Massimo Cugno1, Silvia Berra2, Federica Depetri3, Silvana Tedeschi4, Samantha Griffini3, Elena Grovetti3, Sonia Caccia2, Donata Cresseri5, Piergiorgio Messa5, Sara Testa6, Fabio Giglio7, Flora Peyvandi3, Gianluigi Ardissino6. 1. Medicina Interna, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy massimo.cugno@unimi.it. 2. L. Sacco Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy. 3. Medicina Interna, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy. 4. Laboratorio di Genetica Medica, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy. 5. Unità Operativa di Nefrologia, Dialisi e Trapianto Renale, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy. 6. Center for Hemolytic Uremic Syndrome Prevention, Control and Management, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy. 7. Hematology and Bone Marrow Transplantation Unit, Istituto di Ricovero e Cura a Carattere Scientifico S. Raffaele Scientific Institution, Milan, Italy.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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 CFHR3-CFHR1. 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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 CFHR3-CFHR1. 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. CONCLUSIONS: 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.
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