Toshihiko Shirai

Late development of antidesmoglein 1 antibodies in pemphigus vulgaris: correlation with disease progression.

The coexistence of antidesmoglein 3 (Dsg3) and antidesmoglein 1 (Dsg1) autoantibodies is well described in patients with pemphigus vulgaris (PV); however, there is little evidence of sequential development of these two autoantibodies. Autoantibody responses to Dsg3 and Dsg1 were studied in seven PV patients over time by enzyme‐linked immunosorbent assay, using baculovirus expressed recombinant fusion proteins. All patients had anti‐Dsg3 IgG antibodies at presentation. Two patients developed anti‐Dsg1 later in the course of the disease. The transition in autoantibody profile was associated with disease progression to generalized PV involving mucous membranes and skin in both patients; one patient initially presented with a predominantly mucosal phenotype, the other with herpetiform pemphigus‐like features. These findings demonstrate that there is an extension of autoimmune response from anti‐Dsg3 only to both anti‐Dsg3 and anti‐Dsg1 in some patients, which is associated with an alteration in clinical expression in PV.

Polymorphisms of HLA class II genes and autoimmune responses to Ro/SS-A-La/SS-B among Japanese subjects

OBJECTIVE To investigate HLA class II allele associations with autoantibody responses to Ro/SS-A and La/SS-B among Japanese subjects. METHODS Haplotype and allele distributions, along with molecular polymorphisms, of HLA class II genes were analyzed by polymerase chain reaction-restriction fragment length polymorphism in 41 Japanese women with precipitating autoantibodies to Ro/SS-A and/or La/SS-B. RESULTS Among women with both Ro/SS-A and La/SS-B antibodies, the HLA class II haplotype DRB1*08032/DQA1*0103/DQB1*0601 and DRB1*08032 allele showed significantly increased frequencies compared with patients with anti-Ro/SS-A alone or with normal controls. All women with both anti-Ro/SS-A and anti-La/SS-B, but not those with anti-Ro/SS-A alone, carried DRB1 alleles that shared the same amino acid residues at positions 14-31 and 71 of the hypervariable regions of the DRB1 chain. All anti-Ro/SS-A positive women carried 1 or 2 alleles of DQB1*06 and DQB1*03 subtypes that shared the same amino acid residues at positions 71-77 of the DQB1 chain. HLA class II allele distributions did not differ among 3 anti-Ro/SS-A positive groups with different disease expressions, i.e., patients with systemic lupus erythematosus, patients with primary Sjögrens syndrome, and women with no apparent symptoms of rheumatic disease. CONCLUSION HLA class II allele distributions differ among anti-Ro/SS-A positive subjects according to the presence or absence of coexisting anti-La/SS-B antibodies, but not according to disease expression. Our findings suggest that different HLA class II molecules might control the development of anti-Ro/SS-A and/or anti-La/SS-B antibodies in the autoimmune response to the Ro/SS-A-La/SS-B complex.

8-Methoxypsoralen plus UVA induces the 72-kDa heat shock protein in organ-cultured normal human skin

Abstract The proteins induced by heat and other stressors, called heat shock proteins (HSP) or stress proteins, are considered to play a general role in protection from cellular injury. Exposure to UVA (320400 nm) following application of 8‐methoxypsoralen (8‐MOP), termed PUVA is commonly used in the field of dermatology. In order to understand the induction of HSP in PUVA‐treated human skin, indirect immunofluorescence using a monoclonal antibody specific for the 72 kDa HSP (HSP 72) was carried out in organ‐cultured normal human skin that was treated with PUVA. When the organ‐cultured skin was treated at 37°C for 1 h with 8‐MOP at a final concentration of 10 or 100 μg/mL and exposed to UVA (51.3 kJ/m2), nuclear immunofluorcscence of HSP 72 was detected in the epidermal cells 12 h after UVA irradiation. In contrast, the induction of HSP 72 was not detected either by UVA irradiation or 8‐MOP treatment. These results suggest that PUVA treatment is one of the stressors for human skin, and DNA damage caused by PUVA induces HSP 72.

Induction and repair of UVB-induced cyclobutane pyrimidine dimers and (6-4) photoproducts in organ-cultured normal human skin

SummaryTo examine the induction and repair of UV-induced DNA damage, indirect immunofluorescence was performed on UVB-irradiated organ-cultured normal human skin using monoclonal antibodies specific for either cyclobutane pyrimidine dimers or (6-4) photoproducts. Nuclear immunofluorescence of cyclobutane pyrimidine dimers and (6-4) photoproducts were observed in a dosedependent manner after UVB irradiation. The intensity of nuclear immunofluorescence of the upper epidermal layers was stronger and clearer than that of the lower epidermal layers. DNA repair time-course studies showed that both types of DNA damage could be repaired within 24 h after UVB irradiation.

Cutaneous Bronchogenic Cyst

A 22-year-old man had a small asymptomatic papule on his left neck that had been present since early childhood. There was no history of trauma or infection to the affected site prior to onset. On close examination, a !-mm papule was present on his left neck (Fig. !). General physical examination revealed no other abnormalities. This skin lesion was excised under local anesthesia. At operation, small amounts of clear mucoid fluid were expressed from the cyst by lateral compression, however, there was no evidence of extension or connections to other structures or to deep tissues. The postoperative course was uneventful. Microscopic examination revealed a cyst lined by ciliated pseudostratified columnar epithelium intermingled with goblet cells in the upper-to-mid dermis (Fig. 2). The cytoplasm of these goblet cells stained positively with diastase resistant PAS and alcian blue (at pH 2.5) (Fig. 3). In the connective tissues surrounding the cyst, groups of seromucous glands were observed, but, smooth muscles, cartilages, and thyroid tissues could not be identified. Based on these histologic features, a diagnosis of cutaneous bronchogenic cyst of the neck was made.

Expression of E‐Cadherin in Skin Carcinomas

In this study, we investigated the expression of E‐cadherin in 31 cases of human skin carcinoma including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), Pagets disease, Bowens disease (invasive type), and trichilemmal carcinoma, by immunohistochemical staining using a monoclonal antibody specific for E‐cadherin. Similar to the E‐cadherin expression in normal epidermis, E‐cadherin was strongly expressed in all samples of BCC on the cell borders, whereas marked decrease or loss of E‐cadherin expression was found in the tumor cells of SCC, Pagets disease, and Bowens disease (invasive type). On the other hand, E‐cadherin expression of trichilemmal carcinoma was slightly reduced. Considering the clinical and histological features of these skin carcinoma, the reduction of E‐cadherin expression is considered to be associated with the invasion and metastasis of human skin carcinoma.

Age‐related decrease in the inductability of heat shock protein 72 in normal human skin

In order to know the effect of chronological ageing on the induction of heat shock protein (HSP) in normal human skill, the 72‐kDa HSP (HSP72) was examined in organ‐cultured samples of normal human skin which were obtained from 30 individuals (age range 17–86 years. The skin explants were first incubated al 37°C for 24 h. and then heat‐treated at 45°C for 1 h. After heat treatment, the skin explants were incubated al 37°C for 1 or 3h. Immunohistological analysis, using a monoclonal antibody specific for the HSP72. revealed that although the time course of the heat‐induced HSP72 expression was similar in the young and aged groups, a lower level of induction of HSP72 was observed in the aged group. This result indicates that there is an age‐related dysfunction of the heat shock response in normal human skin.

Lichen planus pemphigoides‐like lesions induced by cinnarizine

A 72‐year‐old woman developed a lichen planus pemphigoides‐like eruption following the administration of cinnarizine. The eruption recurred on challenge with the drug. Direct immunofluorescence studies of the lesions demonstrated deposition of IgG, IgM and C3 on colloid bodies and fibrin at the epidermal basement membrane zone. Circulating IgG antibasement membrane zone antibodies were detected at high titres, with no complement‐ fixing activities. To our knowledge, this is the first report of immunologically defined lichen planus pemphigoides induced by a drug.

Atypical pemphigus associated with monoclonal IgA gammopathy

We describe a 60-year-old woman with atypical pemphigus and IgA-lambda monoclonal gammopathy. Histopathologic study of vesiculopustular lesions showed intraepidermal acantholytic and neutrophilic blisters. Direct immunofluorescence revealed intercellular IgG deposition with concurrent deposits of IgA and C3. Indirect immunofluorescence and immunoblotting studies revealed that the patient had circulating IgG anti-intercellular antibodies that recognized the 150 kd desmoglein (pemphigus foliaceus antigen) in bovine desmosome preparation. Immunoblot studies with human epidermal extract showed that the IgG of this patient exclusively reacted with the 140 kd protein (between the 150 kd human desmoglein and the 130 kd human pemphigus vulgaris antigen), the nature of which is currently unknown. The patient also had IgA anti-intercellular autoantibodies, which reacted with the desmoglein in the bovine desmosome sample but did not show any reactivity in human epidermal extract.

Polymorphisms of HLA-DR and -DQ genes in Japanese patients with bullous pemphigoid.

Bullous pemphigoid (BP), an autoimmune skin disease of the elderly, is mediated by autoantibodies that bind to hemidesmosomes of epidermal basal cells. This study investigated BP‐associated HLA‐DR and ‐DQ genes among Japanese patients. We analyzed HLA‐DR and ‐DQ genes among 23 Japanese BP patients based on the polymerase chain reaction‐restriction fragment length polymorphism. Eighteen of these 23 patients (78%) carried at least one allele of HLA‐DRB1*04 or DRB1*1101, with significant increases in HLA‐DRB1*04 (*0403, *0406)/DQA1*0301/DQB1*0302 and DRB1*1101/DQA1*0505/DQB1*0302 haplotypes as well as the individual alleles DRB1*1101 and DQB1*0302 (corrected p<0.05 for each comparison), when compared to control subjects. These data differ from the accepted DQB1*0301 (DQ7) association with the same disease among Caucasians. These findings indicate that different HLA class II haplotypes genetically influence susceptibility to BP among different ethnic groups. Our findings, together with previous reports on Caucasian patients with the pemphigoid group of bullous diseases, suggest that HLA‐DRB1 molecules might participate in the regulation of autoimmune responses to BP antigens.