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Notes: Background: The nephron reduction in IgA nephropathy is critical for the newly established prognosis of this disease. A high immunoglobulin A inbred strain of ddY mouse (HIGA mouse) showed progressive mesangial sclerosis with elevated renal expression of transforming growth factor (TGF)-β,1 however, the progression of the renal lesion of this mouse is relatively mild with rare association of active crescentic glomerulonephritis. However, although nephron reduction causes progressive renal injury, the modifications of glomerular lesions by nephron reduction are dependent upon the pathological background of each strain. Thus, we investigated the influence of nephron reduction by heminephrectomy on the renal lesions of the HIGA mouse.Methods: Five-week-old HIGA mice were heminephrectomized (Nx), and were evaluated in comparison with a sham-operated group (S) at 40 weeks old. Measurements of renal function, blood pressure and serum levels of immunoglobulins (IgG, IgA, and IgM) were performed. Histological findings, including glomerular enlargement, matrix expansion, immunoglobulin depositions (IgG, IgA, and IgM), expressions of cytokines (TGF-β, TNF-α, and IL-6) and extracellular matrix proteins were analysed. PCNA and TUNEL stainings were performed. In addition, mRNA expressions of renin-angiotensin systems (RAS; angiotensinogen and angiotensin converting enzyme (ACE)) were also investigated.Results: The physiological and serological data showed no significant difference between Nx and S. In Nx, the glomerular tuft area and ratio of mesangial matrix area for one tuft were significantly increased and glomerular IgG and IgM deposits were significantly expanded in the paramesangium. However, IgA was not significantly increased. The glomerular expressions of cytokines (TGF-β, TNF-α, and IL-6) and extracellular matrix proteins (fibronectin, collagen type I and IV) were significantly increased in this group. In contrast to the significant decrease of PCNA-positive cells, TUNEL-positive cells were significantly increased in Nx. The total mRNA expression of ACE was also significantly increased in the renal cortex of Nx.Conclusion: Heminephrectomy of HIGA mice may be a potential model for the research into the progressive glomerulosclerosis of human IgA nephropathy. The pathological role of apoptosis is apparently involved in these disease processes, possibly through up-regulated RAS.

Notes: IgA nephropathy (IgAN) was first reported by Berger in 1968, and characterized by diffuse IgA deposits in glomerular mesangium and mesangial proliferative glomerulonephritis. Clinically, patients with IgAN have frequently episodic macroscopic haematuria accompanied with pharyngitis, tonsillitis, gastroenteritis, bronchitis, or sinusitis. These findings suggest that IgAN is related to inflammatory and immune responses to mucosal infections.We have reported that primary IgAN patients with acute onset are often associated with mucosal infections such as pharyngitis and tonsillitis, and Haemophilus parainfluenzae (HP) is more frequently isolated from the pharynx of patients with IgAN than from those with other diseases.1 We also demonstrated glomerular deposition of outer membrane of HP (OMHP) antigens and the presence of IgA antibody against OMHP in patients with IgAN.1 These findings suggest that HP has a role in the aetiology of primary IgAN.In the present study, we attempt to develop an experimental model of IgAN induced by oral and intraperitoneal immunization of OMHP antigens, and evaluate the difference in immunological and histopathological changes between these two administration routes.Four-week-old female C3H/HeN mice were fed mouse chow. One hundred and twenty mice were divided into oral (PO group) and intraperitoneal (IP group) administration groups of OMHP antigens and each control groups. Mice of the PO group received OMHP antigens for daily drinking water and intragastric intubation once a week, and mice in the IP group received intraperitoneal injection of 0.1 mL of OMHP antigens, once a week. Six mice from each group were killed at 10, 20, 30, 40 and 50 weeks of age to examine sequential glomerular changes. We also measured serum IgG, IgA, IgM antibody against OMHP antigens, and serum IL-10 and IFN γ by ELISA. Throughout experiments, haematuria and proteinuria were analysed every 5 weeks.IgA antibodies against OMHP significantly increased in PO and IP groups compared with the control, and the degree of increase in IgA antibodies against OMHP was more prominent in the PO group. In the IP group, IgG and IgM antibodies against OMHP increased more markedly. Glomerular deposition of IgA and increase of mesangial matrix were observed in the PO group from 40 weeks of age and in the IP group from 30 weeks of age, respectively. Mice in both groups showed glomerular deposition of OMHP antigens. Haematuria was not detected in any group. Serum IL-10 tended to increase in the PO and IP groups, and IFN γ did not increase significantly in any group.These results suggest that oral administarion of OMHP antigens induce glomerular deposition of IgA and mesangial proliferation with increase of IgA antibodies against OMHP antigens in mice, and these observations in the PO group resemble the changes of human IgAN more closely than in the IP group.

Notes: IgA nephropathy (IgAN) is characterized by the presence of IgA deposits, predominantly in the glomerular mesangium, and by mesangial proliferative glomerulonephritis (GN). Concerning its pathogenesis, several investigators have suggested that the glomerular IgA deposits in IgAN are antibodies (Ab) to viral, bacterial or dietary antigens. Thus, the Ab are probably produced as part of the specific host immune response to various environmental antigens. Such reports strengthen the possibility of a relationship between mucosal immunity and the pathogenesis of IgAN. Nevertheless, attempts to isolate a specific IgA circulating immune complex-associated antigen in patients with IgAN have been unsuccessful.We have shown that mucosal infections such as pharyngitis are often associated with the acute onset of IgAN.1 IgAN is, then, an immune complex disease that is caused by a poor mucosal immune response to environmental antigens to which the patient has been chronically exposed. We have observed previously that Haemophilus parainfluenzae (HP) is more commonly isolated from the pharynx of patients with IgAN than from those with other glomerular diseases.2 We have also identified the glomerular deposition of outer membranes of HP antigens (OMHP) and an increased serum concentration of IgA-Ab against OMHP in patients with IgAN.2 Furthermore, we have shown that patients with IgAN have a specific increase in the production of IgA-Ab against OMHP via polyclonal activation against these, with switching of production from one isotype to another (e.g. from IgM to IgA3), and that a significant relationship between IgA-Ab against OMHP and renal lesions exists in patients with IgAN,4 and that OMHP stimulate tonsillar B-lymphocytes to produce specific IgA1-Ab against OMHP and tonsillar T-lymphocytes in patients with IgAN.5,6Our objective was to investigate the production of IgA and several cytokines by tonsillar lymphocytes from patients with IgAN induced by stimulation with OMHP. We used tonsillar lymphocytes from the palatine tonsils of 18 patients with IgAN and 25 patients with chronic tonsillitis but without renal diseases as controls. There were no significant differences in the backgrounds of the two groups. Haemophilus parainfluenzae was detected in the tonsils of all 43 patients before tonsillectomy. We examined production of total IgA, IgA-Ab against OMHP, IL-4, IL-6, IL-10, and TGF-β in the culture supernatants after lymphocyte incubation with OMHP. The spontaneous production of total IgA and TGF-β by tonsillar lymphocytes from patients with IgAN was higher than that by tonsillar lymphocytes from controls (P 〈 0.05). Stimulation with OMHP in vitro enhanced the production of HP-specific IgA by tonsillar lymphocytes from patients with IgAN (P 〈 0.01), but not by tonsillar lymphocytes from controls. Outer membranes of HP stimulation also enhanced the production of TGF-β and IL-10 by tonsillar lymphocytes from patients with IgAN (P 〈 0.001).Our results suggest that the infection of HP in the tonsil may be involved in the aetiology of IgAN.

Notes: Aim:  To investigate the expression of syndecan-1 in thyroid neoplasia. Syndecan-1 is a proteoglycan regulating cell adhesion. Previous studies have demonstrated that decreased expression of syndecan-1 is linked to malignant progression.Methods and results:  Syndecan-1 expression in thyroid neoplasia was studied immunohistochemically. Syndecan-1 was expressed in stromal cells as well as neoplastic epithelial cells. Stromal syndecan-1 expression was observed more frequently in papillary carcinomas larger than 10 mm in size than in microcarcinomas and in widely invasive than in minimally invasive follicular carcinomas. Furthermore, poorly differentiated carcinomas showed this phenomenon more than well-differentiated carcinomas, but the expression in undifferentiated carcinomas was similar to that of poorly differentiated carcinomas. Epithelial syndecan-1 expression was more frequently observed in anaplastic (undifferentiated) carcinomas than in papillary and follicular carcinomas. No significant difference in epithelial expression was found between well and poorly differentiated carcinomas, but undifferentiated carcinomas expressed epithelial syndecan-1 more frequently than did poorly differentiated carcinomas.Conclusions:  These results are in contrast to those previously reported for carcinomas at other sites. It is suggested that the role of syndecan-1 in thyroid carcinomas might be unique. Stromal syndecan-1 expression followed by its epithelial expression is significantly related to progression, including dedifferentiation of thyroid carcinoma.

Notes: Aims:  The tumour suppressor gene maspin is reported to inhibit the motility, invasiveness and metastasis of breast cancer cells. Maspin is expressed in normal mammary myoepithelial cells but is down-regulated during the progression of ductal carcinoma. However, we recently reported that maspin expression was frequently observed in invasive ductal carcinoma (IDC) with an aggressive phenotype, and it was a strong indicator of a poor prognosis. To our knowledge, to date, there has been no report investigating maspin expression in a large series of ductal carcinoma in situ (DCIS).Methods and results:  To clarify whether there is down-regulation during the progression of ductal carcinoma, we immunohistochemically investigated the expression of maspin in 145 DCIS, 92 invasive ductal carcinomas with a predominant intraductal component as well as 94 usual ductal hyperplasias and 27 atypical ductal hyperplasias. The expression of maspin in carcinoma cells was observed in 9.6% (14 of 145) of DCIS and 18.5% (17 of 92) of IDC with a predominant intraductal components. It significantly correlated with larger tumour size (P = 0.013; P = 0.042), higher histological grade (P = 0.015; P = 0.0003) and the presence of comedo-necrosis (P = 0.000005; P = 0.0074) in DCIS and IDC with a predominant intraductal components, respectively. In epithelial cells, the expression of maspin was observed in only one case of usual ductal hyperplasia, and all cases of atypical ductal hyperplasia were negative.Conclusions:  These results and our previous investigation in which 27.4% of IDC were positive for maspin suggest that the expression of maspin in epithelial cells could be up-regulated during the progression of ductal carcinoma, and that it could be correlated with the acquisition of an aggressive phenotype.