Mitochondrial antigens as targets of cellular and humoral auto-immunity in primary biliary cirrhosis

Several factors point toward an auto-immune pathogenesis for primary biliary cirrhosis (PBC), mostly based on the presence of serum auto-antibodies to mitochondrial antigens (AMAs) and autoreactive T cells (both helper and cytotoxic). Interestingly, epitopes recognized by AMA and T-cell clones are located within overlapping areas of the antigens. Moreover, a role for an imbalance in cytokine pattern and for natural-killer lymphocytes has also been proposed. Despite several experimental reports, no clear evidence is available regarding the interaction of these factors leading to bile duct destruction. This article reviews the current reports regarding the auto-immune reaction against mitochondrial auto-antigens in PBC.     

IMMUNOHISTOCHEMICAL STUDY ON THE DISTRIBUTION AND SIGNIFICANCE OF MONONUCLEAR CELLS IN HUMAN BREAST CARCINOMA

Lymphocyte subsets in the tumor nests of breast carcinoma were immunohistochemically investigated and a quantitative analysis was added. The majority of cases showed predominance of T cell and suppressor T cell (T8). A decrease in number of lymphocyte subsets and the helper T (T4)/T8 ratio in the stroma of tumor nests correlated well with the progression of clinical stage and the presence of metastasis. This correlation could not be found in the peripheral region of the tumor nests. Macrophages and NK cells were infrequently observed only in the peripheral region of ductal carcinoma. T cell infiltration was prominent in medullary carcinoma with lymphocyte infiltration (MC), and macrophages, NK cells, and T zone histiocytes were frequently encountered. For the purpose of knowing the activity of T cells, IL-2 receptor (Tac) and transferrin receptor were examined irnmunohistochemically. The fact that a few activated T cells were found only in the peripheral region of tumor nest suggested the local immune response in ductal carcinoma not to be so active as to reject the tumor cells. Since numerous activated T cells were recognized in the tumor nests of MC, this type of breast carcinoma was thought to have a higher immune reactivity. There was little evidence indicating NK cells to play a role for natural cytotoxicity in breast carcinoma. ACTA PATHOL. JPN. 36 1455-1468, 1968     

T cell immunity and primary biliary cirrhosis

T lymphocytes play a pivotal role in the autoimmune response in primary biliary cirrhosis (PBC). Recent studies have shown that there is overlapping in the PDC-E2-specific T and B cell epitopes. In addition, helper T and cytotoxic T cell epitopes all contain a shared peptide sequence. In addition, recognition of exogenous antigens including bacterial antigens by autoantigen-specific T cell and the mechanism of molecular mimicry provide a clue to clarifying the pathogenesis of PBC. Furthermore, the findings that autoantigen-immune complexes cross present and also that the presentation of autoantigen is of a higher relative efficiency, define a unique role of autoantibodies in the pathogenesis of the autoimmune disease. The mechanism of immune-mediated bile duct damage in PBC, including the possible role of T cell-mediated cytotoxicity and molecular mimicry is discussed.     

Prognostic significance of histologic grade and nuclear expression of beta-catenin in synovial sarcoma

Synovial sarcoma, which has a wide spectrum of biologic behavior, warrants accurate grading to assess the patient's prognosis. We studied the clinicopathologic and immunohistochemical features of 44 cases of synovial sarcoma in patients treated primarily or secondarily at the National Cancer Center, Tokyo, to identify independent prognostic factors. There were local recurrences in 16 patients (36%), and 25 (57%) developed metastases, primarily to the lungs. The estimated cumulative 5-year and 10-year survival rates were 68% and 41%, respectively. Variables associated with an adverse outcome included tumor size > 6.7 cm; initial treatment outside the National Cancer Center; poorly differentiated subtype; high nuclear atypia; mitosis count > 27/10 high-power fields; tumor necrosis; absence of stromal calcification; nuclear expression of beta-catenin, which was found in 25 cases (57%); Ki-67 (MIB-1) index > 27%; and histologic grade 3. Nuclear accumulation of beta-catenin as a cell-signaling event may play an important role in the progression of synovial sarcoma and therefore might be predictive of short survival. However, multivariate analysis clearly showed that only histologic grade, as defined by using categorized variables for the MIB-1 index and tumor necrosis, was an independent prognostic factor. Most variables were correlated with lung metastasis and histologic grade. High-grade synovial sarcoma assessed by a histologic grading system based on the proliferative activity of the neoplastic cells can be viewed as high risk with the patients most likely to die of disease within 10 years after surgery and in need of improved chemotherapy. HUM PATHOL 32:257-263.     

High-grade dysplasia associated with fundic gland polyposis in a familial adenomatous polyposis patient, with special reference to APC mutation profiles.

We report a patient with familial adenomatous polyposis who developed high-grade dysplasia against a background of fundic gland polyposis. Two large high-grade dysplasia lesions were found in the gastric body, where numerous fundic gland polyps were present. In both lesions, the dysplastic epithelium covered non-neoplastic oxyntic glands that occasionally exhibit cystic changes. A genetic analysis for APC (adenomatous polyposis coli) revealed a somatic 50-bp deletion involving codons 1502-1517 and 2-bp deletion at codon 1465 in each lesion of high-grade dysplasia. In contrast, six of the 18 fundic gland polyps were found to harbor an identical mutation: 1-bp insertion at codon 1556. Both lesions of high-grade dysplasia and the fundic gland polyps were similarly located in the fundic gland area and were caused by the inactivation of APC; however, their mutation profiles of APC were different. These results imply that fundic gland polyps and high-grade dysplasia of the stomach have distinct preferences for APC genotypes in their development.     

Tacrolimus reduces urinary excretion of leukotriene E(4) and inhibits aspirin-induced asthma to threshold dose of aspirin

BACKGROUND: The exact mechanism of aspirin-induced asthma is not clear. It has been postulated that precipitation of asthma attacks by aspirin is linked to inhibition of COX activity and massive release of cysteinyl leukotriene into the airway. Tacrolimus, a macrolide-derived immunosuppressant, is used for immunosuppression in organ transplantation and also for allergic diseases such as atopic dermatitis. OBJECTIVE: We evaluated the effects of tacrolimus in aspirin-induced asthma by using a double-blind, crossover study design. METHODS: Twelve patients with aspirin-induced asthma (male:female, 3:9; mean age +/- SD, 36.7 +/- 7.2 years) received either tacrolimus (0.1 mg/kg) or placebo 2 hours before the threshold dose of oral aspirin. RESULTS: In the placebo arm, oral aspirin significantly decreased FEV 1 concomitant with significant increases in sputum eosinophilic cationic protein and urinary leukotriene E(4) levels. Tacrolimus significantly inhibited bronchoconstriction and abrogated aspirin-induced increase in both sputum eosinophilic cationic protein and urinary leukotriene E(4) levels. CONCLUSION: The current study suggested that tacrolimus inhibited bronchoconstriction to a threshold dose of aspirin by inhibition of cysteinyl leukotriene excretion.     

Sustained interleukin-6 signalling leads to the development of lymphoid organ-like structures in the lung

A variety of pathological changes are seen in lymphoproliferative disorders of the lung but the histogenesis of these abnormalities is not yet fully understood. We previously showed that adenovirus vector-mediated transient expression of both the human interleukin-6 (IL-6) and IL-6 receptor (IL-6R) genes, but not the IL-6 gene alone, in the rat lung induced lymphocytic alveolitis. In the present study, we explored the lung pathology of human IL-6 and IL-6R double transgenic mice to elucidate the effects of prolonged IL-6 signalling on the lung. The transgenic animals developed mononuclear cell accumulation in peribronchovascular regions, but little infiltration into alveolar spaces. Immunohistochemical analysis revealed that the cellular accumulations contained not only mixtures of inflammatory cells but also lymphoid tissue-like structures. As the expression of CXCL13/BLC, the indispensable chemokine for lymphoid organogenesis, was recognized in the B cell follicles of the pulmonary lesions, we speculate that this chemokine plays an inductive role in the development of the lymphoid tissue-like structures. These structures were distinguished from bronchus-associated lymphoid tissues (BALTs) by their location and by the lack of lymphoepithelium, which is a characteristic of BALT. These findings imply that IL-6 signalling may play a role in the pathogenesis of lymphoproliferative disorders of the lung.     

Leiomyosarcoma of the thoracic aorta associated with dissecting aneurysm

An autopsy case report of leiomyosarcoma of the thoracic aorta is presented. The patient was a 75-year-old Japanese woman who complained of hypertension, melena and lumbago. The autopsy revealed severe occlusion of the thoracic aorta due to the tumor. Histologically the tumor consisted of fascicular proliferation of atypical fusiform cells. Metastases were seen in the bilateral adrenal glands, pancreatic tail and bones (vertebrae and femur). At the distal portion of the aortic tumor, there was a secondary dissecting aneurysm.     

A novel presenilin 1 mutation (Y154N) in a patient with early onset Alzheimer's disease with spastic paraparesis

Early onset familial Alzheimer's disease with spastic paraparesis (FAD-SP) has been associated with mutations of the presenilin 1 gene (PSEN1). We report a pedigree of FAD-SP due to a novel missense mutation of PSEN1 (Y154N). The symptoms of the proband were characterized by presenile dementia in her 40s, preceded by spastic paraparesis in her 30s, whereas the mother of the proband presented with spastic paraparesis in her 40s, followed by symptoms of dementia in her mid 60s. The mutation was found only in the proband, and not in a normal family member, normal Japanese control subjects, patients with sporadic Alzheimer's disease or patients with familial spastic paraparesis without dementia. Thus, Y154N is a novel PSEN1 mutation responsible for FAD-SP of Japanese origin.