Takashi Yoshimasu

Susceptibility of T cell receptor-α chain knock-out mice to ultraviolet B light and fluorouracil: a novel model for drug-induced cutaneous lupus erythematosus

The anticancer agent 5‐fluorouracil (FU) frequently induces cutaneous lupus erythematosus (LE) lesions on sun exposed sites. Based on this observation, we have tried to establish a cutaneous LE model of C57BL/6 J (B6) mice, B6 T cell receptor (TCR)‐α–/– mice and B6 TCR‐δ–/– mice treated with FU and/or ultraviolet B light (UVBL) in order to clarify the role of T cells and the cytokine profile of cutaneous lupus lesions. Cutaneous LE‐like skin lesions could be induced in TCR‐α–/– mice with low FU (0·2 mg) plus UVBL, and in B6 mice treated with a high dose of FU (2·0 mg) plus UVBL. In contrast, low FU plus UVBL induced such skin lesions in TCR‐δ–/– mice at a very low incidence. Specifically, the skin lesions of TCR‐α–/– mice with low FU plus UVBL appeared more rapidly and were more severe than lesions in B6 mice. The former had the common characteristic features of human chronic cutaneous LE such as typical histology, positive IgG at the dermoepidermal junction, low antinuclear antibody and low mortality. Furthermore, a Th1 response was induced in the development of drug‐induced cutaneous LE. FU and UVBL‐induced cutaneous LE‐like eruption is an excellent model for better understanding the pathomechanisms of skin lesion development in LE.

Mast cells and histamine metabolism in skin lesions from MRL/MP-lpr/lpr mice.

It is likely that mast cell and histamine metabolism are involved in autoimmune tissue injury such as cutaneous lupus erythematosus (LE) because different histamine receptors can regulate Th1 and Th2 cells. In order to verify the role of the axis of mast cell-histamine metabolism-histamine receptor, the autoimmune mouse has been investigated. The MRL/Mp-lpr/lpr (MRL/lpr) mouse is a good model for the spontaneous development of skin lesions similar to those seen in human LE. In skin lesions from MRL/l mice, there are many infiltrating T cells and mast cells in the dermis and impaired histamine metabolism, in which the low activity of histamine-N-methyltransferase and the related prolonged effects of histamine in the skin tissue seem to play a definite pathological role in the development of spontaneous lupus-like eruptions. The expression of H2R on the mast cell decreases within these skin lesions at 5 months of age. It is interesting that the activity of HMT runs in parallel with the expression of H2R over the time course of the skin changes in MRL/l mice, but the relationship between these two observations remains obscure. The accumulation of mast cells expressing H2R and prolonged effects of histamine may occur to regulate the production of Th1 and Th2 cytokines in the skin lesions of MRL/l mice.

The protective effects of ultraviolet A1 irradiation on spontaneous lupus erythematosus-like skin lesions in MRL/lpr mice.

We investigated the effects of ultraviolet A1 (UVA1) irradiation on spontaneous lupus erythematosus- (LE-) like skin lesions of MRL/lpr mice, using a disease prevention model. UVA1 irradiation significantly inhibited the development of LE-like skin lesions, without obvious changes of the disease including renal disease and serum antinuclear antibody levels. Besides the massive infiltration of mast cells in the LE-like skin lesions, in the nonlesional skins, more mast cells infiltrated in the UVA1-irradiated group compared with the nonirradiated group. Although apoptotic cells were remarkably seen in the dermis of UVA1-irradiated mice, those cells were hardly detectable in the dermis of the nonirradiated mice without skin lesions. Further analysis showed that some of those apoptotic cells were mast cells. Thus, UVA1 might exert its effects, at least in part, through the induction of the apoptosis of pathogenic mast cells. Our results supported the clinical efficacy of UVA1 irradiation for skin lesions of lupus patients.

Effects of sarpogrelate hydrochloride on skin ulcers and quality of life in patients with systemic sclerosis

5‐Hydroxytryptamine 2A serotonin receptor (5‐HT2A) is associated with the contraction of vascular smooth muscle, platelet aggregation and thrombus formation and coronary artery spasms. Sarpogrelate hydrochloride (sarpogrelate) is a selective 5‐HT2A antagonist and was supposed to be effective for Raynaud’s phenomenon with collagen disease. Sarpogrelate has not been investigated regarding the effects, safety and quality of life (QOL) in patient with skin ulcers of collagen disease. Eleven patients with skin ulcers and systemic sclerosis (SSc) were administrated sarpogrelate p.o. three times a day for 3–6 months. The area (mean ± standard error) of skin ulcer at the pretreatment, and after 3 and 6 months of sarpogrelate intake was 2.1 ± 0.8, 0.2 ± 0.1 and 0.1 ± 0.1 mm2, respectively. The reduction of skin ulcer area was significant after 3 months of sarpogrelate intake. In assessment of QOL, scores of symptoms and emotions but not of functioning were significantly improved after sarpogrelate intake. The global score (mean ± SE) of Skindex‐16 at pretreatment, and after 3 and 6 months of sarpogrelate intake was 31.8 ± 8.7, 23.7 ± 8.3 and 10.9 ± 4.6, respectively. The score was significantly improved after 6 months of sarpogrelate intake. There were no obvious side‐effects during this study. Sarpogrelate was considered to be a useful drug to improve skin ulcers and QOL in patients with SSc.

Comparison of anti 60 and 52 kDa SS-A/Ro antibodies in the pathogenesis of cutaneous lupus erythematosus

Anti SS-A/Ro antibodies are involved in the pathogenesis of cutaneous lupus erythematosus (CLE) in a part through antibody dependent cellular cytotoxicity (ADCC). However, it is still obscure which and how anti 60 and anti 52 kDa Ro antibodies are involved. To address the issue, we examined both types of anti Ro antibodies of sera from patients with systemic LE (SLE) or discoid LE (LE). The titer of anti 60 kDa antibody in SLE was significantly much higher than that of DLE or control. The positive ratio of DLE showed more higher tendency than control, but it was not statistically significant. The similar tendency was observed in the titer of anti 52 kDa antibody. An association between the anti 60 kDa antibody and the anti 52 kDa antibody was statistically significant in SLE patients. Although the relative index (RI) was statistically significant in DLE, they included many negative sera, which biased the statistics. Both anti 60 kDa antibody and anti 52 kDa antibody could induce significant ADCC of ultraviolet B (UVB) light-irradiated keratinocytes from neonatal foreskins and/or normal adults, in which anti 60 kDa antibody showed higher cytotoxicity than anti 52 kDa antibody. The autologous combination studies (keratinocytes and monospecific anti 60 or anti 52 kDa antibody from patients) suggested anti 60 kDa antibody was more potent to induce ADCC activity than anti 52 kDa antibody. Taken together, it is likely that anti 60 kDa antibody dependent keratinocyte damage plays more significant role in the pathogenesis of SLE skin lesions than anti 52 kDa dependent damage. However, both type antibodies seemed to have little contribution to the pathogenesis of DLE skin lesion.

Eradication therapy for urticaria with high titers of anti H. pylori IgG antibody.

BACKGROUND It is known that idiopathic chronic urticaria occasionally develops with Helicobacter pylori (H. pylori) infection, but the association between urticaria and H. pylori remains unknown. METHODS We focused on the relationship between the titer of anti H. pylori IgG antibodies and urticaria. Sixty-five patients with idiopathic urticaria were divided into 3 groups by a difference of their titers. All patients in the high titer (≥40U/ml) group underwent endoscopy of the upper gastrointestinal tract with antral biopsy for the Rapid Urease Test (RUT) or a culture test. We investigated the relationship between the efficacy of eradication therapy against H. pylori and urticaria. RESULTS The positive rate for H. pylori was 100% (20/20) by RUT or culture test in the high titer group. A CR using antihistamines alone was 0% (0/20) in the high titer group, 27.2% (3/11) in the low titer group and 38.2% (13/34) in the negative group respectively. A CR or PR using antihistamines was 70% (14/20) in the high titer group, 81.8% (9/11) in the low titer group and 97.1% (33/34) in the negative group. After successful eradication therapy, the CR was increased to 56% (9/16) in the high titer group. CONCLUSIONS Regardless of acute or chronic urticaria, a high titer of anti H. pylori IgG antibody can be an indicator for undergoing upper endoscopy, and eradication therapy is strongly recommended. It will be necessary to develop diagnostic criteria for urticaria associated with H. pylori.

Skin Metastasis of Neuroendocrine Carcinoma Derived from the Mediastinum

We report a 46‐year‐old Japanese man with a metastatic skin tumor on his left palmar region. He underwent resection for a mediastinal neuroendocrine carcinoma in February of 1998. After the operation, he immediately noticed an elevated tumor on his left palm. In September 1999, a brain tumor was discovered. The skin and brain tumors were subsequently removed surgically. Neuron specific enolase (NSE) in the serum was elevated to 25 ng/ml. A skin biopsy specimen from the left palmar site revealed multiple tumor nests which showed the same histological features as the primary mediastinal tumor. Immunostaining was positive for chromogranin, synaptophysin, and NSE but negative for S‐100 protein and CD57. To our knowledge, this is the first report of cutaneous metastasis of a neuroendocrine tumor derived from the mediastinum.

Identification of 736T>A mutation of lipase H in Japanese siblings with autosomal recessive woolly hair

Woolly hair is characterized by fine and tightly curled hair. It has recently been revealed that both LPAR6 and lipase H (LIPH) mutations cause autosomal recessive woolly hair (ARWH)/hypotrichosis. This notion has provided critical evidence to the concept that LPA6 activation by LIPH‐catalyzed lipid mediator lysophosphatidic acid has a key role in regulation of hair follicle development. Very recently, novel mutations in exon 6, homozygous 736T>A and compound heterozygous 736T>A and 742C>A have been identified in Japanese ARWH/hypotrichosis patients. Here, we report on siblings (a 7‐year‐old Japanese girl and her 5‐year‐old brother) both showing woolly hair. Determination of their genomic sequence showed presence of a homozygous 736T>A transition in exon 6 of the LIPH gene changing cysteine at position 246 to serine, without any mutation in the LPAR6 gene. Additionally, the same mutation was found in one out of a 100 alleles of Japanese healthy controls and identified homozygously in three out of four other Japanese sporadic cases with woolly hair. Collectively, it has been suggested that 736T>A transition is highly specific and common in ARWH/hypotrichosis of Japanese origin.

The Expression of Histamine Receptors in Skin Lesions of MRL/MPlpr/ lpr Mice

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease accompanied with systemic organs dis- order including skin changes. The MRL/MP-lpr/lpr (MRL/l) mouse is a model of human LE. MRL/l mice skin lesions ex- hibit a decreased activity in histamine-N-methyltransferase (HMT) and impaired histamine metabolism. In order to clarify the role of histamine receptors (HRs) including H1R, H2R and H3R in MRL/l skin lesions, the relationship between HRs and skin lesions was assessed by immunohistochemical staining and RT-PCR methods. The expression of H2R was seen in the non-lesional skin of 2-month-old (mo) MRL/l mice; H2R expression continued for a couple of months, and then de- creased in the skin lesions of 5-mo MRL/l mice. In MRL/l skin lesions, a dense mast cell infiltration expressed H2R was seen. In conclusion, an increased expression of H2R in mast cells may be associated with histamine metabolism in skin le- sions from MRL/l mice.

Multiple courses of pulse corticosteroid therapy for alopecia areata.

Various systemic corticosteroid therapies are used for alopecia areata (AA). Pulse therapy using methylprednisolone is a treatment approach for AA. The efficacy of multiple courses of pulse therapy for various severities of AA was evaluated. AA patients with less than 50% hair loss, less than or equal to 6 months after AA onset, needed 1.9 courses of pulse therapy for vellus hair to develop. On the other hand, AA patients with more than 50% hair loss, less than 6 months after AA onset, needed more courses of pulse therapy for vellus hair to develop. Regardless of the disease duration, AA patients with less than 50% hair loss showed a good response rate (100%) after both a short period and a long period after therapy. After receiving multiple courses of pulse therapy, the AA patients with more than 50% hair loss also showed improvement with limited adverse reactions.