anti-BP180 IgG Research Articles

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.

Nail abnormalities in subepidermal blistering diseases: a cross-sectional study.

Nail involvement in subepidermal autoimmune blistering diseases (SEABD) is not common. Although these changes can be transient, permanent changes can also occur. This study addresses nail involvement manifestations and their associated factors in patients with SEABD. From March 2020 to March 2021, we enrolled 56 patients with SEABD who were being examined at a tertiary skin hospital and checked their nail changes. We investigated the association between the SEABD subtypes and treatments that patients were receiving and the nail abnormalities. Additional factors including age, gender, duration since diagnosis, presence of mucosal involvement, and anti-bp230 and anti-bp180 IgG antibody quantitative levels (in those patients with bullous pemphigoid) were analyzed. The most common nail abnormalities were ridging, onycholysis, and onychoschizia. We observed a lower prevalence of onycholysis in EBA, a lower prevalence of periungual bullae in MMP, and a higher prevalence of scarring loss in EBA. Rituximab and dapsone were effective in preventing onycholysis as well as prednisolone in preventing subungual hematoma. Multiple lesions were found to be more common in the foot digits including great toes, probably because of higher exposure to trauma. In summary, in patients with SEABD and concomitant nail involvement, the underlying disease control, proper treatment, and avoidance of trauma may be helpful.

Anti-BP180 IgG antibody ELISA values correlate with adverse pregnancy outcomes in pemphigoid gestationis.

Adverse pregnancy outcomes (APO) occur in 35% of patients with pemphigoid gestationis (PG). No biological predictor of APO has been established yet. To assess a potential relationship between the occurrence of APO and the serum value of anti-BP180 antibodies at the time of PG diagnosis. Multicentre retrospective study conducted from January 2009 to December 2019 in 35 secondary and tertiary care centres. (i) diagnosis of PG according to clinical, histological and immunological criteria, (ii) ELISA measurement of anti-BP180 IgG antibodies determined at the time of PG diagnosis with the same commercial kit and (iii) obstetrical data available. Of the 95 patients with PG included, 42 had one or more APO, which mainly corresponded to preterm birth (n= 26), intrauterine growth restriction (IUGR) (n= 18) and small weight for gestational age at birth (n= 16). From a ROC curve, we identified a threshold of 150 IU ELISA value as the most discriminating to differentiate between patients with or without IUGR, with 78% sensitivity, 55% specificity, 30% positive and 91% negative predictive value. The threshold >150 IU was confirmed using a cross-validation based on bootstrap resampling, which showed that the median threshold was 159 IU. Upon adjusting for oral corticosteroid intake and main clinical predictors of APO, an ELISA value of >150 IU was associated with the occurrence of IUGR (OR=5.11; 95% CI: 1.48-22.30; p=0.016) but not with any other APO. The combination of blisters and ELISA values higher than 150 IU led to a 2.4-fold higher risk of all-cause APO (OR: 10.90; 95% CI: 2.33-82.3) relative to patients with blisters but lower values of anti-BP180 antibodies (OR of 4.54; 95% CI 0.92-34.2). These findings suggest that anti-BP180 antibody ELISA value in combination with clinical markers is helpful in managing the risk of APO, in particular IUGR, in patients with PG.

007 Antibodies to the BP180 C-terminus cause autoimmune blistering disease through activation of the C5a/C5aR1 axis and Fcγ receptors

Bullous pemphigoid (BP) is a rare autoimmune blistering disease characterized by autoantibodies targeting BP180 with the non-collagenous 16A (NC16A) domain representing the immunodominant site. The role of additional extracellular targets of the BP180 C-terminus has not yet been unequivocally demonstrated. Here, we showed that BP180 ectodomain-reactive sera depleted for NC16A IgG induced dermal-epidermal separation in control skin after incubation with normal human leukocytes indicating the pathogenic potential of anti-BP180 C-terminal IgG.

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.

Serum autoantibody reactivity in bullous pemphigoid is associated with neuropsychiatric disorders and the use of antidiabetics and antipsychotics: a large, prospective cohort study.

Bullous pemphigoid (BP), the by far most frequent autoimmune blistering skin disease (AIBD), is immunopathologically characterized by autoantibodies against the two hemidesmosomal proteins BP180 (collagen type XVII) and BP230 (BPAG1 or dystonin). Several comorbidities and potentially disease-inducing medication have been described in BP, yet a systematic analysis of these clinically relevant findings and autoantibody reactivities has not been performed. To determine associations of autoantibody reactivities with comorbidities and concomitant medication. In this prospective multicenter study, 499 patients diagnosed with BP in 16 European referral centers were included. The relation between anti-BP180 NC16A and anti-BP230 IgG ELISA values at the time of diagnosis as well as comorbidities and concomitant medication collected by a standardized form were analysed. An association between higher serum anti-BP180 reactivity and neuropsychiatric but not atopic and metabolic disorders was observed as well as with the use of insulin or antipsychotics but not with dipeptidyl peptidase-4 (DPP4) inhibitors, inhibitors of platelet aggregation and L-thyroxine. The use of DPP4 inhibitors was associated with less anti-BP180 and anti-BP230 reactivity compared with BP patients without these drugs. This finding was even more pronounced when compared with diabetic BP patients without DPP4 inhibitors. Associations between anti-BP180 and anti-BP230 reactivities were also found in patients using insulin and antipsychotics, respectively, compared with patients without this medication, but not for the use of inhibitors of platelet aggregation, and L-thyroxine. Taken together, these data imply a relation between autoantibody reactivities at the time of diagnosis and both neuropsychiatric comorbidities as well as distinct concomitant medication suggesting a link between the pathological immune mechanisms and clinical conditions that precede the clinically overt AIBD.

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.

Anti-BP230 Only Bullous Pemphigoid Constitutes a Distinct Disease Subgroup with Characteristic Serological and Clinical Features

Anti-BP230 Only Bullous Pemphigoid Constitutes a Distinct Disease Subgroup with Characteristic Serological and Clinical Features

Rapid Disease Control in First-Line Therapy-Resistant Mucous Membrane Pemphigoid and Bullous Pemphigoid with Omalizumab as Add-On Therapy: A Case Series Of 13 Patients.

The role of IgE autoantibodies has been demonstrated in the pathogenesis of bullous pemphigoid for many years. Recently, omalizumab (OMZ), a humanized monoclonal anti-IgE antibody that depletes total serum IgE, has been used off-label in a few case series of bullous pemphigoids demonstrating a rapid efficacy and allowing significant improvements or complete remission as add-on therapy in first-line treatment-resistant patients. Herein, we report the largest retrospective study to evaluate OMZ effectiveness in patients with subepidermal autoimmune blistering diseases. Our series included 13 patients from a single center with bullous pemphigoid or mucous membrane pemphigoid, of whom 7 had mucous membrane involvement. OMZ was added to the unchanged immunosuppressive therapies. Detailed clinical and immunological data during the first year were collected, notably for specific anti-BP180-NC16A IgE and IgG, and the median total follow-up was 30 months (range: 3–81). Our series demonstrated that OMZ induced a significant improvement in pruritus, urticarial score, and daily blister count on day 15, allowing disease control to be achieved in a 1-month median time and complete remission (CR) in a 3-month median time in 85% of these patients previously in therapeutic impasse. At the end of the follow-up, 31% of patients achieved CR on minimal therapy after OMZ weaning without relapses, and 54% achieved CR on OMZ continuation with a minimal dose of concomitant treatment. Two patients experienced therapeutic failure (15%). At baseline, clinical variables reflecting activity were significantly positively correlated with eosinophil blood count, total IgE serum level, specific anti-BP180 IgE and IgG. While baseline anti-BP180 IgG and specific anti-BP180 IgE were significantly positively correlated, only the two patients who experienced a therapeutic failure with OMZ did not fit with this correlation, demonstrating elevated levels of anti-BP180 IgG with no measurable BP180-specific IgE. Follow-up of immunological variables demonstrated a rapid decrease of eosinophilia towards normalization, whereas a slower decline towards negativation was observed over 1 year for anti-BP180 IgG and anti BP180 IgE in patients who responded to OMZ. This case series demonstrated that OMZ is a rapidly effective biologic therapy for refractory bullous pemphigoid and mucous membrane pemphigoid, permitting rapid disease control and reduction of concomitant therapeutics.

The impact of lesional inflammatory cellular infiltrate on the phenotype of bullous pemphigoid

The influence of cutaneous cellular infiltration on the phenotype of bullous pemphigoid (BP) remains to be established. To evaluate the main histopathological characteristics of patients with BP and to assess the association between the composition of lesional inflammatory infiltrate and the various clinical, immunological and immunopathological aspects of the disease. Retrospective study encompassing patients diagnosed with BP throughout the years 2009-2020 in a specialized tertiary referral centre. The study encompassed 136 patients with BP, of whom 27 (19.9%) demonstrated a cell-poor inflammatory infiltrate in lesional skin specimens. Overall, 78 (57.4%), 71 (52.2%) and 5 (3.7%) specimens were found to include eosinophil-predominant, lymphocyte-predominant and neutrophil-predominant inflammatory infiltrates, respectively. Relative to the remaining patients with BP, those with an eosinophil-predominant inflammatory infiltrate had higher (90.8% vs. 77.2%; P=0.030) whilst those with a cell-poor inflammatory infiltrate lower (70.3% vs. 88.7%; P=0.017) seropositivity of anti-BP180 NC16A IgG. The latter subgroup presented with higher prevalence of mucosal involvement (25.9% vs. 8.3%; P=0.011) and a non-inflammatory clinical phenotype (50.0% vs. 17.1%; P=0.041). Patients with lymphocyte-predominant inflammatory infiltrate manifested with higher severity BPDAI scores and a lower frequency of the non-inflammatory subtype (11.1% vs. 36.4%; P=0.035), whilst those with a neutrophilic infiltrate presented with lower mean (SD) levels of anti-BP180 NC16A IgG [269.3 (227.6) vs. 722.7 (1499.6) U/mL; P=0.003]. Eosinophil-predominance and high cellularity in the lesional inflammatory infiltrate of BP skin are associated with increased seropositivity of anti-BP180 NC16A IgG. Lymphocyte-predominant infiltrates predict a more severe phenotype, pointing towards a pathogenic role of autoreactive lymphocytes.

Neutrophil to lymphocyte ratio is predictive of severe complications and mortality in patients with dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid: A retrospective longitudinal observational study

Neutrophil to lymphocyte ratio is predictive of severe complications and mortality in patients with dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid: A retrospective longitudinal observational study

Defining dipeptidyl peptidase-4 inhibitors-related bullous pemphigoid: A single-centre retrospective study.

Many studies have corroborated the association of dipeptidyl peptidase-4 inhibitors (DPP4i) use with bullous pemphigoid (BP). It has been speculated that this drug-induced variant presents with a different clinical spectrum than conventional BP. To determine the prevalence of DPP4i-induced cases of BP and to evaluate whether gliptin-related BP has specific clinicopathological and immunological features. We conducted a retrospective, observational study of BP cases attended at our centre between January 2000 and June 2020. Epidemiological, clinical, histopathological and laboratory data were collected. A total of 257 cases of BP were collected; 51 (24.3%) were on treatment with DPP4i. When analysing DPP4i-induced BP cases, generalized BP was the predominant pattern and scalp/mucosal involvement was found in 13 patients. Gliptin-related BP cases were associated to a decrease in the eosinophilic infiltrate (p=0.000) and both the detection rate and concentration of anti-BP180 IgG were lower (p=0.004, p=0.001, respectively) than non-DPP4i cases. Retrospective, single-centre study. Our large DPP4i-induced BP case series has highlighted that DPP4i-induced BP is characterized by generalized lesions and scalp involvement. Lower titres of anti-BP180 antibodies and a decrease in eosinophils infiltrating into the skin may be distinct features of DPP4i-related BP.

Coexistence of bullous pemphigoid with neuropsychiatric comorbidities is associated with anti-BP230 seropositivity.

While clustering of bullous pemphigoid (BP) with neuropsychiatric diseases is well-established, the clinical and immunological profile of BP patients with this comorbidity remains to be decisively determined. To evaluate the burden of neurological and psychiatric comorbidities among patients with BP and to elucidate the clinical, immunological and immunopathological features of patients with BP and comorbid neuropsychiatric conditions. We performed a retrospective study encompassing patients diagnosed with BP throughout the years 2009-2020 in a specialized tertiary referral centre. Multivariate logistic regression model was used to identify predictors of neuropsychiatric conditions among patients with BP. The study included 273 patients with BP, of whom 123 (45.1%) presented with comorbid neuropsychiatric disease. Compared to the remaining patients with BP (n=150), those with pre-existing neuropsychiatric diseases demonstrated older mean [standard deviation (SD)] age [81.7 (9.1) vs. 76.9 (10.1); P<0.001], female preponderance (65.0% vs. 49.3%; P=0.009), higher seropositivity rate of anti-BP230 (67.7% vs. 36.5%; P=0.006) and higher levels of anti-BP180 NC16A IgG [651.3 (1279.6) vs. 370.4 (818.6) U/mL; P=0.039]. In multivariate analysis, anti-BP230 seropositivity was independently associated with coexistence of BP with neuropsychiatric conditions [adjusted odds ratio (OR), 3.43; 95% CI, 1.24-9.52; P=0.018]. In a sensitivity analysis confined to patients with neurological diseases (n=103), older age [82.1 (8.4) vs. 77.2 (10.3); P<0.001] and increased anti-BP230 seropositivity (68.0% vs. 39.7%; P=0.018) were identified. The coexistence of BP with neuropsychiatric diseases is independently associated with the generation of anti-BP230 antibodies.

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.

Anti-BP180 and anti-BP230 enzyme-linked immunosorbent assays for diagnosis and disease activity tracking of bullous pemphigoid: A prospective cohort study.

Autoantibodies against BP180 and BP230 play major roles in bullous pemphigoid (BP). We are the first to describe the values of serum anti-BP180 IgG and anti-BP230 IgG enzyme-linked immunosorbent assays (ELISA) for diagnosis and disease monitoring of BP among Thai patients. We aimed to determine the diagnostic performance of anti-BP180 IgG and anti-BP230 IgG in BP, to correlate disease activity with autoantibody levels through follow-ups, and to relate BP comorbidities with disease activity and autoantibody levels. Consecutive patients suspected of having BP were included. Skin biopsy, direct immunofluorescence, and serum anti-BP180 IgG and anti-BP230 IgG tests were performed. BP disease area index (BPDAI) was evaluated at diagnosis and throughout follow-ups. Of 131 patients, 68 were diagnosed with BP, and 63 were included as controls. Sensitivity and specificity of serum anti-BP180 IgG were 69.1% and 90.5%, respectively, while those of serum anti-BP230 IgG were 55.9% and 85.5%, respectively. Using anti-BP180 and anti-BP230 IgG antibodies resulted in a 7% increase in sensitivity compared with using anti-BP180 IgG antibody alone. Significant correlation with BPDAI was found for both autoantibodies at diagnosis but only for anti-BP180 IgG at follow-ups (p = 0.013). BP patients with positivity to anti-BP180 or anti-BP230 IgG had significantly higher BPDAI than did those without (p = 0.005). BP was associated with neurological diseases (p = 0.025), while patients with diabetes had higher disease activity (p = 0.010). While both serum autoantibodies are useful for diagnosing BP in patients with suspicious clinical features, only anti-BP180 IgG allowed prediction of disease activity over time.

Role of eosinophils and MMP-9 in autoimmune blistering disease bullous pemphigoid

Abstract Bullous pemphigoid (BP) is an autoimmune inflammatory subepidermal blistering disease associated with autoantibodies against two hemidesmosomal components, the BP230 and BP180 and an inflammatory infiltrate including eosinophils and neutrophils. BP180-specific IgG autoantibodies from BP patients induce BP-like skin lesions in BP180 humanized mice (hBP180 mice). Subepidermal blistering induced by anti-BP180 IgG depends on complement, mast cells, and neutrophils. Since mouse eosinophils lack IgE receptors for human IgE, we generated a humanized IgE receptor FceRI mouse strain (hFceRI) and crossed hFceRI mice onto hBP180 mice to generate hFceRI/hBP180 mice. Anti-BP180 IgE, when injected i.d. into hFceRI/hBP180 mice, trigger infiltration of dominant eosinophils and minor neutrophils and subsequent subepidermal blistering 48 h post IgE injection. In this study, we tested if anti-BP180 IgE-induced BP depends on eosinophils, neutrophils or both. We found that anti-BP180 IgE induce BP in hFceRI/hBP180 mice and neutrophil-deficient but not eosinophil-deficient hFceRI/hBP180 mice. Eosinophil-deficient hFceRI/hBP180 mice reconstituted with eosinophils but not neutrophils from hFceRI/hBP180 mice became susceptible to anti-BP180 IgE-induced BP. Increased MMP-9 was present in diseased mouse blister fluid. MMP-9-deficient and eosinophil-deficient hFceRI/hBP180 mice reconstituted with MMP-9-sufficient but not MMP-9-deficient eosinophils when injected with anti-BP180 IgE developed BP. These data suggest that eosinophils and MMP-9 are critical for BP and could be therapeutic targets for BP treatment.

Correlation of dermal and blood eosinophilia with bullous pemphigoid disease severity.

BackgroundBullous pemphigoid (BP) is an autoimmune subepidermal blistering disease associated with immune response against BP-180 and BP-230. Peripheral blood eosinophilia and dermal infiltration of eosinophils are common findings in BP.ObjectiveThe aim of our study was to demonstrate a statistical correlation between dermal and peripheral blood eosinophilia, anti BP-180, and anti BP-230 IgG and clinical severity of BP.MethodsA total of 27 patients with newly diagnosed BP were included. Severity of disease was assessed according to the bullous pemphigoid disease activity index (BPDAI). Anti-BP-180 and anti-BP-230 titers, peripheral blood eosinophilia, and dermal eosinophil infiltration and tissue inflammation severity were assessed for each patient.ResultsA significant correlation was found between the serum levels of anti-BP-180 and anti-BP-230, and dermal eosinophilia and tissue inflammation severity with objective and subjective BPDAI scores. In addition, there was a significant correlation between the percentage of peripheral blood eosinophils and subjective BPDAI scores and urticarial/eczematous lesions. Moreover, the mucosal component did not show any correlation with autoantibody levels and inflammation severities.ConclusionAnti-BP-180 and anti-BP-230 levels, tissue inflammation severity, and dermal eosinophilia had a strong and significant correlation with BP severity. In addition, percentage of peripheral blood eosinophilia showed a correlation with subjective BPDAI scores.

BP180-specific IgG is associated with skin adverse events, therapy response, and overall survival in non-small cell lung cancer patients treated with checkpoint inhibitors

Anti-programmed cell death protein 1 (PD1)/programmed death-ligand 1(PD-L1) therapy frequently entails immune-related adverse events (irAEs), and biomarkers to predict irAEs are lacking. Although checkpoint inhibitors have been found to reinvigorate T cells, the relevance of autoantibodies remains elusive. Our aim was to explore whether IgG autoantibodies directed against coexpressed antigens by tumor tissue and healthy skin correlate with skin irAEs and therapy outcome. We measured skin-specific IgG via enzyme-linked immunosorbent assay in patients with non-small cell lung cancer (NSCLC) who received anti-PD1/PD-L1 treatment between July 2015 and September 2017 at the Kantonsspital St. Gallen. Sera were sampled at baseline and during therapy after 8weeks. Analysis of publicly available tumor expression data revealed that NSCLC and skin coexpress BP180, BP230, and type VII collagen. A skin irAE developed in 16 of 40 recruited patients (40%). Only elevated anti-BP180 IgG at baseline significantly correlated with the development of skin irAEs (P=.04), therapy response (P=.01), and overall survival (P=.04). The patients were recruited in a single tertiary care center. Our data suggest that the level of anti-BP180 IgG of NSCLC patients at baseline is associated with better therapy response and overall survival and with a higher probability to develop skin irAEs during anti-PD1/PD-L1 treatment.

025 Analysis of the related factors that leading to the resistance of topical treatment for bullous pemphigoid patients

Based on clinical and laboratory data, we analyzed the related factors leading to the resistance of topical treatment for BP patients. Totally 64 BP patients were enrolled in the study, and divided into two groups according to different methods of treatment. One of the groups contained 22 patients that showed effective to topical treatment. Another group contained 42 patients, who got more than 3 new blisters in the continuous 3 days during 4 weeks of the topical treatment, which showed resistant to topical treatment. The types of lesions, the BPDAI (Bullous Pemphigoid Disease Area Index score, Bullous Pemphigoid Diseases Area Index) , the concentration of albumin, eosinophil counts, the titer of anti-BP180 and anti-BP230 IgG, the concentration of total IgE, the titer of anti-BP180 and anti- BP230 IgE of the two groups were analyzed by GraphPad Prism5 software, and Mann Whitney inspection methods were used for statistical analysis. The results of analysis will be helped to select the proper treatments for different BP patients. The results showed that the main lesion type of the group that showed effective to topical treatment was simple blister (68 %), and the type of erythema with blister (63%) was the major type of the patients that resistant to topical treatment. The BPDAI, EOS counts, the concentration of total IgE, the titer of anti-BP180 IgG, anti-BP230 IgG, and anti-BP230 IgE were significantly higher in the group of patients that effective to topical treatment (P < 0.05). There’s no difference of the concentration of albumin and the titer of anti-BP180 IgE between the two groups. So according to our study, in addition to BPDAI and anti-BP180 IgG titer, we can also select appropriate treatments for BP patients according to their lesion type, peripheral eosinophil counts, the concentration of total IgE, and the titer of anti-BP230 IgE.

IL-17A is functionally relevant and a potential therapeutic target in bullous pemphigoid

IL-17A has been identified as key regulatory molecule in several autoimmune and chronic inflammatory diseases followed by the successful use of anti-IL-17 therapy, e.g. in ankylosing spondylitis and psoriasis. Bullous pemphigoid (BP) is the most frequent autoimmune blistering disease with a high need for more specific, effective and safe treatment options. The aim of this study was to clarify the pathophysiological importance of IL-17A in BP. We found elevated numbers of IL-17A+ CD4+ lymphocytes in the peripheral blood of BP patients and identified CD3+ cells as major source of IL-17A in early BP skin lesions. IL17A and related genes were upregulated in BP skin and exome sequencing of 51 BP patients revealed mutations in twelve IL-17-related genes in 18 patients. We have subsequently found several lines of evidence suggesting a significant role of IL-17A in the BP pathogenesis: (i) IL-17A activated human neutrophils in vitro, (ii) inhibition of dermal-epidermal separation in cryosections of human skin incubated with anti-BP180 IgG and subsequently with anti-IL-17A IgG-treated leukocytes, (iii) close correlation of serum IL-17A levels and diseases activity in a mouse model of BP, (iv) IL17A-deficient mice were protected against autoantibody-induced BP, and (v) pharmacological inhibition of lL-17A reduced the induction of BP in mice. Our data give evidence for a pivotal role of IL-17A in the pathophysiology of BP and advocate IL-17A inhibition as potential novel treatment for this disease.