BP180 Is Critical in the Autoimmunity of Bullous Pemphigoid

Liu, Yale; Li, Liang; Xia, Yumin

doi:10.3389/fimmu.2017.01752

Cited by 87 publications

(92 citation statements)

References 198 publications

(275 reference statements)

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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 . However, complement activation and inflammatory cell recruitment are Fc‐dependent; in other words, they are IgG subclass‐dependent but not epitope‐dependent.…”

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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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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“…Collagen XVII and integrin α6β4 are transmembrane proteins that bind laminin-332 in the basement membrane (17). Collagen XVII acts as an anchor protein connecting extracellular and intracellular hemidesmosomal proteins (18). The importance of collagen XVII for the integrity of the dermoepidermal junction is demonstrated in inherited skin diseases caused by mutations in the COL17A1 gene, including junctional epidermolysis bullosa (JEB), and in numerous subepidermal blistering skin disorders with autoantibodies to collagen XVII (BP180), such as bullous pemphigoid (BP), linear IgA bullous dermatosis, lichen planus pemphigoides, and pemphigoid gestationis [ Figure 1; (19,20)].…”

Section: Structure Of Collagen XVII Interactions Of Its Subunits Anmentioning

confidence: 99%

The Role of Collagen XVII in Cancer: Squamous Cell Carcinoma and Beyond

et al. 2020

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Alterations in the extracellular matrix (ECM) likely facilitate the first steps of cancer cell metastasis and supports tumor progression. Recent data has demonstrated that alterations in collagen XVII (BP180), a transmembrane protein and structural component of the ECM, can have profound effects on cancer invasiveness. Collagen XVII is a homotrimer of three α1 (XVII) chains. Its intracellular domain contains binding sites for plectin, integrin β4, and BP230, while the extracellular domain facilitates interactions between the cell and the ECM. Collagen XVII and its shed ectodomain have been implicated in cell motility and adhesion and are believed to promote tumor development and invasion. A strong association of collagen XVII ectodomain shedding and tumor invasiveness occurs in squamous cell carcinoma (SCC). Aberrant expression of collagen XVII has been reported in many epithelial cancers, ranging from squamous cell carcinoma to colon, pancreatic, mammary, and ovarian carcinoma. Thus, in this review, we focus on collagen XVII's role in neoplasia and tumorigenesis. Lastly, we discuss the importance of targeting collagen XVII and its ectodomain shedding as a novel strategy to curb tumor growth and reduce metastatic potential.

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“…Two hemidesmosomal autoantigens have been identified – BP180 [BP antigen (BPAG) 2, collagen XVII] and BP230 (BPAG1, BPAG1e) – with BP180 being a critical transmembrane protein mediating adhesion of the basal epidermal keratinocytes to dermal adhesion proteins such as laminin 332 . The noncollagenous domain 16A (NC16A) of the BP180 ectodomain is the immunodominant epitope in patients with BP, and antibody (Ab) titres against BP180‐NC16A correlate to disease activity, as opposed to anti‐BP230 Ab titres . This finding of a correlation of BP180 but not BP230 Ab titres to disease activity is consistent with an exclusively intracellular expression of BP230 in keratinocytes, making it inaccessible for immunoglobulins (and the immune system) unless keratinocytes are damaged …”

Section: Introductionmentioning

confidence: 99%

Normal human skin is superior to monkey oesophagus substrate for detection of circulating BP 180‐ NC 16A‐specific IgG antibodies in bullous pemphigoid

et al. 2019

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Summary Background Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering skin disease. Two antigens have been identified as targets of circulating autoantibodies (autoAbs) – BP180 and BP230 – with BP180 being a critical transmembrane adhesion protein of basal keratinocytes of the epidermis. The noncollagenous domain 16A (NC16A) of BP180 is the immunodominant epitope in patients with BP, and anti‐BP180‐NC16A IgG antibodies (Abs) correlate to disease activity. Routine serological testing and follow‐up of BP relies on indirect immunofluorescence (IIF) of serum Abs, commonly performed on monkey oesophagus (ME), and/or enzyme‐linked immunosorbent assay (ELISA) testing on recombinantly produced fragments of BP180 and BP230 (BP180‐NC16A, BP230‐C/N). Objectives To determine if NC16A epitopes are well represented on ME substrate. Methods Sera from different BP cohorts were tested by IIF on ME and normal human skin (NHS). To confirm findings, affinity‐purified anti‐BP180‐NC16A/BP230 polyclonal Abs and recombinant anti‐BP180‐NC16A/BP230 monoclonal antibodies (mAbs) were used. Results For sensitive detection of BP180‐NC16A‐specific IgG Abs, sections of NHS are superior to the widely used ME. Confirmation comes from polyclonal affinity‐purified anti‐BP180‐NC16A/BP230 Abs, and by mAbs cloned from a patient with active BP. Conclusions Use of NHS is preferable over ME in routine IIF testing for BP. These results are of clinical relevance because anti‐BP180‐NC16A IgG titres are correlated to disease activity and detecting them reliably is important for screening, diagnosis and follow‐up of patients with BP.

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BP180 Is Critical in the Autoimmunity of Bullous Pemphigoid

Cited by 87 publications

References 198 publications

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

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

The Role of Collagen XVII in Cancer: Squamous Cell Carcinoma and Beyond

Normal human skin is superior to monkey oesophagus substrate for detection of circulating BP 180‐ NC 16A‐specific IgG antibodies in bullous pemphigoid

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