Anti-desmoglein Autoantibodies Research Articles

Rituximab – An effective first line treatment in pemphigus vulgaris patients

: Rituximab is a humanized chimeric anti-CD20 monoclonal antibody that quickly lowers blood serum levels of anti-desmoglein autoantibodies, causing pemphigus lesions to heal. To evaluate the efficacy of Rituximab in treating pemphigus vulgaris. : We identified and included 14 patients (3 males and 11 females), in the age group of 14 years to 67 years, of severe pemphigus vulgaris from 2016 to 2022 treated at our institution with rituximab infusion in our retrospective case study. Baseline anti-desmoglein antibodies 1 and 3 levels were elevated in all the patients. 12 of these patients received rituximab infusion as first-line treatment. 11(out of 14) patients received two doses of rituximab (1 gram in each) as intravenous infusions, as per the rheumatoid arthritis protocol; whereas, 3 (out of 14) received a single dose of intravenous rituximab infusion (1 gram). These patients were kept on maintenance dose of prednisolone/ mycophenolate mofetil post rituximab infusion. : 14 patients of pemphigus vulgaris were enrolled in the study. The follow-up period ranged from 2 months to 6 years. All 14 patients responded well to therapy. No serious adverse events were observed. 10 (71.4%) of the 14 patients exhibited complete remission; whereas, 4 (28.6%) showed partial remission. Those with partial remission experienced relapse but the subsequent episode was less severe than the first episode. However, 2 patients who were non-responders to high doses of systemic steroids expired. : For treating patients with pemphigus vulgaris, rituximab infusion was found to be safe and effective. Hence, it should be considered as first-line for management of pemphigus vulgaris.

Rituximab in the Management of Autoimmune Bullous Diseases: A Treatment-Resistant Case Series from a Single Central European Referral Center.

Background and Objectives: Rituximab (RTX) has been the predominant treatment for autoimmune bullous diseases (AIBDs). The objective of this research was to assess the advantages and safety characteristics of RTX treatment in individuals with AIBD. This assessment focused on clinical remission and a reduction in glucocorticosteroid usage, its effect on the titers of autoantibodies targeting desmoglein-1 (DSG-1) and desmoglein-3 (DSG-3), and adverse occurrences during a 12-month follow-up period in a dermatology department within a Central European university context. Materials and Methods: Our case series involved eleven patients, including eight patients with pemphigus vulgaris, two with pemphigus foliaceus, and one with epidermolysis bullosa acquisita. They received a 1 g dose of rituximab, repeated over a two-week interval. Results: The reduction in a prednisone-equivalent dosage after 2, 6, and 12 months following the second RTX infusion was 65.05%, 73.99%, and 76.93%, in that order. The titers of antibodies against DSG-1 exhibited reductions of 43.29%, 75.86%, and 54.02% at 2, 6, and 12 months, respectively. By contrast, the antibody concentrations targeting DSG-3 displayed a decrease of 27.88%, 14.48%, and 5.09% at the corresponding time points. Over the course of the 12-month monitoring period, 18.18% of patients experienced disease relapse, while the remaining individuals achieved either complete or partial remission with minimal or no therapy. Adverse effects were noted in 36.36% of the patient population; they were mild, and no serious adverse effects were reported. Conclusions: RTX represents an efficacious and well-tolerated therapeutic option for the management of AIBD and merits consideration in cases of refractory AIBD. However, further research is imperative to delineate the most optimal dosage, dosing frequency, and total quantity of maintenance infusions required. Additionally, there is a compelling need for studies that explore the impact of RTX on individuals with AIBD who do not exhibit a significant reduction in anti-desmoglein autoantibody levels.

Integrative single-cell analysis reveals distinct adaptive immune signatures in the cutaneous lesions of pemphigus

Pemphigus, an autoimmune bullous disease affecting the skin and mucosal membranes, is primarily driven by anti-desmoglein (Dsg) autoantibodies. However, the underlying immune mechanisms of this disease remain largely elusive. Here, we compile an unbiased atlas of immune cells in pemphigus cutaneous lesions at single-cell resolution. We reveal clonally expanded antibody-secreting cells (ASCs) that exhibit variable hypermutation and accumulation of IgG4 class-switching in their immunoglobulin genes. Importantly, pathogenic Dsg-specific ASCs are localized within pemphigus lesions and can evolve from both Dsg-autoreactive and non-binding precursors. We observe an altered distribution of CD4+ T cell subsets within pemphigus lesions, including an imbalance of Th17/Th2 cells. Significantly, we identify a distinct subpopulation of Th17 cells expressing CXCL13 and IL-21 within pemphigus lesions, implying its pivotal role in B cell recruitment and local production of autoantibodies. Furthermore, we characterize multiple clonally expanded CD8+ subpopulations, including effector GMZB+ and GMZK+ subsets with augmented cytotoxic activities, within pemphigus lesions. Chemokine-receptor mapping uncovers cell-type-specific signaling programs involved in the recruitment of T/B cells within pemphigus lesions. Our findings significantly contribute to advancing the understanding of the heterogeneous immune microenvironment and the pathogenesis of pemphigus cutaneous lesions, thereby providing valuable insights for potential therapeutic interventions in this disease.

Treatment of pemphigus vulgaris and foliaceus with efgartigimod, a neonatal Fc receptor inhibitor: a phase II multicentre, open‐label feasibility trial*

Pemphigus vulgaris and pemphigus foliaceus are potentially life-threatening autoimmune disorders triggered by IgG autoantibodies against mucosal and epidermal desmogleins. There is an unmet need for fast-acting drugs that enable patients to achieve early sustained remission with reduced corticosteroid reliance. To investigate efgartigimod, an engineered Fc fragment that inhibits the activity of the neonatal Fc receptor, thereby reducing serum IgG levels, for treating pemphigus. Thirty-four patients with mild-to-moderate pemphigus vulgaris or foliaceus were enrolled in an open-label phase II adaptive trial. In sequential cohorts, efgartigimod was dosed at 10 or 25mgkg-1 intravenously with various dosing frequencies, as monotherapy or as add-on therapy to low-dose oral prednisone. Safety endpoints comprised the primary outcome. The study is registered at ClinicalTrials.gov (identifier NCT03334058). Adverse events were mostly mild and were reported by 16 of 19 (84%) patients receiving efgartigimod 10mgkg-1 and 13 of 15 (87%) patients receiving 25mgkg-1 , with similar adverse event profiles between dose groups. A major decrease in serum total IgG and anti-desmoglein autoantibodies was observed and correlated with improved Pemphigus Disease Area Index scores. Efgartigimod, as monotherapy or combined with prednisone, demonstrated early disease control in 28 of 31 (90%) patients after a median of 17days. Optimized, prolonged treatment with efgartigimod in combination with a median dose of prednisone 0·26mgkg-1 per day (range 0·06-0·48) led to complete clinical remission in 14 of 22 (64%) patients within 2-41weeks. Efgartigimod was well tolerated and exhibited an early effect on disease activity and outcome parameters, providing support for further evaluation as a therapy for pemphigus.

Longitudinal Pathogenic Properties and N-Glycosylation Profile of Antibodies from Patients with Pemphigus after Corticosteroid Treatment.

Pemphigus vulgaris is an autoimmune disease that occurs due to pathogenic autoantibodies that recognize the following epidermal adhesion proteins: desmogleins. Systemic corticosteroids usually decrease the titers of anti-desmoglein autoantibodies and improve patients’ conditions. Since modifications of IgG N-glycosylation have been described in some autoimmune diseases, we hypothesized that changes in the pathogenic activity of pemphigus IgG could be related to changes in their N-glycosylation profile. The purpose of this study was to assess, longitudinally, the pathogenicity of pemphigus serum IgG and their N-glycosylation profile during phases of disease activity and clinical remission. The pathogenic activity of serum IgG was measured in vitro on immortalized keratinocytes, by immunofluorescence and dissociation assays, and IgG N-glycans were analyzed by mass spectrometry. We showed (i) a correlation between pemphigus clinical activity and the pathogenicity of serum IgG at baseline and at month 6, while the persistence of the in vitro pathogenic activity of IgG during its evolution, even in patients in clinical remission, seemed to be predictive of relapse; (ii) that modifications of the N-glycan structure were altered the in vitro pathogenicity of patients’ autoantibodies; (iii) that the pathogenic properties of pemphigus IgG did not appear to be related to the disparity in IgG N-glycans during the course of pemphigus.

Quantitative Estimation of Antidesmoglein Autoantibodies by ELISA in Pemphigus Patients and its Correlation with Disease Activity.

Quantitative Estimation of Antidesmoglein Autoantibodies by ELISA in Pemphigus Patients and its Correlation with Disease Activity.

Stabilization of desmoglein-2 binding rescues arrhythmia in arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (AC) is a genetic disease causing arrhythmia and sudden cardiac death with only symptomatic therapy available at present. Mutations of desmosomal proteins, including desmoglein-2 (Dsg2) and plakoglobin (Pg), are the major cause of AC and have been shown to lead to impaired gap junction function. Recent data indicated the involvement of anti-Dsg2 autoantibodies in AC pathogenesis. We applied a peptide to stabilize Dsg2 binding similar to a translational approach to pemphigus, which is caused by anti-desmoglein autoantibodies. We provide evidence that stabilization of Dsg2 binding by a linking peptide (Dsg2-LP) is efficient to rescue arrhythmia in an AC mouse model immediately upon perfusion. Dsg2-LP, designed to cross-link Dsg2 molecules in proximity to the known binding pocket, stabilized Dsg2-mediated interactions on the surface of living cardiomyocytes as revealed by atomic force microscopy and induced Dsg2 oligomerization. Moreover, Dsg2-LP rescued disrupted cohesion induced by siRNA-mediated Pg or Dsg2 depletion or l-tryptophan, which was applied to impair overall cadherin binding. Dsg2-LP rescued connexin-43 mislocalization and conduction irregularities in response to impaired cardiomyocyte cohesion. These results demonstrate that stabilization of Dsg2 binding by Dsg2-LP can serve as a novel approach to treat arrhythmia in patients with AC.

Pemphigus.

Pemphigus is a group of IgG-mediated autoimmune diseases of stratified squamous epithelia, such as the skin and oral mucosa, in which acantholysis (the loss of cell adhesion) causes blisters and erosions. Pemphigus has three major subtypes: pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus. IgG autoantibodies are characteristically raised against desmoglein 1 and desmoglein 3, which are cell-cell adhesion molecules found in desmosomes. The sites of blister formation can be physiologically explained by the anti-desmoglein autoantibody profile and tissue-specific expression pattern of desmoglein isoforms. The pathophysiological roles of T cells and B cells have been characterized in mouse models of pemphigus and patients, revealing insights into the mechanisms of autoimmunity. Diagnosis is based on clinical manifestations and confirmed with histological and immunochemical testing. The current first-line treatment is systemic corticosteroids and adjuvant therapies, including immunosuppressive agents, intravenous immunoglobulin and plasmapheresis. Rituximab, a monoclonal antibody against CD20+ B cells, is a promising therapeutic option that may soon become first-line therapy. Pemphigus is one of the best-characterized human autoimmune diseases and provides an ideal paradigm for both basic and clinical research, especially towards the development of antigen-specific immune suppression treatments for autoimmune diseases.

Pemphigus, a pathomechanism of acantholysis.

Autoantibodies to the desmosomal proteins desmoglein 1 and 3 cause pemphigus foliaceus and pemphigus vulgaris, which are characterised by keratinocyte dissociation (acantholysis) and intraepidermal blister formation. The passive transfer of pathogenic anti-desmoglein antibodies induces blisters in mice in vivo and the loss of keratinocyte adhesion in vitro. The pathogenetic mechanisms of acantholysis due to anti-desmoglein autoantibodies are not fully understood. However, recent studies have revealed that signalling-dependent and signalling-independent pathways are operative in the loss of cell adhesion. In this review, we focus on the pathomechanism of acantholysis due to autoantibodies to desmogleins and recent therapeutic approaches.

Salivary Samples for the Diagnosis of Pemphigus vulgaris Using the BIOCHIP Approach: a Pilot Study

Pemphigus vulgaris (PV) is a rare autoimmune intraepithelial blistering skin disease characterized by the presence of circulating autoantibodies against desmoglein 3 (DSG3) and desmoglein 1 (DSG1), resulting in loss of the normal epithelial cell-to-cell adhesion, through a process called acantholysis. In recent years, a BIOCHIP-based indirect immunofluorescence technique for the determination of anti-DSG3 and anti-DSG1 autoantibodies has been described. Even though, the use of saliva anti-DSG3 and anti-DSG1 ELISA for the diagnosis of PV has been already reported, there are no studies concerning the utilization of saliva by the BIOCHIP approach. In the present pilot study, ELISA and BIOCHIP were performed, using salivary and serum samples from the same patients to investigate if the detection of anti-desmoglein autoantibodies in salivary samples by BIOCHIP could be used as a test for the diagnosis of PV. There was a strong correlation between ELISA and BIOCHIP results both for anti-DSG3 and anti-DSG1 serum autoantibodies. Autoantibodies to DSG3 were detected in 8 out of 8 salivary samples by ELISA and in 6 out of 8 salivary samples by the BIOCHIP approach. Autoantibodies to DSG1 were negative in all salivary samples using both ELISA and BIOCHIP. There were no positive results in the negative control group. In conclusion, the results of this pilot study indicate lack of correlation between serum and salivary results using both ELISA and BIOCHIP, indicating that saliva may not be the ideal substrate for the laboratory diagnosis of PV using these approaches.

Clinical efficacy of rituximab in the treatment of pemphigus: A retrospective study.

Pulsed corticosteroids have been used successfully for the management of pemphigus. However, prolonged use of glucocorticoids may be associated with adverse effects and some patients show a poor response to conventional therapy. Biologics have shown a promising role in such cases; however, there is limited data from the Indian subcontinent. The primary objective was to assess the efficacy and adverse effects of rituximab in pemphigus. The secondary objective was to measure the cumulative doses of corticosteroids required for these patients. We undertook a retrospective review of records of 25 pemphigus patients (pemphigus vulgaris: 21, pemphigus foliaceus: 4) who had received rituximab infusion (rheumatoid arthritis protocol in 21 patients, modified in 4). Oral prednisolone was administered in dosages up to 0.5 mg/kg of body weight and tapered over the next 3-4 months according to the disease activity. However, other immunosuppressive agents such as cyclophosphamide and azathioprine were continued for one year after clinical remission was achieved. Complete remission was observed in 22 (88%) patients. The mean time to disease control and complete remission was 1.10 and 4.36 months, respectively. Four (16%) patients experienced relapse after a mean duration of 11.75 months. The mean total dose of oral steroids administered was equivalent to 3535.64 mg of prednisolone. Exacerbation of disease was noted in two patients after the first dose of rituximab and infectious complications, pneumonia and cellulitis, developed in one patient each. A small sample size, the retrospective nature of the study and unavailability of follow-up anti-desmoglein autoantibodies levels were limitations. Rituximab is an effective agent in the treatment of pemphigus. The use of rituximab enabled use of a lower initial dose of oral prednisolone in pemphigus and hence reduced its total cumulative dose. Severe side effects were rare.

The pathogenic activity of anti-desmoglein autoantibodies parallels disease severity in rituximab-treated patients with pemphigus vulgaris.

Pemphigus vulgaris (PV) is an autoimmune blistering disease mediated by IgG autoantibodies targeting desmogleins (Dsgs). The anti-CD20 monoclonal antibody rituximab is increasingly used in corticosteroid-resistant PV patients. In a subset of rituximab-treated patients in remission, high ELISA index values have been reported; however, their significance remains so far unclear. To address the discrepancy between anti-Dsg3 serum antibody titers and disease severity. 6 rituximab-treated PV patients were prospectively followed-up for two years and anti-Dsg3 autoantibodies levels and pathogenic activity were measured. All patients achieved complete remission without any serious side effects. Both anti-Dsg3 autoantibodies (p = 0.031) and their pathogenic activity (p = 0.003) were significantly related to disease severity. However, in selected patients, the dissociation index was a more sensitive indicator for PV clinical activity than the ELISA index. Our findings have demonstrated the existence of non-pathogenic autoantibodies in PV patients in remission, establishing the basis for the design of a system able to precisely monitor the course of disease.

Detailed profiling of anti-desmoglein autoantibodies identifies anti-Dsg1 reactivity as a key driver of disease activity and clinical expression in pemphigus vulgaris

With their near-universal presence in patients and ease of clinical measurement, anti-desmoglein (Dsg) antibodies serve as primary candidates for creating prognostic tools in Pemphigus vulgaris (PV). Although the desmoglein compensation hypothesis postulates a clear relationship between anti-Dsg autoantibodies and clinical phenotype in PV, recent studies have questioned the fidelity of this hypothesis as a predictor of lesion morphology. Moreover, few studies address the association of anti-Dsg antibodies to other clinical parameters such as disease phase and age at onset. Using the largest patient repository to date in PV, we present a detailed analysis of anti-desmoglein antibody profiles across a comprehensive range of dynamic (disease phase, therapy, lesion morphology) and temporal (disease duration, age at sampling, age at onset) clinical parameters. Our data highlight the non-traditional but key role of anti-Dsg1 levels in tracking disease activity. We show that declining anti-Dsg1 levels may predict progression from active phase to early remission and long-term maintenance of remission, regardless of lesion morphology. In contrast, many remittent patients have elevated levels of anti-Dsg3 without lesional activity. Furthermore, we describe a unique subset of remittent patients that develop chronic transient lesions (lasting <1 week) in the setting of elevated anti-Dsg3 levels but do not meet the consensus criteria for active phase. Re-classification of patients with transient lesions as “active” may shed new light on pathophysiological processes underlying cycles of blister formation and rapid spontaneous healing in PV. Additionally, we provide evidence for the potential attenuation of the immune response with prolonged disease duration. Our data fit into the broader effort of immunoprofiling to promote data-informed decision-making regarding diagnosis, prognosis and treatment of complex diseases.

Pemphigus Disease Activity Measurements

Recently, the clinical pemphigus disease activity indexes of Pemphigus Disease Area Index (PDAI), Autoimmune Bullous Skin Disorder Intensity Score (ABSIS), and Pemphigus Vulgaris Activity Score (PVAS) were validated to correlate with physician global assessment. The antidesmoglein (anti-Dsg) autoantibodies are known to correlate mostly with pemphigus disease activity. The correlation between these indexes and anti-Dsg1 and anti-Dsg3 enzyme-linked immunosorbent assay values has not been previously evaluated. To evaluate the PDAI, ABSIS, and PVAS in a large number of patients with pemphigus vulgaris and to compare the interrater reliability of these indexes and the convergent validity according to anti-Dsg values. A cross-sectional study was performed in 2012 in a referral university center for autoimmune bullous diseases. One hundred patients with confirmed diagnoses of pemphigus vulgaris and clinical pemphigus lesions (mean [SD] age, 43.3 [1.7] years; age range, 14-77 years; female-male ratio, 1:3) were studied. Three dermatologists familiar with immunobullous diseases and the indexes rated the patients. All 100 patients were evaluated with the PDAI, ABSIS, and PVAS. Three dermatologists independently rated all 3 indexes for each of the patients on the same day. Serum anti-Dsg1 and anti-Dsg3 enzyme-linked immunosorbent assay values were measured simultaneously. Analyses of interrater reliabilities, convergent validities according to anti-Dsg titers, correlation between the distribution and types of lesions with disease activity, predictors of higher titers of antibody (multiple regression analysis), and cutoff values of measures for 2 titers of anti-Dsg with optimal area under the curve, sensitivity, and specificity were performed. The interrater reliabilities were highest for the PDAI, followed by the ABSIS and the PVAS (intraclass correlation coefficients of 0.98 [95% CI, 0.97-0.98], 0.97 [95% CI, 0.96-0.98], and 0.93 [95% CI, 0.90-0.95], respectively). The convergent validity was highest for the PDAI, followed by the PVAS and the ABSIS (Spearman ρ = 0.67, 0.52, and 0.33, respectively). Head, neck, and trunk involvement were predictors of higher titers of anti-Dsg1. Among the 3 studied indexes, the PDAI had the highest validity and is recommended for use in multicenter studies for rare diseases, such as pemphigus vulgaris.

Pemphigus vulgaris in a Welsh pony stallion: case report and demonstration of antidesmoglein autoantibodies

To describe the clinical, histological and immunological findings of an equine case of pemphigus vulgaris, including the demonstration of antidesmoglein (anti-Dsg) autoantibodies. The diagnosis of pemphigus vulgaris was confirmed in a 9-year-old Welsh pony stallion with both direct and indirect immunofluorescence and immunoprecipitation studies, the latter identifying circulating anti-Dsg3 IgG. Treatment with immunosuppressive medications was initiated. Lesions were seen in the perineal area, sheath, mane, tail, eyelids, coronary bands and mucosa of the mouth and oesophagus. Initial corticosteroid treatment improved the clinical signs, but the onset of laminitis necessitated a reduction in dosage, which was associated with a recurrence of lesions and development of oral ulcers. A corneal ulcer developed after 60days of treatment. Despite treatment with azathioprine, gold salts and dapsone, the disease progressed and the pony was euthanized. Postmortem examination showed additional lesions of the cardia of the stomach. Pemphigus vulgaris is rarely diagnosed in equids. We describe a case that was substantiated by the demonstration of anti-Dsg3 IgG. Response to treatment was poor, with the best response to high doses of prednisolone. Equine pemphigus vulgaris is likely to carry a poor prognosis and if there is no response to treatment, humane euthanasia is warranted.

Are clinical phenotype and autoantibody profile always concordant in pemphigus? A study in a cohort of pemphigus patients

The clinical phenotype of different forms of pemphigus is reportedly defined by the anti-desmoglein (Dsg) autoantibody profile. In routine practice, however, this is not always the case. To verify the relationship between the anti-Dsg1 and -3 autoantibody profiles and titers on the one hand and the clinical phenotype and disease activity on the other. we followed-up clinically and serologically 20 pemphigus patients, including 3 mucosal pemphigus (mPV), 9 mucocutaneous pemphigus (mcPV), and 8 cutaneous pemphigus (PF). We found that the cutaneous and/or mucosal involvement and the autoantibody profile were only concordant in mPV patients. On the contrary, in other clinical forms this correlation was often absent. 1) The discrepancy between autoantibody profile and the clinical phenotype, at least in PF patients, appears to be due to non-pathogenic anti-Dsg3 antibodies; 2) in a proportion of patients the relationship between the Dsg1 and Dsg3 ELISA titers and the disease severity was absent; 3) in some patients, the anti-Dsg1 and -3 autoantibodies were lacking at diagnosis, suggesting a role of other antigens in the pathogenesis of the disease and, lastly, 4) the pure cutaneous and mucosal forms tend to respond more efficiently to the therapy than the mucocutaneous forms and have a persistent response.

Epitope Spreading Is Rarely Found in Pemphigus Vulgaris by Large-Scale Longitudinal Study Using Desmoglein 2–Based Swapped Molecules

Epitope spreading is involved in inducing and maintaining self-reactivity. Epitope spreading in pemphigus vulgaris (PV), caused by IgG autoantibodies to desmoglein 3 (Dsg3) and Dsg1, was previously analyzed using Dsg3/Dsg1 extracellular domain-swapped molecules. However, precise identification of the responsible epitopes in each molecule by using only this method was problematic. In this study, we studied epitope spreading in PV by a novel immunoprecipitation-immunoblot method using Dsg3 (or Dsg1)/Dsg2 domain-swapped molecules, which overcomes the problems associated with the previous approaches. We analyzed the antigenic epitopes recognized by 212 sera collected from 53 PV patients at multiple disease stages. The major epitopes were present at the N-terminal region of Dsgs and were unchanged over the course of the disease in both anti-Dsg3 mucosal dominant-type PV and anti-Dsg3/Dsg1 mucocutaneous-type PV. These N-terminal epitopes were calcium dependent. Circulating antibodies in paraneoplastic pemphigus and pemphigus herpetiformis had unique epitope distributions, although the Dsg N-termini still contained the major epitopes. These results suggest that, after onset, intramolecular and intermolecular epitope spreading among extracellular domains on Dsg3 and Dsg1 is rare in PV and has no correlation with disease course.

Possible role of superantigens in inducing autoimmunity in pemphigus patients

The diagnostic and pathological relevance of anti-desmoglein autoantibodies in common forms of pemphigus has been well established, and T cells have been shown to play a role in the onset and progression of these diseases. The role of superantigens in provoking polyclonal activation of T cells with many different fine specificities, possibly including autoreactive T cells and T-cell mediated autoantibody response, is unknown. Further, abnormal T-cell function may lead to opportunistic infections particularly with Candida. The response of T cells of pemphigus patients to recall antigens of these opportunists is not clear. The aim of this study was to investigate the in vitro response of T lymphocytes from pemphigus patients to common bacterial superantigens such as streptococcal pyrogenic exotoxin A and staphylococcal enterotoxin B, and recall antigens such as Candida antigen. Changes in CD3(+) CD4(+) and CD3(+) CD8(+) T-cell sub-populations and expression of naive/memory markers (CD45RA(+) /RO(+)) on different T cells were analyzed by flow cytometry. Significant elevation in CD3(+) CD4(+) and expression of the memory (CD45RO(+)) markers on these cells was observed both in pemphigus vulgaris and pemphigus foliaceus patients, as compared to healthy controls, upon stimulation with streptococcal pyrogenic exotoxin A and staphylococcal enterotoxin B. However, only memory T cells (CD45RO(+)) were significantly increased upon Candida antigen stimulation. Our study suggests that CD4(+) memory T lymphocytes may modulate the pathogenic autoantibody response in pemphigus patients, and also emphasizes the possibility that the superantigen-reactive T cells participate in the triggering of autoimmunity in pemphigus.

口腔咽頭粘膜に限局した尋常性天疱瘡の２例

Intractable oropharyngeal mucosa disease is common and its diagnosis may be delayed if the mucosal lesion is simply a symptom of systemic disease. We report two cases of pemphigus vulgaris localized in the oropharyngeal mucosa. Case 1: A 50-year-old man showed multiple oropharyngeal erosiones and was biopsied at his first visit. The histopathological diagnosis was pemphigus vulgaris and antidesmogleinauto antibody 3 based on a blood examination positive. Case 2: A 66-year-old woman originally diagnosed histopathologically with inflamed mucosa was reconsiderd for pemphigus vulgaris and checked for antidesmogleinauto antibodies 1 and 3, both found to be positive. Based on the additional immunopathological findings of the earlier rechecked specimen, the definitive diagnosis was pemphigus vulgaris. Both cases were treated by steroids. The numerical value of antidesmogleinauto antibody gradually decreased based on the recovery from symptoms. We found antidesmogleinauto antibody blood testing to be valuable for diagnosis and for evaluating therapeutic effect and symptom progress. It is also important to check for antidesmogleinauto antibody early with such intractable oropharyngeal mucosal disease patients.

Autoantibodies in the Autoimmune Disease Pemphigus Foliaceus Induce Blistering via p38 Mitogen-Activated Protein Kinase-Dependent Signaling in the Skin

Pemphigus foliaceus (PF) is a human autoimmune blistering disease in which a humoral immune response targeting the skin results in a loss of keratinocyte cell-cell adhesion in the superficial layers of the epidermal epithelium. In PF, desmoglein-1-specific autoantibodies induce blistering. Evidence is beginning to accumulate that activation of signaling may have an important role in the ability of pathogenic pemphigus IgGs to induce blistering and that both p38 mitogen-activated protein kinase (MAPK) and heat shock protein (HSP) 27 are part of this signaling pathway. This study was undertaken to investigate the ability of PF IgGs to activate signaling as well as the contribution of this signaling pathway to blister induction in an in vivo model of PF. Phosphorylation of both p38 MAPK and HSP25, the murine HSP27 homolog, was observed in the skin of PF IgG-treated mice. Furthermore, inhibition of p38 MAPK blocked the ability of PF IgGs to induce blistering in vivo. These results indicate that PF IgG-induced blistering is dependent on activation of p38 MAPK in the target keratinocyte. Rather than influencing the immune system, limiting the autoantibody-induced intracellular signaling response that leads to target end-organ damage may be a more viable therapeutic strategy for the treatment of autoimmune diseases. Inhibition of p38 MAPK may be an effective strategy for the treatment of PF.