Application of the solid phase C1q and Raji cell radioimmune assays for the detection of circulating immune complexes in glomerulonephritis.

The C1q solid phase and Raji cell radioimmune assays were used to determine the frequency of detectable circulating immune complexes in patients with glomerulonephritis. In this study, 46% of 56 patients with glomerulonephritis had evidence of circulating immune complexes. More important, circulating immune complexes were associated with some, but not other, types of glomerulonephritis. Thus, immune complexes were detected in lupus glomerulonephritis (9/9 patients), rapidly progressive glomerulonephritis (5/6 patients), and acute nephritis (5/6 patients), but not in IgA-IgG glomerulonephritis (0/7 patients), or membranous glomerulonephritis (0/8 patients). The Raji cell radioimmune assay and the C1q solid phase radioimmune assay showed concordance of 79% in the detection of circulating immune complexes. Serial determinations, in general, showed either persistence of a negative or positive result of conversion of positive to negative.

Candidate gene region for polycystic ovary syndrome on chromosome 19p13.2.

CONTEXT: Polycystic ovary syndrome (PCOS) is a common endocrine disorder that is believed to have a genetic basis. However, no specific susceptibility gene or region has been conclusively identified. OBJECTIVE: The objective of this study was to duplicate a previous study that localized a PCOS susceptibility region to chromosome 19p13.2 and to narrow the susceptibility region. DESIGN: This study was designed to test for genetic linkage and association between PCOS and short tandem repeat polymorphisms in 367 families, by analysis of linkage and family-based association. SETTING: The study was conducted at academic medical centers. PATIENTS OR OTHER PARTICIPANTS: We studied 367 families of predominantly European origin with at least one PCOS patient. Families included 107 affected sibling (sister) pairs (ASPs) in 83 families, and 390 trios with both parents and an affected daughter. The data set comprises two independent groups. Set 1 consists of 44 ASPs and 163 trios. Set 2 consists of 63 ASPs and 227 trios. INTERVENTION(S): The intervention was the drawing of blood for DNA extraction. MAIN OUTCOME MEASURE: We employed measures of evidence for linkage and association between PCOS and 19 STRs. RESULTS: Linkage with PCOS was observed over a broad region of chromosome 19p13.2. The strongest evidence for association was observed with D19S884 (chi2 = 11.85; nominal P < 0.0006; permutation P = 0.034) and duplicated our earlier findings. CONCLUSIONS: The present analysis suggests that a PCOS susceptibility locus maps very close to D19S884. Additional studies that systematically characterize DNA sequence variation in the immediate area of D19S884 are required to identify the PCOS susceptibility variant.

IgA nephropathy--accumulated experience and current concepts.

Primary IgA nephropathy is the most common form of glomerulonephritis in Australia. The condition presents in a variety of ways, but commonly with synpharyngitic hematuria, most often in young men in the third and fourth decades. The course of the disease is indolent but there is progression to renal failure in up to one quarter of cases. Renal biopsy morphology is variable but the essential immunofluorescence finding is diffuse mesangial IgA staining of greater intensity but often in association with other immunoglobulins. C3 is usually also present. Mesangial cellularity is increased in some two-thirds of cases, one third being of a minor focal or variable extent and one-third diffuse. Focal segmental lesions, hyaline nodules and vascular changes are frequent. Crescents are also often present. The etiology of the disease is uncertain but has been linked with HLA antigens, elevated serum IgA levels, IgA polymers, immune complexes and impaired T cell function. Secondary forms of mesangial IgA deposition occur with mucosal defects, hyperglobulinemia or impaired hepatobiliary clearance, and these may offer some insight into the immunopathogenesis of the primary disease.

Vascular IgA deposits in clinically normal skin of patients with renal disease.

Direct immunofluorescent tests for IgA deposits were done on biopsies of normal appearing skin from 49 patients with proven renal disease and 7 healthy individuals, in order to evaluate the method in the diagnosis of IgA nephropathy. Many of the 28 patients with IgA nephropathy had high levels of IgA deposition, often accompanied by notable deposits of IgM, Clq and fibrin, and less frequently by C3 and IgG, in small vessels of the superficial dermis. However, some of the 21 patients with other renal diseases had heavy deposits of IgA, limiting the usefulness of the test as a diagnostic aid.

Typing of intraglomerular mononuclear cells associated with transplant glomerular rejection.

To investigate the pathogenesis of glomerular injury in renal allografts, we have analyzed intraglomerular mononuclear cells from 20 biopsies with typical features of transplant glomerular rejection (TGR) (segmental or global occlusion of capillaries by swollen cells). Ten biopsies showing cellular rejection but no glomerular pathology were selected as controls. Microwave fixation and an avidin-biotin immunoperoxidase technique were used with the following monoclonal antibodies; Leu1 and OKT3 (pan T cell), Leu 3 a + b and OKT4 (helper T cell), OKT8 (cytotoxic T cell), OKB7 (B cell), OKM1 (monocyte) and OKDR (DR positive cell). The results showed a significant increase of T cells, helper T cells, cytotoxic T cells and monocytes in the patients with TGR compared with the controls (all p less than 0.001, Mann-Whitney U test). Of the T cell subsets, cytotoxic T cells outnumbered helper T cells by a mean ratio of 3.2:1. In the interstitium, the distribution of mononuclear cells was not different between the two patient groups. In both, T cells and monocytes were predominant and few B cells were found. The percentage of cytotoxic T cells was similar to that of helper T cells. In this study, there were at least four TGR patients without cytomegalovirus (CMV) infection and the distribution of intraglomerular mononuclear cells in these patients was indistinguishable from that of other TGR patients. There was no significant association of the distribution of mononuclear cells with the severity of glomerular damage. These results suggest that T cells, predominantly of the cytotoxic subset and monocytes are involved in the mediation of TGR.(ABSTRACT TRUNCATED AT 250 WORDS)

Thin membrane nephropathy: a clinico-pathological study.

Thin membrane nephropathy is common, representing approximately 11% of non-transplant renal biopsies. A family history of renal disease is present in at least 40% of patients. Electron microscopy is essential for its diagnosis. There are no immunofluorescence markers but light microscopic changes, usually mild, are invariably present and predict the ultrastructural findings although there is no correlation with their degree. The extent of the morphological changes bears no obvious relationship either to clinical or familial features. Immunogold studies indicate that there is reduction or loss of the subepithelial portion of the basement membrane, which apparently contains normal amounts of type IV collagen. Unnecessary urological investigations may be avoided by awareness of the condition and microscopic examination of urine for dysmorphic red blood cells. Prospective long-term studies are necessary to determine the nature and consequences of the condition.

Quantitation of glomerular angiotensin II receptors in IgA nephropathy.

Mesangial cells have receptors for angiotensin II (AII) and contract in its presence. All is known also to increase the uptake of macromolecules by the mesangium. As a first step towards the investigation of a possible role for local disturbances of the renin-angiotensin system (RAS) in immune mediated mesangial proliferative glomerulonephritis, glomerular All receptors have been quantitated retrospectively in biopsy tissue from 20 patients with IgA nephropathy for comparison with 16 biopsies that showed only minor abnormalities by light microscopy and negative immunofluorescence. An autoradiographic technique using 125I labelled [Sar1, Ile8] All facilitated the quantitation of All receptors in frozen tissue sections. Following exposure to the treated sections, x-ray film was analyzed by computerized micro-densitometry. The data obtained were optical densities of areas corresponding to the presence of glomeruli verified by reference to adjacent sections stained with periodic acid-Schiff (PAS). There was no significant difference between patients 0.67 +/- 0.16 (mean +/- SD) and controls 0.61 +/- 0.15. Among patients there was no statistically significant correlation of glomerular All receptor density with either the degree of mesangial proliferation or the extent of hyperplasia of the juxtaglomerular apparatus (JGA). There was no apparent relationship with hypertension. The absence of an increase in glomerular All receptors despite proliferation of the glomerular mesangium may represent a local down regulation in patients with IgA nephropathy.

Glomerular IgG subclass distribution in human glomerulonephritis.

IgG subclass distribution was determined in glomerular immune deposits found in patients with membranous, mesangiocapillary, lupus and antiglomerular basement membrane antibody induced glomerulonephritis. In each disease category IgG3 was the predominant subclass found. In membranous, lupus and anti-glomerular basement membrane antibody induced nephritis the other subclasses were detected in significant but lesser amounts although in anti-glomerular basement membrane antibody induced nephritis IgG2 deposition was minimal. Particularly striking was the excess of IgG3 compared with other subclasses in mesangiocapillary glomerulonephritis and the greater amount of IgG4 in membranous glomeruli compared to the other disease categories. These findings indicate a difference between the distribution of IgG subclasses in normal plasma and glomerular immune deposits and may be of importance in the pathogenesis of the types of glomerulonephritis studied.

The syndrome of IgA nephropathy.

A review is presented of the current knowledge concerning the syndrome of IgA nephropathy. Primary and secondary forms can now be delineated and this division has improved understanding of immunopathogenetic mechanisms giving rise to glomerular mesangial IgA deposits. Attention is paid to disorders of antigen exclusion at mucosal surfaces, defective reticulo-endothelial sequestration, and altered immunoglobulin A production and regulation. Particular reference is made to these mechanisms with respect to primary IgA nephropathy, Henoch-Schoenlein purpura and mesangial IgA nephritis associated with alcoholic cirrhosis.

The effect of treatment with prednisolone or cyclophosphamide-warfarin-dipyridamole combination on the outcome of patients with membranous nephropathy.

Between 1973 and 1986, 109 patients with membranous nephropathy have been evaluated with respect to clinical presentation, pathological features and factors determining prognosis. Secondary disease was present in 21, and a further 21 were lost or followed for less than 12 months. The remaining 67 with idiopathic membranous nephropathy were allotted to one of three groups. Group 0 (26 patients) received no active treatment, Group 1 (12 patients) a combination of cyclophosphamide, dipyridamole and warfarin, and Group 2 (21 patients) high dose alternate day prednisolone therapy. Eight patients received other treatment or presented with end stage renal disease. No significant difference in outcome could be detected between the groups. Remission rates were equivalent as were numbers of patients judged as having progressive disease. There was no statistical difference with respect to duration of nephrotic syndrome, plasma creatinine at the end of study and change in plasma creatinine. No demonstrable benefit was obtained in predicting the outcome of disease or response to treatment from conventional pathological grading of stages I to IV as approximately equal numbers of each stage fell into good and bad categories of outcome. Similarly unusual histological features such as mesangial proliferation and immunofluorescence for deposits other than IgG and C3 were not helpful. A different approach to treatment of idiopathic membranous nephropathy is strongly recommended.

Membranous nephropathy with graft-versus-host disease in a bone marrow transplant recipient.

A 43-year-old man developed the nephrotic syndrome 26 months after allogeneic bone-marrow transplantation for chronic myeloid leukemia. This occurred during an exacerbation of graft-versus-host disease (GVHD) and both problems remitted after therapy with cyclosporine and prednisolone. Renal biopsy showed ultrastructural and immunofluorescence evidence of membranous nephropathy. Anti-nuclear antibodies (but not antiglomerular or anti-renal tubular epithelial antibodies) were detected in his serum. Experimental GVHD in mice has been associated with immune complex glomerulonephritis and the presence of IgG autoantibodies which has been attributed to abnormal T (donor)/B (recipient) cell co-operation. This association can be extrapolated to the human GVHD where autoantibody formation is better described than immune complex glomerulonephritis.

Controlled trial of phenytoin therapy in IgA nephropathy.

IgA nephropathy, a condition thought to cause slowly progressive renal damage, is frequently associated with high serum IgA levels. As phenytoin sodium lowers serum IgA concentrations, a controlled trial of therapy with this drug was conducted over a two-year period in patients with IgA nephropathy. Despite significant depression of serum IgA concentrations in the treatment group, there was no significant change in any other clinical, biochemical or pathological parameter, in either control or treatment groups. Indeed, there was evidence for a slow progression of renal damage in both groups. These observations suggest that the elevated serum IgA concentrations in IgA nephropathy are not of primary pahtogenetic significance but are rather a consequence of a basic abnormality in antigen processing and IgA production.

Plasmapheresis in glomerulonephritis.

Plasmapheresis together with immunosuppressive drug therapy has been used in the treatment of 17 patients with glomerulonephritis [Goodpasture's syndrome (4), systemic lupus erythematosus (4), mesangiocapillary glomerulonephritis (2), glomerulonephritis associated with cirrhosis (2), nonspecific mesangial proliferative glomerulonephritis (3), Henoch-Schoenlein purpura glomerulonephritis (1) and glomerulonephritis associated with infective endocarditis (1)]. Use of the Haemonetics Model 30 blood cell separator, exchanging two liters of plasma with 5% albumin in Hartmann's solution has provided a safe, effective but relatively expensive procedure, capable of producing a marked reduction of fibrinogen, complement components, anti-glomerular basement membrane antibody and immune complex concentrations. Removal of one or more of these factors is felt to be at least partly responsible for the improvement in renal function and clinical well-being demonstrated in patients with Goodpasture's syndrome, systemic lupus erythematosus and other forms of glomerulonephritis associated with the presence of circulating immune complexes.

Smoking in Maywood: the unhealthy southern migrant hypothesis among African Americans.

OBJECTIVES: This paper examines the "unhealthy Southern migrant" hypothesis with regard to cigarette smoking among African Americans. METHODS: Using data collected in 1992 from a sample of 1,518 African Americans in Maywood, Illinois, as part of the International Collaborative Study of Hypertension in Blacks, logistic regression analysis was conducted to examine and compare smoking behavior and sociodemographic characteristics of Southern and Midwestern-born respondents. RESULTS: African Americans born in the South were less likely (OR = .69, CI = 95%, 0.53, 0.90) to be smokers than those born in the Midwest, after controlling for other sociodemographic variables, prior smoking status, and age of arrival to Maywood. CONCLUSIONS: The results do not support the "unhealthy Southern migrant" hypothesis, with regard to cigarette smoking, and indicate the need to identify factors that protect Southern-born African-American migrants from smoking.

Human and mouse microglia express connexin36, and functional gap junctions are formed between rodent microglia and neurons.

Microglia, the tissue macrophages of the central nervous system (CNS), intimately interact with neurons physically and through soluble factors that can affect microglial activation state and neuronal survival and physiology. We report here a new mechanism of interaction between these cells, provided by the formation of gap junctions composed of connexin (Cx) 36. Among eight Cxs tested, expression of Cx36 mRNA and protein was found in microglial cultures prepared from human and mouse, and Cx45 mRNA was found in mouse microglial cultures. Electrophysiological measurements found coupling between one-third of human or mouse microglial pairs that averaged below 30 pico-Siemens and displayed electrical properties consistent with Cx36 gap junctions. Importantly, similar frequency of low-strength electrical coupling was also obtained between microglia and neurons in cocultures prepared from neocortical or hippocampal rodent tissue. Lucifer yellow dye coupling between neurons and microglia was observed in 4% of pairs tested, consistent with the low strength and incidence of electrical coupling. Cx36 expression level and/or the degree of coupling between microglia did not significantly change in the presence of activating agents, including lipopolysaccharide, granulocyte-macrophage colony-stimulating factor, interferon-gamma, and tumor necrosis factor-alpha, except for some reduction of Cx36 protein when exposed to the latter two agents. Our findings that intercellular coupling occurs between neuronal and microglial populations through Cx36 gap junctions have potentially important implications for normal neural physiology and microglial responses in neuronopathology in the mammalian CNS.