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Background
This is an autoimmune disease characterized by antibodies directed against antigens present within the basement membranes of the glomerulus and lung alveoli. This leads to a simultaneous rapidly progressive glomerulonephritis and a necrotizing hemorrhagic interstitial pneumonitis. Patients may present with respiratory symptoms such as hemoptysis. As the kidney disease progresses, a rapidly progressive renal failure may ensue.
PATHOGENESIS CHARACTERIZATION Anti-basement membrane antibodies Experimental model of Masugi or nephrotoxic nephritis produced similar lesions by injecting anti-rat kidney antibodies, prepared in rabbits by immunization with rat kidney tissue
Antibodies bind along the glomerular basement membrane
Antibodies cross react with other basement membranes such as lung alveoli
GBM antigen Component of the noncollagenous domain (NC1) of the alpha 3 chain of collagen type IV Goodpasture disease. Characterization of a single conformational epitope as the target of pathogenic autoantibodies.
Hellmark T, Burkhardt H, Wieslander J.
Department of Nephrology, Lund University, 22185 Lund, Sweden.
J Biol Chem 1999 Sep 3;274(36):25862-8 Abstract quote
Goodpasture disease is a prototype autoimmune disease characterized by the formation of autoantibodies against the heterotrimeric basement membrane collagen type IV, which causes a rapidly progressive glomerulonephritis. The pathogenic antibody response is directed to the non-collagenous (NC1) domain of the alpha3 chain of type IV collagen (alpha3(IV)NC1), but not to the homologous region of the alpha1(IV)NC1. To identify the conformation-dependent immunodominant epitope on the alpha3(IV)NC1, a variety of recombinant NC1 domains were constructed by replacing single residues of alpha3(IV) with the corresponding amino acids from the nonreactive alpha1(IV) chain.
Replacement mutations were identified that completely destroyed the Goodpasture epitope in the alpha3(IV) chain. Based on the identification of these critical positions, the epitope was finally reconstructed within the frame of the alpha1(IV) chain. The substitution of nine discontinuous positions in the alpha1(IV)NC1 with amino acid residues from the alpha3 chain resulted in a recombinant construct that was recognized by all patients' sera (n = 20) but by none of the sera from healthy controls (n = 10).
This provides, for the first time, the molecular characterization of a single immunodominant conformational epitope recognized by pathogenic autoantibodies in a human autoimmune disease, representing the basis for the development of new epitope-specific strategies in the treatment of Goodpasture disease.
The goodpasture autoantigen. Mapping the major conformational epitope(s) of alpha3(IV) collagen to residues 17-31 and 127-141 of the NC1 domain.
Netzer KO, Leinonen A, Boutaud A, Borza DB, Todd P, Gunwar S, Langeveld JP, Hudson BG.
Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
J Biol Chem 1999 Apr 16;274(16):11267-74 Abstract quote
The Goodpasture (GP) autoantigen has been identified as the alpha3(IV) collagen chain, one of six homologous chains designated alpha1-alpha6 that comprise type IV collagen (Hudson, B. G., Reeders, S. T., and Tryggvason, K. (1993) J. Biol. Chem. 268, 26033-26036).
In this study, chimeric proteins were used to map the location of the major conformational, disulfide bond-dependent GP autoepitope(s) that has been previously localized to the noncollagenous (NC1) domain of alpha3(IV) chain.
Fourteen alpha1/alpha3 NC1 chimeras were constructed by substituting one or more short sequences of alpha3(IV)NC1 at the corresponding positions in the non-immunoreactive alpha1(IV)NC1 domain and expressed in mammalian cells for proper folding. The interaction between the chimeras and eight GP sera was assessed by both direct and inhibition enzyme-linked immunosorbent assay. Two chimeras, C2 containing residues 17-31 of alpha3(IV)NC1 and C6 containing residues 127-141 of alpha3(IV)NC1, bound autoantibodies, as did combination chimeras containing these regions. The epitope(s) that encompasses these sequences is immunodominant, showing strong reactivity with all GP sera and accounting for 50-90% of the autoantibody reactivity toward alpha3(IV)NC1. The conformational nature of the epitope(s) in the C2 and C6 chimeras was established by reduction of the disulfide bonds and by PEPSCAN analysis of overlapping 12-mer peptides derived from alpha1- and alpha3(IV)NC1 sequences.
The amino acid sequences 17-31 and 127-141 in alpha3(IV)NC1 have thus been shown to contain the critical residues of one or two disulfide bond-dependent conformational autoepitopes that bind GP autoantibodies.
Presentation of the Goodpasture autoantigen to CD4 T cells is influenced more by processing constraints than by HLA class II peptide binding preferences.
Phelps RG, Jones VL, Coughlan M, Turner AN, Rees AJ.
Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland, United Kingdom.
J Biol Chem 1998 May 8;273(19):11440-7 Abstract quote
Class II molecules are believed to influence immune responses by selectively binding antigen-derived peptides for recognition by T cells. In Goodpasture's (anti-glomerular basement membrane) disease, autoimmunity to the NC1 domain of the alpha3-chain of type IV collagen (alpha3(IV)NC1) is strongly associated with HLA-DR15.
We have examined the influence of the peptide binding preferences of DR15 molecules on the selection of alpha3(IV)NC1-derived peptides displayed bound to DR15 molecules on the surface of alpha3(IV)NC1-pulsed DR15-homozygous Epstein-Barr virus-transformed human B cells.
The preferences of DR15 molecules were investigated using a panel of 24 overlapping peptides spanning the sequence of alpha3(IV)NC1. The alpha3(IV)NC1-derived peptides selected for display to T cells were determined by biochemical analysis as reported previously (Phelps, R. G., Turner, A. N., and Rees, A. J. (1996) J. Biol. Chem. 271, 18549-18553). Three nested sets of naturally presented alpha3(IV)NC1 peptides were detectable bound to DR15 molecules. Peptides representative of each nested set bound to DR15 molecules, but almost two-thirds of the alpha3(IV)NC1 peptides studied had as good or better DR15 affinity than those identified as naturally processed.
Thus alpha3(IV)NC1 presentation to T cells is determined more by "processing factors" than by the preferences of relatively indiscriminate DR15 molecules. The results have important implications for the use of class II peptide binding data to aid identification of potential T cell epitopes, especially for antigens which, like alpha3(IV)NC1, contain many sequences able to bind class II molecules.
Properties of HLA class II molecules divergently associated with Goodpasture's disease.
Phelps RG, Jones V, Turner AN, Rees AJ.
Department of Clinical and Surgical Sciences (Internal Medicine), University of Edinburgh, Royal Infirmary, Edinburgh EH3 9YW, UK.
Int Immunol 2000 Aug;12(8):1135-43 Abstract quote
Goodpasture's disease provides an opportunity to analyse molecular mechanisms that may underlie MHC class II associations with autoimmune disease because it is caused by autoimmunity to a defined antigen [the 230 amino acid NC1 domain of the alpha3 chain of type IV collagen (alpha3(IV)NC1)] and has strong HLA class II associations.
We compared the alpha3(IV)NC1 peptide binding of class II molecules with strong positive (DR15) and dominant negative (DR7/1) associations using an inhibition binding assay and short synthetic peptides spanning the sequence of alpha3(IV)NC1. DR15 in general bound the peptides with low affinity (three of 23 < 100 nM) compared to DR1 and DR7 (12 and 10 < 100 nM respectively), and no peptide bound DR15 with much higher affinity (>10-fold) than both DR1 and DR7.
Thus DR15 molecules are unlikely to increase susceptibility to Goodpasture's disease by presenting a particular alpha3(IV)NC1-derived peptide uniquely well and DR1/7 are unlikely to protect by their inability to present particular peptides. However DR1/7 could protect by capturing alpha3(IV)NC1 peptides and preventing their display bound to DR15; the binding data suggest that all the major (biochemically detectable) alpha3(IV)NC1 peptides presented bound to DR15 by DR15 homozygous antigen-presenting cells (APC) would bind preferentially to DR1/7 in DR15, 1/7 heterozygote APC.
DISEASE ASSOCIATIONS CHARACTERIZATION Anti-GBM disease: predictive value of clinical, histological and serological data.
Herody M, Bobrie G, Gouarin C, Grunfeld JP, Noel LH.
Department of Nephrology, Hopital du Val-de-Grace, Paris, France.
Clin Nephrol 1993 Nov;40(5):249-55 Abstract quote
Twenty-nine patients with anti-glomerular basement membrane (GBM) disease, defined by circulating anti-GBM antibodies and/or linear deposits of immunoglobulin G along GBM, were studied retrospectively to identify prognostic indicators of renal outcome and pulmonary involvement.
Patients consisted of 18 males and 11 females aged 6 to 76 years (mean 35.2 +/- 20.2). Goodpasture syndrome developed in 14, disease was confined to renal manifestations in 14 and isolated pulmonary involvement was present in a single case. Pulmonary disease was significantly associated with current smoking (p < 0.01). Among the 29 patients, end-stage renal failure requiring dialysis was initially observed in 16 (55%). Ten of them had anti-GBM glomerulonephritis (GN) and 4 presented with Goodpasture syndrome; the two other patients died very soon after the beginning of the disease. The 17 patients with an unfavourable renal evolution (group 1) and the 12 patients with favourable evolution or chronic renal failure (group 2) were compared.
No significant difference was noted between the two groups concerning the age at onset of the disease, sex, cigarette smoking or pulmonary involvement. Conversely, creatininemia over 600 mumol/l, oligoanuria, absence of normal glomeruli, a high percentage of circumferential crescents, circulating anti-GBM antibodies detected by immunofluorescence, and a high level of circulating anti-GBM antibodies evaluated by ELISA were features which indicate an unfavourable renal course (p < 0.01).
Course and prognosis of anti-basement membrane antibody (anti-BM-Ab)-mediated disease: report of 35 cases.
Merkel F, Pullig O, Marx M, Netzer KO, Weber M. Medizinische Klinik IV,
University of Erlangen-Nurnberg, Germany.
Nephrol Dial Transplant 1994;9(4):372-6 Abstract quote
Anti-basement membrane antibody (anti-BM Ab) mediated disease is reported to be a rare disorder frequently leading to severe deterioration of renal function. It was our purpose to work out parameters necessary to predict the outcome reliably and to examine, who will benefit most from therapy.
Data from 35 patients were evaluated retrospectively. Diagnosis was based on the detection of linear IgG staining (n = 28) along the glomerular basement membrane (GBM) in renal biopsies and/or on the demonstration of anti-BM Ab both by ELISA and immunoblotting (n = 35). Patients were followed up for at least 6 months. Several variables were analysed as to whether they are appropriate prognostic factors. Twenty patients (57%) presented with Goodpasture's syndrome, 13 (37%) had anti-GBM glomerulonephritis alone, whereas two patients suffered solely from pulmonary haemosiderosis. Frequent initial symptoms were haemoptysis (n = 18), haematuria (n = 26), proteinuria (n = 26) and elevated serum creatinine (n = 27). Among all, 10 patients improved, having stable renal function. Twenty-one patients developed end-stage renal failure and four died. Parameters indicating a poor prognosis were a serum(s)-creatinine greater than 600 mumol/l and crescent formation in more than 50% of the glomeruli on renal biopsy. By combining these two parameters the outcome could be reliably predicted. The initial antibody titre and cigarette smoking were without predictive value.
In conclusion, the earlier therapy starts, the better will be the result. Patients presenting early with a serum creatinine < 200 mumol/l and without severe glomerular alterations gained the most benefit from therapy, indicating that outcome may be improved by early diagnosis.
LABORATORY/RADIOLOGIC/OTHER CHARACTERIZATION Comparison of anti-GBM antibodies in sera with or without ANCA.
Hellmark T, Niles JL, Collins AB, McCluskey RT, Brunmark C.
Department of Nephrology, University Hospital, Lund, Sweden.
J Am Soc Nephrol 1997 Mar;8(3):376-85 Abstract quote
An appreciable percentage of patients with serum anti-glomerular basement membrane (anti-GBM) antibodies also have antineutrophil cytoplasmic antibodies (ANCA), against either myeloperoxidase (MPO-ANCA), or proteinase 3 (PR3-ANCA). In sera without ANCA, the anti-GBM antibodies have been shown to react mainly with the noncollagenous domain (NC1) of Type IV collagen, and especially with its alpha 3 chain, alpha 3(IV)NC1. In most sera, the antibodies can be partially blocked by a monoclonal antibody (Mab17) against alpha 3(IV)NC1, suggesting that a limited region is recognized. Although there is evidence that some anti-GBM antibodies that coexist with ANCA react with alpha 3(IV)NC1, extensive analysis of the specificity of such anti-GBM antibodies has not been reported.
In the study presented here, sera were analyzed from 332 patients tested both for anti-GBM antibodies and ANCA (MPO or PR3-ANCA) and found to have one or more positive tests. Of the 100 sera with anti-GBM antibodies, 38 also had ANCA-25 with MPO-ANCA (66%), 12 with PR3-ANCA (32%), and one with both (2%). Of the 232 sera with ANCA only, 153 had MPO-ANCA (66%), 75 had PR3-ANCA (32%), and four had both (2%). Sera was also analyzed from 259 other patients who had positive ANCA tests and were not tested for anti-GBM antibodies: 138 had MPO-ANCA (54%), and 121 had PR3-ANCA (46%). The relative frequencies of MPO or PR3-ANCA in patients with coexisting anti-GBM antibodies did not differ significantly from those in all patients with ANCA (P = 0.35). Seventeen sera with anti-GBM antibodies only and 16 sera with anti-GBM antibodies plus ANCA were selected for further studies to compare the specificity of anti-GBM antibodies in sera with or without ANCA. Using enzyme-linked immunosorbent assays (ELISA), all sera in both groups were found to react with the NC1 domain (as a hexamer) of bovine Type IV collagen and with alpha 3 (IV)NC1 monomers. Furthermore, all but six sera also reacted with one or more of the alpha 1, 2, and 4 (IV)NC1 monomers, generally with considerably lower titers. Reactivity to alpha 3(IV)NC1 was partially blocked by Mab17, with comparable degrees of inhibition in both groups. Western blot analysis with the human NC1 domains revealed no differences in reactivity between the two groups.
Thus, differences in antigen specificities of anti-GBM antibodies in sera with or without ANCA were not detected. The anti-GBM response in both situations is hypothesized to be driven by the same immunogen, which is probably derived from NC1 domains of endogenous Type IV collagen.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION General Lungs may show red-brown consolidation VARIANTS
HISTOLOGICAL TYPES CHARACTERIZATION General KIDNEYS Focal proliferative glomerulonephritis in early cases
Crescentic glomerulonephritis in patients with rapidly progressive glomerulonephritisLUNGS Acute focal necrosis of alveolar walls with intra-alveolar hemorrhage, fibrous thickening of the septae, hypertrophy of the lining septal cells and organization of blood within alveolar spaces Goodpasture's syndrome: diagnosis by transbronchial lung biopsy.
Abboud RT, Chase WH, Ballon HS, Grzybowski S, Magil A.
Ann Intern Med 1978 Nov;89(5 Pt 1):635-8 Abstract quote
A 28-year-old man developed recurrent hemoptyses, breathlessness, anemia, and bilateral pulmonary infiltrates after mild smoke inhalation. He had no laboratory evidence of kidney involvement. Transbronchial lung biopsy showed erythrocytes, iron-containing macrophages within alveolar spaces, normal basement membranes, and strongly positive linear staining of alveolar septa for immunoglobulin G (IgG). Serum antiglomerular basement-membrane antibody was strongly positive by radioimmunoassay. Kidney biopsy showed normal findings by light and electron microscopy but strongly positive linear staining of glomerular capillaries for IgG. Follow-up 9 months later while the patient was taking prednisone revealed no clinical evidence of pulmonary or renal disease.
This case shows that immunopathologic study of transbronchial lung biopsies is helpful in differentiating between Goodpasture's syndrome and idiopathic pulmonary hemosiderosis, while the absence of clinical and microscopic evidence of kidney disease does not exclude Goodpasture's syndrome.
VARIANTS Recurrent Goodpasture's disease due to a monoclonal IgA-kappa circulating antibody.
Fervenza FC, Terreros D, Boutaud A, Hudson BG, Williams RA Jr, Donadio JV Jr, Schwab TR.
Department of Biochemistry and Molecular Biology, University of Utah, Salt Lake City, UT, USA.
Am J Kidney Dis 1999 Sep;34(3):549-55 Abstract quote
We describe the case of a 54-year-old man who first presented with a clinical syndrome manifested by recurrent pulmonary hemorrhage, hematuria, and mild renal insufficiency.
Direct immunofluorescence of renal biopsy sections showed linear deposition of IgA-kappa in the glomerular (GBM) and tubular basement membranes. Serum protein immunoelectrophoresis was positive for a monoclonal immunoglobulin A (IgA)-kappa protein. Serum analysis showed circulating IgA anti-GBM antibodies. Treatment with high-dose steroids, cyclophosphamide, and plasma exchange resulted in resolution of the clinical picture.
To the best of our knowledge, this is the first report of Goodpasture's disease associated with the presence of a circulating monoclonal IgA-kappa antibody.
SPECIAL STAINS/IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION Direct immunofluorescence (DIF) Homogenous, diffuse linear pattern along the basement membranes of septal walls and along the glomerular basement membranes
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES Glomerular basement membrane thinning in a patient with hematuria and hemoptysis mimicking Goodpasture's syndrome.
Coleman M, Stirling JW, Langford LR, Frith PA, Barratt LJ.
Department of Pathology, Repatriation General Hospital, Adelaide, Australia.
Am J Nephrol 1994;14(1):47-54 Abstract quote
Ultrastructural morphometric studies of glomerular basement membrane (GBM) thickness are described in two renal biopsy specimens from a patient who presented with hemoptysis and hematuria mimicking Goodpasture's syndrome.
Significant GBM abnormality, with attenuation as the main lesion, identified in a biopsy specimen taken during active clinical disease appeared to have resolved in a second biopsy specimen taken during the recovery phase. There was no evidence of glomerulonephritis. Concurrent lung biopsy studies showed focal alveolar-capillary wall basal lamina changes of uncertain diagnostic significance. These observations suggest the alternative possibilities that GBM attenuation may be either an acquired consequence of systemic disease or may be part of an hitherto unrecognized primary multisystem abnormality of basal lamina affecting, in this case, glomerular and pulmonary laminae, resulting in hematuria and hemoptysis.
The morphometric studies in this case indicate that simple-mean measurements of GBM thickness are inadequate alone for the quantitative study of this lamina because significant inter- and intraglomerular membrane variation, if irregularly distributed, can remain undetected.
Pulmonary renal syndrome in childhood: a report of twenty-one cases and a review of the literature.
von Vigier RO, Trummler SA, Laux-End R, Sauvain MJ, Truttmann AC, Bianchetti MG.
Department of Pediatrics, University of Bern, Switzerland.
Pediatr Pulmonol 2000 May;29(5):382-8 Abstract quote
In adults, the term specific pulmonary renal syndrome describes disorders with pulmonary and glomerular manifestations and includes Wegener's granulomatosis, Goodpasture disease, and systemic lupus erythematosus. Nonspecific pulmonary renal syndrome refers to either pulmonary disease complicating glomerular disease, or glomerular diseases following pulmonary disease. Since little is known regarding pulmonary renal syndrome in childhood, we reviewed the charts of 21 pediatric patients with pulmonary renal syndromes treated by the Department of Pediatrics, University of Bern between 1991 and 1998; we also reviewed the pediatric literature that deals with specific pulmonary renal syndromes.
Specific pulmonary renal syndrome was noted in 3 children with systemic vasculitis (Wegener granulomatosis, N = 2; microscopic polyangiitis, N = 1) and 2 with systemic lupus erythematosus. Nonspecific pulmonary renal syndrome was observed in 12 patients with pulmonary edema (N = 9), pulmonary thromboembolism (N = 2), and pulmonary infection (N = 1) complicating the course of a glomerular disease, and in 4 children with a pulmonary disease followed by a glomerular disease. Review of the literature disclosed 52 cases of specific pulmonary renal syndrome other than systemic lupus erythematosus: Wegener granulomatosis (N = 28), Goodpasture disease (N = 13), and Henoch-Schonlein purpura (N = 11). In addition, hemolytic uremic syndrome complicated pneumococcal pneumonia in 32 cases.
We conclude that pulmonary renal syndromes need to be looked for in childhood. Apart from Wegener granulomatosis, Goodpasture disease, and systemic lupus erythematosus, Henoch-Schonlein purpura and hemolytic-uremic syndrome occasionally have both pulmonary and renal features.
PROGNOSIS AND TREATMENT CHARACTERIZATION Recurrence Recurrent Goodpasture's disease.
Levy JB, Lachmann RH, Pusey CD. Renal Unit,
Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom.
Am J Kidney Dis 1996 Apr;27(4):573-8 Abstract quote
Goodpasture's disease is usually a monophasic illness that can be successfully treated in a large proportion of patients. Recurrent disease is rare.
We report a case of Goodpasture's disease in which recurrent pulmonary hemorrhage and glomerulonephritis were observed over 12 years. A
ntiglomerular basement membrane autoantibody was monitored throughout this period, and we demonstrate the close association of antibody levels with disease recurrence.
Treatment Plasma exchange to remove the anti-basement membrane antibodies
Immunosuppressive therapyGoodpasture's syndrome in childhood: treatment with plasmapheresis and immunosuppression.
McCarthy LJ, Cotton J, Danielson C, Graves V, Bergstein J.
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis
J Clin Apheresis 1994;9(2):116-9 Abstract quote
Goodpasture's syndrome rarely affects children. Therefore, we present our experience in a young boy whose pulmonary hemorrhage was dramatically resolved by three plasma exchanges. We believe the hemorrhage was caused primarily by acute capillaritis. He received cytoxan and steroids and a series of plasma exchanges which removed/suppressed his anti-glomerular basement membrane (anti-GBM) antibody production. However, after a year, his renal function did not return, and he required renal transplantation and continues to do well.
Goodpasture syndrome: molecular and clinical advances.
Kelly PT, Haponik EF.
Department of Internal Medicine, Bowman Gray School of Medicine, Winston-Salem, North Carolina 27157-1054.
Medicine (Baltimore) 1994 Jul;73(4):171-85 Abstract quote
Goodpasture syndrome is a rare but important autoimmune disorder characterized by pulmonary hemorrhage and glomerulonephritis.
Typically striking young men, it is rapidly progressive and fatal unless treated early. Although the pathogenesis is largely unknown, recent investigations have established that antibodies are directed against the noncollagenous domain of the alpha 3 chain of type IV collagen. Differences in expression and exposure of this chain account for the tissue selectivity of the antibodies and the pulmonary and renal targets of clinical disease. Certain individuals appear at risk by virtue of HLA association, but why only some develop GS remains unclear. Intriguing observations suggest that cigarette smoking, infection, or chemicals expose the antigen, leading to antibody production in genetically susceptible individuals. Before plasmapheresis was available to remove antibodies, prognosis was bleak, and most patients died or were left with permanent renal impairment.
Current combination therapy with plasmapheresis and immunosuppressive drugs is unlikely to be successful unless instituted early in appropriate patients. Fortunately, the autoimmune process is limited, as demonstrated by the small number of reported cases of recurrent disease.
CD28-B7 blockade prevents the development of experimental autoimmune glomerulonephritis.
Reynolds J, Tam FW, Chandraker A, Smith J, Karkar AM, Cross J, Peach R, Sayegh MH, Pusey CD.
Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London W12 ONN, United Kingdom.
J Clin Invest 2000 Mar;105(5):643-51 Abstract quote
Experimental autoimmune glomerulonephritis (EAG), an animal model of Goodpasture's disease, can be induced in Wistar Kyoto (WKY) rats by a single injection of rat glomerular basement membrane (GBM) in adjuvant. EAG is characterized by circulating and deposited anti-GBM antibodies, accompanied by focal necrotizing glomerulonephritis with crescent formation. The role of T cells in the pathogenesis of EAG remains unclear. T-cell costimulation is provided by ligation of CD28 with either B7.1 (CD80) or B7.2 (CD86) on antigen-presenting cells, and can be inhibited by a soluble form of CTLA4 (CTLA4-Ig) that binds to both B7.1 and B7.2.
We examined the effect of CD28-B7 blockade on the development of EAG using native CTLA4-Ig or mutant CTLA4-Ig (Y100F-Ig), which selectively blocks B7.1. Native CTLA4-Ig treatment ameliorated EAG by several measures, including the levels of circulating anti-GBM antibodies, albuminuria, the deposition of IgG and fibrin in the glomeruli, the severity of glomerular abnormalities, and the numbers of infiltrating T cells and macrophages. Y100F-Ig resulted in a similar reduction in the severity of nephritis, but produced no overall reduction in circulating anti-GBM antibodies, although there was a reduction in IgG2a antibodies.
We concluded that CD28-B7 blockade reduced autoantibody production and cellular infiltration of glomeruli, and prevented target organ injury.
Our results suggest a key role for B7. 1 in costimulation of Th1-like autoimmune responses in the rat, and show that glomerular injury in EAG is largely dependent on cell-mediated mechanisms.
Cotran R., etal. Robbins Pathologic Basis of Disease. WB Saunders. 1999
Last Updated 4/1/2001
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