Accumulating data on cellular and molecular pathways help to develop novel therapeutic strategies in skin inflammation and autoimmunity. Examples are psoriasis and atopic dermatitis, two clinically ...and immunologically well-defined disorders. Here, the elucidation of key pathogenic factors such as IL-17A/IL-23 on the one hand and IL-4/IL-13 on the other hand profoundly changed our therapeutic practice. The knowledge on intracellular pathways and governing factors is shifting our attention to new druggable molecules. Multiple cytokine receptors signal through Janus kinases (JAKs) and associated signal transducer and activators of transcription (STATs). Inhibition of JAKs can simultaneously block the function of multiple cytokines. Therefore, JAK inhibitors (JAKi) are emerging as a new class of drugs, which in dermatology can either be used systemically as oral drugs or locally in topical formulations. Inhibition of JAKs has been shown to be effective in various skin disorders. The first oral JAKi have been recently approved for the treatment of rheumatoid arthritis and psoriatic arthritis. Currently, multiple inhibitors of the JAK/STAT pathway are being investigated for skin diseases like alopecia areata, atopic dermatitis, dermatomyositis, graft-versus-host-disease, hidradenitis suppurativa, lichen planus, lupus erythematosus, psoriasis, and vitiligo. Here, we aim to discuss the immunological basis and current stage of development of JAKi in dermatology.
Lichen planus – a clinical guide Solimani, Farzan; Forchhammer, Stephan; Schloegl, Alexandra ...
Journal der Deutschen Dermatologischen Gesellschaft,
June 2021, 2021-06-00, 20210601, Letnik:
19, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Summary
Lichen planus (LP) is a chronic lichenoid inflammatory disorder of the skin, mucosa and of the appendages. LP is classically characterized by the presence of a rich infiltration of ...inflammatory T cells, which migrate in the upper part of the dermis, arranged in a band‐like pattern. Different sub types of the disease have been so far described. Albeit LP is clinically well defined, the disease still represents a therapeutic enigma. Especially with regard to mucosal or scalp affecting LP types, which often present a recalcitrant and treatment unresponsive course, efficacious therapeutic options are still lacking. Thus, LP represents a disease with a high psychosocial burden. Yet, development in the deciphering of LP pathogenesis reveals possible new druggable targets, thus paving the way for future therapeutic options. In this clinical guide, we summarize the current clinical knowledge and therapeutic standards and discuss the future perspective for the management of LP.
Lichen planus (LP) is a common, chronic relapsing inflammatory disorder of the skin and mucous membranes which often poses a major therapeutic challenge due to its refractory course. Novel ...pathogenesis-based therapies are urgently needed. As several studies have shown that IL-17 may contribute to LP pathogenesis, we investigated whether therapeutic targeting of IL-17
T cells leads to clinical improvement of mucosal and cutaneous LP lesions. A total of five patients with lichen planus were treated in a compassionate use trial with either secukinumab (anti-IL-17; 3 patients with acute and chronic recalcitrant muco-cutaneous LP), ustekinumab (anti-IL-12/IL-23; 1 patient with recalcitrant oral LP) or guselkumab (anti-IL-23; 1 patient with recalcitrant oral LP). The clinical course of the patients was assessed by the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) reflecting both extent and severity of disease and functional sequelae of oral involvement for at least 12 weeks. The inflammatory infiltrate in lesional and post-lesional skin was analyzed by immunohistochemistry before and after treatment. Furthermore, the cytokine profile of peripheral blood T cells from the treated patients was assessed by flow cytometry and/or ELISpot assay. Treatment with secukinumab induced rapid and prolonged clinical amelioration of muco-cutaneous LP. Clinical improvement was accompanied by a strong reduction of the Th1 and Th17/Tc17 cellular mucosal and cutaneous infiltrate. Moreover, long-term treatment of one patient with recalcitrant oral LP with ustekinumab led to healing of the ulcerative oral lesions and a reduction of peripheral blood and lesional IL-17
T cells. Finally, treatment with guselkumab led to a marked clinical improvement in a patient with recalcitrant erosive oral LP. These findings show for the first time that therapeutic targeting of Th17/Tc17 cells leads to a pronounced clinical amelioration of mucosal and cutaneous LP and strongly suggests that IL-17-producing T cells are central to disease pathogenesis. Thus, therapeutic targeting of Th17/Tc17 cells opens new therapeutic avenues in the treatment of recalcitrant LP.
In pemphigus, elucidating the disease-causing immune mechanism and developing new therapeutic strategies are needed. In this context, the second messenger 3',5'-cyclic adenosine monophosphate (cAMP) ...is gaining attention. cAMP is important in hematological and auto-inflammatory disorders. A class of enzymes called phosphodiesterases (PDEs) control intracellular cAMP levels. In pemphigus, cAMP levels increase following IgG binding to Dsg3. This appears to be a mechanism to preserve epithelial integrity.
To determine whether apremilast, an inhibitor of the PDE4 normally used in psoriasis, may be of benefit in the blistering skin disorder pemphigus.
Here we report of a 62 years old patient with chronic debilitating and recalcitrant pemphigus not responding to several previous treatments, who received treatment with apremilast over a period of 32 weeks. Desmoglein autoantibody levels were assessed by Enzyme-linked Immunosorbent Assay (ELISA), whereas disease severity and quality of life were assessed by the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS). In an attempt to explain the effects of apremilast in pemphigus, peripheral blood mononuclear cells (PBMCs) were analyzed for the duration of treatment by flow cytometry for the distribution of specialized T cell subsets. The frequencies of circulating T helper (Th) 1, Th2, Th17, Th17.1 and T follicular helper (Tfh) 1, Tfh2, Tfh17, and Tfh17.1 were analyzed by CCR6, CXCR3, and CXCR5 expression of CD4
T cells. Further, based on the different expressions of CXCR5, CD127, and CD25, we analyzed the T regulatory (Treg) and T follicular regulatory (Tfreg) compartment.
In response to apremilast treatment, Dsg-specific autoantibody titers decreased, blistering ceased and lesions healed, showing a long-lasting effect. While the frequencies of most of the Th and Tfh cell subsets remained unchanged, we observed a continuous increase in Treg and Tfreg cell levels.
Our findings are encouraging and warrant extension of the beneficial effect of PDE4 inhibition on a larger cohort of pemphigus patients.
Oral lichen planus (OLP) is a chronic inflammatory disease of the oral mucosa. Several clinical subtypes of OLP have been reported, including the reticular and erosive one. On the one hand, reticular ...OLP is usually asymptomatic and is characterized by white streaks surrounded by well-defined erythematous borders. On the other hand, erosive OLP shows ulcerations and erosions surrounded by erythematous mucosa. While reticular OLP is relatively easy to control, erosive OLP is extremely painful and refractory to therapies, limiting the quality of life of the patients. In addition, treating erosive OLP is extremely tricky, and a gold standard treatment has not yet been established. However, several therapeutic approaches have been reported as effective, including systemic corticosteroids, systemic retinoids, and anti-interleukin (IL)-17/anti-IL-23 drugs. Indeed, our group and other several authors reported the effectiveness of anti-IL17, anti-IL12/23, and anti-IL23 agents in refractory OLP, highlighting the urgency of clinical studies on the use of anti-IL agents in OLP patients. In this paper, we reviewed the English- and German-language literature about therapeutic strategies for treating OLP, focusing on new systemic therapies for erosive OLP.
Bullous pemphigoid is an autoimmune blistering disease caused by autoantibodies against components of the cutaneous basement membrane zone. Autoantibodies lead to complement-dependent and ...-independent inflammation and blistering. Blister fluid is a valuable biologic resource, as it provides insight into both systemic and local microenvironment responses. Here, we utilized liquid chromatography with tandem mass spectrometry to characterize the bullous pemphigoid blister fluid proteome. We then depleted exosomes to better understand the exosomal versus non-exosomal proteome. We identified 339 proteins in the blister fluid of bullous pemphigoid patients. Gene ontology demonstrated enrichment of several key biologic processes including innate immune response, neutrophil degranulation, platelet degranulation, and complement activation. Exosome depletion resulted in a significant decrease in normalized reporter intensities of 192 proteins, consistent with our observation of a large number of exosomal proteins found in the blister fluid. We then compared the bullous pemphigoid blister fluid proteome to prior proteomic datasets in suction blister fluid, snake bites, and thermal burns, identifying 76 proteins unique to bullous pemphigoid. These include major basic protein, eosinophil peroxidase, galectin-10, and the immunoglobulin epsilon heavy constant region, consistent with tissue eosinophilia. We lastly validated several previously reported blister fluid exosomal components. Blister fluid in bullous pemphigoid contains a mixture of numerous biologic processes. While many of these processes are shared with blistering from alternative causes, we have identified several notable features unique to bullous pemphigoid.
Analysis of T lymphocyte proliferation and activation after antigenic or mitogenic stimulation is a vital parameter used in the diagnosis of various immuno-deficiencies and during the monitoring of ...treatment responses. Most applied techniques are based on the incorporation of tritiated thymidine (
3
H-TdR) or ELISPOT analysis, both rely on rather time-consuming/-intensive
ex vivo
protocols or encompass inherent drawbacks such as the inability to distinguish specific cell populations (
3
H-TdR, ELISPOT) or focus on a single cytokine (ELISPOT). Here we aimed at characterizing the rapid expression of intracellular CD154 (CD40L) as a marker for rare antigen-specific CD4+ T cells in pemphigus vulgaris (PV). Upon stimulation with human desmoglein (Dsg) 3, the major autoantigen in PV, the expression of CD154 was significantly increased in PV patients compared to healthy controls (HC) and correlated with anti-Dsg3 IgG titers. Patients with active disease showed higher numbers of Dsg3-reactive CD4+ T cells in CXCR5+ T follicular helper cells. In remittent PV and HC, CXCR5+CD4+ T cells remained largely unaffected by Dsg3. IL-17 and IL-21 expression were significantly induced only in CD154+CD4+ T cells from PV patients, lending themselves as potential novel treatment targets. Additionally, stimulation with immunodominant Dsg3-derived epitopes strongly induced a CD4+ T cell response
via
CD40-CD154 interaction similar to the human Dsg3 protein. We here established a rapid
ex vivo
assay allowing the detection of Dsg3-reactive CD4+ T cells from activated systemically available PBMCs, which further supports the crucial concept of antigen-specific T cells in the pathogenesis of PV.
Bullous pemphigoid (BP) is the most common autoimmune bullous disease, characterized by severe pruritus and skin blistering. The loss of tolerance against Collagen XVII, also referred to as BP180, is ...the main pathogenic event of BP, leading to production of IgG autoantibodies which mainly target the juxtamembranous extracellular non-collagenous 16th A (NC16A) domain of BP180. A complex inflammatory network is activated upon autoantibody binding to the basement membrane zone; this inflammatory loop involves the complement cascade and the release of several inflammatory cytokines, chemokines and proteases from keratinocytes, lymphocytes, mast cells and granulocytes. Collectively, these events disrupt the integrity of the dermal-epidermal junction, leading to subepidermal blistering. Recent advances have led to identify novel therapeutic targets for BP, whose management is mainly based on the long-term use of topical and systemic corticosteroids. As an example, targeting type-2 T-helper cell-associated cytokines, such as Interleukin-4 and interleukin-13 has shown meaningful clinical efficacy in case series and studies; targeting IL-17 and IL-23 has also been tried, owing to an important role of these cytokines in the chronic maintenance phase of BP. In this review article, we discuss the complex cytokine milieu that characterized BP inflammation, highlighting molecules, which are currently investigated as present and future therapeutic targets for this life-threatening disease.
The autoimmune dermatosis pemphigus foliaceus (PF) is predominantly caused by IgG autoantibodies against the desmosomal cadherin desmoglein (Dsg) 1. The exact mechanisms that lead to the ...characteristic epidermal blistering are not yet fully understood. In the present study, we used a variety of biophysical methods to examine the fate of membrane-bound Dsg1 after incubation with PF patients' IgG. Dispase-based dissociation assays confirmed that PF-IgG used for this study reduced intercellular adhesion in a manner dependent on phospholipase C (PLC)/Ca
and extracellular signal-regulated kinase (ERK) 1/2 signaling. Atomic force microscopy (AFM) revealed that Dsg1 binding on single molecule level paralleled effects on keratinocyte adhesion under the different conditions. Stimulated emission depletion (STED) super-resolution microscopy was used to investigate the localization of Dsg1 after PF-IgG incubation for 24 h. Under control conditions, Dsg1 was found to be in part co-localized with desmoplakin and thus inside of desmosomes as well as extra-desmosomal along the cell border. Incubation with PF-IgG reduced the extra-desmosomal Dsg1 fraction. In line with this, fluorescence recovery after photobleaching (FRAP) experiments demonstrated a strongly reduced mobility of Dsg1 in the cell membrane after PF-IgG treatment indicating remaining Dsg1 molecules were primarily located inside desmosomes. Mechanistically, experiments confirmed the involvement of PLC/Ca
since inhibition of PLC or 1,4,5-trisphosphate (IP3) receptor to reduce cytosolic Ca
reverted the effects of PF-IgG on Dsg1 intra-membrane mobility and localization. Taken together, our findings suggest that during the first 24 h PF-IgG induce redistribution predominantly of membrane-bound extradesmosomal Dsg1 in a PLC/Ca
dependent manner whereas Dsg1-containing desmosomes remain.
Paraneoplastic autoimmune multi-organ syndrome (PAMS) is a rare clinical condition characterized by variable and heterogeneous clinical phenotypes in the presence of neoplasias which largely depend ...on the activation of humoral and cellular immune responses. Clinically, these patients present with a spectrum of antibody-driven pemphigus-like lesions to graft-vs.-host-disease-like exanthemas with a lichenoid inflammatory infiltrate in the skin. PAMS is occasionally associated with thymoma, in which altered immune surveillance eventually leads to multiorgan autoimmunity which often includes variable cutaneous symptoms. This disorder is associated with a profound disturbance of peripheral immune tolerance against human autoantigens.
We here present a patient with relapsing thymoma who developed PAMS with several cutaneous and extracutaneous autoimmune disorders.
Peripheral blood mononuclear cells (PBMC), sera, and lesional skin biopsies were obtained at different clinical disease stages. Peripheral T cell subsets were characterized phenotypically and the cytokine profile of the peripheral blood T cellular response against distinct epidermal and dermal autoantigens of the skin was analyzed by ELISpot assay. Serological screening was performed by ELISA and immunoblot analysis. Skin biopsies were subjected to immunohistochemical analysis of distinct T cell subsets. Thymoma tissue was analyzed for the presence of T regulatory cells and compared with adult thymus and indolent thymoma.
In the present case, thymoma was the cause of the observed multi-organ autoimmune syndromes as its recurrence and surgical removal was associated with the relapse and regression of the cutaneous symptoms, respectively. Initially, the patient presented with two autoimmune disorders with Th2/Th1 imbalance, myasthenia gravis (MG) and pemphigus foliaceus (PF), which regressed upon immunosuppressive treatment. Months later, the patient developed a lichenoid exanthema with a Th1-dominated skin infiltrate. Further clinical evaluation revealed the recurrence of the thymoma and the lichenoid exanthema gradually regressed upon thymectomy. Our contention that T cell recognition against distinct cutaneous autoantigens, such as desmoglein 1 (Dsg1), shifted from a Th2 to a Th1-dominated immune response could not be fully substantiated as the patient was on a stringent immunosuppressive treatment regimen. We could only observe a decrease of the initially present serum IgG autoantibodies against Dsg1. Phenotypic analysis of the associated thymoma showed a lower number of T regulatory cells compared to adult thymus and indolent thymoma, suggesting that impaired thymus-derived immune surveillance had a direct impact on the outcome of the observed cutaneous autoimmune disorders.
PDF
