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. 2008 Jun;30(4):246-56.
doi: 10.1016/j.jaut.2007.10.004. Epub 2007 Nov 28.

Spontaneous recovery from early glomerular inflammation is associated with resistance to anti-GBM glomerulonephritis: tolerance and autoimmune tissue injury

Julie Robertson  1 , Jean Wu, Jon Arends, Cindy Zhou, Horacio E Adrogue, Jarvis T Chan, Yahuan Lou
Affiliations

Spontaneous recovery from early glomerular inflammation is associated with resistance to anti-GBM glomerulonephritis: tolerance and autoimmune tissue injury

Julie Robertson et al. J Autoimmun. 2008 Jun.

Abstract

Different susceptibility to anti-GBM glomerulonephritis (GN) among animal strains has been reported. Using our rat model for T cell-mediated anti-GBM GN, this study initiated an investigation on the mechanism related with GN susceptibility. Anti-GBM GN was induced either through immunization with the nephritogenic T cell epitope pCol(28-40) from Col4alpha3NC1 or through the transfer of specific T cells. WKY rats were highly susceptible to GN while immuno-compatible LEW rats were GN-resistant. GN-resistance in LEW rats was not associated to the immune response to pCol(28-40). First, both strains mounted a Th1 T cell response to pCol(28-40) with identical specificities; transfer of T cells from LEW to WKY rats induced glomerular injury. Second, co-transfer of antibody from WKY to LEW failed to induce GN. Time-course studies revealed that LEW rats did develop T cell-mediated inflammation in glomeruli at early stages similar to WKY rats, as evidenced by histopathology, proteinuria, CD4(+) T cell infiltration in glomeruli, and glomerular expression of inflammatory molecules. However, glomerular inflammation in LEW rats was transient followed by a full recovery. Thus, GN-resistance in LEW rats was due to its ability to contain early T cell-mediated autoimmune glomerular damage. Our model may reveal a potential tolerance mechanism after autoimmune tissue damage has been initiated.

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Figures

Figure 1
Figure 1. LEW and WKY rats are immuno-compatible
A. Mixed lymphocyte reactions between rat strains as indicated; LEW vs LEW serves as negative control, while LEW vs SD a positive control; the responsiveness is expressed as 3H-thymidin incorporation. B. Skin allograft rejection; days of rejection are counted from day of grafting until the graft is completely rejected; inset shows a LEW skin graft in WKY at 4 weeks.
Figure 2
Figure 2. LEW rats mount a pathogenic T cell response to pCol(28-40) similar to WKY rats
A. T cell response to pCol(28-40) in LEW (●) and WKY rats (○) after immunization; the responsiveness of T cells is expressed as 3H-thymidin incorporation. B. A T cell line from LEW or WKY rats responds to pCol(28-40) at the presence of thymocytes from WKY rats . C. A T cell line from LEW (■) responds to a set of pCol(28-40) with single substitution in almost identical pattern to those of WKY (□). D. RT-PCR detection of IL-4 or INF-γ in a T cell line from LEW rats after stimulation with pCol(28-40). E. Glomerular injury in pCol(28-40)-specific T cell recipients as indicated; severity of glomerular injury is expressed as glomerular injury score. F. Proteinuria in pCol(28-40)-specific T cell recipients as indicated; transfer of WKY's T cells to WKY recipient serves as a positive control; albumin is indicated by an arrow.
Figure 3
Figure 3. Antibody response in LEW rats immunized with pCol(28-40)
A. Circulating antibody activity to pCol(28-40) from immunized LEW or WKY rats; sera from CFA immunized WKY were used as a negative control; B. Reactivity of circulating antibody from immunized WKY or LEW to a set of pCol(28-40) with single substitution. Antibody activities are expressed as normalized OD. C. Indirect immunofluorescence shows absence of anti-GBM antibody in circulation of LEW and WKY rats; SR-13 serves as a positive control. D. Direct immunofluorescence shows absence of GBM-bound IgG in an immunized LEW rat.
Figure 4
Figure 4. Renal histopathology of LEW or WKY rats after immunization with pCol(28-40)
A. Kidney section of an immunized LEW rats at 40 days post immunization shows normal glomeruli. B. Kidney section from WKY shows glomeruli with fibrous crescent. C. A group of kidney sections under high magnification from the immunized rats as indicated; lymphocyte infiltration is notable in LEW at day 20 (arrows); crescent lesion (arrow heads) is shown in glomerulus of WKY at day 30.
Figure 5
Figure 5. Transient glomerular inflammation in LEW rats after GN induction with pCol(28-40)
A. Summary of renal pathology of different animal groups; severity of glomerulonephritis is expressed as glomerular injury score (0-100). B. Summary of albuminuria in the immunized rats at an early or later stage as indicated; albuminuria is expressed as mg/dl.
Figure 6
Figure 6. Flow cytometry detection of a transient CD4+ T cell-mediated glomerular inflammation in LEW rats after GN induction with pCol(28-40)
Leukocytes were isolated from glomeruli of WKY or LEW rats at indicated times and stained with anti-CD4 and anti-CD8 antibodies.
Figure 7
Figure 7. Glomeruli of LEW rats express inflammatory molecules similar to those of WKY rats at an early stage after GN-induction
Glomerular expression of inflammatory molecules as indicated. Only one representative array is shown. Arrows indicate the same set of genes, which includes Bmp2, caspase-1, IL-4Rα, MIP-2α, Frag1, TGF-β1i4, Il-1R1.
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References

    1. Couser WG. Glomerulonephritis. Lancet. 1999;353:1509–1515. - PubMed
    1. Steblay RW. Glomerulonephritis induced in sheep by injection of heterologous GBM and Freund's complete adjuvant. J. Exp. Med. 1962;116:253–258. - PMC - PubMed
    1. Wieslander J, Bygren P, Heinegard D. Isolation of the specific glomerular basement membrane antigen involved in Goodpasture syndrome. Proc. Natl. Acad. Sci. USA. 1984;81:1544–1548. - PMC - PubMed
    1. Neilson EG, Kalluri R, Sun S, Gunwar MJ, Danoff T, Mariyama M, Myers JC, Reeders ST, Hudson BG. Specificity of Goodpasture autoantibodies for the recombinant noncollagenous domains of human type IV collagen. J. Biol. Chem. 1993;268:8402–8405. - PubMed
    1. Kalluri R, Gattone VH, Jr, Noelken ME, Hudson BG. The α3(IV) chain of type IV collagen induces autoimmune Goodpasture syndrome. Proc. Natl. Acad. Sci. USA. 1994;91:6201–6205. - PMC - PubMed

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