Published in:Journal of the American Society of Nephrology
Language:
English
DOI:
10.1681/asn.2020081224
ISSN:
1046-6673;
1533-3450
Origination:
Footnote:
Description:
<jats:sec>
<jats:title>Significance Statement</jats:title>
<jats:p>Atypical hemolytic uremic syndrome (aHUS) is often related to complement dysregulation, but its pathophysiology remains unknown in at list 30% of patients. Anti-factor H autoantibodies of the IgG class are responsible for 10% of patients with aHUS; autoantibodies of IgM class have not been reported. The authors found anti-factor H IgM autoantibodies in seven of 186 patients with aHUS, with a frequency six-fold higher in patients with a history of hematopoietic stem cell transplantation. The purified IgM autoantibodies recognize the active site of the factor H molecule and inhibit its binding to C3b. These findings indicate that some forms of aHUS of unknown origin could be placed within the setting of autoimmune diseases, stemming from the presence of IgM autoantibodies specific for factor H’s active site.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Background</jats:title>
<jats:p>Atypical hemolytic uremic syndrome (aHUS), a severe thrombotic microangiopathy, is often related to complement dysregulation, but the pathomechanisms remain unknown in at least 30% of patients. Researchers have described autoantibodies to complement factor H of the IgG class in 10% of patients with aHUS but have not reported anti-factor H autoantibodies of the IgM class.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Methods</jats:title>
<jats:p>In 186 patients with thrombotic microangiopathy clinically presented as aHUS, we searched for anti-factor H autoantibodies of the IgM class and those of the IgG and IgA classes. We used immunochromatography to purify anti-factor H IgM autoantibodies and immunoenzymatic methods and a competition assay with mapping mAbs to characterize interaction with the target protein.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Results</jats:title>
<jats:p>We detected anti-factor H autoantibodies of the IgM class in seven of 186 (3.8%) patients with thrombotic microangiopathy presented as aHUS. No association was observed between anti-factor H IgM and homozygous deletions involving <jats:italic toggle="yes">CFHR3-CFHR1</jats:italic>. A significantly higher proportion of patients with bone marrow transplant–related thrombotic microangiopathy had anti-factor H IgM autoantibodies versus other patients with aHUS: three of 20 (15%) versus four of 166 (2.4%), respectively. The identified IgM autoantibodies recognize the SCR domain 19 of factor H molecule in all patients and interact with the factor H molecule, inhibiting its binding to C3b.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Conclusions</jats:title>
<jats:p>Detectable autoantibodies to factor H of the IgM class may be present in patients with aHUS, and their frequency is six-fold higher in thrombotic microangiopathy forms associated with bone marrow transplant. The autoantibody interaction with factor H’s active site may support an autoimmune mechanism in some cases previously considered to be of unknown origin.</jats:p>
</jats:sec>