anti-BP180 Autoantibodies Research Articles

Bullous Pemphigoid Severity and Levels of Antibodies to BP180 and BP230

The correlation between serum levels of autoantibodies against bullous pemphigoid (BP) antigens 180 (BP180) and 230 (BP230) with BP disease severity is unclear. To investigate the correlation of anti-BP180 and anti-BP230 immunoglobulin G (IgG) antibody levels with BP disease severity. A search was performed of the Cochrane Central Register of Controlled Trials, Embase, and PubMed databases from their respective inception to April 11, 2024. Studies evaluating the correlation between serum levels of anti-BP180 or anti-BP230 IgG measured using enzyme-linked immunosorbent assay (ELISA) and disease severity assessed per the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) or BP Disease Area Index (BPDAI) were included. No language or geographic restrictions were imposed. Nearly 0.4% of initially identified studies met the selection criteria. One researcher extracted data and another researcher confirmed data. The risk of bias was independently assessed by these researchers using the Quality Assessment of Diagnostic Accuracy Studies 2 tool, with discrepancies resolved by discussion with a third researcher. A random-effects model meta-analysis and a subgroup analysis were conducted based on the ELISA kit manufacturers. Pooled correlation coefficients of antibody levels with ABSIS and BPDAI. In all, 14 studies with 1226 participants were analyzed. The risk of bias of included studies was generally low. The meta-analysis found anti-BP180 autoantibody levels showed moderate correlation with objective BPDAI (r = 0.56; 95% CI, 0.46-0.64) at baseline, strong correlation (r = 0.63; 95% CI, 0.39-0.79) at 3-month follow-up, and moderate correlation (r = 0.53; 95% CI, 0.25-0.72) at 6-month follow-up. Anti-BP180 autoantibody levels also showed moderate correlation (r = 0.52; 95% CI, 0.39-0.62) with ABSIS at baseline, strong correlation (r = 0.62; 95% CI, 0.39-0.79) at 3-month follow-up, and moderate correlation (r = 0.53; 95% CI, 0.25-0.72) at 6-month follow-up. By contrast, anti-BP230 autoantibody levels showed no association with objective BPDAI and ABSIS at diagnosis and follow-up. The subgroup analysis found similar results when using different ELISA kits. The findings of this systematic review and meta-analysis indicated that anti-BP180 autoantibody levels may serve as an adjunctive tool for monitoring BP disease severity and guiding clinical care for patients with BP.

Polarization of circulating Follicular Helper T cells correlates with the severity of Bullous Pemphigoid.

T-follicular-helper (Tfh) cells form a distinct population of T-helper cells with different polarizations (type 1, type 2 and type 17) that regulates humoral responses and may participate in the pathophysiology of B-cell mediated autoimmune diseases, such as bullous pemphigoid (BP), a dermatosis mediated by auto-antibodies specific for hemidesmosomal proteins. The aim was to evaluate the impact of superpotent topical corticosteroid (TCS) treatment, which is more effective and safer than high doses of oral corticosteroids and recommended first-line treatment of BP, on circulating Tfh cells. We compared by flow cytometry the frequency, polarization and activation of blood Tfh cells from patients with BP at baseline and longitudinally after initiation of TCS treatment to age- and sex-matched healthy subjects. We observed that circulating Tfh cells were more frequent in patients with BP at baseline than in healthy subjects and exhibited an activated phenotype. We further showed a decrease of type 1 and an increase of type 17 Tfh cells in the blood of patients, which resulted in a higher (type 2+type 17) to type 1 Tfh cell ratio. This ratio correlated positively with disease severity as measured by the Bullous Pemphigoid Disease Area Index. Remarkably, along TCS treatment, although the frequency of Tfh cells returned to a level similar to control, the activated phenotype persisted. Interestingly serum IL-21 levels and the Tfh cell subset ratio, similarly to disease activity and serum anti-BP180 and anti-BP230 auto-antibodies, were decreased under the TCS treatment. Overall, our findings suggest an involvement of the polarization of Tfh cells in the pathophysiology of BP and open the door to a modulation of their activity for therapeutic purposes.

Anti-BP230 IgE autoantibodies in bullous pemphigoid intraindividually correlate with disease activity

BackgroundBullous pemphigoid (BP), the most common subepidermal autoimmune blistering disease, is classically defined by the presence of IgG autoantibodies directed against the hemidesmosomal proteins BP180 (type XVII collagen) and BP230 and the predominance of skin lesions. Several studies have addressed the role of anti-BP180 IgE in patients and experimental models, while data on anti-BP230 IgE are scarce. ObjectiveTo assess anti-BP230 IgE level by ELISA in BP sera and to correlate it with disease severity and clinical characteristics. MethodsBP sera underwent anti-BP230 IgE ELISA and Western blotting against human BP230 fragments. ResultsWe demonstrate that 36/154 (23%) of BP sera were positive for anti-BP230 IgE. Anti-BP230 IgE levels had no correlation with clinical phenotype or disease activity per se. Interestingly, anti-BP230 IgE was significantly associated with disease activity within individuals during the course of the disease. Additionally, anti-BP230 IgE and total IgE levels showed a significant correlation. Notably, anti-BP230 IgG correlated interindividually with disease activity. By Western blotting, the C-terminal domain of BP230 fragments (C2; amino acids 2024–2349 and C3; amino acids 2326–2649), provided the best serological assay for anti-BP230 IgE detection. ConclusionAs a complementary tool, IgE immunoblotting is recommended to obtain an optimal serological diagnosis, particularly in patients with severe disease without IgG reactivity by BP180- or BP230-specific ELISA. Although the detection of serum anti-BP230 IgE is not of major diagnostic significance, it may be relevant for therapeutic decisions, e.g., for anti-IgE-directed treatment, which has been successfully used in case series of BP.

Clinical manifestation variability of bullous pemphigoid.

Bullous pemphigoid (BP) is arare autoimmune blistering disease predominantly affecting the elderly population. The present study aims to identify clinical factors that may influence outcomes of BP, including skin phenotype, serology, mucosal involvement, pruritus, and triggers. Aretrospective analysis was conducted on 70 cases with BP registered from January 2019 to December 2022. The Bullous Pemphigoid Disease Activity Index (BPDAI) score was used to assess disease intensity. The BPDAI-Pruritus score and amodified Brest questionnaire were used to document pruritus. Anti-BP180 and anti-BP230 autoantibodies were regularly recorded. Peripheral blood eosinophil counts were documented during flare-up and remission phases of BP. Of the cases, 81.4% were identified with bullous BP, 12.9% with nonbullous BP and 5.7% with localized BP. Oral involvement was documented in 17.1% of cases. Increased peripheral eosinophilia was prominent in the nonbullous phenotype and returned to normal level during remission in both phenotypes. The outcomes of BP depended on the disease phenotype and trigger types. Bullous BP showed more intense disease activity, while nonbullous BP demonstrated more intense pruritus. BP associated with diabetes mellitus (DM) or psoriasis manifested as amore severe disease, predominantly with the bullous phenotype and pruritus, compared to cases without comorbidities. New triggers, including SARS-CoV-2 infection and vaccination, were documented (Tab. 6, Ref. 43). Text in PDF www.elis.sk Keywords: bullous pemphigoid, nonbullous pemphigoid, pruritus, comorbidity, eosinophilia, new triggers.

IgE anti-BP180 NC16A autoantibody in both serum and blister fluid samples does not correlate with disease activity of bullous pemphigoid.

The correlation between IgE anti-BP180 NC16A autoantibody and disease activity of bullous pemphigoid (BP) remains disputable. To determine the levels of IgE anti-BP180 NC16A autoantibody and its clinical significance in untreated BP patients. IgG and IgE anti-BP180 NC16A autoantibody in serum and blister fluid samples of 34 untreated BP patients was detected by enzyme-linked immunosorbent assay (ELISA), and correlation with clinical and pathological features of BP were statistically analysed. The Bullous Pemphigoid Disease Area Index (BPDAI) was used to measure disease activity of BP. The mean baseline level of IgG anti-BP180 NC16A autoantibody in serum and blister fluid samples of untreated BP patients was 75.3U/mL and 1.54U/mL, respectively (A450, cutoff: 0.126). IgE anti-BP180 NC16A autoantibody was positive in 21.9% serum and 14.7% blister fluid samples of untreated BP patients. IgE anti-BP180 NC16A autoantibody levels in serum samples positively correlated with those from blister fluid samples (r = 0.983, p < 0.05). However, IgE anti-BP180 NC16A autoantibody level in both serum and blister fluid samples of untreated BP patients did not correlate with IgG anti-BP180 NC16A autoantibody, age, extent of elevated peripheral blood eosinophils, BPDAI erosion/blister score, BPDAI urticaria/erythema score, BPDAI pruritus score, BPDAI without damage score, or BPDAI total score (all p > 0.05). No significant correlation was identified between disease activity and positive or negative anti-BP180 NC16A IgE autoantibody. Conclusion: IgE anti-BP180 NC16A autoantibody in both serum and blister fluid samples does not appear to correlate with disease activity of BP.

Analysis of the clinical characteristics of pembrolizumab-induced bullous pemphigoid.

Pembrolizumab, a programmed cell death protein 1 checkpoint inhibitor, is a novel drug used to treat a variety of advanced malignancies. However, it can also result in many immune-related adverse events, with cutaneous toxicities being the most frequent. Regarding pembrolizumab-induced skin adverse reactions, bullous pemphigoid (BP) has the worst effects on quality of life. Recently, there have been more and more reports of BP incidents resulting from pembrolizumab therapy in patients with cancer. This study aimed to define the clinical characteristics, diagnosis and management of pembrolizumab-induced BP and identify potential differences between classical BP and pembrolizumab-induced BP. Case reports, case series, and case analyses of pembrolizumab-induced BP up to 10 December 2022 were collected for retrospective analysis. Our study included 47 patients (33 males and 14 females) from 40 studies. The median age was 72 years (range 42-86 years). The median time to cutaneous toxicity was 4 months (range 0.7-28 months), and the median time to bullae formation was 7.35 months (range 0.7-32 months). The most common clinical features were tense bullae and blisters (85.11%), pruritus (72.34%), and erythema (63.83%) on the limbs and trunk. In 20 of the 22 cases tested, the serum anti-BP180 autoantibodies were positive. However, in 10 cases (91.90%, 10/11) the circulating autoantibodies of anti-BP230 were negative. 40 patients had skin biopsies and the skin biopsy revealed subepidermal bullae or blister eosinophil infiltration in 75.00% of patients with pembrolizumab-induced BP, 10.00% of patients with lymphocyte infiltration and 20.00% of patients with neutrophil infiltration. There were 20 patients (50%) with eosinophilic infiltration around the superficial dermis vessels, 8 patients (20.00%) with lymphocyte infiltration around the superficial dermis vessels, and 4 patients (10.00%) with neutrophil infiltration around the superficial dermis vessels. Direct immunofluorescence detected linear immunoglobulin G (IgG) IgG and/or complement C3 along the dermo-epidermal junction in 36 patients (94.74%) with BP. IgG positivity was detected by indirect immunofluorescence in 81.82% of patients with BP. All patients were in complete remission (95.65%,44/46) or partial remission (4.35%, 2/46) of BP, whereas 9/46 patients had a relapse or refractory. The majority of patients achieved BP remission after discontinuation of pembrolizumab with a combination of topically and systemically administered steroid treatments, or other medications. The median duration of BP remission was 2 months (range 0.3-15 months). A thorough diagnosis of pembrolizumab-induced BP should be made using clinical signs, biochemical markers, histopathological and immunopathological tests. Pembrolizumab-induced BP had similar clinical characteristics to classic BP. Temporary or permanent discontinuation of pembrolizumab therapy may be required in patients with perbolizumab-induced BP depending on the severity of BP and the response to medication. Pembrolizumab-induced BP may be effectively treated using topical and systemic steroid treatments in combination with other medications (e.g., doxycycline, niacinamide, dapsone, rituximab, intravenous immunoglobulins, dupilumab, cyclophosphamide, methotrexate, mycophenolate mofetil, and infliximab). Clinicians should provide better management to patients with BP receiving pembrolizumab to prevent progression and ensure continuous cancer treatment.

Analysis of the autoimmune response to BP180 in Chinese stroke patients

BackgroundSignificant association between bullous pemphigoid (BP) and stroke has been reported. This study aimed to evaluate the level of anti-BP180 antibody in stroke patients to explore the relationship between BP and stroke in their pathogenesis. MethodsWe collected serum samples from stroke patients and matched controls between February 2019 and June 2020. The anti-BP180 antibody levels were measured by enzyme-linked immunosorbent assay (ELISA). ResultsA total of 1183 stroke patients including 970 with cerebral infarction (CI), 192 with intracerebral hemorrhage (ICH), 21 with CI and ICH, and 855 controls were enrolled in this study. Anti-BP180 autoantibody values were significantly higher in stroke patients than in controls (p<0.001). Anti-BP180 autoantibody-positive rates were 12.51% (148) in stroke patients and 4.68% (40) in controls (p<0.001, OR=2.65). In anti-BP180 autoantibody-positive subjects, the values were significantly higher in stroke patients than in controls (p<0.001). However, only 10 (6.76%) stroke patients and 3 (7.5%) controls had high values (> 100 RU/mL) (p=0.87). Stratified analysis showed that anti-BP180 antibody positive rates were independent of age, sex, and stroke subtypes in the stroke group. Positive rates in patients with both CI and ICH were nearly two times higher than those in patients with either CI or ICH alone (p=0.11, OR=1.94). Study limitationsThis study had a limited sample size and lacked quantitative criteria for stroke severity. ConclusionsAnti-BP180 antibody values and positive rates were higher in stroke patients than in controls, suggesting that stroke patients may have higher of developing BP.

What's new in the pathogeneses and triggering factors of bullous pemphigoid.

Bullous pemphigoid (BP) is a subepidermal blistering disease induced by autoantibodies to type XVII collagen (COL17, also called BP180) and BP230. Previous studies using patients' samples and animal disease models elucidated the complement-dependent and complement-independent pathways of blister formation, the pathogenic roles of immune cells (T and B cells, macrophages, mast cells, neutrophils, eosinophils), and the pathogenicity of IgE autoantibodies in BP. This review introduces the recent progress on the mechanism behind the epitope-spreading phenomenon in BP, which is considered to be important to understand the chronic and intractable disease course of BP, and the pathogenicity of anti-BP230 autoantibodies, mainly focusing on studies that used active disease models. To clarify the pathogenesis of BP, the mechanism behind the breakdown of immune tolerance to BP antigens should be investigated. Recent studies using various experimental models have revealed important roles for regulatory T cells in the maintenance of self-tolerance to COL17 and BP230 as well as in the suppression of inflammation triggered by the binding of antibodies to COL17. Notably, physical stresses such as trauma, thermal burns, bone fractures, irradiation and ultraviolet exposure, some pathologic conditions such as neurological diseases and hematological malignancies, and the use of dipeptidyl peptidase-IV inhibitors and immune checkpoint inhibitors have been reported as triggering factors for BP. These factors and certain underlying conditions such as genetic background, regulatory T-cell dysfunction or aging might synergistically affect some individuals and eventually induce BP. Further studies on the breakdown of self-tolerance and on the identification of key molecules that are relevant to blister formation and inflammation may expand our understanding of BP's etiology and may lead to the development of novel therapeutic approaches.

Type XVII collagen: Relevance of distinct epitopes, complement-independent effects, and association with neurological disorders in pemphigoid disorders.

Pemphigoid diseases (PD) are autoimmune skin blistering diseases characterized by autoantibodies directed against proteins of the cutaneous basement membrane zone (BMZ). One of the major antigens is type XVII collagen (BP180), a transmembrane glycoprotein, which is targeted in four PDs: bullous pemphigoid, mucous membrane pemphigoid, linear IgA dermatosis, and pemphigoid gestationis. To date, different epitopes on BP180 have been described to be recognized by PD disease patients’ autoantibodies. Different BP180 epitopes were associated with distinct clinical phenotypes while the underlying mechanisms are not yet fully understood. So far, the main effects of anti-BP180 reactivity are mediated by Fcγ-receptors on immune cells. More precisely, the autoantibody–antigen interaction leads to activation of complement at the BMZ and infiltration of immune cells into the upper dermis and, by the release of specific enzymes and reactive oxygen species, to the degradation of BP180 and other BMZ components, finally manifesting as blisters and erosions. On the other hand, inflammatory responses independent of Fcγ-receptors have also been reported, including the release of proinflammatory cytokines and internalization and depletion of BP180. Autoantibodies against BP180 can also be found in patients with neurological diseases. The assumption that the clinical expression of PD depends on epitope specificity in addition to target antigens, autoantibody isotypes, and antibody glycosylation is supported by the observation that epitopes of PD patients differ from those of PD patients. The aim of the present review is to describe the fine specificities of anti-BP180 autoantibodies in different PDs and highlight the associated clinical differences. Furthermore, the direct effects after binding of the autoantibodies to their target are summarized.

Dipeptidyl Peptidase 4 Inhibitor‒Associated Bullous Pemphigoid Is Characterized by an Altered Expression of Cytokines in the Skin

Dipeptidyl peptidase 4 inhibitors (DPP4is), commonly used drugs for treatment of type 2 diabetes, increase the risk for bullous pemphigoid (BP). Currently, the mechanism leading to the loss of immunological tolerance of the cutaneous adhesion molecule BP180 as well as similarities and differences in disease progression between DPP4i-associated BP (DPP4i-BP) and DPP4i-independent regular BP are largely unknown. We analyzed the expression of 32 cytokines and two proteases by Luminex and ELISA assays in samples taken from lesional and nonlesional skin of patients with regular BP or DPP4i-BP and healthy controls. Cytokines mediating B-cell survival and targeting such as BAFF, CCL4, CXCL12, and IL-6 were expressed at a higher level in the lesional regular BP skin than the levels in the lesional DPP4i-BP skin. The DPP4i-BP samples had increased levels of eosinophilic cytokines CCL1, CCL17, CCL26, and IL-5, which correlated with the serum level of anti-BP180 NC16A IgG autoantibodies. The mRNA expression of BAFF, IL6, CCL1, CCL17, CCL26, and IL5 measured by qPCR correlated with the protein levels. Taken together, the cutaneous cytokine profiles were found to provide distinctive molecular fingerprints between regular BP and DPP4i-BP.

050 Eotaxin-1 and matrix metalloproteinase-9 are critical in anti-BP180 IgE-induced experimental bullous pemphigoid

Bullous pemphigoid (BP) is the most common autoimmune blistering disease characterized by chronic subepidermal blistering, autoantibodies directed against hemidesmosomal components, and a predominant eosinophil infiltrate. BP autoantibodies recognize two hemidesmosomal proteins of basal keratinocytes: BP230 (also termed BPAG1) and BP180 (also termed BPAG2 or collagen XVII) with the NC16A domain of the human BP180 antigen containing the major autoantibody-reactive epitopes. Anti-BP180 autoantibodies belong to IgG and IgE isotypes.

Deciphering the Contribution of BP230 Autoantibodies in Bullous Pemphigoid.

Bullous pemphigoid (BP) is a subepidermal autoimmune blistering disease predominantly affecting elderly patients and carries significant morbidity and mortality. Patients typically suffer from severe itch with eczematous lesions, urticarial plaques, and/or tense blisters. BP is characterized by the presence of circulating autoantibodies against two components of the hemidesmosome, BP180 and BP230. The transmembrane BP180, also known as type XVII collagen or BPAG2, represents the primary pathogenic autoantigen in BP, whereas the intracellular BP230 autoantigen is thought to play a minor role in disease pathogenesis. Although experimental data exist suggesting that anti-BP230 antibodies are secondarily formed following initial tissue damage mediated by antibodies targeting extracellular antigenic regions of BP180, there is emerging evidence that anti-BP230 IgG autoantibodies alone directly contribute to tissue damage. It has been further claimed that a subset of patients has a milder variant of BP driven solely by anti-BP230 autoantibodies. Furthermore, the presence of anti-BP230 autoantibodies might correlate with distinct clinical features. This review summarizes the current understanding of the role of BP230 and anti-BP230 antibodies in BP pathogenesis.

A 1,035-Subject Study Suggesting a History of Bone Fracture as a Possible Factor Associated with the Development of Anti-BP180 Autoantibodies

Bullous pemphigoid (BP) is an autoimmune blistering disorder that presents as tense blister formation on the body (Schmidt and Zillikens, 2013). BP autoantibodies target two hemidesmosomal components in basal keratinocytes: BP180 and BP230 (Schmidt and Zillikens, 2013). In BP, 80‒90% of autoantibodies target the NC16A domain of BP180 (Ishiko et al., 1993). It remains largely unclear why anti-BP180 autoantibodies develop in certain individuals, and there is limited information about the prevalence of anti-BP180 autoantibodies in healthy individuals.

Assessing Disease Outcome Measures in Bullous Pemphigoid on Standard-Of-Care Therapies

Bullous pemphigoid (BP) is an autoimmune blistering disease resulting in pruritus and cutaneous blistering. Longitudinal studies characterizing the disease course of patients with BP on conventional therapy are lacking. We sought to characterize the changes in disease activity and pruritus of patients with BP on standard-of-care treatments. We conducted a retrospective cohort study on patients with BP on standard-of-care therapy. Generalized Estimating Equations were used to estimate the mean and standard errors for Bullous Pemphigoid Disease Activity Index (BPDAI) total activity score, BPDAI pruritus component score, and anti-BP180 autoantibody levels (BP180) over time. A total of 80 patients with BP showed consistent reductions in BPDAI total activity score and BPDAI pruritus component score, with a nadir at 4 months. BP180 decreased over time, with the largest reductions at 6 and 9 months. Median partial/complete remission was at 6.7 months, with relapses at a median time of 15.9 months. Receiving operating characteristic analysis determined an optimal BPDAI total activity score cutoff of 3.3 to discriminate partial/complete remission incidence (area under the curve = 0.895, sensitivity = 0.844, specificity = 0.78). In conclusion, in patients with BP on standard-of-care therapy, a natural course of BPDAI total activity score and BPDAI pruritus component score over time was comprehensively projected. BPDAI ≤ 3.3 was associated with partial/complete remission. These results provide reference data to guide future clinical trial design for BP.

Immunological features and factors associated with mucocutaneous bullous pemphigoid - a retrospective cohort study.

The features of bullous pemphigoid (BP) patients presenting with mucosal lesions are not established. We aimed to elucidate the clinical and immunological features of BP patients with mucosal involvement, and to identify factors associated with mucosal lesions. A retrospective study encompassing all consecutive patients diagnosed with BP throughout the years 2009-2019 in a tertiary referral center. The study encompassed 273 patients with BP, of whom 31 (11.4%) presented with mucosal lesions. The oral mucosa was the most frequently affected mucosal surface (71.0%), followed by the genital (25.8%) and the nasal (22.6%) mucosae. Relative to other patients with BP, patients with mucosal involvement had a more prominent palmoplantar involvement (67.7% vs. 37.2%; P=0.001); lower seropositivity rate (18.2% vs. 54.2%; P=0.027) and lower levels (29.3 ±64.5 vs. 129.5 ±304.4U/ml; P=0.016) of anti-BP230 autoantibodies; and decreased peripheral eosinophil counts (760.0 ±638.6 vs. 1296.3 ±1013.7; P<0.001). Absence of anti-BP230 autoantibodies (OR, 5.32; 95% CI, 1.07-26.32; P=0.026) and lack of peripheral eosinophilia (OR, 4.31; 95% CI, 1.14-16.39; P=0.021) were associated with the presence of mucosal involvement in BP. Mucosal involvement is present in a notable subgroup of patients with BP and is associated with the absence of both anti-BP230 antibodies and peripheral eosinophilia.

Analysis of the Clinical Characteristics of Dipeptidyl Peptidase-4 Inhibitor-Induced Bullous Pemphigoid.

To analyze and discuss the clinical characteristics of dipeptidyl peptidase-4 inhibitor (DPP4i)-induced bullous pemphigoid (BP). We collected case reports of DPP4i-induced BP by searching databases from 2006 to mid-May 2021, as a retrospective analysis. Relevant case reports and case analyses of DPP4i-induced BP were included. The median time of symptom onset was 9 months (range 0.5-59 months). BP most often occurred in patients receiving vildagliptin (52.63%) followed by linagliptin (27.19%) and sitagliptin (17.54%). Tense bullae and blisters (85.51%) and erythema (82.61%) on the extremities and trunk were the most common presenting symptoms. In total, 64.06% of BP patients were anti-BP180 autoantibody positive, 58.97% were BP180NC16a autoantibody positive, and 31.25% were anti-BP230 autoantibody positive. Skin biopsy revealed subepidermal bulla eosinophil infiltration in 93.85% of BP patients, lymphocyte infiltration in 56.93%, and neutrophil infiltration in 44.62%. Direct immunofluorescence was positive in 98.94% of BP patients with linear deposition of IgG (97.80%) and/or complement C3 (98.94%) along the basement membrane zone. Indirect immunofluorescence was positive in 87.88% of BP patients. Complete remission of BP was achieved in 83.64% of patients on DPP4i withdrawal and after 4 months (range 0.13-72 months) of follow-up. This review analyzes and discusses the clinical characteristics of DPP4i-induced BP and provides a reference for the safe and reasonable clinical application of DPP4i. DPP4i drugs are related to the occurrence of BP in diabetic patients, especially elderly men taking vildagliptin.

Risk Factors for Mucosal Involvement in Bullous Pemphigoid and the Possible Mechanism: A Review.

Bullous pemphigoid (BP) is the most common type of autoimmune bullous disease and is characterized by the presence of circulating anti-BP180 and/or anti-BP230 autoantibodies. Patients with BP often present with tense blisters and erythema, mainly on the trunk and limbs, but a few patients also have mucosal involvement. In this article, we discuss the fact that BP patients with mucosal involvement tend to have more serious conditions and their disease is more difficult to control. Potential risk factors for mucous involvement include earlier age at onset, drugs such as dipeptidyl peptidase-4 inhibitors, cancer, and blood/serum biomarkers, including lower eosinophil count, higher erythrocyte sedimentation rate, IgG autoantibodies against both the NH2- and COOH-termini of BP180, and the absence of anti-BP230 antibodies. IgA and C3 deposition at the dermo-epidermal junction may also be present. Understanding these risk factors may benefit earlier diagnosis of these patients and promote the development of novel treatments. What's more, it's helpful in deeper understanding of BP development and the relationship between BP and mucous membrane pemphigoid (MMP).

Autoreactive Peripheral Blood T Helper Cell Responses in Bullous Pemphigoid and Elderly Patients With Pruritic Disorders.

Bullous pemphigoid (BP) is a prototypic autoimmune disorder of the elderly, characterized by serum IgG autoantibodies, namely anti-BP180 and anti-BP230, directed against components of the basal membrane zone that lead to sub-epidermal loss of adhesion. Pruritus may be indicative of a pre-clinical stage of BP, since a subset of these patients shows serum IgG autoantibodies against BP230 and/or BP180 while chronic pruritus is increasingly common in the elderly population and is associated with a variety of dermatoses. Clinical and experimental evidence further suggests that pruritus of the elderly may be linked to autoimmunity with loss of self-tolerance against cutaneous autoantigens. Thus, the objective of this study was to determine autoreactive T cell responses against BP180 in elderly patients in comparison to patients with BP. A total of 22 elderly patients with pruritic disorders, 34 patients with bullous or non-bullous BP and 34 age-matched healthy controls were included in this study. The level of anti-BP180 and anti-BP230 IgG serum autoantibodies, Bullous Pemphigoid Disease Area Index (BPDAI), and pruritus severity were assessed for all patients and controls. For characterization of the autoreactive T cell response, peripheral blood mononuclear cells were stimulated ex vivo with recombinant BP180 proteins (NH2- and COOH-terminal domains) and the frequencies of BP180-specific T cells producing interferon-γ, interleukin (IL)-5 or IL-17 were subsequently determined by ELISpot assay. Patients with BP showed a mixed Th1/Th2 response against BP180 while autoreactive Th1 cells were identified in a minor subset of elderly patients with pruritic disorders. Furthermore, our T cell characterization revealed that therapeutic application of topical clobetasol propionate ointment in BP patients significantly reduced peripheral blood BP180-specific T cells, along with clinically improved symptoms, strongly suggesting a systemic immunosuppressive effect of this treatment.

Analysis of the autoimmune response against BP180 in patients with Alzheimer's disease.

BackgroundCurrent epidemiological studies suggest a significant correlation between Alzheimer’s disease (AD) and bullous pemphigoid (BP). However, the autoimmune response against BP180 in patients with AD has not been fully understood. investigated.MethodsWe randomly enrolled 48 patients with AD and 50 sex- and age-matched healthy controls. We detected the presence/absence and the level of anti-BP180/BP230 immunoglobulin G (IgG) autoantibodies in the patients’ serum to determine whether said antibodies possess reactivity against the BP180 protein in the human brain and skin.ResultsThe enzyme-linked immunosorbent assay (ELISA) results revealed that the positive rate of anti-BP180 autoantibodies in patients with AD (23/48, 47.9%) was significantly higher than that in controls (4/50, 8.0%; P<0.0001). These ELISA-positive patients were further examined through immunoblotting. Sera from nine patients with AD (9/23, 39.1%) and one control (1/4, 25.0%) reacted with human cutaneous recombinant full-length BP180 and BP180-noncollagenous 16A (NC16A). Sera from 11 (11/23, 47.8%) patients with AD reacted with a 180-kDa protein from the human brain extract, but none of the controls’ sera recognized the corresponding protein band. The majority of the patients in the anti-BP180-positive AD group were men (14/23, 60.9%) who were older (74.0 years) compared with those in the control group (6/25, 24.0%; P<0.05) (72.2 years; P<0.01).ConclusionsAnti-BP180 autoantibodies are present in AD and recognize human recombinant full-length BP180 and a 180-kDa protein from the human brain extract, suggesting that BP180 is a shared autoantigen in AD and BP and may help clarify the mechanism to explain why a high risk of BP exists in AD. Elderly male patients with AD are significantly more likely to develop BP180 serum autoreactivity compared with other patients with AD.

Presence of Cutaneous Complement Deposition Distinguishes between Immunological and Histological Features of Bullous Pemphigoid-Insights from a Retrospective Cohort Study.

The practical implications of complement deposition in direct immunofluorescence (DIF) microscopy and its influence on the disease phenotype are poorly understood. We aimed to investigate whether the presence of complement deposition in DIF microscopy gives rise to differences in the morphological, immunological, and histological characteristics of patients with BP (bullous pemphigoid). We performed a retrospective study encompassing patients with BP in a specialized tertiary referral center. Logistic regression model was utilized to identify variables independently associated with complement deposition. The study included 233 patients with BP, of whom 196 (84.1%) demonstrated linear C3 deposition along the dermal-epidermal junction (DEJ) in DIF analysis. BP patients with C3 deposition had higher mean (SD) levels (645.2 (1418.5) vs. 172.5 (243.9) U/mL; p < 0.001) and seropositivity rate (86.3% vs.64.9%; p = 0.002) of anti-BP180 NC16A and less prevalent neutrophilic infiltrate in lesional skin specimens (29.8% vs. 52.4%; p = 0.041). C3 deposition was found positively associated with the detection of anti-BP180 NC16A autoantibodies (OR, 4.25; 95% CI, 1.38–13.05) and inversely associated with the presence of neutrophils in lesional skin (OR, 3.03; 95% CI, 1.09–8.33). To conclude, complement deposition influences the immunological and histological features of BP. These findings are in line with experimental data describing the pathogenic role of complement in BP.