Wegener granulomatosis.
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Antibodies, Antineutrophil Cytoplasmic↗
Biomedical subjects
R T McCluskey
Publications and source records attributed to R T McCluskey.
Antineutrophil cytoplasmic autoantibody-associated vasculitis presenting as Sjögren's syndrome.
A 63-year-old woman, in whom a diagnosis of Sjögren's syndrome was initially made, proved to have systemic vasculitis with salivary gland involvement and necrotizing and crescentic glomerulonephritis. Antineutrophil cytoplasmic autoantibodies (ANCA) against myeloperoxidase were positive. ANCA-associated vasculitis should be considered in the differential diagnosis of Sjögren's syndrome. A positive finding on immunoassay for ANCA against myeloperoxidase or proteinase 3 may help establish the diagnosis.
Antibodies, Antineutrophil Cytoplasmic↗
Antigen-specific radioimmunoassays for anti-neutrophil cytoplasmic antibodies in the diagnosis of rapidly progressive glomerulonephritis.
Circulating anti-neutrophil cytoplasmic antibodies (ANCA) have been described in most patients with "pauci-immune" necrotizing and crescentic glomerulonephritis. A 29-kDa serine protease (p29 or proteinase 3) and myeloperoxidase are the two best characterized antigens recognized by ANCA. The study presented here was conducted to define the diagnostic value of assays for antibodies against these two antigens in rapidly progressive glomerulonephritis. Radioimmunoassays were developed for anti-p29 and anti-myeloperoxidase antibodies, with purified antigens, and the results of the radioimmunoassays were compared with those obtained by immunofluorescence tests for ANCA. We performed assays on serum samples from 123 patients with the syndrome of rapidly progressive glomerulonephritis, as well as from 200 blood bank donors and from 717 additional control patients. Without knowledge of the results of ANCA tests, the renal pathologic findings in the 123 patients with rapidly progressive glomerulonephritis were analyzed, and 42 were classified as pauci-immune necrotizing and crescentic glomerulonephritis, 18 were classified as anti-glomerular basement membrane nephritis and 63 were classified as other forms of renal disease. We found radioimmunoassays to be more reliable in the diagnosis of pauci-immune necrotizing and crescentic glomerulonephritis than immunofluorescence testing. By radioimmunoassay, ANCA were found in 40 of 42 patients (95% sensitivity) with pauci-immune necrotizing and crescentic glomerulonephritis (14 with anti-p29 and 26 with anti-myeloperoxidase antibodies). The tests for antibodies to p29 and myeloperoxidase were 99.9 and 99.5% specific for pauci-immune necrotizing and crescentic glomerulonephritis, respectively. In the setting of rapidly progressive glomerulonephritis, a positive radioimmunoassay for anti-p29 or anti-myeloperoxidase antibodies (together with a negative test for anti-GBM antibodies) gives a probability of pauci-immune necrotizing and crescentic glomerulonephritis of over 99%.
Autoantibodies↗
Loss of antigens associated with the apical endocytotic pathway in proximal tubules from rats with heymann nephritis.
In addition to the glomerular lesions associated with Heymann nephritis, a rat model of human membranous nephritis, proximal tubule damage, and a perturbation of proximal tubule function also have been reported to occur in this disease. The aim of the present study was to examine in more detail the nature of the apical plasma membrane damage in proximal tubules using specific antibodies directed against clathrin, gp330, and a proton-pumping adenosine triphosphatase, all of which are components of the apical endocytotic apparatus of these epithelial cells. Immunocytochemical studies revealed a marked reduction in staining for all three antigens in proximal tubules from rats with active Heymann nephritis. Furthermore endocytotic uptake of intravenously injected FITC-dextran was considerably lower in diseased animals than in normal rats. Gp330 and rat IgG were identified as components of the luminal debris that accumulated during the course of Heymann nephritis. These results show that perturbation of proximal tubule endocytosis occurs in Heymann nephritis together with a loss of three apical antigens that are normally localized on membrane domains associated with the apical endocytotic pathway in these cells. The results also suggest that antibody-antigen complexes may be shed from the plasma membrane in both the glomerulus and the proximal tubule in this disease.
Adenosine Triphosphatases↗
A cell-mediated reaction against glomerular-bound immune complexes.
Lewis rats were given a single i.v. injection of soluble immune complexes containing human serum albumin (HSA) and rabbit anti-HSA antibodies, prepared in antigen excess. This resulted in localization of HSA and rabbit gamma globulin (RGG) in glomerular mesangial regions without producing definite histologic changes. 24 h after the injection of immune complexes, groups of these rats received lymph node cells or T-cell preparations from syngeneic donors sensitized to RGG, HSA, or ovalbumin; another group received no cells. All of these groups and a group of normal control rats were given injections of [3H]thymidine at 18, 27, and 44 h. The animals were killed 48 h after the time of cell transfer. In histologic sections, glomerular abnormalities were found only in some of the animals that had received immune complexes and lymph node cells or T-cell populations from donors sensitized to HSA or RGG; the lesions were characterized by focal and segmental increase in cells in mesangial regions. Autoradiographs revealed significantly greater numbers of labeled cells in mesangial regions and glomerular capillaries in the groups that had received immune complexes and cells from HSA- or RGG-sensitized donors than in any of the other groups. Electronmicroscopic studies suggested that the increase in cellularity in mesangial regions resulted from an influx of mononuclear phagocytes. The findings indicate that cell-mediated reactions can be initiated by the interaction between sensitized T lymphocytes and antigens present in immune complexes within mesangial regions.
Animals↗
Evidence for a pathogenic role of a cell-mediated immune mechanism in experimental glomerulonephritis.
Lewis rats were injected intravenously with rabbit anti-rat glomerular basement membrane (GBM) antisera in doses that were sufficient to cause glomerular fixation of rabbit gamma globulin (RGG) detectable by immunofluorescence, but which failed to induce histologically detectable lesions. 24 h later, groups of rats received lymph node cells or serum from syngeneic donors that had been immunized with either RGG or ovalbumin; they were injected with [3H]thymidine three times during the next 2 days, and sacrificed 48 or 96 h after transfer. Only the rats given anti-GBM antiserum plus lymph node cells from donors sensitized to RGG showed histological glomerular lesions, in the form of segmental hypercellularly and necrosis. Autoradiographs revealed the greatest number of labeled cells in glomeruli in the same group. In analogous experiments, it was shown that T-cell-enriched populations could induce hypercellular glomerular reactions. On the basis of electronmicroscopic and autoradiographic observations, it appears that the glomerular hypercellularity resulted from both infiltration of mononuclear cells and proliferation of endothelial cells. The findings indicate that interaction of specifically sensitized lymphocytes with glomerular-bound antigen can induce a cell-mediated (delayed-type) reaction in glomeruli.
Animals↗
Immune complex mediated diseases.
Immune complexes formed in the circulation are believed to be the principal pathogenetic agents in certain human diseases, notably in various forms of glomerulonephritis and arteritis. Criteria for the recognition of immune complex deposits in tissue are discussed and recently developed sensitive methods that detect circulating immune complexes are reviewed. In addition, the evidence implicating certain antigens and causative agents in human immune complex mediated glomerulonephritis and arteritis is evaluated.
Animals↗
Glomerular C3 receptors in human renal disease.
The relationship between glomerular C3 receptor activity and intraglomerular C3 deposition was studied in 73 cases of various forms of renal disease. C3 receptor activity was measured by enumeration of complement-coated sheep red blood cells (IgM EAC) that adhered to glomeruli in frozen sections and expressed as a percentage of the mean number present in control kidneys. Adjacent sections were studied for the presence and distribution of C3 deposits. The precise location of corresponding dense deposits was determined through 1-mu sections or electron micrographs. Marked depression of C3 receptor activity was found in most cases in which there was accumulation of C3 along the glomerular basement membrane, irrespective of whether the deposits were in a subepithelial, intramembranous, or subendothelial location. In contrast, when C3 was not detectable or was found exclusively in the mesangium, C3 receptor activity was affected only moderately, if at all. These data are consistent with the hypothesis that the interaction of C3 with podocytes is a major determinant in the loss of C3 receptor activity in glomerular disease, but do not exclude the possibility that interaction with mesangial or endothelial cells may also influence C3 receptor activity.
Adenocarcinoma↗
Immunologic aspects of renal tubular and interstitial diseases.
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Animals↗
Enhanced syngeneic tumor destruction by in vivo inhibition of suppressor T cells using anti-I-J alloantiserum.
The cellular response to a methylcholanthrene-induced sarcoma S1509a has been investigated. Histologic analysis of the in vivo response to S1509a included a study of tumor development in nonimmune, tumor immune, or hyerimmune syngeneic mice, as well as in nonimmune animals treated with antiserum produced to interact solely with determinants encoded by the I-J subregion of the H-2 major histocompatibility complex. Tumors from immune or hyperimmune mice showed marked infiltration by mononuclear and, to a lesser extent, polymorphonuclear cells, with marked tumor cell necrosis. Anti-I-J treated mice displayed similar but quantitatively reduced leukocytic infiltrates and less evidence of tumor cell degeneration. Untreated nonimmune mice, on the other hand, revealed only mild leukocytic infiltration with little or no necrosis of the tumor. Thus, the administration of anti-I-J antiserum, which has been shown to diminish suppressor cell activity, is associated with increased leukocytic infiltration and enhanced syngeneic tumor destruction in vivo in the nonimmune host.
Animals↗
Membranoproliferative glomerulonephritis (MPGN type I) and dense deposit disease (DDD) in children.
A review of the histologic findings in 27 patients originally classified as having some form of membranoproliferative glomerulonephritis (MPGN) revealed 13 with MPGN Type I and 14 with dense deposit disease (DDD). In all 14 cases where electron microscopy was performed, the histologic diagnosis was confirmed. In nine cases the diagnosis of DDD was easily made in histologic sections on the basis of ribbon-like, brightly PAS positive thickening of the GBM, without "splitting" and with relatively slight mesangial proliferation. However, in five cases the picture closely resembled MPGN Type I, with hypercellularity, "splitting" and only focal ribbon-like thickening of the GBM, which required oil immersion for recognition. There was no correlation between the serum C3 levels and the morphologic diagnosis: nine (4 MPGN Type I, 5DDD) had persistently low C3 levels, two (1 MPGN Tye I, 1DDD) were normocomplementemic, and in 16, the C3 levels varied. C3 levels increased with time in nearly all patients. The clinical course was similar in patients with MPGN Type I and DDD. Significant correlations between the rate of development of renal failure and sex, age of onset, nephrotic syndrome or therapy could not be made. The five year survival rate was 87%; 12 developed renal insufficiency by five years. Although morphologically distinct, these findings suggest that DDD is clinically indistinguishable from MPGN Type I.
Cell Membrane↗
Passive transfer of autoimmune disease with isologous IgG1 and IgG2 antibodies to the tubular basement membrane in strain XIII guinea pigs: loss of self-tolerance induced by autoantibodies.
Initiation of an autoimmune tubulointerstitial disease was achieved in strain XIII guinea pigs by passive transfer of functionally pure IgG1 or IgG2 fractions of isologous anti-tubular basement membrane (TBM) serum. IgG2 appeared to be somewhat more effective than IgG1. The immunopathologic features in the IgG1 and IgG2 recipients were similar at the time of sacrifice, 14 days after transfer. The recipients that developed disease had higher than expected anti-TBM titers at 14 days. Furthermore, anti-TBM antibodies were of both IgG isotypes. In contrast, simultaneously administered IgG1 or IgG2 anti-BGG antibodies declined in titer in the recipients and were never found in the isotype fraction that had not been transferred. These findings indicate that the recipients of anti-TBM antibodies of either IgG1 or IgG2 isotype were stimulated to produce anti-TBM autoantibodies, which participated in the pathogenesis of the renal disease. The model demonstrates that autoantibodies may provide a mechanism (autoimmune amplification) for the intensification and perpetuation of antibody-mediated autoimmune diseases.
Animals↗
Mesangial proliferative glomerulonephritis with irregular intramembranous deposits. Another variant of hypocoplementemic nephritis.
Two patients with a persistent mesangial proliferative glomerulonephritis and reduced serum C3 levels have been followed for six and 10 years. Both have had a mild course with normal renal function and spontaneous morphologic improvement. Levels of the fourth component (C4) and second component (C2) of complement, and properdin factor B have been normal; the third component (C3) of complement nephritic factor has not been detected. Ultrastructurally, irregular intramembranous electron-dense deposits are present, primarily within the lamina densa. These deposits are separated by varying lengths of normal-appearing glomerular basement membrane. Intramembranous and subendothelial electron-lucent areas, containing vesicles, are also seen. Subendothelial deposits, mesangial interposition, splitting of the glomerular basement membrane and ribbon-like intramembranous deposits are not found. The disease in these patients was clinically indistinguishable at onset from mrmbranoproliferative glomerulonephritis (MPGN). The possibility of a variant with mild clinical course, no progression and spontaneous morphologic improvement is important in planning and assessing treatment programs in this disease group.
Adolescent↗
Necrotizing arteritis in acute poststreptococcal glomerulonephritis: report of a recovered case.
A patient with biopsy documented acute poststreptococcal glomerulonephritis and arteritis recovered completely with supportive therapy. Illness was preceded by group A streptococcal pharyngitis. At the time of presentation, serum creatinine concentration was 11.5 mg/dl. Serum cryoglobulins containing IgG and C3 were present. The first biopsy, performed during the acute illness, contained glomeruli with typical features of acute PSGN. Medium-sized arteries had extensive necrosis and leukocytic infiltration, and contained IgG, C3, and fibrin. Glomerular filtration rate returned to normal within three weeks; proteinuria cleared by three months, and microscopic hematuria by 11 months. Renal biopsy one year later showed minimal mesangial hypercellularity and no arteritis.
Acute Disease↗
Diminished glomerular accumulation of colloidal carbon in autologous immune complex nephritis.
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Animals↗
Prenatal diagnosis of the congenital nephrotic syndrome.
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Amniotic Fluid↗
Experimental cell-mediated interstitial nephritis induced with exogenous antigens.
The capacity of intrarenal injections of bovine gamma-globulin (BGG) to elicit hypersensitivity reactions was studied in guinea pigs immunized with DNP BGG or BGG immune complexes in CFA or in rats immunized with BGG in CFA. In guinea pigs it was found that heat-aggregated BGG elicited inflammatory reactions in the renal cortex, whereas soluble BGG did not. In rats only aggregated BGG was used, and this was found to be effective. The reactions were characterized by a predominantly mononuclear cell infiltrate. Transfer experiments were performed in rats and it was found that reactivity was transferrable with lymph node cells but not with serum.
Animals↗
Studies of the antigens involved in an immunologic renal tubular lesion in rabbits.
Rabbits injected with nonglomerular components of rabbit kidney incorporated in Freund's complete adjuvant develop a lesion characterized a) extensive interstitial fibrosis, tubular degenerative changes, and sparse focal lymphocytic infiltrates; b) the deposition of IgG and C3 in a granular pattern along the basement membranes of proximal convoluted tubules; and c) functional tubular defects if the lesions are severe. The antibodies were eluted from kidneys with such lesions and labeled with fluorescein isothiocyanate. It was shown that these fluorescein-labeled eluates reacted with the corresponding antigens in the tubular deposits and also with the antigens present in the brush border and/or cytoplasm of the proximal tubules. The antigens are found in proximal tubules of the kidney but not in brain, lung, heart, liver, spleen, bowel, muscles, or urine. They appear to be soluble but may also be present in the plasma membrane.
Animals↗