title: Serological and Genetic Evidence for Altered Complement System Functionality in Systemic Lupus Erythematosus: Findings of the GAPAID Consortium.
abstract: Systemic lupus erythematosus is a chronic autoimmune disease with multifactorial ethiopathogenesis. The complement system is involved in both the early and late stages of disease development and organ damage. To better understand autoantibody mediated complement consumption we examined ex vivo immune complex formation on autoantigen arrays. We recruited patients with SLE (n = 211), with other systemic autoimmune diseases (n = 65) and non-autoimmune control subjects (n = 149). Standard clinical and laboratory data were collected and serum complement levels were determined. The genotype of SNP rs1143679 in the ITGAM gene was also determined. Ex vivo formation of immune complexes, with respect to IgM, IgG, complement C4 and C3 binding, was examined using a functional immunoassay on autoantigen microarray comprising nucleic acids, proteins and lipids. Complement consumption of nucleic acids increased upon binding of IgM and IgG even when serum complement levels were decreased due to consumption in SLE patients. A negative correlation between serum complement levels and ex vivo complement deposition on nucleic acid autoantigens is demonstrated. On the contrary, complement deposition on tested protein and lipid autoantigens showed positive correlation with C4 levels. Genetic analysis revealed that the non-synonymous variant rs1143679 in complement receptor type 3 is associated with an increased production of anti-dsDNA IgG antibodies. Notwithstanding, homozygous carriers of the previously reported susceptible allele (AA) had lower levels of dsDNA specific IgM among SLE patients. Both the non-synonymous variant rs1143679 and the high ratio of nucleic acid specific IgG/IgM were associated with multiple organ involvement. In summary, secondary complement deficiency in SLE does not impair opsonization of nucleic-acid-containing autoantigens but does affect other antigens and potentially other complement dependent processes. Dysfunction of the receptor recognizing complement opsonized immune complexes promotes the development of class-switched autoantibodies targeting nucleic acids.
authors.affiliation: Diagnosticum Zrt, Budapest, Hungary.|MTA-ELTE Immunology Research Group, Eötvös Loránd University, Budapest, Hungary.
authors.forename: József
authors.initials: J
authors.lastname: Prechl
authors.affiliation: MTA-ELTE Immunology Research Group, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Krisztián
authors.initials: K
authors.lastname: Papp
authors.affiliation: Diagnosticum Zrt, Budapest, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Hérincs
authors.affiliation: Diagnosticum Zrt, Budapest, Hungary.
authors.forename: Hajna
authors.initials: H
authors.lastname: Péterfy
authors.affiliation: Department of Rheumatology and Immunology, Clinic Center, University of Pécs, Pécs, Hungary.
authors.forename: Veronika
authors.initials: V
authors.lastname: Lóránd
authors.affiliation: MTA-ELTE Immunology Research Group, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Szittner
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, Bilbao, Spain.
authors.forename: Andone
authors.initials: A
authors.lastname: Estonba
authors.affiliation: Department of NeuroFarBa, University of Florence, Florence, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Rovero
authors.affiliation: Toscana Biomarkers, Siena, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Paolini
authors.affiliation: Progenika Biopharma S.A., a Grifols Company, Derio, Bizkaia, Spain.
authors.forename: Jokin
authors.initials: J
authors.lastname: Del Amo
authors.affiliation: Progenika Biopharma S.A., a Grifols Company, Derio, Bizkaia, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Uribarri
authors.affiliation: Toscana Biomarkers, Siena, Italy.
authors.forename: Maria Claudia
authors.initials: MC
authors.lastname: Alcaro
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, Bilbao, Spain.
authors.forename: Otsanda
authors.initials: O
authors.lastname: Ruiz-Larrañaga
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Migliorini
authors.affiliation: Department of Rheumatology and Immunology, Clinic Center, University of Pécs, Pécs, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Czirják
mesh_terms: D000328:Adult; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D039481:CD11b Antigen / Q000235:genetics; D003165:Complement System Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012698:Serologic Tests
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D039481:CD11b Antigen; C509295:ITGAM protein, human; D003165:Complement System Proteins