Masanobu Miyazaki

Altered production of IgE and IgA induced by IL-4 in peripheral blood mononuclear cells from patients with IgA nephropathy.

In order to elucidate the factors responsible for altered immunoglobulin production in patients with IgA nephropathy (IgAN). the in vitro effects oHL‐4 and intcrferon‐gamma (IFN‐γ) on the synthesis of IgE and IgA by peripheral blood mononuclear cells (PBMC) were studied. Spontaneous IgE and IgA synthesis by PBMC was significantly increased in patients with IgA nephropathy compared with controls. The maximum amounts of IgA and IgE synthesis by PBMC after stimulation with IL‐4 were almost the same both in patients with IgAN and in controls. The enhancement rate of IL‐4‐induccd IgE and IgA synthesis was significantly lower in IgAN than in the controls, suggesting in vivo preactivation of PBMC in IgAN patients. IFN‐γ suppressed IgA and IgE synthesis by PBMC from IgAN patients as well as controls. However, the suppressive effect on IgE synthesis was less prominent in patients with IgAN. These results suggested that altered IL‐4 action might be involved in the development of IgA ncphropathy.

Increase of CD23-Positive Cells in Peripheral Blood from Patients with IgA Nephropathy and Non-lgA Proliferative Glomerulonephritis

CD23 is a surface marker of activated B cells as well as a low-affinity Fc receptor for IgE. In this study, we enumerated CD23-positive peripheral blood lymphocytes and evaluated their clinical significance in patients with IgA nephropathy (IgAN). Twenty-five patients with IgAN and 16 patients with non-IgA proliferative glomerulonephritis (PGN) were studied. Twenty-seven healthy adults served as controls. CD23-bearing cells were enumerated by flow cytometry, and serum IgE levels were measured by latex photometric immunoassay. Significant increases in the number of CD23-positive cells were observed in patients with IgAN (p less than 0.01) and PGN (p less than 0.05) compared with controls. A significant elevation of serum IgE levels was also observed in the patients with IgAN and PGN (p less than 0.05). No positive correlation between the number of CD23-positive cells and serum IgE levels was observed. We also examined the induction of surface CD23 expression on peripheral lymphocytes by interleukin (IL)-2, IL-3, IL-4, IL-5, IL-6, interferon (IFN)-gamma, IFN-alpha, phytohemagglutinin, concanavalin A, pokeweed mitogen, lipopolysaccharide and phorbol myristate acetate. IL-4 was revealed to have a significantly potent effect on the induction of cell surface CD23 compared with other stimulants. It was concluded that many patients with IgAN or PGN show high serum IgE levels and/or high CD23-positive cell counts in their peripheral blood, suggesting that hyperactivation of B cells might be involved in the development of IgAN and non-IgA PGN. It appeared that IL-4 may play a significant role in the etiology of these types of glomerulonephritis.

Homozygous C3 Deficiency Associated with IgA Nephropathy

A 23-year-old male patient with homozygous C3 deficiency who developed asymptomatic proteinuria and hematuria was reported. Renal biopsy disclosed typical IgA nephropathy with deposition of early- and late-complement components except for C3 deposition. C9 and membrane attack complex were detected in the glomeruli despite the absence of C3. It was suggested that there might be some unknown complement activation mechanism which does not require C3 component.

Rheumatoid factors and glomerulonephritis

It is presently unknown whether rheumatoid factors have a pathogenic role in the development of various types of glomerulonephritis with immune deposits. Three isotypes of rheumatoid factors (RFs), which are autoantibodies to IgG, were measured using the solid‐phase fluorescence immunoassay in sera from patients with diffuse proliferative lupus nephritis (DPLN), membranous lupus nephritis (MLN), IgA nephropathy (IgAN) and idiopathic membranous nephropathy (MN). RF activity of immunoglobulins deposited in the glomeruli from these patients was also studied by examining the binding of the FITC‐conjugated human IgG and Fc portion of IgG to the glomeruli of renal biopsy specimens. IgG, IgA and IgM RFs were significantly increased in sera from patients with DPLN. and the increase was significantly lower in patients with MLN. IgAN and MN. Human IgG bound to immunoglobulin on the glomeruli only in DPLN, but not in MLN, IgAN or MN. The Fc portion of IgG was demonstrated to be involved in this reaction. It was suggested that RFs and IgG may play a major role in immune deposits on the glomeruli in DPLN and may be involved in the development of DPLN; however, this is not likely in MLN, IgAN or MN.

Acetazolamide assisted Tc-99m MAG3 renography to assess renal blood flow reserve

Objective: The present study examines whether or not baseline and acetazolamide (ACZ) Tc-99m MAG3 renography can assess renal blood flow reserve.Methods: Renography proceeded for 50 min after sequential injections of 370 MBq Tc-99m MAG3 for baseline renography and 10 min after a 1,000 mg injection of ACZ for ACZ renography. Effective renal plasma flow of renal cortex (cERPF) in each kidney and the percentage change in cERPF of those parameters (ΔERPF) were obtained before and after the administration of ACZ in 10 subjects without hypertension or diabetes (normal group), in 10 with essential hypertension (hypertensive group) and in 10 who had Type 2 diabetes with hypertension (diabetic group). A placebo test was performed in the 10 without hypertension or diabetes using distilled water instead of ACZ (placebo group).Results: The placebo test performed in the 10 without hypertension or diabetes using distilled water instead of ACZ indicated that the parameter variance between the two types of renogram was below 3.2%. The cERPF of baseline and ACZ Tc-99m MAG3 renography and δERPF in the normal, hypertensive and diabetic groups were 89±10 and 110±10 ml/min, 89±14 and 117±22 ml/min, 100±23 and 112±23 ml/min, respectively, and 24.5±13.5%, 26.0±9.7% and 12.3±11.1%, respectively. The difference in the cERPF value was significant in the normal and hypertensive groups whereas this did not change in the diabetic group before or after ACZ administration.Conclusions: We suggested that the δERPF determined by baseline and ACZ Tc-99m MAG3 renography is a useful parameter for assessing renal blood flow reserve.

Interstitial naive and memory T cells in chronic mesangial proliferative glomerulonephritis.

Naohiro Yano, MD, Department of Internal Medicine, Tokai University, Isehara, Kanagawa, 259-11 (Japan) Dear Sir, The degree of cell infiltration in the inter-stitium showed direct correlation with the severity of glomerular damage in typical cases of primary glomerulonephritis [1]. However, the role of interstitial infiltrating cells in the progress of glomerulonephritis has not been clarified. A common finding in previous reports [2, 3] is the dominance of CD4-positive helper/inducer T cells in the interstitium. For further analysis of the phenotypes and the roles of interstitial cells, immunohistochemical staining of CD45RA-positive cells, that is, non-antigen-stimulated ‘naive T cells’ and CD45RO-positive cells, that is, antigen-stimulated ‘memory T cells’ [4, 5] in primary chronic mesangial proliferative glomerulonephritis (CGN) using the avidin-biotin complex peroxidase technique was performed. As shown in table 1, we evaluated renal tissues after separating them into two groups, i.e., mild glomerular change group (grade I or II) and moderate to severe change group (grade III or IV). CD45RO-positive memory T cells were the dominant population of interstitial infiltrating T cells (fig. 1). Memory T cells are known as producers of cytokines [5,6]. In order to evaluate the hypothesis that infiltrating T cells produce cytokines, we attempted immunohistochemical peroxidase-alkaliphosphatase double staining using several anticytokine antibodies, but no clear signals indicating memory T cells produced some cytokines could be obtained. A sophisticated technique such as the in situ hybridization method is required to clarify the role of interstitial memory T cells. Acknowledgement This study was supported by a grant from the Japanese Ministry of Health and Welfare.

Association of IgA Nephropathy and Myasthenia gravis

Three patients with IgA nephropathy associated with myasthenia gravis are described. In all 3 cases, myasthenia gravis emerged after the discovery of glomerulonephritis. Myasthenic symptoms were improved by thymectomy in 2 cases, but progression of the renal disease was not improved. Some systemic abnormalities, including immunological aberrations, were observed in these two disorders. It is postulated that T cell abnormalities in IgA nephropathy might be independent of the development of myasthenia gravis.

Activation of mRNA expression of collagen, collagenase and its inhibitor on renal biopsy specimens in patients with IgA nephropathy

Summary: In situ hybridization of mRNA for collagen IV, collagen VI, stromelysin (MMP‐3) and TIMP1 was examined in renal biopsy specimens from patients with IgA nephropathy (IgAN) or diabetic nephropathy with various degrees of tissue damage. The majority of cells in the glomeruli expressed these mRNA almost simultaneously, but a few cells demonstrated positive expression for only one of these probes. There was a parallel relationship between the degree of tissue damage and that of mRNA expressions of these probes in patients with IgAN, while patients with diabetic nephropathy showed a reverse relationship between these two parameters. It is concluded that patients with mesangial proliferative glomerulonephritis expressed mRNA for collagen collagenase and its inhibitor in the glomeruli in parallel with the progress of tissue damage. In contrast, glomerular samples from patients with diabetic nephropathy showed that there was an inverse relationship between tissue damage and expression of mRNA. It is concluded that expression of collagen, collagenase and its inhibitor parallels the progression of glomerular changes in IgAN, but such parallel expression was not observed in patients with diabetic nephropathy.