive T cells in an antigen-presenting manner. In chronically inflamed skin, B cells may appear in tertiary lymphoid structures. Those abnormal lymph node-like structures comprise a network of immune and stromal cells possibly enriched by vascular structures and thus constitute an ideal niche for local autoimmune responses. In this review, we describe current considerations of different B cell subsets and their assumed role in skin autoimmunity. Moreover, we discuss traditional and B cell-associated approaches for the treatment of autoimmune skin diseases, including drugs targeting B cells (e.g., CD19- and CD20-antibodies), plasma cells (e.g., proteasome inhibitors, CXCR4 antagonists), activated pathways (such as BTK- and PI3K-inhibitors) and associated activator molecules (BLyS, APRIL).

Enhancing intradermal delivery of tofacitinib citrate: Comparison between powder-loaded hollow microneedle arrays and dissolving microneedle arrays.

Autoimmune-mediated inflammatory skin diseases, such as psoriasis, alopecia areata, and vitiligo, have been reported as the 4th leading cause of nonfatal disease burden worldwide. This is mainly related to the poor quality of life experienced by these patients. Although topical and systemic steroids represent the most common treatment, the variability in success rates and side effects often lead to treatment discontinuation. Recent off-label clinical studies using oral Janus Kinase (JAK) inhibitors (e.g., ruxolitinib, tofacitinib, baraticinib) have shown promising results. However, frequent side effects, such as infections and blood clots have been reported. Therefore, the aim of this research was to enhance the intradermal delivery of tofacitinib citrate with MN arrays. Using crosslinked hydrogels containing modifying agents (urea, sorbitol and sodium chloride), hollow MN arrays were fabricated and then loaded with tofacitinib citrate. Their efficiency in intradermal delivery of tofacitinib was compared with dissolving MN arrays and a control (Aqueous cream BP), using neonatal porcine skin. Despite the fact that the hydrogel was only present on the outer surface, hollow MN arrays showed comparable resistance to compression values and insertion capabilities to dissolving MN arrays. Although hollow MN arrays containing NaCl in the formulation led to slightly higher depositions of tofacitinib in epidermis and dermis of neonatal porcine skin when compared to a control cream, dissolving MN arrays showed superiority in terms of tofacitinib deposition in the dermis. Indeed, at 24h of the study, control cream and dissolving MN arrays delivered 143.98 ug/cm2 and 835 ug/cm2 of drug in the dermis, respectively, confirming the enhanced intradermal drug delivery capacity of MN arrays and their potential for treatment of autoimmune skin diseases.

The Antiviral Properties of Cyclosporine. Focus on Coronavirus, Hepatitis C Virus, Influenza Virus, and Human Immunodeficiency Virus Infections.

This review updates current knowledge regarding the risk of viral infections, including COVID-19, in patients treated with cyclosporine. We also shortly refer to bacterial infections and parasitic infestations in patients treated with cyclosporin. Cyclosporine is an immunosuppressive drug, which is widely used in medicine, including in the treatment of autoimmune skin diseases in dermatology, rheumatology, ophthalmology and nephrology, and in organ transplantation. A usual concern associated with immunosuppressive treatment is the potential risk of infections. Interestingly, several data indicate a relatively low risk of infections, especially viral infections, in patients receiving cyclosporine. It was shown that cyclosporine exerts an inhibitory effect on the replication of some viruses, or may have a potentially beneficial effect on the disease course in infections. These include hepatitis C, influenza virus, rotavirus, human immunodeficiency virus and coronavirus infections. Available data indicate that cyclosporine may have a beneficial effect on COVID-19, which is caused by the coronavirus SARS-COV2.

The use of biopharmaceuticals in the treatment of psoriasis

Dermatoses are the group of diseases which involve all layers of the skin from the epidermis through the dermis and subcutaneous tissue, till appendages. The global burden of skin disease in populations is not currently monitored, therefore there is no data on the prevalence of skin diseases in the general population. However, from the epidemiological point of view, it is possible to point out the most common dermatoses and among them distinguish these diseases, which belong to chronic conditions with immunological origin e.g. atopic dermatitis, psoriasis, pemphigus, vitiligo and alopecia areata. Due to conducted studies and better diagnostics, unknown pathomechanisms of dermatoses are discovered and consequently new treatment methods are implemented. The therapeutic progress in the symptomatic treatment of autoimmune skin diseases is related to the introduction on the market of biological medical products called biopharmaceuticals. In this manuscript, the characterization of biopharmaceuticals is presented in terms of their applicability in the treatment of psoriasis. Psoriasis is the chronic dermatological disease with inflammatory response and non-infective character, which shows significant variations in the prevalence of European population. Typical symptoms of psoriasis are red, raised skin areas, covered with silvery scales, mainly appears within the upper and lower extremities face and head. Further in the manuscript, psoriasis is discussed as a public health problem, the pathogenesis of this disease is described and the characterization of the biopharmaceuticals used in psoriasis is presented. In the last part, the results of a systematic literature review (meta-analysis) on the etanercept, the biopharmaceutical used in psoriasis, is discussed.

The HGF Receptor/Met Tyrosine Kinase Is a Key Regulator of Dendritic Cell Migration in Skin Immunity

The Met tyrosine kinase has a pivotal role in embryonic development and tissue regeneration, and deregulated Met signaling contributes to tumorigenesis. After binding of its cognate ligand hepatocyte growth factor, Met signaling confers mitogenic, morphogenic, and motogenic activity to various cells. Met expression in the hematopoietic compartment is limited to progenitor cells and their Ag-presenting progeny, including dendritic cells (DCs). In this study, we demonstrate that Met signaling in skin-resident DCs is essential for their emigration toward draining lymph nodes upon inflammation-induced activation. By using a conditional Met-deficient mouse model (Met(flox/flox)), we show that Met acts on the initial step of DC release from skin tissue. Met-deficient DCs fail to reach skin-draining lymph nodes upon activation while exhibiting an activated phenotype. Contact hypersensitivity reactions in response to various contact allergens is strongly impaired in Met-deficient mice. Inhibition of Met signaling by single-dose epicutaneous administration of the Met kinase-specific inhibitor SU11274 also suppressed contact hypersensitivity in wild-type mice. Additionally, we found that Met signaling regulates matrix metalloproteinase MMP2 and MMP9 activity, which is important for DC migration through extracellular matrix. These data unveil Met signaling in DCs as a critical determinant for the maintenance of normal immune function and suggest Met as a potential target for treatment of autoimmune skin diseases.