Immunological aspects and therapeutic significance of an autoantibody against histone H1 in a rat model of concanavalin A‐induced hepatitis

We previously demonstrated the immunosuppressive activity of anti‐histone H1 autoantibody induced in experimental and clinical liver allograft tolerance. This study aimed to explore the immunological aspects of anti‐histone H1 autoantibody in liver injury induced by concanavalin A (Con A). To establish a Con A‐hepatitis model, 20 mg/kg Con A was intravenously injected into rats, after which liver function and histopathological analyses were performed. In this model, anti‐histone H1 autoantibody was transiently induced in the sera during the natural recovery stage, 3–7 days after Con A injection. To evaluate the therapeutic significance of anti‐histone H1 autoantibody, a polyclonal antibody against histone H1 was intraperitoneally injected immediately after Con A injection. We found that injection of anti‐histone H1 antibody could reduce Con A‐induced liver damage. Further mechanical analyses revealed that anti‐histone H1 antibody altered the intracellular activation of mitogen‐activated protein kinase, nuclear factor‐κB and calcineurin via T‐cell receptor signalling, suggesting that anti‐histone H1 antibody may protect the liver from Con A‐induced injury by inhibiting activation of effector T cells. These findings suggest that anti‐histone H1 autoantibody may be a natural immune regulatory factor that protects inflamed livers suffering from autoimmune hepatitis and may lead to T‐cell unresponsiveness through the selective regulation of mitogen‐activated protein kinase/nuclear factor‐κB and calcineurin signalling.     

Effect of sera on the adhesion of natural killer cells to the endothelium in severe pre-eclampsia

OBJECTIVE: To investigate the effect of serum on the interaction between natural killer (NK) cells and endothelial cells in pre-eclampsia. METHODS: Seven severely pre-eclamptic patients, five normal pregnant women, and four normal non-pregnant women were included in this study. Freshly isolated NK cells labeled with Chromium-51 were incubated on an endothelial cell monolayer in the presence of patient serum. In regard to the characteristics of adhesive molecules, the endothelial cells were blocked by monoclonal antibodies (mAbs) to intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1); the NK cells were blocked by mAbs to leukocyte function-associated antigen (LFA-1) and very late antigen-4 (VLA-4) before co-incubation. After incubation, the adherent cells were solubilized with 1% Triton X. The lysates were collected and counted in a gamma counter. RESULTS: The adhesion of NK cells to the endothelium in the normal pregnancy group decreased significantly in comparison to the non-pregnant group (7%vs 72%; P < 0.01). Adhesion in the severe pre-eclamptic group was significantly higher in comparison to the normal pregnant group (44%vs 7%; P < 0.01). The blocking percentages of mAbs on NK adhesion in the severe pre-eclampsia group were 49 +/- 4% to LFA-1, 61 +/- 48%, 67 +/- 39% to VLA-4, ICAM-1, and 68 +/- 7% to VCAM-1. CONCLUSION: Sera from normal pregnant women suppress the adhesion between NK cells and endothelial cells, whereas the suppressive effect of sera from pre-eclamptic patients has a diminished affect.     

A case of primary breast cancer responding to pre-operative chemotherapy with the combination of paclitaxel and carboplatin for ovarian cancer

A 62-year-old woman was diagnosed with primary left breast cancer during a follow-up for an ovarian tumor. She had at first undergone surgical resection of an ovarian tumor, and a pathological examination had revealed ovarian cancer. Gynecologists decided to treat her ovarian cancer with chemotherapy, and we were initially planning to provide treatment for breast cancer after that was completed. Sentinel lymph node biopsy performed before chemotherapy revealed no axillary metastases. The patient received six courses of intravenous PTX (175 mg/m2 on day 1, every 3 weeks) and intravenous CBDCA (AUC6 on day 1, every 3 weeks) as combination therapy. Abdominal lymph node dissection was performed between chemotherapy courses 3 and 4. The lump in the left breast showed partial clinical response, and partial resection of the left breast was performed after completion of chemotherapy. In Japan, few cases of primary breast cancer treated preoperatively using carboplatin-containing regimens have been described.     

Discoid lupus erythematosus exacerbated by contact dermatitis caused by use of squaric acid dibutylester for topical immunotherapy in a patient with alopecia areata

A 57-year-old Japanese male patient with an 18-year history of discoid lupus erythematosus (DLE) presented with alopecia on his scalp, and was clinically diagnosed to have alopecia areata. He was started on topical immunotherapy with squaric acid dibutylester (SADBE) for the treatment of alopecia areata. The patient was first sensitized with the application of 2% SADBE on the right upper arm, followed subsequently by re-exposure to a low concentration of SADBE to provoke contact dermatitis on the scalp as treatment. Approximately 2 months later, he developed multiple red scaly lesions on his scalp and face, which were diagnosed histopathologically as DLE. DLE is known to be exacerbated by a variety of factors, including sunlight, X-rays, tattoos, burns, and some forms of cutaneous trauma, including dermatitis. However, to the best of our knowledge, there have only been two reported cases of DLE exacerbated by contact dermatitis.     

Geldanamycin and its anti-cancer activities

Geldanamycin is a benzoquinone ansamycin antibiotic that manifests anti-cancer activity through the inhibition of HSP90-chaperone function. The HSP90 molecular chaperone is expressed at high levels in a wide variety of human cancers including melanoma, leukemia, and cancers in colon, prostate, lung, and breast. In cancer cells dependent upon mutated and/or over-expressed oncogene proteins, HSP90 is thought to have a critical role in regulating the stability, folding, and activity of HSP90-associated proteins, so-called “client proteins”. These client proteins include the growth-stimulating proteins and kinases that support malignant transformation. Recently, oncogenic activating BRAF mutants have been identified in variety of cancers where constitutive activation of the MEK/ERK MAPK signaling pathway is the key for tumorigenesis, and they have been shown to be client proteins for HSP90. Accordingly, HSP90 inhibition can suppress certain cancer-causing client proteins and therefore represents an important therapeutic target. The molecular mechanism underlying the anti-cancer effect of HSP90 inhibition is complicated. Geldanamycin and its derivatives have been shown to induce the depletion of mutationally-activated BRAF through several mechanisms. In this review, we will describe the HSP90-inhibitory mechanism, focusing on recent progress in understanding HSP90 chaperone structure–function relationships, the identification of new HSP90 client proteins and the development of HSP90 inhibitors for clinical applications.     

Arthrogryposis multiplex congenita with callosal agenesis and dentato-olivary dysplasia

We report the autopsy case of a boy with arthrogryposis multiplex congenita, associated with callosal agenesis and dentato-olivary dysplasia. The patient manifested with dysmorphic facial features and suffered from intractable epilepsy during the neonatal period. These sets of complications suggest that a common molecular mechanism may be involved in the development of corpus callosum and the folding of the dentate and inferior olivary nuclei. Deep brain structures, including the brainstem and the cerebellum, may be involved in the pathophysiology of symptomatic generalized epilepsy. The differential diagnoses for the clinical and pathological characteristics of this patient are discussed.