A very few cases of biopsy-proven tubulointerstitial nephritis (TIN) in patients with primary biliary cirrhosis (PBC) have been reported. Although the clinical importance of this association has been suggested, information on its clinicopathological features and prognosis is limited.We reviewed 5955 renal biopsies processed at our department, and identified four patients with TIN associated with asymptomatic PBC. We evaluated clinicopathological features and outcomes in these patients, and reviewed the previously reported cases of TIN associated with PBC.Our four patients were female. The patients' age at the time of renal biopsy ranged from 36 to 77. Three patients had been treated with ursodeoxycholic acid. All patients had urinary abnormalities such as proteinuria and elevated levels of urinary β(2)-microglobulin, and three patients had renal insufficiency. All patients had distal renal tubular acidosis (RTA), and two patients also had Fanconi syndrome. Renal biopsy showed severe lymphocyte infiltration in the tubules and interstitium with mild-to-moderate tubular atrophy and fibrosis. All patients responded well to steroid therapy. On review of the previously reported five cases, all patients were female. The patients' age ranged from 42 to 68. Apparent symptoms linked to PBC were not described. All patients had renal insufficiency. Three patients suffering from bone pains or bone fractures also had Fanconi syndrome. Marked or transient improvements were observed after steroid therapy in three patients.TIN and RTA of different types are extremely rare but one of the important extrahepatic complications of PBC. Steroid therapy can be beneficial in treating PBC patients with these renal complications.
Our previous clinicopathologic study revealed an inverse association of liver metastasis of colorectal cancer and stromal expression of matrix metalloproteinase-9 (MMP-9) or urokinase receptor (uPAR). This suggests that host cells, particularly macrophages, expressing matrix-degrading enzymes/factors could be protective for the host against hematogenous metastasis. However, our previous study was unable to differentiate whether our results were causes or effects of widely spread cancer. To solve this point, we designed the present study on colorectal cancers that developed hematogenous metastasis after operation, ie., metachronous hematogenous metastasis. These cancers, being solely micrometastasized at the time of operation, allowed us to eliminate possible systemic effects by widely spread cancer. Sixty-two primary tumors with metachronous metastasis showed a decreased number of MMP-9+ stromal cells and CD68+ macrophages along the invasive margin with unchanged uPAR+ stromal area as compared with those in 72 control cases, which were free from tumor metastasis or recurrence for more than 5 years. Therefore, we judged the decrease of MMP-9+ host cells or macrophages in the primary site is irrelevant of effects of widely spread metastasis but probably related to causes of metastasis. Our data also characterized the metachronous metastasis group by uPAR expression in fibroblasts. The number of uPAR+ cancer cells, although small in number, were also larger in the metachronous metastasis group. Our data revealed that macrophages, a major source of uPAR and one of the sources of MMP-9, could be inhibitory to hematogenous metastasis, while uPAR+ fibroblasts and cancer cells, in turn, facilitate hematogenous metastasis. This suggests the functional multiplicity of matrix degradation processes in cancer tissue.
Abstract CCL28 is a CC chemokine signaling via CCR10 and CCR3 that is selectively expressed in certain mucosal tissues such as exocrine glands, trachea, and colon. Notably, these tissues commonly secrete low-salt fluids. RT-PCR analysis demonstrated that salivary glands expressed CCL28 mRNA at the highest levels among various mouse tissues. Single cells prepared from mouse parotid glands indeed contained a major fraction of CD3−B220low cells that expressed CCR10 at high levels and CCR3 at low levels and responded to CCL28 in chemotaxis assays. Morphologically, these cells are typical plasma cells. By immunohistochemistry, acinar epithelial cells in human and mouse salivary glands were strongly positive for CCL28. Furthermore, human saliva and milk were found to contain CCL28 at high concentrations. Moreover, the C terminus of human CCL28 has a significant sequence similarity to histatin-5, a histidine-rich candidacidal peptide in human saliva. Subsequently, we demonstrated that human and mouse CCL28 had a potent antimicrobial activity against Candida albicans, Gram-negative bacteria, and Gram-positive bacteria. The C-terminal 28-aa peptide of human CCL28 also displayed a selective candidacidal activity. In contrast, CCL27, which is most similar to CCL28 and shares CCR10, showed no such potent antimicrobial activity. Like most other antimicrobial peptides, CCL28 exerted its antimicrobial activity in low-salt conditions and rapidly induced membrane permeability in target microbes. Collectively, CCL28 may play dual roles in mucosal immunity as a chemoattractant for cells expressing CCR10 and/or CCR3 such as plasma cells and also as a broad-spectrum antimicrobial protein secreted into low-salt body fluids.
Growth hormone-releasing hormone (GHRH) is a well-known hypothalamic hormone that stimulates the synthesis and release of growth hormone (GH) as well as the proliferation of GH-producing cells in the anterior pituitary gland.Recent reports have shown GHRH synthesis in pituitary somatotroph adenomas, but GHRH immunoreactivity has not been demonstrated in the previous studies.In order to confirm the role of locally generated GHRH for the progression of somatotroph adenomas, we investigated the expression of GHRH in 25 pituitary somatotroph adenomas immunohistochemically using both conventional avidin-biotin-complex (ABC) method and novel catalyzed signal amplified (CSA) system.In addition, we investigated the expression of GHRH mRNA and GHRH receptor mRNA with in situ hybridization (ISH) using CSA system.The weak immunopositivity of GHRH were observed in only 2 adenomas (8.0%) out of 25 somatotroph adenomas using ABC method.In contrast, 15 adenomas (60.0%) out of 25 somatotroph adenomas were immunopositive for GHRH revealed by CSA system.The expression of GHRH mRNA was confirmed using CSA-ISH system in 13 adenomas (72.2%) out of 18 somatotroph adenomas.In 11 adenomas (61.1%) out of 18 somatotroph adenomas, the expression of GHRH receptor mRNA was demonstrated using CSA-ISH system.This is a first report that clarified histopathologically GHRH production in pituitary somatotroph adenomas.The demonstration of GHRH and its receptor expression is meaningful in clarifying the autocrinc or paracrine regulation of GHRH in GH production and progression of pituitary somatotroph adenomas.
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Vascular endothelial cells (ECs) have been demonstrated to play crucial roles in inflammation and immune responses by expressing various adhesion molecules, such as MHC class II antigens, ICAM-1 and ELAM-1 (E-selectin), and by synthesizing various cystokines including IL-1, IFN-γ and TNF. They act as antigen presenting cells in leading to a cascade of immunologic and inflammatory events. The expression of cell adhesion molecules by ECs, particularly high endothelial venules, mediates permeation of lymphocytes and leucocytes in inflammatory lesions, and subsequently leads to continuous inflammation. Both morphological and functional alterations of ECs named “activation” are induced by cytokines in vitro and inflammatory or immune responses, and the concept of endothelial activation is useful in understanding endothelial cell functions. In addition, the immunoperoxidase technique is useful for studying morphological and functional changes of ECs in inflammatory and immune diseases.
The tumor-host relationship is one of the factors determining the biological behavior of malignant tumors. In colon cancer, the costimulatory molecules B7-1/B7-2 are expressed by macrophages distributed along the invasive margin (tumor-host interface). T-lymphocytes are also distributed in the same area with direct cell-to-cell contact with these B7+ macrophages. The distribution of these macrophages is lower in colon cancer patients with liver metastasis. CD8+ T cells are distributed within cancer cell nests of colon cancer. The survival rate of patients with higher levels of these T-cells is favorable. Our data suggest the presence of a host immune reaction by macrophages and T-lymphocytes, which diminishes the aggressiveness of cancer cells. As shown in the present paper, comparative analysis is required to assess the biological behavior of cancer.
