Alterations of Total Serum Immunoglobulin Concentrations in Pemphigus and Pemphigoid: Selected IgG2 Deficiency in Bullous Pemphigoid
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SUBMITTER: Khil'chenko S
PROVIDER: S-EPMC7493804 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Project description:Pemphigus and bullous pemphigoid are autoantibody-mediated blistering skin diseases. In pemphigus, keratinocytes in epidermis and mucous membranes lose cell-cell adhesion, and in pemphigoid, the basal keratinocytes lose adhesion to the basement membrane. Pemphigus lesions are mediated directly by the autoantibodies, whereas the autoantibodies in pemphigoid fix complement and mediate inflammation. In both diseases, the autoantigens have been cloned and characterized; pemphigus antigens are desmogleins (cell adhesion molecules in desmosomes), and pemphigoid antigens are found in hemidesmosomes (which mediate adhesion to the basement membrane). This knowledge has enabled diagnostic testing for these diseases by enzyme-linked immunosorbent assays and dissection of various pathophysiological mechanisms, including direct inhibition of cell adhesion, antibody-induced internalization of antigen, and cell signaling. Understanding these mechanisms of disease has led to rational targeted therapeutic strategies.
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Project description:Autoimmune bullous disorders are a heterogeneous spectrum of skin disorders characterized by the production of autoantibodies against adhesion molecules of the skin. The 2 major groups of diseases are “pemphigus diseases” and “autoimmune bullous diseases of the pemphigoid type.” Pemphigus diseases are a group of autoimmune blistering diseases of the skin and mucous membranes characterized by intraepithelial cleft and acantholysis. The main subtypes of pemphigus include pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus. Diagnosis is based on clinical manifestations and confirmed with histological, immunofluorescence, and serological testing. Recently multivariant enzyme-linked immunosorbent assay systems have been developed as practical screening tools for patients with suspected autoimmune bullous dermatoses. The current first-line treatment of pemphigus is based on systemic corticosteroids that are often combined with immunosuppressive adjuvants, such as azathioprine, mycophenolate mofetil, and the anti-CD20 monoclonal antibody rituximab, usually at initiation of treatment. Rituximab efficacy is higher when it is administered early in the course of the disease. Therefore, it should be used as first-line treatment to improve efficacy and reduce cumulative doses of corticosteroids and their side effects. Treatment of bullous pemphigoid is based on disease extension. Localized and mild forms can be treated with superpotent topical corticosteroids or with nonimmunosuppressive agents. In patients with generalized disease or whose disease is resistant to the treatments described above, systemic corticosteroids are preferred and effective. Adjuvant immunosuppressants are often combined with steroids for their steroid-sparing effect.
| S-EPMC7319750 | biostudies-literature
Project description:Total knee arthroplasty is one of the safest and most routinely performed orthopedic procedures. As the volume of cases is expected to rise each year, so too will the incidence of uncommon complications. We describe a rare case of bullous pemphigoid, an autoimmune skin blistering disorder, that occurred after total knee arthroplasty in an otherwise healthy patient and led to hospital readmission. Early diagnosis and treatment of this condition may limit its spread and help to avoid comorbid sequelae.
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Project description:IntroductionWe here thought to dissect the inflammatory signature in lesions of three skin disorders, which show a common adaptive immune response against autoantigens of the skin but are characterized by diverging clinical phenotypes. Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are type-2-dependent, IgG autoantibody-driven blistering disorders of mucous membranes and skin, which target desmoglein (Dsg)3 and bullous pemphigoid (BP)180, respectively. In contrast, lichen planus (LP) is a common chronic inflammatory disease of the skin and mucous membranes with a pronounced dermal T cell infiltrate. We previously identified peripheral type 1 and 17 T cell responses against Dsg3 and BP180 in a cohort of LP patients strongly suggesting that the underlying inflammatory T cell signature may drive the evolving phenotype.MethodsParaffin-embedded skin biopsies from well-characterized patients with LP (n=31), BP (n=19), PV (n=9), and pemphigus foliaceus (PF) (n=2) were analysed. Areas with the most prominent inflammatory infiltrate were excised with punch biopsies and tissue microarrays (TMA) containing multiple biopsies were created. Using multicolor immunofluorescence, the inflammatory infiltrate was stained with antibodies against multiple cellular markers, i. e. CD3ϵ, CD4, CD15, TCR-δ, the cytokine IL-17A, and the transcription factors, T-bet and GATA-3.ResultsIn LP, there was a higher number of CD4+ T cells expressing T-bet compared to GATA-3. In contrast, CD4+ T cells in PV and BP skin lesions more frequently expressed GATA-3 than T-bet. IL-17A+ cells and IL-17A+ T cells were found to a similar extent in all the three disorders. IL-17A+ granulocytes were more predominant in BP than in LP or PV. Of note, the majority of IL-17A+ cells in LP were neither T cells nor granulocytes.DiscussionOur findings in inflammatory skin infiltrates clearly show a predominant type 1 signature in LP in contrast to a preponderance of type 2 T cells in PV and BP. In contrast to LP, granulocytes and to a much lesser extent CD3+ T cells were a cellular source of IL-17A in BP and PV. These data strongly suggest that different inflammatory cell signatures drive evolving clinically diverse phenotypes of LP, PV and BP despite common target antigens of the skin.
| S-EPMC10321708 | biostudies-literature
Project description:BACKGROUND:Bullous pemphigoid (BP) is the most common autoimmune blistering disease in the West. Oral steroids are the standard treatment.This is an update of the review published in 2005. OBJECTIVES:To assess treatments for bullous pemphigoid. SEARCH STRATEGY:In August 2010 we updated our searches of the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (Clinical Trials), MEDLINE, EMBASE, and the Ongoing Trials registers. SELECTION CRITERIA:Randomised controlled trials of treatments for participants with immunofluorescence-confirmed bullous pemphigoid. DATA COLLECTION AND ANALYSIS:At least two authors evaluated the studies for the inclusion criteria, and extracted data independently. MAIN RESULTS:We included 10 randomised controlled trials (with a total of 1049 participants) of moderate to high risk of bias. All studies involved different comparisons, none had a placebo group. In 1 trial plasma exchange plus prednisone gave significantly better disease control at 1 month (0.3 mg/kg: RR 18.78, 95% CI 1.20 to 293.70) than prednisone alone (1.0 mg/kg: RR 1.79, 95% CI 1.11 to 2.90), while another trial showed no difference in disease control at 6 months.No differences in disease control were seen for different doses or formulations of prednisolone (one trial each), for azathioprine plus prednisone compared with prednisone alone (one trial), for prednisolone plus azathioprine compared with prednisolone plus plasma exchange (one trial), for prednisolone plus mycophenolate mofetil or plus azathioprine (one trial), for tetracycline plus nicotinamide compared with prednisolone (one trial). Chinese traditional medicine plus prednisone was not effective in one trial.There were no significant differences in healing in a comparison of a standard regimen of topical steroids (clobetasol) with a milder regimen (RR 1.00, 95% 0.97 to 1.03) in one trial. In another trial, clobetasol showed significantly more disease control than oral prednisolone in people with extensive and moderate disease (RR 1.09, 95% CI 1.02 to 1.17), with significantly reduced mortality and adverse events (RR 1.06, 95% CI 1.00 to 1.12). AUTHORS' CONCLUSIONS:Very potent topical steroids are effective and safe treatments for BP, but their use in extensive disease may be limited by side-effects and practical factors. Milder regimens (using lower doses of steroids) are safe and effective in moderate BP. Starting doses of prednisolone greater than 0.75 mg/kg/day do not give additional benefit, lower doses may be adequate to control disease and reduce the incidence and severity of adverse reactions. The effectiveness of adding plasma exchange, azathioprine or mycophenolate mofetil to corticosteroids, and combination treatment with tetracycline and nicotinamide needs further investigation.
| S-EPMC7138251 | biostudies-literature
Project description:Bullous pemphigoid (BP) is a rare autoimmune skin blistering disease, characterized by the presence of autoantibodies against hemidesmosomal autoantigens. Cytokine expression is altered in BP patients, and several of these differently expressed cytokines, including IL-1α, IL-1β, IL-8, and TNF-α, contribute to disease pathogenesis. Since genetic polymorphisms in the genes of these cytokines might be implicated in susceptibility to BP disease, we aimed at testing this implication in susceptibility to BP in an Iranian cohort. Blood samples were collected from the subjects and genomic DNA was extracted. To detect the single nucleotide polymorphisms (SNPs), IL-1α (rs1800587), IL-1β (rs1143627, rs16944, rs1143634), IL-8 (rs4073), and TNF-α (rs1799964, rs1800630, rs1799724, and rs361525) genes were genotyped in BP patients and healthy controls as well as IL-8 (rs4073) in pemphigus vulgaris (PV) patients. Quantitative gene expression was evaluated by RT-PCR analysis. A significant difference was observed in the distribution of genotypes or alleles of IL-8 SNP between the BP patients and controls. The A-allele of IL-8 SNP is significantly more prevalent in the control individuals compared to the BP patient. To further validate this observation, we included PV patients as an additional control. Again, the A-allele of IL-8 SNP is significantly more prevalent in the PV compared to the BP patients. While we observed a trend toward significant differences regarding alleles of TNF-α rs1799724 as well as alleles of TNF-α rs1799964, this difference was, however, not evident after correction for multiple analysis. There was no significant difference in all other studied SNPs. In contrast to IL-1α, IL-1β, and TNF-α, IL-8 gene expression levels were significantly higher in the patients than that of controls. The minor allele in IL-8 SNP might play a protective role in susceptibility to BP in Iranian patients. Although higher expression levels of IL-8 gene was found in the patients compared with healthy controls, these levels, however, suggest no association with the examined polymorphism. Moreover, further investigation revealed an elevation in gene expression between wild and polymorphic genotypes of IL-1α rs1800587 and TNF-α rs361525 in the patient group and these SNPs are therefore associated with altering the levels of gene expression.
| S-EPMC6455081 | biostudies-literature
Project description:Autoimmune bullous dermatoses (AIBDs) are a group of rare chronic inflammatory skin diseases, which clinically manifest as blisters and erosions of the skin and/or mucosa. Immunologically, AIBDs are characterized and caused by autoantibodies targeting adhesion molecules in the skin and mucosa. According to the histological location of the blistering, AIBDs are classified into the following two main subtypes: pemphigus (intraepidermal blistering) and pemphigoid (subepidermal blistering). Most AIBDs were potentially life-threatening diseases before the advent of immunosuppressive drugs, especially systemic steroid therapies, which suppress pathogenic immunological activity. Although there have been recent advancements in the understanding of the pathogenesis of AIBDs, glucocorticosteroids and/or adjuvant immunosuppressive drugs are still needed to control disease activity. However, the long-term use of systemic immunosuppression is associated with major adverse events, including death. Based on the growing understanding of AIBD pathogenesis, novel treatment targets have emerged, some of which are currently being evaluated in clinical trials. Within this article, we review the current clinical trials involving pemphigus and pemphigoid and discuss the rationale that lead to these trials. Overall, we aim to foster insights into translational research in AIBDs to improve patient care.
| S-EPMC6509547 | biostudies-literature
Project description:BackgroundTH17/IL-23 immune axis is considered to be involved in the pathogenesis of autoimmune and chronic inflammatory diseases. Bullous pemphigoid (BP) is the most frequent autoimmune blistering disease, characterized by the presence of autoantibodies against the components of the dermal-epidermal junction. Animal studies and characterization of patient samples point toward a contribution of TH17 cells in BP pathogenesis. However, genetic polymorphisms in the genes of TH17/IL-23 cytokines have not yet been well investigated in BP.MethodsDetection of polymorphisms in IL-17A (rs2275913 and rs3819025), IL-17F (rs2397084 and rs763780), IL-17RA (rs2229151), and IL-23R (rs2201841, rs7530511, rs11209026, and rs10889677) genes were performed following the collection of blood samples and DNA extraction from BP patients and controls. Gene expression of IL-23R was determined by quantitative RT-PCR analysis.ResultsThe prevalence of IL-23R rs7530511 genotypes and alleles, as well as IL-23R rs2201841 alleles, is significantly different between the BP patients and controls. While the minor C-allele of IL-23R rs7530511 is highly present in the patients, the G-allele distribution of IL-23R rs2201841 is significantly more prevalent in the control individuals compared to the BP patients. Genotypes and alleles of other SNPs in IL-17A, IL-17F, and IL-17RA were similarly distributed in patients and controls.ConclusionsNo alteration was found in the gene expression between wild and polymorphic genotypes of IL-23R (rs2201841 and rs7530511) variations, indicating they do not contribute to altering the levels of gene expression in blood. In summary, our data show that the alleles of two SNPs in IL-23R rs2201841 and rs7530511 are associated with BP.
| S-EPMC7767565 | biostudies-literature
Project description:ImportanceDupilumab is a theoretically novel therapy for bullous pemphigoid (BP). However, its effectiveness and safety have yet to be confirmed in a large-scale study.ObjectiveTo assess the efficacy and safety of dupilumab in patients with BP and evaluate factors that potentially affect short-term and long-term outcomes.Design, setting, and participantsA retrospective cohort study was conducted from January 1, 2021, to July 31, 2022. The median (IQR) follow-up period was 24.6 (11.5-38.4) weeks. This multicenter study was performed in 6 dermatology departments of the National Autoimmune Bullous Diseases Cooperative Group of China. Adult patients with BP that received 300 mg of dupilumab every 2 weeks following an initial dose of 600 mg were included. Patients were eligible if they had a clinical presentation of BP combined with immunological or pathological evidence. Patients with drug-induced BP, with less than 4 weeks of follow-up, and who received dupilumab or any other biologics within 6 months were excluded.Main outcomes and measuresThe primary outcome was the proportion of patients who achieved disease control within 4 weeks. Disease control was defined as the absence of new lesions and pruritus, combined with the healing of existing lesions. Complete remission rates, relapse rates, changes in Bullous Pemphigoid Disease Area Index (BPDAI) scores, itching numerical rating scale (NRS) scores, laboratory results within 64 weeks, and adverse events (AEs) were also assessed.ResultsAmong 146 patients (median [IQR] age, 73 [64-85] years; 86 [58.9%] male patients) included in the study, 127 (87.0%) patients achieved disease control within 4 weeks, with a median (IQR) time of 14 (7-14) days. A total of 52 (35.6%) patients achieved complete remission, and 13 (8.9%) patients relapsed during the observation period. The complete remission rate and cumulative relapse rate at week 64 were 62.5% (5 of 8) and 30.9%, respectively. There was rapid and sustained improvement in clinical indicators and laboratory examination results after dupilumab treatment, including BPDAI scores, itching NRS scores, serum anti-BP180 and anti-BP230 antibodies, total IgE levels, and eosinophil count. Of these 146 patients, 107 (73.3%) did not report any AEs. The most common AEs were infections and eosinophilia. Serum anti-BP180 antibody levels of greater than 50 relative units (RU)/mL (OR, 3.63; 95% CI, 0.97-12.61; P = .045) were associated with 4-week disease control, and male patients were more likely to relapse (HR, 10.97; 95% CI, 1.42-84.92; P = .02).Conclusions and relevanceIn this retrospective cohort study, dupilumab treatment was associated with improved clinical symptoms in patients with BP. The safety profile was favorable, although concurrent infection and eosinophilia might pose potential concerns. This study suggests that patients with anti-BP180 antibody levels of at least 50 RU/mL and female sex may respond better.
| S-EPMC10398542 | biostudies-literature
Project description:Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disorder in the elderly. Systemic and topical use of glucocorticoids and immunosuppressants has been shown to be effective in most patients. However, refractory BP patients are challenged to clinicians with severe clinical symptoms, resistance to treatment, and high relapse rate. How to predict and assess the refractory and severity of bullous pemphigoid is the key issue in clinical practice, and the urgent need for precision medicine in refractory patients is driving the search for biomarkers and biologics. Recently, some biomarkers, such as the level of specific autoantibodies and released cytokines, have been proposed as the potential parameters to reflect the disease severity and predict the treatment response and relapse of refractory BP. Moreover, new biologics targeting pathogenic antibodies, complement, Th2 axis, eosinophils, and Th17 axis have shown potent efficacy on refractory BP. Here, we review the literature and give an overview of emerging biomarkers and therapeutic strategies for refractory bullous pemphigoid to improve the prognosis of the patient.
| S-EPMC8421646 | biostudies-literature