Biomedical subjects
D Koffler
Publications and source records attributed to D Koffler.
Resistance to experimental autoimmune myasthenia gravis in genetically inbred rats. Association with decreased amounts of in situ acetylcholine receptor-antibody complexes.
Genetically related susceptibility for experimental autoimmune myasthenia gravis was investigated in nine inbred strains of rats immunized with heterologous acetylcholine (AChR) from Torpedo californica. Wistar Munich and Fischer strain animals consistently developed severe, fatal disease associated with impaired neuromuscular transmission and increased sensitivity to low doses of curare. A lower incidence of disease was induced in Wistar Kyoto, ACI, Brown Norway, Buffalo, and Lewis strain animals. In contrast, Wistar Furth and Copenhagen strain animals were resistant to experimental autoimmune myasthenia gravis, electrophysiologic responses were normal, and animals were insensitive to curare. All strains of animals manifested equivalent amounts of serum antibody to AChR and total muscle AChR was reduced to the same extent in both resistant and susceptible animals. In contrast, the amount of antibody-bound AChR was greater in susceptible Wistar Munich animals than the amount observed in resistant Wistar Furth animals. These data suggest that impaired neurotransmission is correlated with the extent of antibody binding to the AChR. The discordance in the amount of antibody bound to the AChR of resistant and susceptible animals may result from heritable differences in antibody properties. Cross-breeding experiments with Wistar Munich and Wistar Furth animals show that resistance for development of experimental autoimmune myasthenia gravis is recessive and indicate that disease susceptibility is linked to one or two genetic loci.
Reaction of antipolynucleotide antibody from systemic lupus erythematosus patient serum with double-stranded DNA complexed to protein.
Antipolynucleotide antibody from systemic lupus erythematosus patient serum was found to interact with common determinants of double-stranded DNA (dsDNA) complexed to protein within nucleosomes, and with protein-free denatured DNA. In contrast, purified dsDNA isolated from nucleosomes manifested decreased reactivity with antipolynucleotide antibody. These data suggest that immunoassays using denatured DNA antigen substrate are useful for identifying a broad spectrum of antipolynucleotide antibodies that are reactive with dsDNA complexed to protein.
Immunology of systemic lupus erythematosus and related rheumatic diseases.
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Immunopathogenesis of Heymann's nephritis.
Renal localization of the C5b-9 membrane attack complex (MAC) in relation to other complement components and immunoglobulins was studied at different stages of Heymann's nephritis and following reimmunization of Lew rats with stage IV disease. Trace amounts of the MAC were found during stages I and IV of disease, whereas during stages II to III, a period of active glomerular and tubular injury, moderate deposits of MAC were observed in glomeruli, periluminal cytoplasm of proximal tubular epithelial cells, and desquamated intraluminal brush border material. Following reimmunization of stage IV animals, a striking increase in the amount of MAC was observed. Moderate to marked deposition of IgG and C3 was also found during stages II and III at sites containing the MAC. Although a slight decrease in detectable IgG was noted during stage IV, a bright, confluent ribbon-like staining pattern was present in reimmunized animals. These data suggest that the MAC is a mediator for acute in situ immune-complex-induced glomerular and tubular cytoplasmic injury, although subsequent proteinuria may persist without continued complement pathway activation and assembly of the MAC.
Localization of the membrane attack complex (MAC) in experimental immune complex glomerulonephritis.
The role of the membrane attack complex (MAC) as a mediator of renal tissue injury was evaluated in rats affected by bovine serum albumin (BSA)-induced immune complex glomerulonephritis. Immunofluorescence studies revealed concurrent deposits of IgG, BSA, C3, and the MAC along glomerular capillary walls, although the MAC manifested a more restricted distribution than that observed for immune complexes. Immunoelectron microscopic techniques were utilized to demonstrate immune complexes, C3, and the MAC within dense deposits in the subepithelial aspect of the basement membrane. Visceral epithelial foot processes were fused in areas overlying large dense deposits and exhibited intense staining for the MAC, lesser reactivity for C3 but IgG was absent from the foot process membranes. Smaller granular deposits of immune complexes, C3, and the MAC were observed in the subendothelial region of the lamina rara interna and the lamina densa. Immune complexes may activate the classical complement pathway causing diffuse injury to the glomerular basement membrane (GBM), allowing subepithelial accumulation of complexes. These observations implicate the MAC as a mediator of GBM and juxtaposed podocyte membrane injury, thereby contributing to disruption of the glomerular filtration barrier. IgG and C3 were demonstrated within tubulointerstitial regions on the surface of collagen fibers in close proximity to the tubular basement membrane (TBM) of proximal convoluted tubules. Within the TBM, C3 localization was prominent with diminished reactivity for the MAC, but IgG was not detectable. The demonstration of C3 and scant MAC deposits in the TBM of nonimmunized control rats without evidence of interstitial IgG and C3 deposits suggests that both nonimmune and immune processes play a role in the pathogenesis of extraglomerular lesions. Evidence derived from these morphologic studies indicates that the MAC is associated with injury to the GBM, foot process membranes of visceral epithelium, and the TBM. Further experiments designed to selectively enhance or inhibit the deposition of MAC and assess consequent renal dysfunction are required to substantiate hypotheses concerning the in vivo membranolytic potential of the MAC in experimental immune complex glomerulonephritis.
Intrathecal IgG synthesis and blood-brain barrier impairment in patients with systemic lupus erythematosus and central nervous system dysfunction.
Paired serum and cerebrospinal fluid specimens from 19 patients with SLE and central nervous system dysfunction were studied with respect to cerebrospinal fluid IgG index (a measure of intrathecal IgG synthesis), isoelectric focusing using immunoperoxidase staining techniques to detect oligoclonal IgG, and determination of the cerebrospinal fluid/serum albumin quotient (Q albumin) as a measure of blood-brain barrier integrity. Twenty-five patients without neurologic disease and 70 patients with a variety of non-SLE neurologic disorders were also studied for comparison. Of most interest was the observation that 42 percent of the patients with SLE had cerebrospinal fluid oligoclonal IgG, usually in association with elevation of the cerebrospinal fluid IgG index. In addition, two of the cerebrospinal fluid specimens that exhibited oligoclonal IgG also had increased titers of alpha-interferon. Q albumin was normal (under 9.0) in 12 of 13 patients with SLE, who had seizure, psychosis, or cranial neuropathy as principal central nervous system manifestations (mean +/- SD = 5.3 +/- 2.4), but was significantly elevated (mean +/- SD = 27.4 +/- 18.8, p less than 0.001) in five of six patients with diffuse, major central nervous system injury, for example, encephalopathy with coma, transverse myelopathy, paraparesis. Blood-brain barrier impairment was not correlated either with presence of circulating immune complexes or with other clinical or serologic evidence for extra-central nervous system disease activity. Taken together, the data suggest that, within the limitations of the techniques used, impairment of the blood-brain barrier in SLE may be secondary to the central nervous system lesion, rather than a result of systemic immune complex injury. In addition, substantial evidence is provided for an ongoing humoral immune response within the central nervous system in this disorder, which, in certain patients, may be associated with the production of intrathecal alpha-interferon.
Antipolynucleotide antibodies: the rheumatic connection.
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Immunology of myasthenia gravis.
Anti-acetylcholine-receptor antibody is demonstrable in more than 90 per cent of patients with myasthenia gravis. Serum antibody titers do not show a direct correlation with disease severity, although in certain patients antibody levels increase in association with disease activity. Impairment of neuromuscular transmission results from the loss of junctional receptors, either as a result of receptor internalization or destruction of junctional folds containing the acetylcholine receptor. Myasthenia gravis manifests immunologic, genetic, and clinical similarities to rheumatic syndromes, suggesting a generic immune dysfunction common to these disorders.
Cutaneous localization of the membrane attack complex in discoid and systemic lupus erythematosus.
Biopsy specimens of skin lesions from three patients with discoid lupus erythematosus and six patients with systemic lupus erythematosus contained the membrane attack complex, which comprises C5b through C9, as well as immune complexes at the dermal-epidermal junction. The basilar epithelium in these areas was vacuolated and edematous, and the dermis contained an inflammatory infiltrate. In contrast, 19 of 29 specimens of normal-appearing skin from patients with discoid or systemic lupus erythematosus showed only immune complexes at the dermal-epidermal junction, without the membrane attack complex. The other 10 specimens, all from patients without cutaneous involvement, showed neither immune complexes nor membrane attack complexes. These data suggest that immune complexes within skin lesions selectively generate the assembly of the membrane attack complex, which mediates membrane injury. A synergistic interaction of immune complexes and cofactors may be required to activate complement in areas of skin that are predisposed to tissue injury.
introduction to current perspectives on the immunology of systemic lupus erythematosus.
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Staphylococcal protein A fluoroimmunoassay for immune complexes.
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Immunopathogenesis of systemic lupus erythematosus.
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Immunopathology of the membrane attack complex in systemic lupus erythematosus nephritis.
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Renal localization of the membrane attack complex in systemic lupus erythematosus nephritis.
The membrane attack complex (MAC) of the complement system was localized in both glomeruli and peritubular regions of 22 kidneys manifesting systemic lupus erythematosus (SLE) nephritis. A similar distribution was observed for immune complex markers (IgG, Clq, and C3) and MAC in glomeruli, although the deposits of MAC were more discrete and showed lesser immunofluorescence staining intensity compared with immunoglobulins and complement components. In contrast, peritubular immune complexes were present in only 7 out of 22 kidneys, involved comparatively small clusters of tubules, exhibited weaker immunofluorescence staining than MAC, and failed to correlate with interstitial foci of inflammation. Granular or irregular, linear aggregates of the MAC were observed at the periphery of larger groups of tubules contiguous to areas of interstitial inflammation. Comparable amounts of IgG, Clq, C3, and MAC were present in blood vessel walls in areas of fibrinoid necrosis. These data suggest that the MAC is a direct mediator of tissue injury occurring in renal glomeruli, tubules, and blood vessels. The discordance between immune complexes and MAC localized in the peritubular region, but not in glomeruli or blood vessels, raises the possibility that both immune complexes and nonimmune agents, such as bacterial antigens, may activate the classical or alternative complement pathways and thereby play a role in the pathogenesis of tubulointerstitial lesions of SLE nephritis.
Clinical significance of anti-double-stranded DNA antibodies detected by a solid phase enzyme immunoassay.
A solid phase enzyme immunoassay (EIA) detected anti-double-stranded (ds) DNA antibodies in 88% of sera from patients classified clinically as having active systemic lupus erythematosus (SLE) without renal symptoms and 93% with renal disease. Fifty-six percent of sera from patients with inactive SLE were EIA positive for anti-dsDNA antibodies. The EIA had a sensitivity and specificity comparable to radioimmunoassay (RIA) and hemagglutination for patients with active SLE with or without renal disease, but it detected anti-dsDNA antibodies more frequently in patients with inactive SLE than the latter procedures. Precipitating antibodies detected by counterimmunoelectrophoresis (CIE) were less common in patients with renal disease (23% incidence) than clinically active patients without renal disease (79% incidence). Twenty-four SLE sera with elevated levels of C1q binding showed a 96% concordance for a positive EIA for anti-dsDNA antibodies in contrast to 66% concordance by RIA or hemagglutination. These findings suggest that the EIA is a sensitive and specific method for detection and measurement of anti-dsDNA antibodies. Several clinical applications of the EIA are discussed.
Systemic lupus erythematosus.
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Antibodies to nuclear antigens in patients treated with procainamide or acetylprocainamide.
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