Autoimmune Bullous Skin Diseases Research Articles

A deep learning approach for Direct Immunofluorescence pattern recognition of Autoimmune Bullous Diseases.

Artificial intelligence (AI) is reshaping healthcare, using machine and deep learning to enhance disease management. Dermatology has seen improved diagnostics, particularly in skin cancer detection, through the integration of AI. However, the potential of AI in automating immunofluorescence imaging for autoimmune bullous skin diseases remains untapped. While direct immunofluorescence (DIF) supports diagnosis, its manual interpretation can hinder efficiency. The use of deep learning to automatically classify DIF patterns, including the Intercellular Pattern (ICP) and the Linear Pattern (LP), holds promise for improving the diagnosis of autoimmune bullous skin diseases. The objectives of this study are to develop AI algorithms for automated classification of autoimmune bullous skin disease DIF patterns, such as ICP and LP. This aims to enhance diagnostic accuracy, streamline disease management, and improve patient outcomes through deep learning-driven immunofluorescence interpretation. We collected immunofluorescence images from skin biopsies of patients suspected of AIBD between January 2022 and January 2024. Skin tissue was obtained via 5-mm punch biopsy, prepared for direct immunofluorescence. Experienced dermatologists classified the images into three classes: ICP, LP, and negative. To evaluate our deep learning approach, we divided the images into training (436) and test sets (93). We employed transfer learning with pre-trained deep neural networks and conducted 5-fold cross-validation to assess model performance. Our dataset's class imbalance was addressed using weighted loss and data augmentation strategies. The models were trained for 50 epochs using Pytorch, achieving an image size of 224x224 for both CNNs and the Swin Transformer. Our study compared six CNNs and the Swin transformer for AIBDs image classification, with the Swin transformer achieving the highest average validation accuracy of 98.5%. On a separate test set, the best model attained an accuracy of 94.6%, demonstrating 95.3% sensitivity and 97.5% specificity across AIBDs classes. Visualization with Grad-CAM highlighted the model's reliance on characteristic patterns for accurate classification. The study highlighted CNN's accuracy in identifying DIF features. This approach aids automated analysis and reporting, offering reproducibility, speed, data handling, and cost-efficiency. Integrating deep learning in skin immunofluorescence promises precise diagnostics and streamlined reporting in this branch of dermatology.

The Effect of Vitamin D Supplementation on Autoimmune Bullous Skin Disorder Intensity Score on Bullous Pemphigoid and Acute Kidney Injury: A Case Report

Introduction: Bullous pemphigoid is the most common bullous-type autoimmune disease. Hypovitaminosis D is often associated with autoimmune disease and found in 86,7% bullous pemphigoid patients. Vitamin D supplementation in bullous pemphigoid patients ought to ameliorate its clinical symptoms.
 Case presentation: A-58 years old male patient with bullous pemphigoid and acute kidney injury admitted with a chief complaint of infected blisters all over the body. The patient had been treated for 1 week with worsening swallowing pain and low intake. On the 12th day of hospitalization, the patient was given calcitriol supplementation of 0,25 mcg per day. There was an improvement in clinical symptoms shown on autoimmune bullous skin disorder intensity score (ABSIS) from 57 on inpatient day 7 to 17.5 on inpatient day 20. Patient discharged on the 20th day of hospitalization with no emerging blisters and the ability to swallow minced food by mouth.
 Conclusion: Calcitriol supplementation of 0,25 mcg per day for 10 days helps to improve the ABSIS score in bullous pemphigoid patient with acute kidney injury. Administration of calcitriol is considered safe and well tolerated.

Hives but no urticaria—what could it be?

AbstractUrticaria is a common inflammatory dermatosis characterized by transient, usually intensely itching wheals mediated by mast cells. Urticarial lesions can also be mimicked by other skin diseases. Differential diagnoses of urticaria should be considered if the single urticarial skin lesion persists for more than 24 h, if hyperpigmentation, scaling, or blistering occurs, if the lesions are not itching, or if fever or arthralgias are reported. In these cases, histologic examination and thorough serologic diagnostic may help to differentiate other dermatoses, such as vasculitis, autoimmune bullous skin diseases, drug reactions, or autoinflammatory syndromes. This article summarizes common differential diagnoses of urticaria.

The Eotaxin-1/CCR3 Axis and Matrix Metalloproteinase-9 Are Critical in Anti-NC16A IgE-Induced Bullous Pemphigoid.

Bullous pemphigoid (BP) is the most common autoimmune bullous skin disease of humans and is characterized by eosinophilic inflammation and circulating and tissue-bound IgG and IgE autoantibodies directed against two hemidesmosomal proteins: BP180 and BP230. The noncollagenous 16A domain (NC16A) of BP180 has been found to contain major epitopes recognized by autoantibodies in BP. We recently established the pathogenicity of anti-NC16A IgE through passive transfer of patient-derived autoantibodies to double-humanized mice that express the human high-affinity IgE receptor, FcεRI, and human NC16A domain (FcεRI/NC16A). In this model, anti-NC16A IgEs recruit eosinophils to mediate tissue injury and clinical disease in FcεRI/NC16A mice. The objective of this study was to characterize the molecular and cellular events that underlie eosinophil recruitment and eosinophil-dependent tissue injury in anti-NC16A IgE-induced BP. We show that anti-NC16A IgEs significantly increase levels of key eosinophil chemoattractants, eotaxin-1 and eotaxin-2, as well as the proteolytic enzyme matrix metalloproteinase-9 (MMP-9) in the lesional skin of FcεRI/NC16A mice. Importantly, neutralization of eotaxin-1, but not eotaxin-2, and blockade of the main eotaxin receptor, CCR3, drastically reduce anti-NC16A IgE-induced disease activity. We further show that anti-NC16A IgE/NC16A immune complexes induce the release of MMP-9 from eosinophils, and that MMP-9-deficient mice are resistant to anti-NC16A IgE-induced BP. Lastly, we find significantly increased levels of eotaxin-1, eotaxin-2, and MMP-9 in blister fluids of BP patients. Taken together, this study establishes the eotaxin-1/CCR3 axis and MMP-9 as key players in anti-NC16A IgE-induced BP and candidate therapeutic targets for future drug development and testing.

003 Utility of plucked hair direct immunofluorescence as a possible replacement for conventional skin biopsy direct immunofluorescence in immunological activity monitoring and prediction of relapse in pemphigus

Abstract Pemphigus vulgaris (PV) is a potentially lethal chronically relapsing autoimmune bullous disorder with intraepithelial lesions affecting the skin and mucous membranes. The prediction of clinical relapse has been studied with conventional skin biopsy and plucked hair direct immunofluorescence (DIF; Daneshpazhooh M, Naraghi ZS, Ramezani A et al. Direct immunofluorescence of plucked hair for evaluation of immunologic remission in PV. J Am Acad Dermatol 2011; 65:173–7) which can be of use in timing treatment withdrawal and helping with better management. The aims of our study were to determine the association of plucked hair root DIF positivity status at baseline with clinical relapse within the study duration, and to determine the correlation between skin biopsy and plucked hair DIF. Seventy-eight consecutive patients diagnosed with PV in clinical remission on therapy, on minimal therapy or off therapy, were included after obtaining informed consent. Three-monthly follow-up was carried out for 12 months. Immunological monitoring with plucked hair DIF was done at baseline and repeated every 3 months for 1 year or a relapse was experienced, whichever occurred earlier. Conventional skin biopsy DIF was performed at baseline, at 3 months and at the time of relapse. In patients receiving adjuvant therapy during their present remission episode, discontinuation of therapy was done at inclusion, at 3 months and at 6 months, and occurrence of relapse in relation to the time point of discontinuation was assessed. Of 78 patients, 22 had disease relapse and 56 remained in complete remission. Clinical relapse during the study duration was significantly more frequent in patients who had higher mean Autoimmune Bullous Skin Disorder Intensity Score during the preceding active disease episode (P = 0.033), pruritus during the present clinical remission episode (P = 0.007) and early discontinuation (within 3 months of study inclusion) of concomitant adjuvant therapy (P = 0.007). Immunological parameters associated with clinical relapse were baseline IgG (P = 0.005) and C3 positivity (P = 0.047) in plucked hair, greater intensity of IgG and C3 positivity at baseline in plucked hair (IgG, P = 0.002; C3, P = 0.033) and skin biopsy specimens (IgG, P = 0.004; C3, P = 0.0.002), and positive hair DIF at the time of adjuvant therapy withdrawal (P = 0.017). Plucked hair DIF is a reliable technique to assess immunological remission in patients with PV who are in clinical remission and helps to guide treatment according to immunological remission status.

The Management of Autoimmune Bullous Skin Disorders in the Era of COVID-19 Pandemic: A Single Center, Retrospective, Cross-sectional Study

The Management of Autoimmune Bullous Skin Disorders in the Era of COVID-19 Pandemic: A Single Center, Retrospective, Cross-sectional Study

T Regulatory Cell-Associated Tolerance Induction by High-Dose Immunoglobulins in an HLA-Transgenic Mouse Model of Pemphigus.

Pemphigus vulgaris (PV) is a potentially lethal autoimmune bullous skin disorder caused by IgG autoantibodies against desmoglein 3 (Dsg3) and Dsg1. During the last three decades, high-dose intravenous immunoglobulins (IVIgs) have been applied as an effective and relatively safe treatment regime in severe, therapy-refractory PV. This prompted us to study T- and B- cell polarization by IVIg in a human-Dsg3-dependent mouse model for PV. Using humanized mice transgenic for HLA-DRB1*04:02, which is a highly prevalent haplotype in PV, we employed IVIg in two different experimental approaches: in prevention and quasi-therapeutic settings. Our data show that intraperitoneally applied IVIg was systemically distributed for up to 42 days or longer. IVIg-treated Dsg3-immunized mice exhibited, in contrast to Dsg3-immunized mice without IVIg, significantly less Dsg3-specific IgG, and showed induction of T regulatory cells in lymphatic tissue. Ex vivo splenocyte analysis upon Dsg3-specific stimulation revealed an initial, temporarily reduced antigen-induced cell proliferation, as well as IFN-γ secretion that became less apparent over the course of time. Marginal-zone B cells were initially reduced in the preventive approach but re-expanded over time. In contrast, in the quasi-therapeutic approach, a robust down-regulation in both spleen and lymph nodes was observed. We found a significant down-regulation of the immature transitional 1 (T1) B cells in IVIg-treated mice in the quasi-therapeutic approach, while T2 and T3, representing a healthy stage of B-cell development, appeared to be up-regulated by IVIg. In summary, in two experimental settings employing an active PV mouse model, we demonstrate distinct alterations of T- and B-cell populations upon IVIg treatment, compatible with a tolerance-associated polarization in lymphatic tissue. Our data suggest that the clinical efficacy of IVIg is at least modulated by distinct alterations of T- and B-cell populations compatible with a tolerance-associated polarization in lymphatic tissue.

The Importance of Patient-Focused Drug Development in Pemphigus and Pemphigoid

The Importance of Patient-Focused Drug Development in Pemphigus and Pemphigoid

Mixed muco-cutaneous pemphigoid: Clinical and immunological features of 15 cases.

We describe a series of patients whose auto-immune bullous skin disease (AIBD) of the dermal-epidermal junction (DEJ) was characterized by clinical, immunological and ultrastructural features intermediate between bullous pemphigoid (BP) and mucous membrane pemphigoid (MMP), and a recalcitrant course. From the database of the French reference centre for AIBD, we screened all the patients who were referred for an AIBD of the DEJ with a mucosal involvement, who neither met the diagnostic criteria for the diagnosis of BP, nor were typical of MMP. Sera were analysed by NC16A-ELISA and immunobloting against the C-terminal and LAD-1 parts of BP180. Skin biopsies were studied by direct immunoelectron microscopy (IEM). Fifteen patients (4 males, 11 females) of mean age 70.8 ± 11.8 years were included. The mucosal involvement was localized in oral cavity in all cases and in pharyngeal/laryngeal or genital area in 8 (53%), and 6 patients (40%), respectively. No patient had ocular involvement, nor atrophic or fibrosing scars. All patients had extensive skin lesions (mean BPDAI score =65.9 ± 24.4), which predominated on the upper body part. Direct IEM performed on 8 patients showed IgG deposits on the lamina lucida in all cases, and the lamina densa in 5 cases. All sera recognized NC16A, while none recognized BP-230 in ELISA. 10 out of the 13 tested sera (76.9%) contained IgG which recognized the C-terminal domain of BP180 and 10 sera (76.9%) the LAD-1 domain of BP180. Patients poorly responded to super potent topical corticosteroids and were treated with oral corticosteroids ± immunosuppressant in 13 cases (86.6%). This mixed muco-cutaneous pemphigoid differs from BP by the younger age of patients, multiple mucosae involvement, circulating antibodies against both the C- and N-terminal part of BP180, and very poor response to topical CS. It differs from MMP by extensive inflammatory skin lesions, absence of ocular involvement and atrophic/fibrosing scars.

Pruritus Is Associated with an Increased Risk for the Diagnosis of Autoimmune Skin Blistering Diseases: A Propensity-Matched Global Study.

Autoimmune bullous skin diseases (AIBDs), such as bullous pemphigoid (BP) and pemphigus, are characterized and caused by autoantibodies targeting structural proteins. In BP, clinical experience and recent systematic evaluation identified pruritus to be common and an important cause of impaired quality of life. Furthermore, chronic pruritus may be the sole clinical symptom of BP. In pemphigus, a retrospective study recently documented a high prevalence of pruritus. The temporal relation between pruritus and BP/pemphigus are, however, unknown. Likewise, the presence of pruritus in AIBDs other than BP and pemphigus is unknown. To address this, we performed propensity-matched retrospective cohort studies using TriNetX, providing real-world patient data to (i) assess the risk to develop AIBDs following the diagnosis of pruritus and (ii) vice versa. We assessed this in eight AIBDs: BP, mucous membrane pemphigoid (MMP), epidermolysis bullosa acquisita, dermatitis herpetiformis, lichen planus pemphigoides (LPP), pemphigus vulgaris, pemphigus foliaceous, and paraneoplastic pemphigus (PNP). For all AIBDs, pruritus was associated with an increased risk for the subsequent diagnosis of each of the eight investigated AIBDs in 1,717,744 cases (pruritus) compared with 1,717,744 controls. The observed hazard ratios ranged from 4.2 (CI 3.2-5.5; p < 0.0001) in MMP to 28.7 (CI 3.9-211.3; p < 0.0001) in LPP. Results were confirmed in two subgroup analyses. When restricting the observation time to 6 months after pruritus onset, most HRs noticeably increased, e.g., from 6.9 (CI 6.2-7.9; p < 0.0001) to 23.3 (CI 17.0-31.8; p < 0.0001) in BP. Moreover, pruritus frequently developed following the diagnosis of any of the eight AIBDs, except for PNP. Thus, all AIBDs should be considered as differential diagnosis in patients with chronic pruritus.

A clinic-epidemiological study of 148 patients of pemphigus at Lady Reading Hospital, Peshawar: a case series.

A seven-year retrospective study was held at the Department of Dermatology, Lady Reading Hospital, Peshawar, between 2013 to 2020 to determine the demography and clinical features of pemphigus. Among 148 patients included in this study 88 (58%) were females and 60 (40%) were males with a female to male ratio of 1.46:1. Average age at onset of the disease was 38±12 years (range 14-75 years). On the basis of Autoimmune Bullous Skin Disorder Score (ABSIS), 14 (9.3%) patients had mild disease, 58 (38.7%) had moderate disease, and 76 (50.7%) patients had severe disease. In total, 144 (96%) patients had pemphigus vulgaris, 3 (2%) patients had pemphigus foliaceous and 1 (0.7%) patient had paraneoplastic pemphigus. Severe pemphigus was more frequently associated with multiple relapses (p=0.00). This study shows poor prognostic factors like severe pemphigus vulgaris associated with multiple relapses. Five years of follow-up shows that complete remission on minimal therapy was achieved more in patients who received Rituximab.

Lymphocyte-predominant lesional inflammatory infiltrates of the skin are associated with mucosal-dominant phenotype in pemphigus.

Pemphigus is a potentially life-threatening autoimmune blistering disease. To date, studies assessing the association of histopathology with clinical phenotype are lacking. We sought to evaluate the main histopathologic findings and, also, the potential links between cutaneous inflammatory infiltrates and clinical characteristics in pemphigus. We conducted a retrospective cohort study in patients diagnosed with pemphigus vulgaris (PV) and pemphigus foliaceus (PF) in a referral center for autoimmune blistering diseases. A total of 124 patients were included in the study (97 had PV and 27 had PF). On biopsy specimens, PV was more frequently associated with the "row of tombstones" feature (36.1% vs. 11.1%, p=0.013), and PF was associated with acanthosis (44.4% vs. 23.7%, p=0.034). Acantholysis was found in the upper half of the epidermis in PF (96.3% vs. 5.15%, p < 0.001), as opposed to the lower half in PV (75.2% vs. 0%, p=0.002). Patients with lymphocyte-predominant inflammatory infiltrates in lesional skin specimens presented with a higher frequency of the mucosal-dominant phenotype (25.5% vs. 9.1%, p=0.014), higher-density cellular infiltrate (100% vs. 41.6%, p < 0.001), and more frequent acantholytic cells (42.6% vs. 23.4%, p=0.025). Neutrophil-predominant infiltrates in specimens from lesional skin were linked to a milder disease based on median Pemphigus Disease Area Index (38.9% vs. 13.2%, p=0.036) and Autoimmune Bullous Skin Disorder Intensity Score (20.2 vs. 36.3, p=0.019), while eosinophil-predominant inflammatory infiltrates were more often associated with eosinophilic spongiosis (100% vs. 23.1%, p=0.014). Lymphocyte-predominant infiltrates in lesional skin specimens of pemphigus patients predict a mucosal-dominant phenotype, while neutrophil-predominant infiltrates are associated with a milder disease.

B-cell depletion in the treatment of pemphigus: two clinical cases and literature review

Pemphigus presents a group of chronic autoimmune bullous skin disorders with well-known clinical signs, which pathophysiology is mediated by antibodies to various epidermal self-antigens. For a long time, the only therapeutic option for this disease was the lifelong use of non-selective immunosuppressive agents limited by high rate of severe adverse reactions. The article presents two clinical cases of rituximab use (a targeted agent leading to B-cell depletion) in patients with pemphigus (vulgaris and foliaceous) who were previously resistant to high-dose steroid therapy. Treatment with rituximab lead to response and allowed to decrease the prednisone dose in both cases. These results confirm that rituximab can be successfully used in pemphigus as adjuvant therapy if conventional agents for this dermatosis are ineffective.

Deregulated phenotype of autoreactive Th17 and Treg clone cells in pemphigus vulgaris after in-vitro treatment with desmoglein antigen (Dsg-3)

The loss of balance between regulatory T (Treg) and T helper 17 (Th17) causes loss of tolerance against desmoglein (Dsg)-3 leading to pemphigus vulgaris (PV), an autoimmune bullous skin disorder associated with autoantibodies against Dsg-3. We aimed to elucidate the complex relationship of Th17 and Treg cells, their molecules, and the underlying mechanism in the development of PV disease. Using cytokine secretion assays, Th17 and Treg cells were sorted by FACS Aria-III within Dsg-3-responsive PBMC population and homogeneous T cell clones were generated in-vitro. Different cell surface molecules like CD25, GITR, CD122, CD152, CD45RO, IL-23R, STAT3, STAT5, CD127, HLA-DR, CCR4, CCR5, CCR6 and CCR7 were studied. The functional response of Th17 and Treg cells were elucidated by measuring the levels of various cytokines released by IL-10 and IL-17 T cells. The mRNA expression of transcription factors (FoxP3 and RORγt) was also analyzed. IL-17 secreting (Th17) cells with phenotype CD4+IL-17+ were greatly increased and IL-10 secreting (Treg) cells with phenotype CD4+IL-10+ were reduced in PV cases than healthy controls. The qPCR analysis showing high expression of retinoic acid receptor-related orphan receptor gamma (RORγt) mRNA in comparison to forkhead box P3 (FoxP3) mRNA confirmed the development of pro-inflammatory Th17 response in PV. Further, the cytokine profile of pro-inflammatory and anti-inflammatory cytokines suggested defective suppressive functions in Treg cells with high inflammatory response. Our findings indicate that autoantigen Dsg-3 specifically allows the proliferation of IL-17 secreting T cells though has a negative effect on IL-10 secreting T cells leading to dysregulation of immunity in PV patients. This antagonistic relationship between Dsg-3-specific Th17 and Treg cells may be critical for the onset and persistence of inflammation in PV cases.

Bullous Pemphygoid and Novel Therapeutic Approaches.

Bullous pemphigoid is a subepidermal blistering disease associated with autoantibodies (auto-ab) to BP180 and BP230 which affects elderly patients, predominately. Although it is a rare disease, bullous pemphigoid is the most common among the autoimmune bullous skin diseases. Systemic corticosteroids and immunosuppressants represent milestones in the treatment of patients suffering from bullous pemphigoid; however, therapeutic management of patients still represents a clinical challenge, owing to the chronic nature of the disease and to potential adverse effects related to the long-term use of systemic treatments. Recent discoveries on the pathogenesis of bullous pemphigoid have allowed investigation of new target therapies against selective pro-inflammatory mediators. These therapies appear to yield satisfactory results with fewer side effects in cases of refractory disease. The review discusses current evidence on these new therapeutic targets and specific drugs under investigation.

Diagnostic Role of Direct Immunofluorescence Assay in Determining The Etiology of Erythroderma: Experience in a Tertiary Referral Hospital.

Erythroderma is a life-threatening dermatologic emergency which is characterized by diffuse erythema and exfoliation affecting more than 90% of the body surface area. Most common cutaneous diseases associated with erythroderma are systemic contact dermatitis, psoriasis, drug eruption and atopic dermatitis. Clinical-pathological correlation is used to determine the underlying disease. In addition, direct immunofluorescence (DIF) may provide significant clues for etiology of erythroderma especially in the case of autoimmune bullous skin diseases (ABSDs). In our study, we aimed to analyze the demographic data, clinical pre-diagnoses, final diagnosis, histopathological and DIF examination findings, accompanying systemic signs and laboratory abnormalities of erythrodermic patients. We conducted a retrospective study of 31 erythroderma patients in a referral hospital between 2014 and 2021. Cutaneous biopsies were taken from all patients for H&E and DIF examination. Average age was 54.6 ± 23 years, 48.4% of the patients were female (N = 15) whereas 51.6 % of the patients were male (N = 16). Average time between the onset of rash and biopsy was 18.8 days. DIF analysis showed immune deposits in 19.4% (N = 6) of the patients; whereas no immune deposits were detected in 80.6% (N = 25) of the patients. The most frequent final diagnosis was adverse cutaneous drug eruption followed by ABSDs. Our findings suggest that DIF may be used in conjunction with clinical-pathologic and clinical findings to reveal the associated skin diseases in erythrodermic patients. Erythrodermic patients presenting with clinical findings of ABSD should be considered for DIF examination.

Nail changes in pemphigus and bullous pemphigoid: A single-center study in China

Common autoimmune bullous diseases (AIBDs) include pemphigus and bullous pemphigoid (BP), which are primarily caused by IgG autoantibodies against the structural proteins of desmosomes at the cell–cell junction and hemidesmosomes at the epidermal–dermal junction. Few studies have assessed nail changes in patients with pemphigus or BP. In the present study, we collected the clinical data of 191 patients with AIBDs (108 patients with pemphigus and 83 patients with BP) and 200 control subjects. Nail changes were observed in 77.0% (147/191), 77.8% (84/108), and 75.9% (63/83) of patients with AIBDs, pemphigus, and BP, respectively, and 14.5% (29/200) of control subjects. Beau's lines and paronychia were the most common nail involvement, observed in 22.5% (43/191) and 22.5% (43/191) of patients with AIBDs, 25.0% (27/108) and 25.9% (28/108) of patients with pemphigus, 19.3% (16/83) and 18.1% (15/83) of patients with BP, respectively. The autoimmune bullous skin disorder intensity score (ABSIS) and the onset time of patients with pemphigus or BP with nail changes were different. Onychomycosis accounted for 21.5% (41/191) of all patients with AIBDs. The ABSIS was correlated with nail involvement in patients with BP (r = 0.46, p < 0.001), and weakly correlated with nail involvement in patients with AIBDs (r = 0.37, p < 0.001), pemphigus (r = 0.29, p = 0.009), and pemphigus vulgaris (PV; r = 0.35, p = 0.008). No correlation was observed between nail involvement and disease antibody titers. In conclusion, nail changes are frequently observed in patients with pemphigus and BP. The type and onset time of nail changes may indicate the severity of pemphigus and BP, which warrants the attention of dermatologists.

CXCL12/CXCR4 Axis Drives the Chemotaxis and Differentiation of B Cells in Bullous Pemphigoid

Bullous pemphigoid (BP) is an autoimmune bullous skin disease characterized by autoantibodies against the hemidesmosomal proteins in the skin and mucous membranes. The efficiency of B-cell‒targeting biologics in BP indicates the important role of B cells in its pathogenesis. However, abnormal B-cell migration and differentiation in BP require further elucidation. We showed that the number of antibody-secreting cells increased in the circulation and skin lesions of patients with BP and was correlated with disease severity. Bulk RNA sequencing of the peripheral B cells identified 171 upregulated and 408 downregulated genes in patients with BP compared with those in healthy controls, among which CXCR4 was significantly upregulated. Notably, CXCR4+ B cells were enriched in BP skin lesions and exhibited antibody-secreting cell characteristics. Correspondingly, an elevated level of CXCL12, the CXCR4 ligand, was detected in the blister fluid and serum of patients with BP, mediating the chemotaxis and accumulation of CXCR4+ B cells to BP skin lesions. Moreover, CXCL12 activated the transcription factor c-Myc, thus promoting B-cell differentiation into antibody-secreting cells and facilitating autoantibody production, which was blocked by CXCR4 inhibitor invitro. Collectively, our study reveals that the CXCL12/CXCR4 axis plays a pathogenic role in modulating B-cell trafficking and differentiation, thus targeting CXCR4 represents a potential strategy for treating BP and other autoimmune 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.

ODSS vs. ABSIS and PDAI oral parts in pemphigus vulgaris: inter-rater reliability and testing times.

The existence of standard methods for diagnosis and measuring the severity of diseases leads to a more accurate severity assessment, the possibility of following up, and the possibility of comparing the results of studies. This study aimed to compare different pemphigus vulgaris (PV) assessment methods regarding inter-observer reliability and testing times-focusing on oral parts. Two dermatologists evaluated orally involved PV patients by oral parts of Autoimmune Bullous Skin Disorder Intensity Score (ABSIS), Pemphigus Disease Area Index (PDAI), and Oral Disease Severity Score (ODSS). Seventy patients completed the study. The intraclass correlation coefficient showed the evaluators' agreements on ABSIS, PDAI, and ODSS with 0.98, 0.94, and 0.95, respectively. Reliability analyses showed near-perfect relationships between each scoring methods pairs. There was no association between lesion sites and disease severity. The PDAI scoring duration was significantly shorter, and the ABSIS scoring duration was significantly longer. ODSS is valid for evaluating oral involvement in patients with PV and relates to ABSIS and PDAI almost perfectly. Besides, it was shown that the evaluation of patients' oral involvement based on PDAI and ODSS is done in about 1 min, which seems clinically reasonable.