| 1. |
- Bolton, W K, et al.
(författare)
-
Epitope spreading and autoimmune glomerulonephritis in rats induced by a T cell epitope of Goodpasture's antigen
- 2005
-
Ingår i: Journal of the American Society of Nephrology. - 1046-6673. ; 16:9, s. 2657-2666
-
Tidskriftsartikel (refereegranskat)abstract
- An amino-terminal region of a, chain of type IV collagen noncollagenous domain [alpha(3)(IV)NC1] that induces experimental autoimmune glomerulortephritis (EAG) in rats has been identified. Only recombinant antigens that contain a nine-amino acid (AA) span of alpha(3)(IV)NC1, consistent with a T cell epitope, could induce EAG. It was hypothesized that synthetic peptides of this region should induce EAG. Human and rat peptides of this region were synthesized and rats were immunized to define the nephritogenic epitope. A 13-AA rat peptide induced EAG with proteinuria, decreased renal function, and glomerular basement membrane (GBM)-bound deposits in half of the rats. This peptide induces lymph node cell proliferation and development of antibodies to epitopes of alpha(3)(IV)NC1 external to the peptide immunogen. Carboxy-terminal extension to 21 amino acids results in all rats' demonstrating anti-GBM antibody and severe EAG. Asparagine at position 19 is critical for EAG induction. None of the 50 rats that were immunized with peptide that contained human sequence with isoleucine at position 19 developed EAG, whereas rat sequence with asparagine 19 induced EAG. Truncation of amino terminal AA of the peptide aborts EAG induction. These studies demonstrate that a T cell epitope of alpha(3)(IV)NC1 induces lymph node cell proliferation, EAG, and intramolecular epitope spreading; that the length of this peptide influences the formation of anti-GBM antibody; and that the presence of asparagine at position 19 of the peptide is critical to disease induction.
|
|
| 2. |
- Bolton, W Kline, et al.
(författare)
-
Molecular mapping of the Goodpasture's epitope for glomerulonephritis
- 2005
-
Ingår i: Transactions of the American Clinical and Climatological Association. - 0065-7778. ; 116, s. 229-238
-
Tidskriftsartikel (refereegranskat)abstract
- Goodpasture's syndrome is an autoimmune disease characterized by pulmonary hemorrhage, glomerulonephritis, and antiglomerular basement membrane (GBM) antibodies. We have studied a rat model with chimeric proteins (CPs) consisting of portions of the nephritogenic non-collagenous domain of alpha3 type IV collagen (alpha3(IV)NC1) and non-nephritogenic alpha1(IV)NC1. CPs with aminoterminal alpha3 that contains the major epitope for Goodpasture antibody binding induced EAG. We next immunized with D3, an alpha1(IV)NC1 CP with 69AA of alpha3(IV)NC1 (binds Goodpasture sera), D4, the D3 construct shortened by 4 AA (nonbinding), P9 and P10, single AA mutants (nonbinding) and S2, an alpha1(IV)NC1 with nine AA of alpha3(IV)NC1 (binding). GBM, S2 and D3 induced EAG. GBM immunized rats had intense IgG deposits but S2 and D3 rats had minimal deposits. A 13 mer rat peptide encompassing the aminoterminal site induced EAG sans antibody, while peptides not encompassing the region failed to induce GN. Asparagine at position 19 rather than isoleucine was essential for disease induction. These studies define critical limited AA sequences of alpha3(IV)NC1 associated with glomerulonephritis without antibody, and demonstrate that this region contains a T-cell epitope responsible for induction of glomerulonephritis.
|
|
| 3. |
- Kahn, Robin, et al.
(författare)
-
Neutrophil-derived proteinase 3 induces kallikrein-independent release of a novel vasoactive kinin.
- 2009
-
Ingår i: Journal of immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 182:12, s. 7906-7915
-
Tidskriftsartikel (refereegranskat)abstract
- The kinin-forming pathway is activated on endothelial cells and neutrophils when high-molecular weight kininogen (HK) is cleaved by plasma kallikrein liberating bradykinin, a potent mediator of inflammation. Kinins are released during inflammatory conditions such as vasculitis, associated with neutrophil influx around blood vessels. Some patients with vasculitis have elevated plasma levels of neutrophil-derived proteinase 3 (PR3) and anti-PR3 Abs. This study investigated if neutrophil-derived PR3 could induce activation of the kinin pathway. PR3 incubated with HK, or a synthetic peptide derived from HK, induced breakdown and release of a novel tridecapeptide termed PR3-kinin, NH(2)-MKRPPGFSPFRSS-COOH, consisting of bradykinin with two additional amino acids on each terminus. The reaction was specific and inhibited by anti-PR3 and alpha(1)-antitrypsin. Recombinant wild-type PR3 incubated with HK induced HK breakdown, whereas mutated PR3, lacking enzymatic activity, did not. PR3-kinin bound to and activated human kinin B(1) receptors, but did not bind to B(2) receptors, expressed by transfected HEK293 cells in vitro. In human plasma PR3-kinin was further processed to the B(2) receptor agonist bradykinin. PR3-kinin exerted a hypotensive effect in vivo through both B(1) and B(2) receptors as demonstrated using wild-type and B(1) overexpressing rats as well as wild-type and B(2) receptor knockout mice. Neutrophil extracts from vasculitis patients and healthy controls contained comparable amounts of PR3 and induced HK proteolysis, an effect that was abolished when PR3 was immunoadsorbed. Neutrophil-derived PR3 can proteolyze HK and liberate PR3-kinin, thereby initiating kallikrein-independent activation of the kinin pathway.
|
|
| 4. |
- Persson, Ulf, et al.
(författare)
-
Alport syndrome in southern Sweden.
- 2005
-
Ingår i: Clinical Nephrology. - : Dustri-Verlag Dr. Karl Feistle. - 0301-0430. ; 64:2, s. 85-90
-
Tidskriftsartikel (refereegranskat)
|
|
