Humanization of autoantigen

Nishie, Wataru; Sawamura, Daisuke; Goto, Maki; Ito, Kei; Shibaki, Akihiko; McMillan, James R.; Sakai, Kaori; Nakamura, Hideki; Olasz, Edit; Yancey, Kim B.; Akiyama, Masashi; Shimizu, Hiroshi

doi:10.1038/nm1496

Cited by 281 publications

(323 citation statements)

References 16 publications

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“…Neonatal COL17-humanized mice that were passively transferred with either total IgG or IgG affi nity-purifi ed against the NC16A domain of COL17 from BP patients developed diffuse erythema and showed epidermal separation by gentle skin friction at 48 h after transfer (Fig. 2c ) [ 4 ]. Lesional skin specimens demonstrated dermal-epidermal separation and infl ammatory cell infi ltration of neutrophils and lymphocytes.…”

Section: Generation Of Col17-humanized Micementioning

confidence: 98%

“…1c ). Of these, COL17 is thought to be the major autoantigen (autoAg) [ 4 ]. The IgG autoAbs against the COL17 in the DEJ of the skin are considered to trigger the infl ammatory process, resulting in the disruption of dermal-epidermal anchoring [ 2 , 3 ].…”

Section: Pathogenesis Of Bpmentioning

confidence: 99%

“…However, the pathogenic relevance of human autoAbs to COL17 in BP patients has never been proved. In 2007, our group succeeded in confi rming the pathogenicity of BP autoAbs by using the unique technique of "humanization of autoantigen" [ 4 ]. First, we generated murine COL17 -knockout (m Col17 −/− ) mice that developed blisters and erosions on the skin, symptoms that reproduce a human disease called non-Herlitz epidermolysis bullosa, which is caused by null mutations in the COL17A1 gene [ 16 ].…”

Section: Generation Of Col17-humanized Micementioning

confidence: 99%

“…After the transfer of total IgG from BP patients, COL17-humanized mice were treated with a recombinant peptide composed of the NC16A domain. The treated mice showed markedly reduced blister formation [ 4 ]. In addition, we have developed a novel therapeutic strategy of treating BP by using the recombinant Fab fraction of IgG monoclonal antibodies to COL17 to block the complement activation that would otherwise be induced by pathogenic autoantibodies [ 18 ].…”

Section: Generation Of Col17-humanized Micementioning

confidence: 99%

“…In these COL17-humanized mice, the innate expression of human COL17 eliminated all abnormal phenotypes observed in the Col17 -knockout (m Col17 −/− ) mice [ 4 ]. If the expression of human COL17 is induced after birth in the Col17 -knockout (m Col17 −/− ) mice, what kinds of phenotypes will appear?…”

Section: Doxycycline-inducible Bp Modelmentioning

confidence: 99%

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Doxycycline-Inducible Autoimmune Blistering Skin Disease Model

Nishie

Shimizu

2015

Innovative Medicine

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Bullous pemphigoid (BP) is the most common autoimmune blistering disorder. BP autoantibodies target two hemidesmosomal components, collagen XVII (COL17) and BP230, with autoimmunity to COL17 being mainly involved in the development of the disease. BP most commonly affects the elderly, and systemic corticosteroids are widely used to treat blisters on the entire body. Therefore, severe cases are sometimes fatal. Toward developing innovative, disease-specifi c therapies with fewer adverse effects, faithful disease models are essential. However, it has been challenging to reproduce BP in animals, because of inter-species differences in the amino acid sequences of pathological epitopes on human and mouse COL17. Human IgG autoantibodies from BP patients are unable to bind with mouse COL17; thus, the passive transfer of BP-IgG into mice fails to induce blistering disease. To overcome inter-species differences, we have generated genetically modifi ed mice that express human but not mouse COL17 in skin. We call these "COL17-humanized mice". Using these mice, we have produced different BP models to elucidate the BP pathomechanism and to produce novel BP therapies. Currently, another novel model is under development. Here, we introduce the BP models that we have developed by using a novel technique called "humanization of autoantigen".

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Section: Generation Of Col17-humanized Micementioning

confidence: 98%

Section: Pathogenesis Of Bpmentioning

confidence: 99%

Section: Generation Of Col17-humanized Micementioning

confidence: 99%

Section: Generation Of Col17-humanized Micementioning

confidence: 99%

Section: Doxycycline-inducible Bp Modelmentioning

confidence: 99%

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Doxycycline-Inducible Autoimmune Blistering Skin Disease Model

Nishie

Shimizu

2015

Innovative Medicine

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Enzyme-Linked Immunosorbent Assay for the Combination of Bullous Pemphigoid Antigens 1 and 2 in the Diagnosis of Bullous Pemphigoid

Roussel

Bénichou²,

Randriamanantany³

et al. 2011

Arch Dermatol

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Objective: To assess the usefulness of enzyme-linked immunosorbent assay (ELISA) assessment of the combination of bullous pemphigoid antigen 1 (BPAG1) and BPAG2 in the diagnosis of bullous pemphigoid (BP).Design: Retrospective study of serum samples from patients with BP.Setting: Tertiary care center.Patients: A total of 190 patients with newly diagnosed BP and 78 controls with other autoimmune bullous diseases.Intervention: Serum samples were tested using commercialized BPAG1 and BPAG2 ELISA and indirect immunofluorescence (IIF). Main Outcome Measures:The sensitivity and specificity of ELISA for the combination of BPAG1 and BPAG2 in the diagnosis of BP were contrasted with ELISA for each of the antigens alone and with IIF. Results:The sensitivity and specificity of ELISA for the combination of BPAG1 and BPAG2 were 87% and 88%,

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Correlation of Serum Levels of IgE Autoantibodies Against BP180 With Bullous Pemphigoid Disease Activity

et al. 2017

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IMPORTANCE Bullous pemphigoid (BP) is by far the most frequent autoimmune blistering disease. The presence of IgE autoantibodies against the transmembrane protein BP antigen 2 (BP180, type XVII collagen) has previously been reported in 22% to 100% of BP serum samples, and the pathogenic relevance of anti-BP180 IgE has been suggested in various experimental models and by the successful use of omalizumab in individual patients with BP. OBJECTIVES To determine the rate of anti-BP180-reactive IgE in BP, to evaluate the diagnostic relevance of anti-BP180 IgE in BP, and to correlate anti-BP180 IgE with disease activity and the clinical phenotype of patients with BP. DESIGN, SETTING, AND PARTICIPANTS This case-control cohort study examined 3 groups of patients with BP. Sixty-five patients with BP underwent an enzyme-linked immunosorbent assay for IgE antibodies against the 16th noncollagenous domain of BP180 (NC16A); 52 consecutive patients with BP underwent clinical evaluation with the Bullous Pemphigoid Disease Activity Index (BPDAI); and 36 patients with BP without anti-BP180 NC16A IgG reactivity underwent evaluation of the diagnostic importance of serum anti-BP180 IgE. In addition, 49 age-matched control individuals with noninflammatory dermatoses, 127 controls undergoing allergy testing for IgE levels, and 30 controls with pemphigus vulgaris or pemphigus foliaceus were included for comparison. Patients were seen at a university clinic from January 1, 2008, to July 31, 2014. MAIN OUTCOMES AND MEASURES Serum anti-BP180 NC16A IgE and IgG levels and BPDAI scores.RESULTS Of 117 patients with BP (69 women and 48 men), anti-BP180 NC16A serum IgE was detected in 47 (40.2%) and correlated with disease activity as measured by total BPDAI (r = 0.918; P = .06). An intraindividual correlation of anti-BP180 NC16A serum levels with the total BPDAI was observed during the course of the disease in 10 randomly selected patients with BP (r = 0.983; P = .003). Although no association of circulating BP180 NC16A IgE antibodies with urticarial or erythematous lesions was observed (r = 0.481; P = .31), the presence of IgG anti-BP180 NC16A antibodies was associated with the occurrence of erosions and blisters (r = 0.985; P = .006) but not urticarial and erythematous lesions (r = 0.632; P = .23). Assaying for anti-BP180 IgE increased the diagnostic sensitivity by only 2.2% (1 of 46 serum samples) when combined with the IgG anti-BP180 enzyme-linked immunosorbent assay. CONCLUSIONS AND RELEVANCEAlthough detection of serum anti-BP180 IgE is not of diagnostic importance, it may be relevant for therapeutic decisions (eg, the use of anti-IgE treatment). The correlation of serum anti-BP180 NC16A IgE levels with disease activity in patients with BP supports the notion that anti-BP180 IgE is of pathogenic relevance. Our observation that IgG anti-BP180 antibodies are related to the occurrence of blisters and erosions may encourage further studies on the association of fine autoantibody reactivities with clinical features of BP.

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Humanization of autoantigen

Cited by 281 publications

References 16 publications

Doxycycline-Inducible Autoimmune Blistering Skin Disease Model

Doxycycline-Inducible Autoimmune Blistering Skin Disease Model

Enzyme-Linked Immunosorbent Assay for the Combination of Bullous Pemphigoid Antigens 1 and 2 in the Diagnosis of Bullous Pemphigoid

Correlation of Serum Levels of IgE Autoantibodies Against BP180 With Bullous Pemphigoid Disease Activity

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