Shunpei Fukuda

Anti-desmocollin autoantibodies in nonclassical pemphigus.

Despite the established pathogenic role of anti‐desmoglein (Dsg) antibodies in classical pemphigus, the significance of autoantibodies to another desmosomal cadherin, desmocollin (Dsc) is at present unknown. No consistent immunoassay for immunoglobulin (Ig) G autoantibodies to Dscs has been developed.

Coexistence of autoimmune bullous diseases (AIBDs) and psoriasis: A series of 145 cases

BACKGROUND Many case reports have described the coexistence of autoimmune bullous diseases (AIBDs) and psoriasis. Among them, anti-laminin γ1 (p200) pemphigoid is the best known. OBJECTIVES We sought to characterize patients with AIBDs and psoriasis and to investigate common AIBDs occurring in these patients. METHODS This retrospective study included 145 patients with coexisting AIBD and psoriasis given a diagnosis from January 1, 1996, to July 31, 2013, at an academic dermatology department. Of these, 134 were consultation cases regarding AIBD diagnosis. RESULTS Ratio of male to female patients was 5.7:1. Psoriasis onset preceded AIBD onset in most patients. Mean age at AIBD onset was 65.4 years, and mean duration between psoriasis and AIBD onset was 14.6 years. Most cases had single AIBD, whereas 16 cases had combined AIBDs. Bullous pemphigoid was the most prevalent (63.4%) followed by anti-laminin γ1 pemphigoid (37.2%). LIMITATIONS Consultation cases may not have included mild AIBD cases. CONCLUSION This study confirmed the association of psoriasis and anti-laminin γ1 pemphigoid. However, because bullous pemphigoid is a much more common disease, it is seen more frequently in patients with psoriasis than anti-laminin γ1 pemphigoid.

Molecular and clinical characterization in Japanese and Korean patients with Hailey–Hailey disease: Six new mutations in the ATP2C1 gene

BACKGROUND The autosomal dominant disorder Hailey-Hailey disease (HHD) results from mutations in the ATP2C1 gene, which encodes the human secretory pathway Ca2+/Mn2+ -ATPase protein 1. To date, over 90 pathological mutations scattered throughout ATP2C1 have been described with no indication of mutational hotspots or clustering of mutations. No paradigm for genotype-phenotype correlation has emerged. OBJECTIVES To determine the pathogenic ATP2C1 abnormality in additional patients with HHD in order to provide further contributions to the understanding of the molecular basis of this disorder and to add the data to the known mutation database. METHODS In this study, we investigated eight unrelated Japanese and Korean patients with HHD. We performed direct nucleotide sequencing of the ATP2C1 gene in all patients and RT-PCR analysis, using RNA extracted from a skin biopsy, in a patient with the mildest clinical features. RESULTS We identified seven different heterozygous mutations in seven of the eight investigated patients, including three new single nucleotide deletion/duplication mutations: c.520delC; c.681dupA; c.956delC, three new donor splice site mutations: c.360+1G>C; c.899+1G>T; c.1570+2T>C, as well as a previously described nonsense mutation: p.Arg153X. RT-PCR analysis in the mildest affected patient with a heterozygous c.360+1G>C mutation, demonstrated expression of a short in-frame mutant transcript with exon 5 skipping, which may account for the mild phenotype. CONCLUSIONS The results expand the known mutation spectrum in HHD and show the importance of RNA analysis for understanding the genotype-phenotype correlations more precisely.

How do keratinizing disorders and blistering disorders overlap

Inherited keratinizing disorders are caused by mutations in the genes encoding cornified cell envelope proteins, enzymes and their inhibitors, adhesion molecules, cytoskeletal proteins and others in the epidermis. These molecules are known to regulate differentiation, proliferation and cell adhesions. Intriguingly, some keratinizing disorders show blistering skin lesions, while some inherited blistering disorders show abnormal keratinization. Therefore, hereditary keratinizing and blistering diseases are closely related and show overlapping genetic backgrounds. In this review, we overviewed keratinizing and blistering disorders in terms of overlapping of the two disease groups. Gene mutations in desmosomal components cause striate keratoderma, Naxos disease, epidermolytic palmoplantar keratoderma and plakophilin deficiency, which first show skin fragility and blisters and later hyperkeratosis. Gene mutations in hemidesmosomal components cause various forms of epidermolysis bullosa, some of which show hyperkeratosis on the nails, palms and soles, in addition to blister formation. Diseases with gene mutations in calcium pump proteins are Darier disease and Hailey–Hailey disease, which show clinicopathological overlaps and develop both keratinizing and blistering skin lesions. Finally, gene mutations in epidermal keratins cause epidermolysis bullosa simplex, epidermolytic ichthyosis, superficial epidermolytic ichthyosis, epidermolytic palmoplantar keratoderma and pachyonychia congenita/focal palmoplantar keratoderma, which show thickening of the palms and soles with underlying blister formation. In general, responsible proteins for diseases developing both keratinizing and blistering conditions are adhesion molecules, calcium pump proteins and keratins, but not connexins, cornified cell envelop proteins, enzymes or inhibitors. It is still unknown how particular keratinizing diseases develop blisters and vice versa.

Five Japanese cases of antidesmoglein 1 antibody‐positive and antidesmoglein 3 antibody‐negative pemphigus with oral lesions

Background  Oral mucosal lesions develop in pemphigus vulgaris, but not in pemphigus foliaceus. This clinical phenomenon is explained by the ‘desmoglein (Dsg) compensation theory’. Dsg3 and Dsg1 are major autoantigens for pemphigus vulgaris and pemphigus foliaceus, respectively. Dsg3 is overexpressed and Dsg1 is weakly expressed on the oral mucosa. Thus, on the oral mucosa, suppression of Dsg3 function by anti‐Dsg3 autoantibodies is not compensated by weakly expressed Dsg1 in pemphigus vulgaris, while suppression of Dsg1 function by anti‐Dsg1 autoantibodies is perfectly compensated by richly expressed Dsg3 in pemphigus foliaceus.

Interaction of plectin and intermediate filaments.

BACKGROUND Plectin, a member of the plakin family proteins, is a high molecular weight protein that is ubiquitously expressed. It acts as a cytolinker for the three major components of the cyotoskeleton, namely actin microfilaments, microtubules and intermediate filaments. OBJECTIVE The aim of our experiments was to identify new binding sites for intermediate filaments on plectin and to specify these sites. METHODS We introduced truncated forms of plectin into several cell lines and observe interaction between plectin and intermediate filaments. RESULTS We found that a linker region in the COOH-terminal end of plectin was required for the association of the protein with intermediate filaments. In addition, we also demonstrated that a serine residue at position 4645 of plectin may have a role on binding of plectin to intermediate filaments. CONCLUSION A linker region in the COOH-terminal end and serine residue at position 4645 may be important for the binding of plectin to intermediate filaments.

Summary of results of serological tests and diagnoses for 4774 cases of various autoimmune bullous diseases consulted to Kurume University.

Although many new disease entities of autoimmune bullous disease (AIBD) have recently been recognized, satisfactory immunological diagnostic methods and comprehensive classifications for various AIBDs have not been established.

Paraneoplastic Pemphigus Herpetiformis With IgG Antibodies to Desmoglein 3 and Without Mucosal Lesions

BACKGROUND Pemphigus herpetiformis (PH) is a rare clinical entity that combines the clinical features of dermatitis herpetiformis and the immunopathologic features of pemphigus. The target antigen is usually desmoglein 1, with exceptional cases manifesting autoantibodies against desmoglein 3. More recently, it has been found that many patients with PH also demonstrate autoantibodies against desmocollin. The association of PH with a malignant neoplasm is rare. OBSERVATIONS We describe a patient with PH and a lung neoplasm. Immunologic studies demonstrated IgG antibodies to desmoglein 3 and to an unknown 178-kDa protein but no antibodies to desmocollin. CONCLUSIONS The association of PH with a thoracic malignant neoplasm has been reported in only 4 previous cases, and the neoplasm could be responsible for the unusual immunologic profile in the patient described herein. To our knowledge, this is the first report of PH with an associated neoplasm in which only anti-desmoglein 3 antibody was detected.

IgA Anti-p200 Pemphigoid

BACKGROUND Anti-p200 pemphigoid is a rare autoimmune subepidermal blistering disorder. Clinically, it may resemble bullous pemphigoid, linear IgA bullous dermatosis, or dermatitis herpetiformis. Immunologically, anti-p200 pemphigoid is characterized by the development of IgG antibodies directed against a basement membrane zone protein with a molecular weight of 200 kDa. OBSERVATIONS We report the first case, to our knowledge, of anti-p200 pemphigoid associated with IgA antibodies and having clinical features resembling pemphigus herpetiformis or dermatitis herpetiformis localized on traumatized areas. Histopathological examination of lesional skin showed dermal-epidermal separation and microabscesses composed of neutrophils in the dermal papillae. Direct immunofluorescence disclosed the presence exclusively of linear in vivo-bound IgA along the basement membrane zone. With the use of laser scanning confocal microscopy, in vivo-bound IgA was localized above collagen type IV and colocalized with laminin 332. Indirect immunofluorescence showed circulating IgA antibodies against basement membrane zone at a titer of 1:160 that reacted with the floor of an artificial blister of salt-split skin. Western immunoblot analysis using dermal extract confirmed the reactivity of circulating IgA antibodies with the 200-kDa antigen corresponding to laminin γ1; however, immunoblotting using recombinant protein of 107 amino acid C-terminus of laminin γ1 was negative for circulating IgA antibodies. Immunoelectron microscopy disclosed the reactivity of circulating IgA autoantibodies within the lower lamina lucida. CONCLUSION To the best of our knowledge, this is the first case fulfilling the immunopathological criteria for anti-p200 pemphigoid associated with IgA antibodies and having unusual clinical features.

Clinical and immunological profiles in 17 Japanese patients with drug-induced pemphigus studied at Kurume University

Drug‐induced pemphigus (DIP) shows clinical, histopathological and immunological features of pemphigus. However, little is known about immunological profiles in DIP.