Cytokine-induced metallothionein expression and modulation of cytokine expression by metallothionein

A multifunctional protein metallothionein (MT) is induced by various chemicals and cytokines. We have found novel functions of MT as follows: 1) Cytokine expression such as IL-1alpha, IL-6, and TNFalpha responding to lipopolysaccharide is reduced in MT-deficient macrophages compared with in wild-type cells. 2) Nitric oxide production responding to TNFalpha and LPS is reduced in MT-deficient macrophages compared with in wild-type cells. 3) M-CSF expression responding to zinc is reduced in MT-deficient fibroblasts compared with in wild-type cells, and increased in MT-overexpressed fibroblasts compared with in control cells. 4) LIF, a STAT3 activating cytokine, protects the heart from ischemia/reperfusion injury. Transgenic mice overexpressing STAT3 have tolerance to ischemia/reperfusion-induced damage, whereas MT-null mutation cancels the myocardial protection. In this review, we discuss the relation of MT and stress responses from the point of view of cytokine-induced expression of MT and modulation of cytokine expression by MT.     

Development of diagnostically and therapeutically useful human antibody medicines by phage display system

Phage display has been utilized for making recombinant antibody fragments (Fab or single chain Fv) of human, mouse, or other origins. After construction of an antibody combinatorial library, antigen-specific recombinant antibody fragments can be easily isolated by biopanning of the phage library displaying antibody fragment fused with viral coat protein III against antigen proteins, antigen-expressing live cells, or fixed cells. Using this technique, a variety of human recombinant antibody fragments can be retrieved from bone marrow cells, lymph node cells, or peripheral blood cells of patients with infectious diseases, autoimmune diseases, and cancer. To develop diagnostically and therapeutically useful human antibody medicines, we should first select recombinant antibody fragments not only with antigen-binding activity but also with bioactivity such as virus or toxin neutralization, or tumor-specific cytotoxicity. To achieve this goal, several steps in antibody phage display may be improved: 1) a larger library should be constructed for possible isolation of minor populations present in the repertoire; 2) the biopanning procedure should be improved for isolation of antibody fragments reactive with immunologically minor epitopes; 3) the screening procedure should be based on the measurement of the bioactivity as well as the antigen-binding activity; 4) if necessary, the affinity and specificity of selected antibody fragments should be improved. In this review, I discuss how to isolate clinically useful recombinant antibody fragments efficiently using a phage display system introducing our achievements.     

A 10-year-old boy with Marfan syndrome exhibiting cerebrovascular abnormalities

A young male with Marfan syndrome, diagnosed at the age of 10 years, presented with conspicuous elongation and tortuosity of the internal carotid, middle cerebral, vertebral and basilar arteries on cranial magnetic resonance and computed tomography angiography. There is a little mention of cerebral blood vessel examinations in the guidelines of the American Academy of Pediatrics for Marfan syndrome. Guidelines may be provided for the evaluation of cerebrovascular system for the patients with Marfan syndrome who have family history of Marfan syndrome as well as a family history of death from subarachnoid hemorrhage.     

Primary cutaneous Langerhans cell histiocytosis showing malignant phenotype in an elderly woman: report of a fatal case

BACKGROUND: Langerhans cell histiocytosis (LCH) is a proliferating disorder of Langerhans cells (LC) that are characterized by the presence of Birbeck granules. LCH has been considered to be a disease of childhood and there have been limited cases of adult LCH. We report here a fatal case of histiocytic tumor showing Langerhans cell phenotype, arising in the skin of a 74-year-old woman. METHOD: In addition to routine histological and immunohistological sections, electron microscopic examination and human androgen receptor gene (HUMARA) assays were performed. RESULTS: Histological examination revealed a dense dermal infiltrative proliferation of fairly large tumor cells with abundant ill-defined cytoplasms and oval or indented nuclei, in which numerous eosinophils were associated with the tumor nests. Tumor cells were positive with anti-S-100 and CD1a antibodies but negative with HMB-45 antibody or other epithelial or lymphocytic markers. Ultrastructural analysis showed typical Birbeck granules in the cytoplasm of the tumor cells. HUMARA assay of the tumor tissue revealed the nonrandom X inactivation pattern, indicating the clonal proliferation. CONCLUSIONS: We diagnosed this tumor as Langerhans cell histiocytosis with a clonal neoplastic phenotype originated in the skin. Although she demonstrated no recurrence nor metastases for 6 months after surgical resection of primary skin lesion and subsequent radiation therapy, the tumor recurred and extended multisystemically, and she died of multiple organ failure 14 months after initial diagnosis. Therefore, we would like to emphasize this case as LC "sarcoma" or "malignant" LCH.     

Langerhans cell histiocytosis involving the skin of an elderly woman: a satisfactory remission with oral prednisolone alone

Langerhans cell histiocytosis (LCH) is a disorder characterized by neoplastic proliferation of Langerhans cells that rarely involves the skin in adults. A 74-year-old woman presented with a fourteen year history of eosinophilic granuloma and bone involvement caused by LCH. She had received three combination therapy courses of curettage and radiation since 1987 and had remained free of LCH signs for seven years, after which she started to notice brown nodules on her left leg. Biopsy specimens taken from the lesions showed massive proliferations of large histiocytic cells. Immunoperoxidase stainings for CD1a and S-100 protein were positive. Electron microscopy identified Birbeck granules in the cytoplasm of the atypical Langerhans cells. Treatment with oral prednisolone alone has resulted in the patient remaining in complete remission for 12 months.     

Recurrent aciclovir-resistant herpes simplex in a child with Wiskott–Aldrich syndrome

A boy with Wiskott–Aldrich syndrome suffered from thymidine kinase (TK)-altered and aciclovir-resistant herpes simplex virus type 1 (HSV-1) skin infections. He presented with severe herpes simplex around the left eye in March 1993 at the age of 8 years. HSV-1 strain TAS was isolated and was shown to be susceptible to aciclovir (50% inhibitory concentration (IC₅₀) 0.23 μg/mL). He was treated with intravenous (i.v.) high dose aciclovir, 2 mg/kg per h, which produced an improvement. About 1 year later (May 1994), a severe herpes simplex infection appeared on his face, arm, genitalia, back and foot. Treatment with i.v. aciclovir, 2 mg/kg per h, was initiated, but the skin lesions did not improve. HSV-1 strain TAR was isolated and was shown to be resistant to aciclovir (IC₅₀ 36 μg/mL). HSV-1 TAR and TAS were susceptible to vidarabine (IC₅₀ 4.4 and 2.9 μg/mL, respectively). The skin lesions were treated with i.v. vidarabine, 15–20 mg/kg per day, and healed satisfactorily. However, in March 1995, the patient again experienced a severe herpes simplex infection around the left eye. HSV-1 strain R95 was isolated and was shown to be resistant to aciclovir (IC₅₀ 36 μg/mL). Diminished sensitivity of HSV-1 TAR and R95 to aciclovir was associated with reduced viral TK activity and loss of aciclovir phosphorylation activity.     

Identification of differentially expressed genes in psoriasis using expression profiling approaches

To identify differentially expressed genes which play causal roles in pathogenesis and maintenance for psoriasis, we used BodyMapping and introduced amplified fragment length polymorphism approaches. From the BodyMap database, we selected 2007 genes which specifically expressed in epithelial tissues. Among 2007 genes, we surveyed genes which differentially expressed in involved or uninvolved psoriatic lesional skin samples compared with atopic dermatitis, mycosis fungoides, and normal skin samples. As a result of surveying 2007 genes, 241 genes were differentially expressed only in involved psoriatic skin but not in the other samples. Hierarchical cluster analysis of gene expression profiles showed that 13 independent psoriatic-involved skin samples clustered tightly together, reflecting highly similar expression profiles. Using the same 2007 gene set, we examined gene expression levels in five serial lesions from distal uninvolved psoriatic skin to involved psoriatic plaque. We identified seven genes such as alpha-1-microglobulin/bikunin precursor, calnexin, claudin 1, leucine zipper down-regulated in cancer 1, tyrosinase-related protein 1, Yes-associated protein 1, and unc-13-like protein (Coleonyx elegans) which show high-expression levels only in uninvolved psoriatic lesions. These seven genes, which were reported to be related to apoptosis or antiproliferation, might have causal roles in pathophysiology in psoriasis.