Pemphigus vulgaris (PV) is a mucocutaneous blistering disease characterized by IgG autoantibodies against the stratified squamous epithelium. Current understanding of PV pathophysiology does not ...explain the mechanism of acantholysis in patients lacking desmoglein antibodies, which justifies a search for novel targets of pemphigus autoimmunity. We tested 264 pemphigus and 138 normal control sera on the multiplexed protein array platform containing 701 human genes encompassing many known keratinocyte cell-surface molecules and members of protein families targeted by organ-non-specific PV antibodies. The top 10 antigens recognized by the majority of test patients' sera were proteins encoded by the DSC1, DSC3, ATP2C1, PKP3, CHRM3, COL21A1, ANXA8L1, CD88 and CHRNE genes. The most common combinations of target antigens included at least one of the adhesion molecules DSC1, DSC3 or PKP3 and/or the acetylcholine receptor CHRM3 or CHRNE with or without the MHC class II antigen DRA. To identify the PV antibodies most specific to the disease process, we sorted the data based on the ratio of patient to control frequencies of antigen recognition. The frequency of antigen recognition by patients that exceeded that of control by 10 and more times were the molecules encoded by the CD33, GP1BA, CHRND, SLC36A4, CD1B, CD32, CDH8, CDH9, PMP22 and HLA-E genes as well as mitochondrial proteins encoded by the NDUFS1, CYB5B, SOD2, PDHA1 and FH genes. The highest specificity to PV showed combinations of autoantibodies to the calcium pump encoded by ATP2C1 with C5a receptor plus DSC1 or DSC3 or HLA-DRA. The results identified new targets of pemphigus autoimmunity. Novel autoantibody signatures may help explain individual variations in disease severity and treatment response, and serve as sensitive and specific biomarkers for new diagnostic assays in PV patients.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: Dermatitis herpetiformis (DH) is an autoimmune blistering condition seen in the context of celiac disease. While typically managed by gluten-free diet and dapsone, treatment of DH ...refractory to standard treatments is not well defined. OBSERVATIONS: A man in his 80s with DH not controlled by gluten-free diet (with poor adherence), dapsone, and conventional immune-suppressing agents responded to treatment with rituximab according to the lymphoma protocol (4 weekly infusions of 375 mg/m2). Thirteen months after treatment, the patient had achieved complete resolution of pruritus and clinical manifestations of the disease, as well as normalization of antibodies against epidermal and tissue transglutaminases. He achieved complete clinical and serological remission and has remained symptom-free up to 18 months following treatment. CONCLUSIONS AND RELEVANCE: We present here the first case of a patient with DH treated with rituximab who achieved complete clinical and serological remission. We suggest rituximab as a viable treatment option for recalcitrant DH.
While the antigenic specificity and pathogenic relevance of immunologic reactivity to gluten in celiac disease have been extensively researched, the immune response to nongluten proteins of wheat has ...not been characterized. We aimed to investigate the level and molecular specificity of antibody response to wheat nongluten proteins in celiac disease. Serum samples from patients and controls were screened for IgG and IgA antibody reactivity to a nongluten protein extract from the wheat cultivar Triticum aestivum Butte 86. Antibodies were further analyzed for reactivity to specific nongluten proteins by two-dimensional gel electrophoresis and immunoblotting. Immunoreactive molecules were identified by tandem mass spectrometry. Compared with healthy controls, patients exhibited significantly higher levels of antibody reactivity to nongluten proteins. The main immunoreactive nongluten antibody target proteins were identified as serpins, purinins, α-amylase/protease inhibitors, globulins, and farinins. Assessment of reactivity toward purified recombinant proteins further confirmed the presence of antibody response to specific antigens. The results demonstrate that, in addition to the well-recognized immune reaction to gluten, celiac disease is associated with a robust humoral response directed at a specific subset of the nongluten proteins of wheat.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
IMPORTANCE: Autoimmune bullous diseases (AIBDs) are chronic relapsing-remitting conditions with significant morbidity. Skin-related quality of life (SRQL) may vary by AIBD subtype and disease type. ...Disease severity and flare severity can be difficult to define; SRQL can offer a key insight. OBJECTIVES: To investigate the Skindex-16 score as an SRQL measure in AIBD subtypes during flare and nonflare states and to evaluate Skindex-16 construct validity. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cross-sectional study was conducted from September 1, 2016, to February 1, 2020, among 192 patients at the University of Utah Health autoimmune dermatology clinic with pemphigoid, pemphigus, dermatitis herpetiformis, and linear immunoglobulin A disease. Patients had an encounter-associated diagnosis, Skindex-16 scores, and self-reported flare status. Statistical analysis was performed from March 2022 to June 2023. EXPOSURE: Autoimmune bullous disease subtype and patient-reported flare status. MAIN OUTCOMES AND MEASURES: Skindex-16 domain scores (emotions, symptoms, and functioning; range, 0-100, where 0 indicates no effect on SRQL and 100 maximum effect) and individual item scores were described by disease and flare status. Flare scores were expected to be higher by at least the standard error of measurement (SEm). Convergent validity was assessed using Spearman correlation among Skindex-16 scores, serologic titers, and other patient-reported outcome measures. Floor or ceiling domain scores (<20% of sample scoring either lowest or highest possible domain scores, respectively) were assessed for Skindex-16. Structural validity was assessed using confirmatory factor analysis (CFA). RESULTS: The study included 192 patients with 212 visits (median age, 68 years IQR, 58-76 years; 123 of 212 women 58.0%) with Skindex-16 scores (64 in flare state and 148 in nonflare state). Median Skindex-16 domain scores were higher for all disease categories among patients in the flare state compared with those in the nonflare state (pemphigoid emotions: flare, 52.4 (IQR, 38.1-69.0); nonflare, 7 (IQR, 0-17); symptoms: flare, 37.5 (IQR, 29.2-58.0); nonflare, 13 (IQR, 0-25); functioning: flare, 26.7 (IQR, 10.0-56.7); nonflare, 0 (IQR, 0-3); pemphigus emotions: flare, 54.8 (IQR, 31.0-81.0; nonflare, 0 (IQR, 0-19); symptoms: flare, 58.3 (IQR, 41.7-70.8); nonflare, 4 (IQR, 0-12.5); functioning: flare, 26.7 (IQR, 13.3-83.3); nonflare, 0 (IQR, 0-3.33); dermatitis herpetiformis emotions: flare, 72.6 (IQR, 34.7-90.5); nonflare, 14.3 (IQR, 2.4-26.2); symptoms: flare, 69 (IQR, 31.3-85.4); nonflare, 12.5 (IQR, 0-29.2); functioning: flare, 38.3 (IQR, 5.0-63.2); nonflare, 0 (IQR, 0-13.3). This difference exceeded SEm cut points. Cronbach α was greater than 0.80 for all domains and AIBDs. Moderate or low correlations were seen with desmoglein 1 and bullous pemphigoid 180 titers. Moderate correlation existed between Skindex-16 and Patient-Reported Outcomes Measurement Information System Depression scores (emotions: ρ = 0.40; symptoms: ρ = 0.41; functioning: ρ = 0.48), and strong correlation existed between Skindex-16 and patient-reported disease severity (emotions: ρ = 0.71; symptoms: ρ = 0.73; functioning: ρ = 0.66). Floor domain scores greater than 20% were seen among patients in the nonflare state, but ceiling domain scores were rare (<10% for all domains); CFA model fit was poor. CONCLUSIONS AND RELEVANCE: In this cross-sectional study, SRQL was highly associated with flare of AIBDs. Skin-related quality of life was worse during periods without flare among patients with pemphigoid and dermatitis herpetiformis compared with pemphigus, highlighting residual SRQL morbidity. Skindex-16 showed good construct validity, but the poor CFA model fit needs further research. Clinical measurement of SRQL in AIBDs can add critical disease-severity information.
Dermatitis herpetiformis (DH) is characterized by deposition of IgA in the papillary dermis. However, indirect immunofluorescence is routinely negative, raising the question of the mechanism of ...formation of these immune deposits. Sárdy et al. (2002. J. Exp. Med. 195: 747-757) reported that transglutaminase-3 (TG3) colocalizes with the IgA. We sought to create such deposits using passive transfer of Ab to SCID mice bearing human skin grafts. IgG fraction of goat anti-TG3 or control IgG were administered i.p. to 20 mice. Separately, sera from seven DH patients and seven controls were injected intradermally. Biopsies were removed and processed for routine histology as well as direct immunofluorescence. All mice that received goat anti-TG3 produced papillary dermal immune deposits, and these deposits reacted with both rabbit anti-TG3 and DH patient sera. Three DH sera high in IgA anti-TG3 also produced deposits of granular IgA and TG3. We hypothesize that the IgA class anti-TG3 Abs are directly responsible for the immune deposits and that the TG3 is from human epidermis, as this is its only source in our model. These deposits seem to form over weeks in a process similar to an Ouchterlony immunodiffusion precipitate. This process of deposition explains the negative indirect immunofluorescence results with DH serum.
PDF
