A case of childhood bullous pemphigoid with IgG and IgA autoantibodies to various domains of BP180
Authors: Manabu Osawa, Ikuko Ueda-Hayakawa, Taiki Isei, Ken Yoshimura, Shunpei Fukuda, Takashi Hashimoto, Hiroyuki Okamoto
Journal: Journal of the American Academy of Dermatology (2014)

To the Editor: Bullous pemphigoid (BP) is an autoimmune blistering disease that predominantly affects older adults and rarely children.1Korman N. Bullous pemphigoid.J Am Acad Dermatol. 1987; 16: 907-924Abstract Full Text PDF PubMed Scopus (119) Google Scholar The target antigens have been studied in a few cases of childhood BP. Diffuse or annular edematous erythemas developed on the trunk and face, and tense bullae developed on the extremities of a 4-month-old male infant with normal parturition (Fig 1, A-D). There were no mucosal lesions. Peripheral eosinophilia (21%) was found. Direct immunofluorescence of skin biopsy sample revealed subepidermal blister and predominant eosinophil infiltration in the superficial dermis, as well as linear deposition of IgG and C3, but not IgA, to epidermal basement membrane zone. Indirect immunofluorescence demonstrated both IgG and IgA antibodies reactive with epidermal side of 1 mol/L NaCl-split normal human skin. Enzyme-linked immunosorbent assay showed positive reactivity with BP180 but not with BP230. Immunoblot analyses of various antigen sources were performed for two sera samples obtained either at the first visit or 10 days later. Faint IgG, but not IgA, reactivity with BP180 in normal human epidermal extracts was found only at day 10 (Fig 2, A). Both IgG and IgA antibodies reacted with recombinant protein of BP180 NC16a domain, being stronger at day 10 (Fig 2, B).2Matsumura K. Amagai M. Nishikawa T. Hashimoto T. The majority of bullous pemphigoid and herpes gestationis serum samples react with the NC16a domain of the 180-kDa bullous pemphigoid antigen.Arch Dermatol Res. 1996; 288: 507-509Crossref PubMed Scopus (149) Google Scholar IgG, but not IgA, antibodies reacted with recombinant protein of BP180 C-terminal domain only at day 10 (Fig 2, C).3Nie Z. Hashimoto T. IgA antibodies of cicatricial pemphigoid sera specifically react with C-terminus of BP180.J Invest Dermatol. 1999; 112: 254-255Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar Both IgG and IgA antibodies reacted with the 120-kDa LAD-1 in concentrated HaCaT cell culture supernatants only at day 10, although IgA reactivity was faint (Fig 2, D).4Ishii N. Ohyama B. Yamaguchi Z. Hashimoto T. IgA autoantibodies against the NC16a domain of BP180 but not 120-kDa LAD-1 detected in a patient with linear IgA disease.Br J Dermatol. 2008; 158: 1151-1153Crossref PubMed Scopus (38) Google Scholar From the stronger reactivity of IgG antibodies, we diagnosed childhood BP, although concurrence of lamina lucida-type linear IgA bullous dermatosis (LABD) may be considered. Administration of oral prednisolone in combination with intravenous immunoglobulin, followed by diaminodiphenylsulfone, could not suppress development of skin lesions. Subsequently, three courses of intravenous pulse methylprednisolone were administered, resulting in complete remission. No relapse was observed in the following 3 years. Our case showed both IgG and IgA reactivity with various domains of BP180, including NC16a domain specific to BP,2Matsumura K. Amagai M. Nishikawa T. Hashimoto T. The majority of bullous pemphigoid and herpes gestationis serum samples react with the NC16a domain of the 180-kDa bullous pemphigoid antigen.Arch Dermatol Res. 1996; 288: 507-509Crossref PubMed Scopus (149) Google Scholar C-terminal domain specific to anti-BP180-type mucous membrane pemphigoid,3Nie Z. Hashimoto T. IgA antibodies of cicatricial pemphigoid sera specifically react with C-terminus of BP180.J Invest Dermatol. 1999; 112: 254-255Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar and LAD-1, truncated C-terminal domain of BP180, specific to IgA antibodies in lamina lucida-type LABD.4Ishii N. Ohyama B. Yamaguchi Z. Hashimoto T. IgA autoantibodies against the NC16a domain of BP180 but not 120-kDa LAD-1 detected in a patient with linear IgA disease.Br J Dermatol. 2008; 158: 1151-1153Crossref PubMed Scopus (38) Google Scholar Epitope spreading (ES) was reported to occur more frequently during the first 3 months in BP, suggesting ES as an early phenomenon in BP.5Di Zenzo G. Thoma-Uszynski S. Calabresi V. Fontao L. Hofmann S.C. Lacour J.P. et al.Demonstration of epitope-spreading phenomena in bullous pemphigoid: results of a prospective multicenter study.J Invest Dermatol. 2011; 131: 2271-2280Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar Consistent with this speculation, our case showed additional and rapidly increased reactivity of both IgG and IgA with various domains of BP180 during just 10 days. In addition, our case showed both IgG and IgA antibodies to various domains of BP180, and should be a good example to study class switching to IgG and IgA in either BP or LABD, although no significant study in this field has been reported for autoimmune bullous diseases. IgG recognition of extracellular domains of BP180 was also reported to be an early and crucial event in development of BP, followed by ES events toward intracytoplasmic domain of BP180 and BP230.5Di Zenzo G. Thoma-Uszynski S. Calabresi V. Fontao L. Hofmann S.C. Lacour J.P. et al.Demonstration of epitope-spreading phenomena in bullous pemphigoid: results of a prospective multicenter study.J Invest Dermatol. 2011; 131: 2271-2280Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar Our case showed IgG and IgA reactivity with various extracellular domains of BP180, without reactivity with BP230.