Factor I is required for the development of membranoproliferative glomerulonephritis in factor H–deficient mice

The inflammatory kidney disease membranoproliferative glomerulonephritis type II (MPGN2) is associated with dysregulation of the alternative pathway of complement activation. MPGN2 is characterized by the presence of complement C3 along the glomerular basement membrane (GBM). Spontaneous activation of C3 through the alternative pathway is regulated by 2 plasma proteins, factor H and factor I. Deficiency of either of these regulators results in uncontrolled C3 activation, although the breakdown of activated C3 is dependent on factor I. Deficiency of factor H, but not factor I, is associated with MPGN2 in humans, pigs, and mice. To explain this discordance, mice with single or combined deficiencies of these factors were studied. MPGN2 did not develop in mice with combined factor H and I deficiency or in mice deficient in factor I alone. However, administration of a source of factor I to mice with combined factor H and factor I deficiency triggered both activated C3 fragments in plasma and GBM C3 deposition. Mouse renal transplant studies demonstrated that C3 deposited along the GBM was derived from plasma. Together, these findings provide what we believe to be the first evidence that factor I–mediated generation of activated C3 fragments in the circulation is a critical determinant for the development of MPGN2 associated with factor H deficiency

Linkage of Chromosome 2 with ANA and Anti-Chromatin Abs in (129 × C57BL/6)F2<i>.Apcs^−/−</i> Mice

<p>These associations were not detected in (129 × C57BL/6)F2 animals. Centimorgan positions were deduced by interval mapping, anchoring marker locations to data from <a href="http://www.informatics.jax.org" target="_blank">http://www.informatics.jax.org</a>. Dotted lines and the dashed line indicate the threshold over which linkages were considered suggestive or significant, respectively, as defined in Materials and Methods.</p

Interval Mapping Scans Showing QTL on Chromosome 1 with ANA and Anti-Chromatin Abs

<p>Centimorgan positions were deduced by interval mapping, anchoring marker locations to data from <a href="http://www.informatics.jax.org" target="_blank">http://www.informatics.jax.org</a>. Dotted lines indicate the threshold over which linkage was considered suggestive, and dashed lines indicate the threshold over which linkage was considered significant, as defined in Materials and Methods. See <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0020243#pbio-0020243-t003" target="_blank">Table 3</a> for additional details.</p

Auto-Ab Profiles

<div><p>(A) ANA titres in C57BL/6 mice, C57BL/6.<i>Apcs </i>^−/− mice, and C57BL/6.129(D1Mit105–223) congenic mice at 1 y of age. Small symbols represent one mouse; large symbols, a variable number of animals as indicated in parentheses. Serum sample were titrated to endpoint.</p> <p>(B and C) Anti-ssDNA (B) and anti-chromatin (C) Ab levels in the same cohorts of mice as in (A). The Ab levels are expressed in AEUs related to a standard positive sample, which was assigned a value of 100 AEU.</p> <p>(D) Anti-dsDNA Ab levels. Serum samples were screened at 1:20. Samples that were positive were titrated to endpoint. The symbols are as in (A).</p></div

Auto-Ab Profiles

<div><p>(A) ANA titres in the (129 × C57BL/6)F2.<i>Apcs</i>^−/− mice and (129 × C57BL/6)F2 at 1 y of age. A small circle represents one mouse; a large circle, a variable number of animals, as indicated in parentheses. Serum samples were titrated to endpoint.</p> <p>(B) ANA titres in the (129 × C57BL/6)F2.<i>Apcs </i>^−/− mice and a selected number of wild-type (129 × C57BL/6)F2 animals carrying the Chromosome 1 region between D1Mit105 and D1Mit223 (80–106 cM) of 129 origin. The symbols are as in (A).</p> <p>(C and D) Anti-chromatin Ab levels expressed in AEUs related to a standard positive sample, which was assigned a value of 100 AEU. The comparison is between the same groups of mice as in (A) and (B), respectively. The symbols are as in (A).</p></div

Interval Mapping Scans Showing QTL on Chromosome 3 with ANA, Anti-Chromatin, and Anti-ssDNA Abs

<p>See <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0020243#pbio-0020243-t003" target="_blank">Table 3</a> for additional details. Centimorgan positions were deduced by interval mapping, anchoring marker locations to data from <a href="http://www.informatics.jax.org" target="_blank">http://www.informatics.jax.org</a>. Dotted lines indicate the threshold over which linkage was considered suggestive, the dashed line indicate the threshold over which linkage was considered significant, and dotted/dashed lines indicate highly significant linkage, as defined in Materials and Methods.</p