In vitro and in vivo Properties of Autoantibodies eluted from Kidneys of Sheep with Autoimmune Glomerulonephritis

Steblay, Raymond William; Rudofsky, Ulrich H.

doi:10.1038/2181269a0

Cited by 15 publications

(6 citation statements)

References 6 publications

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“…Historically, anti-GBM GN was among the earliest of recognized human autoimmune diseases (3), and the discovery of the anti-GBM Ab was considered a milestone in autoimmune disease research (4,5). The anti-GBM Ab has been regarded as a prototypical example for autoantibodies that mediate autoimmune diseases (4,5).…”

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A Self T Cell Epitope Induces Autoantibody Response: Mechanism for Production of Antibodies to Diverse Glomerular Basement Membrane Antigens

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Borillo

et al. 2004

The Journal of Immunology

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The anti-glomerular basement membrane (GBM) Ab has been regarded as a prototypical example of pathogenic autoantibodies. However, the mechanism for elicitation of this Ab remains unknown. In the present paper, we report that the Ab to diverse GBM Ags was induced by a single nephritogenic T cell epitope in a rat model. The T cell epitope pCol28–40 of noncollagen domain 1 of collagen type IV α3 chain not only uniformly induced severe glomerulonephritis but also elicited anti-GBM Ab in 76% of the immunized rats after prominent glomerular injury. Furthermore, we demonstrated that the anti-GBM Ab was not related to the peptidic B cell epitope nested in pCol28–40; that is, 1) elimination of the B cell epitope, either by substitution of the critical residues of the B cell epitope or by truncation, failed to abrogate anti-GBM Ab production, and 2) the anti-GBM Ab, eluted from the diseased kidneys, reacted only with native GBM, but not with pCol28–40. Confocal microscopy and immunoprecipitation further demonstrated that the eluted anti-GBM Ab recognized conformational B cell epitope(s) of multiple native GBM proteins. We conclude that autoantibody response to diverse native GBM Ags was induced by a single nephritogenic T cell epitope. Thus, anti-GBM Ab may actually be a consequence of T cell-mediated glomerulonephritis.

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confidence: 99%

A Self T Cell Epitope Induces Autoantibody Response: Mechanism for Production of Antibodies to Diverse Glomerular Basement Membrane Antigens

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Borillo

et al. 2004

The Journal of Immunology

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“…A ntiglomerular basement membrane (GBM) 3 disease, or Goodpasture's syndrome, was one of the earliest recognized human autoimmune diseases (1,2). Clinical symptoms of the disease include glomerulonephritis (GN) and/or pulmonary hemorrhage (1).…”

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“…Clinical symptoms of the disease include glomerulonephritis (GN) and/or pulmonary hemorrhage (1). Historically, the discovery of anti-GBM Ab was a milestone in autoimmune disease research (3). Collagen IV ␣3 NC domain (Col4␣3NC) was identified to be the responsible autoantigen (4,5).…”

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confidence: 99%

T Cell Epitope Mimicry in Antiglomerular Basement Membrane Disease

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Borillo

et al. 2006

The Journal of Immunology

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Antiglomerular basement membrane (GBM) disease or Goodpasture’s syndrome is among the earliest recognized human autoimmune diseases. Although collagen 4α3 NC1 (Col4α3NC1) has been identified as the responsible autoantigen, it remains unknown how autoimmunity to this autoantigen is provoked. We have demonstrated in our rat model that a single nephritogenic T cell epitope pCol28–40 of Col4α3NC1 induces glomerulonephritis. We hypothesized that microbial peptides that mimic this T cell epitope could induce the disease. Based on the critical residue motif (xxtTxNPsxx) of pCol28–40, seven peptides derived from human infection-related microbes were chosen through GenBank search and synthesized. All peptides showed cross-reactivity with pCol28–40-specific T cells at various levels. Only four peptides induced transient proteinuria and minor glomerular injury. However, the other three peptides induced severe proteinuria and modest to severe glomerulonephritis in 16–25% of the immunized rats. Unexpectedly, the most nephritogenic peptide, pCB, derived from Clostridium botulinum, also induced modest (25%) to severe (25%) pulmonary hemorrhage, another important feature of anti-GBM disease; this was not correlated with the severity of glomerulonephritis. This finding suggests that subtle variations in T cell epitope specificity may lead to different clinical manifestations of anti-GBM disease. In summary, our study raises the possibility that a single T cell epitope mimicry by microbial Ag may be sufficient to induce the anti-GBM disease.

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“…An autoimmunity of unknown cause to glomerular basement membrane could exist in rare cases, for nephritogenic mucoproteins derived from the basement membrane have been identified in normal blood and urine,8 and classical nephrotoxic nephritis in animals is easily induced with basement-membrane antigens. 9 Granular fluorescence is seen much more often in nephrotic syndrome and represents one of the best examples of an "immune-complex disease." The antigen is outside the glomeruli and may even be outside the kidney.…”

Section: Pathogenesis Of Nephrosismentioning

confidence: 99%

Failure to control venereal disease.

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In vitro and in vivo Properties of Autoantibodies eluted from Kidneys of Sheep with Autoimmune Glomerulonephritis

Cited by 15 publications

References 6 publications

A Self T Cell Epitope Induces Autoantibody Response: Mechanism for Production of Antibodies to Diverse Glomerular Basement Membrane Antigens

A Self T Cell Epitope Induces Autoantibody Response: Mechanism for Production of Antibodies to Diverse Glomerular Basement Membrane Antigens

T Cell Epitope Mimicry in Antiglomerular Basement Membrane Disease

Failure to control venereal disease.

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