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E-cadherin is an additional immunological target for pemphigus autoantibodies.

ABSTRACT: Pemphigus foliaceus (PF) and pemphigus vulgaris (PV) are autoimmune blistering diseases characterized by autoantibodies against desmoglein (Dsg)1 and Dsg3, respectively. The role of classical cadherins as immunological targets of pemphigus autoantibodies is unknown. In this study, we tested the reactivity of sera from patients with PF, Fogo Selvagem (FS), and PV by immunoprecipitation coupled with immunoblotting (IP-IB) and ELISA techniques using a baculovirus-expressed ectodomain of E-cadherin. By IP-IB, anti-E-cadherin reactivity was detected in all tested sera of PF (n=13) and FS (n=15) patients, and in 79% of mucocutaneous-type PV patients (n=33), but in none of the mucosal-type PV patients (n=7). By ELISA, anti-E-cadherin IgG was detected in most pemphigus sera that produced strong E-cadherin bands by IP-IB. The immunoreactivity of PF/FS sera with E-cadherin was also demonstrated by IP-IB using human epidermal extracts. However, immunofluorescence staining of A431DE cells (E-cadherin positive, Dsg1 negative) with pemphigus sera showed negative results. Immunoadsorption and competitive ELISA analysis suggest that most of the anti-E-cadherin antibodies cross-react with Dsg1, whereas others may represent independent antibodies that do not cross-react with Dsg1. The functional relevance of these anti-E-cadherin IgG autoantibodies detected in these pemphigus sera remains to be defined.

SUBMITTER: Evangelista F

PROVIDER: S-EPMC7521598 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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E-cadherin is an additional immunological target for pemphigus autoantibodies.

Evangelista Flor F Dasher David A DA Diaz Luis A LA Prisayanh Phillip S PS Li Ning N

The Journal of investigative dermatology 20080124 7

Pemphigus foliaceus (PF) and pemphigus vulgaris (PV) are autoimmune blistering diseases characterized by autoantibodies against desmoglein (Dsg)1 and Dsg3, respectively. The role of classical cadherins as immunological targets of pemphigus autoantibodies is unknown. In this study, we tested the reactivity of sera from patients with PF, Fogo Selvagem (FS), and PV by immunoprecipitation coupled with immunoblotting (IP-IB) and ELISA techniques using a baculovirus-expressed ectodomain of E-cadherin. ...[more]

PMID: 18219275

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Project description:A loss of epidermal cohesion in pemphigus vulgaris (PV) results from autoantibody action on keratinocytes (KCs) activating the signaling kinases and executioner caspases that damage KCs, causing their shrinkage, detachment from neighboring cells, and rounding up (apoptolysis). In this study, we found that PV antibody binding leads to activation of epidermal growth factor receptor kinase, Src, p38 MAPK, and JNK in KCs with time pattern variations from patient to patient. Both extrinsic and intrinsic apoptotic pathways were also activated. Although Fas ligand neutralizing antibody could inhibit the former pathway, the mechanism of activation of the latter remained unknown. PV antibodies increased cytochrome c release, suggesting damage to mitochondria. The immunoblotting experiments revealed penetration of PVIgG into the subcellular mitochondrial fraction. The antimitochondrial antibodies from different PV patients recognized distinct combinations of antigens with apparent molecular sizes of 25, 30, 35, 57, 60, and 100 kDa. Antimitochondrial antibodies were pathogenic because their absorption abolished the ability of PVIgG to cause keratinocyte detachment both in vitro and in vivo. The downstream signaling of antimitochondrial antibodies involved JNK and late p38 MAPK activation, whereas the signaling of anti-desmoglein 3 (Dsg3) antibody involved JNK and biphasic p38 MAPK activation. Using KCs grown from Dsg3(-/-) mice, we determined that Dsg3 did not serve as a surrogate antigen allowing antimitochondrial antibodies to enter KCs. The PVIgG-induced activation of epidermal growth factor receptor and Src was affected neither in Dsg3(-/-) KCs nor due to absorption of antimitochondrial antibodies. These results demonstrated that apoptolysis in PV is a complex process initiated by at least three classes of autoantibodies directed against desmosomal, mitochondrial, and other keratinocyte self-antigens. These autoantibodies synergize with the proapoptotic serum and tissue factors to trigger both extrinsic and intrinsic pathways of cell death and break the epidermal cohesion, leading to blisters. Further elucidation of the primary signaling events downstream of PV autoantigens will be crucial for the development of a more successful therapy for PV patients.

Project description:Coronavirus disease 2019 (COVID-19) is often associated with interstitial pneumonia. However, there is insufficient knowledge on the presence of autoimmune serological markers in patients with COVID-19. We analyzed the presence and role of autoantibodies in patients with COVID-19-associated pneumonia. We prospectively studied 33 consecutive patients with COVID-19, 31 (94%) of whom had interstitial pneumonia, and 25 age-matched and sex-matched patients with fever and/or pneumonia with etiologies other than COVID-19 as the pathological control group. All patients were tested for the presence of antinuclear antibodies (ANAs), anti-antiphospholipid antibodies, and anti-cytoplasmic neutrophil antibodies (ANCAs). Clinical, biochemical, and radiological parameters were also collected. Fifteen of 33 patients (45%) tested positive for at least one autoantibody, including 11 who tested positive for ANAs (33%), 8 who tested positive for anti-cardiolipin antibodies (immunoglobulin (Ig)G and/or IgM; 24%), and 3 who tested positive for anti-β2-glycoprotein antibodies (IgG and/or IgM; 9%). ANCA reactivity was not detected in any patient. Patients that tested positive for auto-antibodies had a significantly more severe prognosis than other patients did: 6 of 15 patients (40%) with auto-antibodies died due to COVID-19 complications during hospitalization, whereas only 1 of 18 patients (5.5%) who did not have auto-antibodies died (P = 0.03). Patients with poor prognosis (death due to COVID-19 complications) had a significantly higher respiratory rate at admission (23 breaths per minute vs. 17 breaths per minute; P = 0.03) and a higher frequency of auto-antibodies (86% vs. 27%; P = 0.008). In conclusion, auto-antibodies are frequently detected in patients with COVID-19 possibly reflecting a pathogenetic role of immune dysregulation. However, given the small number of patients, the association of auto-antibodies with an unfavorable prognosis requires further multicenter studies.

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E-cadherin is an additional immunological target for pemphigus autoantibodies.

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E-cadherin is an additional immunological target for pemphigus autoantibodies.

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