Vancomycin Mediates IgA Autoreactivity in Drug-Induced Linear IgA Bullous Dermatosis.
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ABSTRACT:
SUBMITTER: Yamagami J
PROVIDER: S-EPMC8054301 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ImportanceNeonatal linear immunoglobulin A (IgA) bullous dermatosis (LABD) is a rare disease that can be fatal when associated with respiratory failure. All previously reported cases of neonatal LABD have been in newborns with healthy asymptomatic mothers, and the pathogenic IgA was of unknown origin.ObjectiveTo clarify the origin of IgA associated with LABD in neonates born of healthy asymptomatic mothers.Design, setting, and participantsThis case study analyzed the laboratory findings of a single breast-fed newborn male with neonatal LABD admitted to the Keio University Hospital in Tokyo and his healthy asymptomatic mother. The healthy newborn developed life-threatening blisters and erosions of the skin and mucous membranes on day 4 after birth. Blood serum, skin, and maternal breast milk were examined for IgA autoantibodies.Main outcomes and measuresHistopathologic and immunofluorescence analyses of specimens (serum, skin, and breast milk) from the patient and his mother.ResultsHistopathologic evaluation of the newborn's skin revealed subepidermal blisters with neutrophil infiltrates, and immunofluorescence testing showed linear IgA deposition along the basement membrane zone (BMZ), which lead to the diagnosis of neonatal LABD. Indirect immunofluorescence using normal human skin after treatment with 1-mol/L sodium chloride showed the patient to have circulating IgA binding to the dermal side of BMZ. Immunohistochemical staining proved the deposition of secretory IgA in the neonatal skin by demonstrating the presence of J chain-not been seen in other LABD cases-indicating that the autoantibodies producing the blisters were derived from the maternal breast milk. Although no circulating IgA against the skin was detected in mother's sera, the breast milk contained IgA that reacted with the dermal side of the BMZ. No new blister formation was observed after cessation of breastfeeding.Conclusions and relevanceThe results of this case study suggest a passive transfer of pathogenic IgA to a newborn from an asymptomatic mother via breast milk. In prior reports, no serum from asymptomatic mothers of newborns with LABD had IgA autoantibodies binding to skin components; however, in this case, we found that the maternal breast milk contained IgA autoantibodies associated with neonatal LABD. In neonatal LABD, maternal breast milk should be examined for IgA autoantibodies and breast milk feeding should be discontinued as soon as neonatal LABD is suspected.
| S-EPMC8280969 | biostudies-literature
Project description:BACKGROUND:Linear IgA bullous dermatosis (LABD) is a rare autoimmune subepithelial vesiculobullous disease due to IgA autoantibodies directed against different antigens of the basement membrane zone (BMZ) of the skin and/or mucosae. It affects mainly preschool-aged children and adults, with only few studies on large series. The aim of this study was to assess possible differences between adults and children regarding clinical presentation, immunopathologic features, management and course of the disease. METHODS:A retrospective review of 38 LABD patients, followed-up from November 2006 to September 2018, was performed. RESULTS:Of 38 patients, 27 were adults and 11 children. Mean age at diagnosis was 5.4 years and 60.6 years in the pediatric and adult group, respectively. Considering both groups, limbs were the most commonly involved site (73.7%), followed by trunk (55.3%), head (36.8%) and buttocks (13.2%). Interestingly, head (p = 0.008), particularly perioral (p = 0.001), involvement, as well as "string of pearls" arrangement (p = 0.03), were more prevalent in children. Mucosal involvement was seen in 9 (23.7%) patients and was more frequent in children than adults (45.5% vs 14.8%, respectively, p = 0.09). Linear IgA deposits along the BMZ were observed in 30 patients (78.9%), while linear/granular IgA deposits in 8 patients (21.1%). Dapsone was the most commonly used drug (78.9%) and complete remission was achieved in most cases (81.6%). CONCLUSIONS:Our epidemiological and clinicopathological findings relative to a large cohort of LABD patients are mostly consistent with the literature data. Interestingly, head, notably perioral, involvement and "string of pearls" arrangement occurred more frequently in the paediatric than adult group. The above clinical parameters may be regarded as diagnostic tools for LABD in children.
| S-EPMC6534856 | biostudies-other
Project description:Relapsing linear acantholytic dermatosis (RLAD) is a rare disease that manifests as recurring episodes of crusted and vesicular lesions distributed in a Blaschkoid pattern with histology resembling Hailey-Hailey disease. RLAD, in the presence of generalized disease, has been shown to be a type 2 mosaic form of Hailey-Hailey disease. RLAD, without systemic disease, has been hypothesized to be type 1 mosaic Hailey-Hailey disease, but this assertion has lacked genetic conformation. To determine the genetic abnormalities causing RLAD, we performed exome sequencing of affected tissue and blood in one patient. Exome sequencing of a punch biopsy revealed a c.238A>T, p.(Lys80*) variant in ATP2C1 found in 26% of the reads from lesional skin but absent in germline DNA. This somatic variant causes a truncated protein that would likely result in loss of function. Our findings indicate that, in this patient, RLAD is a clinical presentation of type 1 segmental Hailey-Hailey disease. What's already known about this topic? Relapsing linear acantholytic dermatosis (RLAD) is postulated to be a mosaic form of Hailey-Hailey disease. This hypothesis has remained unproven for type 1 disease and the putative gene and driving genetic variants have remained unknown. What does this study add? Exome sequencing, performed on lesional skin and matched blood, found RLAD lesions to be mosaic for variants causing a premature stop codon in ATP2C1. Our findings support the hypothesis that RLAD is a type 1 segmental form of Hailey-Hailey disease caused by postzygotic variants in ATP2C1.
| S-EPMC7269095 | biostudies-literature
Project description:Bullous pemphigoid (BP) is an autoimmune disease characterized by tense blisters that are usually preceded by urticarial eruptions. Affected patients exhibit IgG and/or IgE autoantibodies against BP180 and/or BP230. Their relative importance in disease pathogenesis has not been fully elucidated.The aim of this study was to provide a better characterization of the circulating and tissue-resident IgE in patients with BP at the serological, structural and functional levels.Sera (n = 19) and skin (n = 33) from patients with BP were analysed via enzyme-linked immunosorbent assay (ELISA) and immunofluorescence, respectively.The results obtained show that many patients with BP exhibit elevated IgE levels in the serum and in the skin. In the skin, it is very rarely and only sparsely found along the basement membrane zone, but is prominently present on mast cells and eosinophils. At least a portion of these IgE antibodies are BP-specific, as evidenced by serum ELISA and by the colocalization of BP180 and Fc?RI-bound IgE on mast cells and/or eosinophils. An important role of these immune reactants can be inferred from our additional finding that cross-linking of IgE, derived from BP sera, on Fc?RI-expressing rat basophils with BP180 results in robust degranulation of these cells.We propose the existence of a disease pathway alternative to IgG and complement that may well be responsible for some of the clinical features of this autoimmune disease.
| S-EPMC5814899 | biostudies-other
Project description:Several sporadic cases, in which direct and indirect immunofluorescence studies simultaneously detected IgG and IgA autoantibodies to keratinocyte cell surfaces, have been reported mainly under the name of IgG/IgA pemphigus. However, there have been no systematic studies for this condition. In this study, we collected 30 cases of this condition from our cohort of more than 5,000 autoimmune bullous disease cases, which were consulted for our diagnostic methods from other institutes, and summarized their clinical and immunological findings. Clinically, there was no male-female prevalence, mean age of disease onset was 55.6?years, and mean duration before this condition was suspected was 18?months. The patients showed clinically bullous and pustular skin lesions preferentially on the trunk and extremities, and histopathologically intraepidermal pustules and blisters with infiltration of neutrophils and eosinophils. Immunologically, ELISAs frequently detected IgG and IgA autoantibodies to both desmogleins and desmocollins. From the characteristic clinical, histopathological, and immunological features, which are considerably different from those in classical IgG types of pemphigus, we propose this disease as a new disease entity with preferential name of intercellular IgG/IgA dermatosis (IGAD). This was the largest study of IGAD to date.
| S-EPMC5950707 | biostudies-literature
Project description:We used transcriptome profiling by RNAseq to identify the gene expression signatures elucidated in S. coelicolor in response to the three different glycopeptide compounds that share high degree of structural similarities and the same primary mode of action: dalbavancin, vancomycin and chlorobiphenyl-vancomycin.
2021-02-15 | E-MTAB-9846 | biostudies-arrayexpress
Project description:BACKGROUND:Vancomycin is a prevalent cause of the severe hypersensitivity syndrome drug reaction with eosinophilia and systemic symptoms (DRESS), which leads to significant morbidity and mortality and commonly occurs in the setting of combination antibiotic therapy, affecting future treatment choices. Variations in HLA class I in particular have been associated with serious T cell-mediated adverse drug reactions, which has led to preventive screening strategies for some drugs. OBJECTIVE:We sought to determine whether variation in the HLA region is associated with vancomycin-induced DRESS. METHODS:Probable vancomycin-induced DRESS cases were matched 1:2 with tolerant control subjects based on sex, race, and age by using BioVU, Vanderbilt's deidentified electronic health record database. Associations between DRESS and carriage of HLA class I and II alleles were assessed by means of conditional logistic regression. An extended sample set from BioVU was used to conduct a time-to-event analysis of those exposed to vancomycin with and without the identified HLA risk allele. RESULTS:Twenty-three subjects met the inclusion criteria for vancomycin-associated DRESS. Nineteen (82.6%) of 23 cases carried HLA-A*32:01 compared with 0 (0%) of 46 of the matched vancomycin-tolerant control subjects (P = 1 × 10-8) and 6.3% of the BioVU population (n = 54,249, P = 2 × 10-16). Time-to-event analysis of DRESS development during vancomycin treatment among the HLA-A*32:01-positive group indicated that 19.2% had DRESS and did so within 4 weeks. CONCLUSIONS:HLA-A*32:01 is strongly associated with vancomycin-induced DRESS in a population of predominantly European ancestry. HLA-A*32:01 testing could improve antibiotic safety, help implicate vancomycin as the causal drug, and preserve future treatment options with coadministered antibiotics.
| S-EPMC6612297 | biostudies-literature
Project description:IgA is the most prevalent antibody type on mucosal surfaces and the second most prevalent antibody in circulation, yet its role in immune defense is not fully understood. Here we show that IgA is carried inside cells during virus infection, where it activates intracellular virus neutralization and innate immune signaling. Cytosolic IgA-virion complexes colocalize with the high-affinity antibody receptor tripartite motif-containing protein 21 (TRIM21) and are positive for lysine-48 ubiquitin chains. IgA neutralizes adenovirus infection in a TRIM21- and proteasome-dependent manner in both human and mouse cells. Translocated IgA also potently activates NF-κB signaling pathways in cells expressing TRIM21, whereas viral infection in the absence of antibody or TRIM21 is undetected. TRIM21 recognizes an epitope in IgG Fc that is not conserved in IgA; however, fluorescence anisotropy experiments demonstrate that direct binding to IgA is maintained. We use molecular modeling to show that TRIM21 forms a nonspecific hydrophobic seal around a β-loop structure that is present in IgG, IgM, and IgA, explaining how TRIM21 achieves such remarkable broad antibody specificity. The findings demonstrate that the antiviral protection afforded by IgA extends to the intracellular cytosolic environment.
| S-EPMC4169910 | biostudies-literature
Project description:ImportanceErosive pustular dermatosis (EPD) is a rare condition that typically affects actinically damaged skin of the scalp. Characterized by sterile pustules, erosions, and crusts, EPD is difficult to treat and heals slowly. The exact cause of EPD is unknown, although trauma is an inciting factor.ObjectiveTo describe 3 women who presented with prolonged facial erosions after cosmetic resurfacing procedures, specifically fully ablative carbon dioxide laser or medium-depth chemical peel.Design, setting, and participantsThis case series describes the clinical features, histopathological findings, laboratory results, and treatment of 3 patients with an ultimate diagnosis most consistent with facial EPD. Patients were evaluated between September 10, 2010, and May 6, 2016, in a dermatology clinic in an academic medical center. The patients were 3 women seeking diagnostic evaluation and therapeutic options for nonhealing facial erosions occurring after ablative procedures (carbon dioxide laser resurfacing or Jessner solution/trichloroacetic acid chemical peel).Main outcomes and measuresHistologic examination and wound culture from initial presentation as well as clinical follow-up documenting improvement with therapeutic interventions.ResultsAll 3 patients were women in their 50s or 60s for whom EPD was deemed to be the best diagnosis, after infection, immunobullous disorders, and other pustular dermatoses were considered. Histologic features were nonspecific. Treatment included a combination of topical and systemic therapies, such as corticosteroids, dapsone, isotretinoin, and/or antibiotics. Watchful waiting (tincture of time) appeared to be central to the healing process.Conclusions and relevanceAfter cosmetic resurfacing, patients may develop EPD isolated to the face. As a diagnosis of exclusion that should be considered in patients who have nonhealing wounds following ablative procedures, EPD is challenging to treat and may require the use of anti-inflammatory agents. Recognizing this condition is important, especially as cosmetic procedures become more widespread.
| S-EPMC5817600 | biostudies-literature
Project description:Adolescent cocaine abuse increases the risk for developing addiction in later life, but the underlying molecular mechanism remains poorly understood. Here, we establish adolescent cocaine-exposed (ACE) male mouse models. A subthreshold dose of cocaine (sdC) treatment, insufficient to produce conditioned place preference (CPP) in adolescent mice, induces CPP in ACE mice during adulthood, along with more activated CaMKII-positive neurons, higher dual specificity protein kinase-phosphatase-1 (Dusp1) mRNA, lower DUSP1 activity and lower DUSP1 expression in CaMKII-positive neurons in the medial prefrontal cortex (mPFC). Overexpressing DUSP1 in CaMKII-positive neurons suppresses neurons activity and blocks sdC-induced CPP in ACE mice during adulthood. On the other hand, depleting DUSP1 in CaMKII-positive neurons activates more neurons, and further enhances sdC-induced behavior in ACE mice during adulthood. Also, ERK1/2 might be a downstream signal of DUSP1 in the process. Our findings reveal a role of mPFC DUSP1 in ACE-induced higher sensitivity to the drug in adult mice. DUSP1 might be a potential pharmacological target to predict or treat the susceptibility to addictive drugs caused by adolescent substance use.
| S-SCDT-10_15252-EMBR_202356981 | biostudies-other