Autoantibodies to BPAG1e Trigger Experimental Bullous Pemphigoid in Mice

Makita, Eiko; Matsuzaki, Yasushi; Fukui, Tomohisa; Matsui, Akinobu; Minakawa, Satoko; Nakano, Hajime; Ito, Koichi; Kijima, Hiroshi; Sawamura, Daisuke

doi:10.1016/j.jid.2020.08.031

Cited by 23 publications

(19 citation statements)

References 46 publications

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“…It is quite possible that anti-BP230 autoantibodies are sufficient to mediate the development of BP in affected patients. Recent experimental findings utilizing the adoptive transfer of splenocytes from BP230 immunized conditional BP230 knockouts provide significant support to a direct pathogenic mechanism [ 46 ]. The mechanism by which blistering is induced remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…A novel tissue-specific conditional knockout mouse model has been very useful to gain significant insight into the effect of autoimmunity against BP230 [ 46 ]. To investigate the role of BPAG1 antibodies in the pathogenicity of BP, Makita et al generated a mouse model with the conditional knockout of BPAG1 confined to keratin-5 expressing stratified epithelial cells.…”

Section: The Pathogenic Contribution Of Bp230 Autoantibodiesmentioning

confidence: 99%

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Deciphering the Contribution of BP230 Autoantibodies in Bullous Pemphigoid

2022

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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.

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Section: Discussionmentioning

confidence: 99%

Section: The Pathogenic Contribution Of Bp230 Autoantibodiesmentioning

confidence: 99%

Deciphering the Contribution of BP230 Autoantibodies in Bullous Pemphigoid

2022

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“…Collectively, these events lead to dermal- epidermal detachment. Antibodies targeting BP230 develop in most BP patients due to intermolecular epitope spreading, but demonstrate pathogenicity in animal models as well as correlation with disease activity in humans ( 6 , 7 ).…”

Section: Introductionmentioning

confidence: 99%

Case Report: Bullous Pemphigoid Associated With Morphea and Lichen Sclerosus: Coincidental Diseases or Pathogenetic Association?

et al. 2022

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Bullous pemphigoid (BP) represents the most common autoimmune bullous disease and is characterized by IgG autoantibodies targeting collagen XVII (BP180). BP has reportedly been occurred in association with other inflammatory skin diseases. Here, we describe the unusual occurrence of BP in a female patient with a concomitant history of generalized morphea (localized scleroderma, LoS) and cutaneous and genital lichen sclerosus (LiS). The occurrence of BP was associated with elevated serum levels of anti-BP180 IgG autoantibodies, which decreased upon clinical remission. Autoimmune bullous diseases and sclerosing dermatitis are immunologically distinct entities, whose association has been rarely described. In this study, we provide a literature review on cases of BP developed in patients with either LoS or LiS. Further, we discussed immunological mechanisms which may have favored the emergence of BP in our patient.

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“…In a large cohort of patients from Germany, in a recent study, the most frequently targeted antigen was BP180 (15). Their injection produces blisters in the skin of neonatal mice (16,17). In MMP, the antigens are a subunit of human integrins b4 and a6.…”

Section: Introductionmentioning

confidence: 99%

Molecular Basis for Global Incidence of Pemphigoid Diseases and Differences in Phenotypes

2022

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Pemphigoid (Pg) diseases are a group of potentially fatal autoimmune mucocutaneous diseases. They have different clinical phenotypes, involving only the skin or multiple mucous membranes. They occur globally and frequently affect the elderly. The common marker among all variants is the presence of autoantibodies targeting the dermal-epidermal or mucosal-submucosal junctions, or basement membrane zone (BMZ). Four target antigens in the BMZ were studied. These included BPAG1, BPAG2 and subunits of α6 and β4 human integrins. Our objective was to find a molecular basis for the global incidence of Pg diseases and a mechanism that will explain the vast differences in clinical phenotypes and outcomes. All the variants of Pg that were analyzed had a statistically significant association with HLA-DQβ1*03:01 in ten countries on four continents. This explains the reason for global incidence. Prediction models discovered multiple peptides in each of the four antigens that serve as T cell epitopes. These T cell epitopes were shown to bind to HLA-DQβ1*03:01. In addition, structure modelling demonstrated the peptide-HLA complex bound to the T cell receptor. These autoreactive T cells would stimulate B cells to produce specific anti-BMZ autoantibodies. Anti-BMZ autoantibodies with different specificities will produce different phenotypes, which will account for involvement of different tissues and organs in different molecules. The contribution this study makes is that it provides a molecular basis of why a similar disease occurs in different racial groups. Furthermore, it provides the basis for the production of autoantibodies with different specificities, which resultantly produces different phenotypes.

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Autoantibodies to BPAG1e Trigger Experimental Bullous Pemphigoid in Mice

Cited by 23 publications

References 46 publications

Deciphering the Contribution of BP230 Autoantibodies in Bullous Pemphigoid

Deciphering the Contribution of BP230 Autoantibodies in Bullous Pemphigoid

Case Report: Bullous Pemphigoid Associated With Morphea and Lichen Sclerosus: Coincidental Diseases or Pathogenetic Association?

Molecular Basis for Global Incidence of Pemphigoid Diseases and Differences in Phenotypes

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