Mechanisms of Autoantibody-Induced Pathology

Ludwig, Ralf J.; Vanhoorelbeke, Karen; Leypoldt, Frank; Kaya, Ziya; Bieber, Katja; McLachlan, Sandra M.; Komorowski, Lars; Luo, Jie; Cabral-Marques, Otávio; Hammers, Christoph M; Lindstrom, Jon; Lamprecht, Peter; Fischer, Andrea; Riemekasten, Gabriela; Tersteeg, Claudia; Sondermann, Peter; Rapoport, Basil; Wandinger, Klaus‐Peter; Probst, Christian; Beidaq, Asmaa El; Schmidt, Enno; Verkman, A. S.; Manz, Rudolf A.; Nimmerjahn, Falk

doi:10.3389/fimmu.2017.00603

Cited by 356 publications

(315 citation statements)

References 493 publications

(498 reference statements)

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“…Pemphigus is a life‐threatening autoimmune disease characterized by mucocutaneous blister formation which is mainly mediated by IgG autoantibodies formed against the desmosomal adhesion proteins, desmoglein 3 (Dsg3) and/or Dsg 1 . Nowadays, other pathogenic mechanisms such as apoptolysis, elevated proinflammatory cytokines and aberrant cell signalling pathways (p38MAPK‐signaling pathway) have been suggested in this regard . Pemphigus vulgaris (PV), as the most common clinical variant, plays a significant role in increasing the prevalence among distinct ethnic groups such as Iranians, Indians and Jews .…”

Section: Introductionmentioning

confidence: 99%

The association between ST18 gene polymorphism and severe pemphigus disease among Iranian population

Etesami

Hassan

Ghandi

et al. 2018

Experimental Dermatology

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Recently, ST18 polymorphism has played a role in increasing the risk of pemphigus among some populations such as Egyptian and Jewish. In addition, a variant within the ST18 promoter gene was shown to induce ST18 upregulation and cytokine secretion leading to keratinocyte susceptibility to anti-desmoglein antibodies. Thus, the present study aimed to assess the ST18 single nucleotide polymorphisms (SNP) relationship with pemphigus, disease severity and family history among Iranian population. A total of 111 pemphigus patients and 201 healthy controls were genotyped for three ST18 SNPs rs2304365, rs10504140 and rs4074067 by using TETRA-ARMS PCR method. The results indicated that risk allele A in rs2304365 was significantly higher in pemphigus patients, compared with the amount in the control group (OR = 2.43 CI = 1.49-3.975, P < 0.001). Thus, A allele represents a risk factor for pemphigus. Further, the patients carrying the risk allele had a more severe disease and a higher age of disease onset while no relationship was observed between the number of relapses and positive family history of pemphigus with the risk allele. Finally, dominant model was regarded as the strongest inheritance model for the associated risk. The present study confirmed the relationship between ST18 gene with pemphigus disease, a more severe disease, and a higher age of disease onset.

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Section: Introductionmentioning

confidence: 99%

The association between ST18 gene polymorphism and severe pemphigus disease among Iranian population

Etesami

Hassan

Ghandi

et al. 2018

Experimental Dermatology

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“…Blistering mechanisms in pemphigoid have been well studied using in vivo animal models, ex vivo assay and in vitro assays . Pathogenic NC16A‐IgGs activate the complement system and recruit inflammatory cells, including neutrophils, eosinophils and mast cells, at the BMZ, causing clinical disease to develop, accompanied by inflammation .…”

Section: Discussionmentioning

confidence: 99%

Fc‐binding proteins enhance autoantibody‐induced BP180 depletion in pemphigoid

Iwata

Kamaguchi

Ujiie

et al. 2019

The Journal of Pathology

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Immunoglobulins (Igs) consist of two antigen‐binding regions (Fab) and one constant region (Fc). Protein A and protein G are bacterial proteins used for the purification of IgG by virtue of their high affinities for the Fc fragment. Rheumatoid factors are autoantibodies against IgG Fc fragments, which are present in the body under physiological conditions. Little is known about the influence of Fc‐binding proteins on the pathogenicity of antibody‐induced autoimmune diseases. Pemphigoid diseases are a group of autoimmune subepidermal blistering disorders that includes bullous pemphigoid and mucous membrane pemphigoid. IgGs targeting the non‐collagenous NC16A domain of the 180‐kDa bullous pemphigoid antigen (BP180) are known to induce skin fragility in mice and the depletion of BP180 in keratinocytes. In this study, mAb against NC16A in combination with Fc‐binding proteins was found to enhance BP180 depletion. Although mAb against the C‐terminus of BP180 does not show pathogenicity in vivo or in vitro, mAb treatment with Fc‐binding proteins clearly induced skin fragility in mice and BP180 depletion in keratinocytes. Anti‐BP180 mAbs and Fc‐binding proteins were colocalized in the cytoplasm and at the basement membrane zone. Cell adhesion strengths were decreased in parallel with BP180 amounts. Clinically, bullous pemphigoid patients had higher rheumatoid factor titers than controls. Anti‐BP180 mAb in combination with high‐titer rheumatoid factor serum was found to enhance BP180 depletion. Furthermore, saliva from mucous membrane pemphigoid patients contained larger quantities of bacteria and Fc‐binding proteins than controls. Our results suggest that Fc‐binding proteins (rheumatoid factor or protein G) may enhance the pathogenicity of autoantibodies in pemphigoid diseases. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…Pemphigus vulgaris (PV) represents an autoimmune disease characterized by suprabasal blister formation due to loss of keratinocyte cohesion in stratified epithelia such as skin and oral mucosa that are subjected to substantial shear forces . In line with this, it was demonstrated that desmosomes experience tension when keratinocytes are exposed to mechanical strain .…”

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confidence: 87%

A new ex vivo human oral mucosa model reveals that p38 MAPK inhibition is not effective in preventing autoantibody‐induced mucosal blistering in pemphigus

et al. 2019

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Summary Background Pemphigus vulgaris (PV) is an autoimmune disease characterized by blister formation in the epidermis and oral mucosa due to loss of keratinocyte cohesion. Autoantibodies present in patients with PV (PV‐IgG) are known to primarily target desmoglein (Dsg)1 and Dsg3 in desmosomes. The mucosal‐dominant subtype of PV (mdPV) is caused by PV‐IgG autoantibodies against the cadherin‐type adhesion molecule Dsg3. p38 mitogen‐activated protein kinase (p38MAPK) signalling has been characterized as an important pathway downstream of PV‐IgG binding and its inhibition is protective in ex vivo human skin. However, the role of p38MAPK signalling in mdPV is unknown as no experimental model has been available. Objectives To establish a human ex vivo oral mucosa culture, and evaluate the p38MAPK dependency of blister formation and of ultrastructural alterations of desmosomes induced by mdPV‐IgG. Methods Human labial mucosa was injected with mdPV‐IgG as well as AK23, a pathogenic mouse monoclonal Dsg3 antibody, in the presence or absence of p38MAPK inhibitors. Viability was evaluated by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay and apoptosis by terminal deoxynucleotidyl transferase dUTP nick‐end labelling assay. Blister score was determined following haematoxylin and eosin staining and Dsg3 distribution by immunostaining. Samples were processed for transmission electron microscopy to analyse desmosome ultrastructure. Results Both AK23 and mdPV‐IgG induced blisters and caused reduction in desmosome size and number in labial mucosa. Inhibition of p38MAPK was not effective in preventing these alterations. Conclusions In contrast with human epidermis, PV‐IgG and AK23 induce blisters and desmosome ultrastructural changes in labial mucosa via a mechanism not dependent on p38MAPK. What's already known about this topic? Pemphigus vulgaris IgG (PV‐IgG) induces blistering as well as a reduction in desmosome number and size mediated by p38 mitogen‐activated protein kinase (p38MAPK) signalling in ex vivo human skin. What does this study add? This study establishes a new human ex vivo mucosa model to test pathomechanisms mediated by PV‐IgG. The study demonstrates that both AK23 and mucosal‐dominant PV induce blisters and associated ultrastructural changes in labial mucosa via a mechanism not dependent on p38MAPK signalling. What is the translational message? This study highlights the respective tissue‐specific responses of oral mucosa and skin related to PV pathogenesis, similar to the patient situation.

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Mechanisms of Autoantibody-Induced Pathology

Cited by 356 publications

References 493 publications

The association between ST18 gene polymorphism and severe pemphigus disease among Iranian population

The association between ST18 gene polymorphism and severe pemphigus disease among Iranian population

Fc‐binding proteins enhance autoantibody‐induced BP180 depletion in pemphigoid

A new ex vivo human oral mucosa model reveals that p38 MAPK inhibition is not effective in preventing autoantibody‐induced mucosal blistering in pemphigus

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