{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T09:34:22Z","timestamp":1787909662601,"version":"build-2784847793"},"reference-count":108,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T00:00:00Z","timestamp":1654041600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Dr Sullivan"},{"name":"Wallace Chair of Pediatrics"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,8,19]]},"abstract":"<jats:title>Summary<\/jats:title>\n               <jats:p>The classical pathway of the complement cascade has been recognized as a key activation arm, partnering with the lectin activation arm and the alternative pathway to cleave C3 and initiate the assembly of the terminal components. While deficiencies of classical pathway components have been recognized since 1966, only recently have gain-of-function variants been described for some of these proteins. Loss-of-function variants in C1, C4, and C2 are most often associated with lupus and systemic infections with encapsulated bacteria. C3 deficiency varies slightly from this phenotypic class with membranoproliferative glomerulonephritis and infection as the dominant phenotypes. The gain-of-function variants recently described for C1r and C1s lead to periodontal Ehlers Danlos syndrome, a surprisingly structural phenotype. Gain-of-function in C3 and C2 are associated with endothelial manifestations including hemolytic uremic syndrome and vasculitis with C2 gain-of-function variants thus far having been reported in patients with a C3 glomerulopathy. This review will discuss the loss-of-function and gain-of-function phenotypes and place them within the larger context of complement deficiencies.<\/jats:p>","DOI":"10.1093\/cei\/uxac056","type":"journal-article","created":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T16:43:38Z","timestamp":1654101818000},"page":"151-160","source":"Crossref","is-referenced-by-count":16,"title":["The yin and the yang of early classical pathway complement disorders"],"prefix":"10.1093","volume":"209","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4018-1646","authenticated-orcid":false,"given":"Kathleen E","family":"Sullivan","sequence":"first","affiliation":[{"name":"Division of Allergy Immunology, The Children\u2019s Hospital of Philadelphia , 3615 Civic Center Blvd., Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,6,1]]},"reference":[{"key":"2022101210064048200_CIT0001","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1007\/s10875-020-00758-x","article-title":"human inborn errors of immunity: 2019 update of the IUIS phenotypical classification.","volume":"40","author":"Bousfiha","year":"2020","journal-title":"J Clin Immunol"},{"key":"2022101210064048200_CIT0002","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1007\/s10875-021-00980-1","article-title":"The ever-increasing array of novel inborn errors of immunity: an interim update by the IUIS committee.","volume":"41","author":"Tangye","year":"2021","journal-title":"J Clin Immunol"},{"key":"2022101210064048200_CIT0003","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/BF02918259","article-title":"Complement deficiency states and meningococcal disease.","volume":"12","author":"Figueroa","year":"1993","journal-title":"Immunol Res"},{"key":"2022101210064048200_CIT0004","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1128\/CMR.4.3.359","article-title":"Infectious diseases associated with complement deficiencies.","volume":"4","author":"Figueroa","year":"1991","journal-title":"Clin Microbiol Rev"},{"key":"2022101210064048200_CIT0005","doi-asserted-by":"crossref","first-page":"500","DOI":"10.3389\/fimmu.2018.00500","article-title":"Functional complement analysis can predict genetic testing results and long-term outcome in patients with complement deficiencies.","volume":"9","author":"Blazina","year":"2018","journal-title":"Front Immunol"},{"key":"2022101210064048200_CIT0006","doi-asserted-by":"crossref","first-page":"13093","DOI":"10.1021\/bi801131h","article-title":"Interaction of human C1q with IgG and IgM: revisited.","volume":"47","author":"Gadjeva","year":"2008","journal-title":"Biochemistry"},{"key":"2022101210064048200_CIT0007","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1016\/j.bbapap.2008.04.029","article-title":"Interaction of the globular domain of human C1q with Salmonella typhimurium lipopolysaccharide.","volume":"1784","author":"Roumenina","year":"2008","journal-title":"Biochim Biophys Acta"},{"key":"2022101210064048200_CIT0008","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.imlet.2004.06.015","article-title":"Structural and functional anatomy of the globular domain of complement protein C1q.","volume":"95","author":"Kishore","year":"2004","journal-title":"Immunol Lett"},{"key":"2022101210064048200_CIT0009","doi-asserted-by":"crossref","first-page":"4351","DOI":"10.4049\/jimmunol.172.7.4351","article-title":"Mutational analyses of the recombinant globular regions of human C1q A, B, and C chains suggest an essential role for arginine and histidine residues in the C1q-IgG interaction.","volume":"172","author":"Kojouharova","year":"2004","journal-title":"J Immunol"},{"key":"2022101210064048200_CIT0010","doi-asserted-by":"crossref","first-page":"4719","DOI":"10.1128\/iai.64.11.4719-4725.1996","article-title":"Interaction between complement subcomponent C1q and the Klebsiella pneumoniae porin OmpK36.","volume":"64","author":"Alberti","year":"1996","journal-title":"Infect Immun"},{"key":"2022101210064048200_CIT0011","first-page":"92","article-title":"The human c1q globular domain: structure and recognition of non-immune self ligands.","volume":"2","author":"Gaboriaud","year":"2011","journal-title":"Front Immunol"},{"key":"2022101210064048200_CIT0012","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1002\/1521-4141(200206)32:6<1726::AID-IMMU1726>3.0.CO;2-R","article-title":"Direct binding of C1q to apoptotic cells and cell blebs induces complement activation.","volume":"32","author":"Nauta","year":"2002","journal-title":"Eur J Immunol"},{"key":"2022101210064048200_CIT0013","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.jmb.2011.02.029","article-title":"Investigations on the C1q-calreticulin-phosphatidylserine interactions yield new insights into apoptotic cell recognition.","volume":"408","author":"Paidassi","year":"2011","journal-title":"J Mol Biol"},{"key":"2022101210064048200_CIT0014","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.4049\/jimmunol.180.4.2329","article-title":"C1q binds phosphatidylserine and likely acts as a multiligand-bridging molecule in apoptotic cell recognition.","volume":"180","author":"Paidassi","year":"2008","journal-title":"J Immunol"},{"key":"2022101210064048200_CIT0015","doi-asserted-by":"crossref","first-page":"3111","DOI":"10.1016\/j.febslet.2008.08.001","article-title":"The lectin-like activity of human C1q and its implication in DNA and apoptotic cell recognition.","volume":"582","author":"Paidassi","year":"2008","journal-title":"FEBS Lett"},{"key":"2022101210064048200_CIT0016","doi-asserted-by":"crossref","first-page":"4714","DOI":"10.1046\/j.1432-1033.2003.03870.x","article-title":"Interaction of the C1 complex of complement with sulfated polysaccharide and DNA probed by single molecule fluorescence microscopy.","volume":"270","author":"Tissot","year":"2003","journal-title":"Eur J Biochem"},{"key":"2022101210064048200_CIT0017","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1007\/s10875-021-01183-4","article-title":"Prevalence of pathogenic and potentially pathogenic inborn error of immunity associated variants in children with severe sepsis.","volume":"42","author":"Kernan","year":"2022","journal-title":"J Clin Immunol"},{"key":"2022101210064048200_CIT0018","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1093\/cid\/ciu274","article-title":"Invasive pneumococcal disease in children can reveal a primary immunodeficiency.","volume":"59","author":"Gaschignard","year":"2014","journal-title":"Clin Infect Dis"},{"key":"2022101210064048200_CIT0019","doi-asserted-by":"crossref","first-page":"265","DOI":"10.3109\/00365548.2013.877156","article-title":"Recurrent invasive pneumococcal disease in children: epidemiological, microbiological, and clinical aspects from a Danish 33-year nationwide survey (1980\u20132013).","volume":"46","author":"Ingels","year":"2014","journal-title":"Scand J Infect Dis"},{"key":"2022101210064048200_CIT0020","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1097\/01.md.0000152371.22747.1e","article-title":"Hereditary C2 deficiency in Sweden: frequent occurrence of invasive infection, atherosclerosis, and rheumatic disease.","volume":"84","author":"Jonsson","year":"2005","journal-title":"Medicine (Baltim)"},{"key":"2022101210064048200_CIT0021","first-page":"1128","article-title":"The prevalence of a mutation which causes C2 deficiency in SLE.","volume":"21","author":"Sullivan","year":"1994","journal-title":"J Rheumatol"},{"key":"2022101210064048200_CIT0022","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1093\/rheumatology\/key419","article-title":"A case of systemic lupus erythematosus with C1q deficiency, increased serum interferon-alpha levels and high serum interferogenic activity.","volume":"58","author":"Bolin","year":"2019","journal-title":"Rheumatology (Oxford)"},{"key":"2022101210064048200_CIT0023","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.coi.2014.10.005","article-title":"Type I interferonopathies: mendelian type I interferon up-regulation.","volume":"32","author":"Crow","year":"2015","journal-title":"Curr Opin Immunol"},{"key":"2022101210064048200_CIT0024","doi-asserted-by":"crossref","first-page":"73ra20","DOI":"10.1126\/scitranslmed.3001201","article-title":"Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus.","volume":"3","author":"Garcia-Romo","year":"2011","journal-title":"Sci Transl Med"},{"key":"2022101210064048200_CIT0025","doi-asserted-by":"crossref","first-page":"5566","DOI":"10.1038\/s41467-020-19412-6","article-title":"Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis.","volume":"11","author":"Moreira-Teixeira","year":"2020","journal-title":"Nat Commun"},{"key":"2022101210064048200_CIT0026","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.autrev.2015.02.001","article-title":"Hereditary angioedema and lupus: a French retrospective study and literature review.","volume":"14","author":"Gallais Serezal","year":"2015","journal-title":"Autoimmun Rev"},{"key":"2022101210064048200_CIT0027","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1002\/art.39589","article-title":"Effects of complement C4 gene copy number variations, size dichotomy, and C4A deficiency on genetic risk and clinical presentation of systemic lupus erythematosus in East Asian populations.","volume":"68","author":"Chen","year":"2016","journal-title":"Arthritis Rheumatol"},{"key":"2022101210064048200_CIT0028","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1086\/518257","article-title":"Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans.","volume":"80","author":"Yang","year":"2007","journal-title":"Am J Hum Genet"},{"key":"2022101210064048200_CIT0029","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s42358-019-0076-6","article-title":"Impact of C4, C4A and C4B gene copy number variation in the susceptibility, phenotype and progression of systemic lupus erythematosus.","volume":"59","author":"Pereira","year":"2019","journal-title":"Adv Rheumatol"},{"key":"2022101210064048200_CIT0030","doi-asserted-by":"crossref","first-page":"36","DOI":"10.3389\/fimmu.2016.00036","article-title":"Early components of the complement classical activation pathway in human systemic autoimmune diseases.","volume":"7","author":"Lintner","year":"2016","journal-title":"Front Immunol"},{"key":"2022101210064048200_CIT0031","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1177\/0961203311411598","article-title":"Complement and antibody primary immunodeficiency in juvenile systemic lupus erythematosus patients.","volume":"20","author":"Jesus","year":"2011","journal-title":"Lupus"},{"key":"2022101210064048200_CIT0032","doi-asserted-by":"crossref","first-page":"e99","DOI":"10.1016\/S2665-9913(19)30142-0","article-title":"Contribution of rare and predicted pathogenic gene variants to childhood-onset lupus: a large, genetic panel analysis of British and French cohorts.","volume":"2","author":"Belot","year":"2020","journal-title":"Lancet Rheumatol"},{"key":"2022101210064048200_CIT0033","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1007\/s10875-015-0212-y","article-title":"Early complement component deficiency in a single-centre cohort of pediatric onset lupus.","volume":"35","author":"Bhattad","year":"2015","journal-title":"J Clin Immunol"},{"key":"2022101210064048200_CIT0034","doi-asserted-by":"crossref","first-page":"712","DOI":"10.3390\/jcm9030712","article-title":"New horizons in the genetic etiology of systemic lupus erythematosus and lupus-like disease: monogenic lupus and beyond.","volume":"9","author":"Demirkaya","year":"2020","journal-title":"J Clin Med"},{"key":"2022101210064048200_CIT0035","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.rdc.2017.04.005","article-title":"Genomics of systemic lupus erythematosus: insights gained by studying monogenic young-onset systemic lupus erythematosus.","volume":"43","author":"Hiraki","year":"2017","journal-title":"Rheum Dis Clin North Am"},{"key":"2022101210064048200_CIT0036","first-page":"106","article-title":"SLE syndrome and functional deficiency of C1q in members of a large family.","volume":"55","author":"Hannema","year":"1984","journal-title":"Clin Exp Immunol"},{"key":"2022101210064048200_CIT0037","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1002\/art.1780390419","article-title":"Homozygous hereditary C1q deficiency and systemic lupus erythematosus.","volume":"39","author":"Slingsby","year":"1996","journal-title":"Arthritis Rheum"},{"key":"2022101210064048200_CIT0038","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1078\/0171-2985-00141","article-title":"C1q, autoimmunity and apoptosis.","volume":"205","author":"Botto","year":"2002","journal-title":"Immunobiology"},{"key":"2022101210064048200_CIT0039","first-page":"455","article-title":"Hereditary C1q deficiency and systemic lupus erythematosus.","volume":"87","author":"Bowness","year":"1994","journal-title":"Q J Med"},{"key":"2022101210064048200_CIT0040","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0171-2985(98)80032-6","article-title":"C1q and systemic lupus erythematosus.","volume":"199","author":"Walport","year":"1998","journal-title":"Immunobiology"},{"key":"2022101210064048200_CIT0041","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.jaut.2015.06.002","article-title":"Marked variability in clinical presentation and outcome of patients with C1q immunodeficiency.","volume":"62","author":"van Schaarenburg","year":"2015","journal-title":"J Autoimmun"},{"key":"2022101210064048200_CIT0042","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.jaci.2013.07.035","article-title":"Successful cure of C1q deficiency in human subjects treated with hematopoietic stem cell transplantation.","volume":"133","author":"Arkwright","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"2022101210064048200_CIT0043","doi-asserted-by":"crossref","first-page":"108330","DOI":"10.1016\/j.celrep.2020.108330","article-title":"Complement C4A regulates autoreactive B cells in murine lupus.","volume":"33","author":"Simoni","year":"2020","journal-title":"Cell Rep"},{"key":"2022101210064048200_CIT0044","first-page":"1710","article-title":"Hereditary C4 deficiency- genetic studies and linkage to the HLA.","volume":"11","author":"Ballow","year":"1979","journal-title":"Transplant Proc"},{"key":"2022101210064048200_CIT0045","first-page":"29","article-title":"DNA analysis in a MHC heterozygous patients with complete C4 deficiency-homozygosity for C4 gene deletion and C4 pseudogene.","volume":"8","author":"Fredrikson","year":"1991","journal-title":"Exp Clin Immunogenet"},{"key":"2022101210064048200_CIT0046","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1093\/infdis\/162.1.248","article-title":"C4B deficiency: a risk factor for bacteremia with encapsulated organisms.","volume":"162","author":"Bishof","year":"1990","journal-title":"J Infect Dis"},{"key":"2022101210064048200_CIT0047","doi-asserted-by":"crossref","first-page":"42628","DOI":"10.1038\/srep42628","article-title":"Association between C4, C4A, and C4B copy number variations and susceptibility to autoimmune diseases: a meta-analysis.","volume":"7","author":"Li","year":"2017","journal-title":"Sci Rep"},{"key":"2022101210064048200_CIT0048","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1086\/342777","article-title":"Genetic sophistication of human complement components C4A and C4B and RP-C4-CYP21-TNX (RCCX) modules in the major histocompatibility complex.","volume":"71","author":"Chung","year":"2002","journal-title":"Am J Hum Genet"},{"key":"2022101210064048200_CIT0049","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/0002-9343(83)91208-1","article-title":"Genetic deficiency of C4 presenting with recurrent infections and a SLE-like disease. Genetic and immunologic studies.","volume":"75","author":"Mascart-Lemone","year":"1983","journal-title":"Am J Med"},{"key":"2022101210064048200_CIT0050","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s11882-002-0070-6","article-title":"Navigating the maze of complement genetics: a guide for clinicians.","volume":"2","author":"Colten","year":"2002","journal-title":"Curr Allergy Asthma Rep"},{"key":"2022101210064048200_CIT0051","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1146\/annurev.iy.10.040192.004113","article-title":"Complement deficiencies.","volume":"10","author":"Colten","year":"1992","journal-title":"Annu Rev Immunol"},{"key":"2022101210064048200_CIT0052","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1097\/00005792-198409000-00001","article-title":"Complement deficiency states and infection: epidemiology, pathogeneisis and consequences of neisserial and other infections in an immune deficiency.","volume":"63","author":"Ross","year":"1984","journal-title":"Medicine"},{"key":"2022101210064048200_CIT0053","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1001\/archderm.1982.01650200052016","article-title":"C2 deficient systemic lupus erythematosus.","volume":"118","author":"Vandersteen","year":"1982","journal-title":"Arch Dermatol"},{"key":"2022101210064048200_CIT0054","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1161\/01.ATV.0000127302.24266.40","article-title":"Lack of complement factor C3, but not factor B, increases hyperlipidemia and atherosclerosis in apolipoprotein E-\/- low-density lipoprotein receptor-\/- mice.","volume":"24","author":"Persson","year":"2004","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2022101210064048200_CIT0055","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1097\/00006454-199205000-00011","article-title":"Inherited C3 deficiency and meningococcal disease in a teenager.","volume":"11","author":"Peleg","year":"1992","journal-title":"Pediatr Infect Dis J"},{"key":"2022101210064048200_CIT0056","first-page":"247","article-title":"Inherited C3 deficiency of the complement system.","volume":"21","author":"Grumach","year":"1988","journal-title":"Braz J Med Biol Res"},{"key":"2022101210064048200_CIT0057","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1172\/JCI114821","article-title":"Molecular basis of hereditary C3 deficiency.","volume":"86","author":"Botto","year":"1990","journal-title":"J Clin Invest"},{"key":"2022101210064048200_CIT0058","doi-asserted-by":"crossref","first-page":"4957","DOI":"10.1073\/pnas.89.11.4957","article-title":"Homozygous hereditary C3 deficiency due to a partial gene deletion.","volume":"89","author":"Botto","year":"1992","journal-title":"Proc Natl Acad Sci"},{"key":"2022101210064048200_CIT0059","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1159\/000163873","article-title":"Complement C3 deficiency: human, animal, and experimental models.","volume":"62","author":"Singer","year":"1994","journal-title":"Pathobiology"},{"key":"2022101210064048200_CIT0060","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/0002-9343(85)90296-7","article-title":"Hypomorphic variant of the slow allele of C3 associated with hypocomplementemia and hematuria.","volume":"78","author":"McLean","year":"1985","journal-title":"Am J Med"},{"key":"2022101210064048200_CIT0061","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/S0022-3476(78)81215-3","article-title":"Hypomorphic variant of C3, arthritis, and chronic glomerulonephritis.","volume":"93","author":"McLean","year":"1978","journal-title":"J Pediatr"},{"key":"2022101210064048200_CIT0062","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1111\/nep.13722","article-title":"Baseline characteristics of patients with atypical haemolytic uraemic syndrome (aHUS): the Australian cohort in a global aHUS registry.","volume":"25","author":"Soraru","year":"2020","journal-title":"Nephrology (Carlton)"},{"key":"2022101210064048200_CIT0063","article-title":"Genetic atypical hemolytic-uremic syndrome.","volume-title":"GeneReviews((R)).","author":"Noris","year":"1993"},{"key":"2022101210064048200_CIT0064","doi-asserted-by":"crossref","first-page":"e99128","DOI":"10.1172\/jci.insight.99128","article-title":"Germline mutations in the alternative pathway of complement predispose to HELLP syndrome.","volume":"3","author":"Vaught","year":"2018","journal-title":"JCI Insight"},{"key":"2022101210064048200_CIT0065","doi-asserted-by":"crossref","first-page":"e1001013","DOI":"10.1371\/journal.pmed.1001013","article-title":"Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort.","volume":"8","author":"Salmon","year":"2011","journal-title":"PLoS Med"},{"key":"2022101210064048200_CIT0066","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/ki.2012.63","article-title":"Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.","volume":"82","author":"Servais","year":"2012","journal-title":"Kidney Int"},{"key":"2022101210064048200_CIT0067","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1016\/j.kint.2017.04.017","article-title":"C5 nephritic factors drive the biological phenotype of C3 glomerulopathies.","volume":"92","author":"Marinozzi","year":"2017","journal-title":"Kidney Int"},{"key":"2022101210064048200_CIT0068","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1681\/ASN.2015040348","article-title":"A familial C3GN secondary to defective C3 regulation by complement receptor 1 and complement factor H.","volume":"27","author":"Chauvet","year":"2016","journal-title":"J Am Soc Nephrol"},{"key":"2022101210064048200_CIT0069","doi-asserted-by":"crossref","first-page":"2260","DOI":"10.1093\/ndt\/gfx369","article-title":"C3 glomerulonephritis secondary to mutations in factors H and I: rapid recurrence in deceased donor kidney transplant effectively treated with eculizumab.","volume":"33","author":"Garg","year":"2018","journal-title":"Nephrol Dial Transplant"},{"key":"2022101210064048200_CIT0070","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1182\/blood-2016-08-737163","article-title":"Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy.","volume":"129","author":"Chauvet","year":"2017","journal-title":"Blood"},{"key":"2022101210064048200_CIT0071","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1124\/pharmrev.120.000072","article-title":"Therapeutic targeting of the complement system: from rare diseases to pandemics.","volume":"73","author":"Garred","year":"2021","journal-title":"Pharmacol Rev"},{"key":"2022101210064048200_CIT0072","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/ajmg.c.31552","article-title":"The 2017 international classification of the Ehlers-Danlos syndromes.","volume":"175","author":"Malfait","year":"2017","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"2022101210064048200_CIT0073","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/s41436-020-00985-y","article-title":"Prospective clinical investigations of children with periodontal Ehlers-Danlos syndrome identify generalized lack of attached gingiva as a pathognomonic feature.","volume":"23","author":"Kapferer-Seebacher","year":"2021","journal-title":"Genet Med"},{"key":"2022101210064048200_CIT0074","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/j.ajhg.2016.08.019","article-title":"Periodontal Ehlers-Danlos syndrome is caused by mutations in C1R and C1S, which encode subcomponents C1r and C1s of complement.","volume":"99","author":"Kapferer-Seebacher","year":"2016","journal-title":"Am J Hum Genet"},{"key":"2022101210064048200_CIT0075","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10048-018-0560-x","article-title":"Periodontal Ehlers-Danlos syndrome is associated with leukoencephalopathy.","volume":"20","author":"Kapferer-Seebacher","year":"2019","journal-title":"Neurogenetics"},{"key":"2022101210064048200_CIT0076","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1111\/jcpe.12807","article-title":"Periodontal manifestations of Ehlers-Danlos syndromes: a systematic review.","volume":"44","author":"Kapferer-Seebacher","year":"2017","journal-title":"J Clin Periodontol"},{"key":"2022101210064048200_CIT0077","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1212\/WNL.0b013e3181c7da7c","article-title":"Comparison of clinical, familial, and MRI features of CADASIL and NOTCH3-negative patients.","volume":"74","author":"Pantoni","year":"2010","journal-title":"Neurology"},{"key":"2022101210064048200_CIT0078","doi-asserted-by":"crossref","first-page":"3447","DOI":"10.1161\/STROKEAHA.114.004236","article-title":"Features of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy.","volume":"45","author":"Nozaki","year":"2014","journal-title":"Stroke"},{"key":"2022101210064048200_CIT0079","doi-asserted-by":"crossref","first-page":"e689","DOI":"10.1212\/NXI.0000000000000689","article-title":"Complement factor I deficiency: a potentially treatable cause of fulminant cerebral inflammation.","volume":"7","author":"Altmann","year":"2020","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"2022101210064048200_CIT0080","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.3389\/fimmu.2019.01150","article-title":"Classical and non-classical presentations of complement factor I deficiency: two contrasting cases diagnosed via genetic and genomic methods.","volume":"10","author":"Shields","year":"2019","journal-title":"Front Immunol"},{"key":"2022101210064048200_CIT0081","doi-asserted-by":"crossref","first-page":"724361","DOI":"10.3389\/fimmu.2021.724361","article-title":"Gain-of-function mutations R249C and S250C in complement C2 protein increase C3 deposition in the presence of C-reactive protein.","volume":"12","author":"Urban","year":"2021","journal-title":"Front Immunol"},{"key":"2022101210064048200_CIT0082","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1016\/j.jaci.2020.02.014","article-title":"Gain-of-function mutation in complement C2 protein identified in a patient with aHUS.","volume":"146","author":"Urban","year":"2020","journal-title":"J Allergy Clin Immunol"},{"key":"2022101210064048200_CIT0083","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.3390\/cancers14051270","article-title":"In silico designed gain-of-function variants of complement C2 support cytocidal activity of anticancer monoclonal antibodies.","volume":"14","author":"Urban","year":"2022","journal-title":"Cancers (Basel)"},{"key":"2022101210064048200_CIT0084","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1177\/1076029618771750","article-title":"Clinical manifestation of patients with atypical hemolytic uremic syndrome with the C3 p.I1157T variation in the Kinki Region of Japan.","volume":"24","author":"Matsumoto","year":"2018","journal-title":"Clin Appl Thromb Hemost"},{"key":"2022101210064048200_CIT0085","doi-asserted-by":"crossref","first-page":"4948","DOI":"10.1182\/blood-2008-01-133702","article-title":"Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome.","volume":"112","author":"Fremeaux-Bacchi","year":"2008","journal-title":"Blood"},{"key":"2022101210064048200_CIT0086","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1056\/NEJMoa072618","article-title":"Complement C3 variant and the risk of age-related macular degeneration.","volume":"357","author":"Yates","year":"2007","journal-title":"N Engl J Med"},{"key":"2022101210064048200_CIT0087","doi-asserted-by":"crossref","first-page":"e94165","DOI":"10.1371\/journal.pone.0094165","article-title":"Analysis of rare variants in the C3 gene in patients with age-related macular degeneration.","volume":"9","author":"Duvvari","year":"2014","journal-title":"PLoS One"},{"key":"2022101210064048200_CIT0088","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1038\/ni.1755","article-title":"Structure of complement fragment C3b-factor H and implications for host protection by complement regulators.","volume":"10","author":"Wu","year":"2009","journal-title":"Nat Immunol"},{"key":"2022101210064048200_CIT0089","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1007\/s10875-012-9767-z","article-title":"Mutations of complement factor I and potential mechanisms of neuroinflammation in acute hemorrhagic leukoencephalitis.","volume":"33","author":"Broderick","year":"2013","journal-title":"J Clin Immunol"},{"key":"2022101210064048200_CIT0090","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s10875-007-9105-z","article-title":"Primary immunodeficiency diseases in Australia and New Zealand.","volume":"27","author":"Kirkpatrick","year":"2007","journal-title":"J Clin Immunol"},{"key":"2022101210064048200_CIT0091","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/s10875-015-0137-5","article-title":"Spectrum and management of complement immunodeficiencies (excluding hereditary angioedema) across Europe.","volume":"35","author":"Turley","year":"2015","journal-title":"J Clin Immunol"},{"key":"2022101210064048200_CIT0092","doi-asserted-by":"crossref","first-page":"1936","DOI":"10.3389\/fimmu.2019.01936","article-title":"Clinical and genetic spectrum of a large cohort with total and sub-total complement deficiencies.","volume":"10","author":"El Sissy","year":"2019","journal-title":"Front Immunol"},{"key":"2022101210064048200_CIT0093","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.clim.2010.02.021","article-title":"The French national registry of primary immunodeficiency diseases.","volume":"135","author":"group CTFPs.","year":"2010","journal-title":"Clin Immunol"},{"key":"2022101210064048200_CIT0094","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.3389\/fimmu.2019.01272","article-title":"The German national registry of primary immunodeficiencies (2012\u20132017).","volume":"10","author":"El-Helou","year":"2019","journal-title":"Front Immunol"},{"key":"2022101210064048200_CIT0095","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1023\/A:1020660416865","article-title":"Primary immunodeficiency in Iran: first report of the National Registry of PID in Children and Adults.","volume":"22","author":"Aghamohammadi","year":"2002","journal-title":"J Clin Immunol"},{"key":"2022101210064048200_CIT0096","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1007\/s10875-011-9594-7","article-title":"Nationwide survey of patients with primary immunodeficiency diseases in Japan.","volume":"31","author":"Ishimura","year":"2011","journal-title":"J Clin Immunol"},{"key":"2022101210064048200_CIT0097","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.3389\/fimmu.2019.01754","article-title":"The Kuwait National Primary Immunodeficiency Registry 2004\u20132018.","volume":"10","author":"Al-Herz","year":"2019","journal-title":"Front Immunol"},{"key":"2022101210064048200_CIT0098","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1007\/s10875-015-0226-5","article-title":"Clinical features, non-infectious manifestations and survival analysis of 161 children with primary immunodeficiency in Mexico: a single center experience over two decades.","volume":"36","author":"Lugo Reyes","year":"2016","journal-title":"J Clin Immunol"},{"key":"2022101210064048200_CIT0099","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.clim.2014.10.003","article-title":"Primary immunodeficiencies in the Netherlands: national patient data demonstrate the increased risk of malignancy.","volume":"156","author":"Jonkman-Berk","year":"2015","journal-title":"Clin Immunol"},{"key":"2022101210064048200_CIT0100","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.3389\/fimmu.2020.01491","article-title":"Primary immunodeficiencies in Russia: data from the National Registry.","volume":"11","author":"Mukhina","year":"2020","journal-title":"Front Immunol"},{"key":"2022101210064048200_CIT0101","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s12865-014-0031-6","article-title":"Primary immunodeficiency in infection-prone children in southern Sweden: occurrence, clinical characteristics and immunological findings.","volume":"15","author":"Brodszki","year":"2014","journal-title":"BMC Immunol"},{"key":"2022101210064048200_CIT0102","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1007\/s10875-015-0206-9","article-title":"Report of the Tunisian Registry of primary immunodeficiencies: 25-years of experience (1988\u20132012).","volume":"35","author":"Mellouli","year":"2015","journal-title":"J Clin Immunol"},{"key":"2022101210064048200_CIT0103","doi-asserted-by":"crossref","first-page":"837243","DOI":"10.3389\/fimmu.2022.837243","article-title":"The spectrum of inborn errors of immunity in the United Arab Emirates: 5 year experience in a Tertiary Center.","volume":"13","author":"Shendi","year":"2022","journal-title":"Front Immunol"},{"key":"2022101210064048200_CIT0104","author":"USIDNET.","year":"2022"},{"key":"2022101210064048200_CIT0105","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1002\/art.40158","article-title":"Brief report: deficiency of complement 1r subcomponent in early-onset systemic lupus erythematosus: the role of disease-modifying alleles in a monogenic disease.","volume":"69","author":"Demirkaya","year":"2017","journal-title":"Arthritis Rheumatol"},{"key":"2022101210064048200_CIT0106","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1016\/j.jaci.2020.04.002","article-title":"Janus kinase inhibition in complement component 1 deficiency.","volume":"146","author":"Wolf","year":"2020","journal-title":"J Allergy Clin Immunol"},{"key":"2022101210064048200_CIT0107","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1093\/rheumatology\/kem023","article-title":"Rheumatological manifestations, organ damage and autoimmunity in hereditary C2 deficiency.","volume":"46","author":"Jonsson","year":"2007","journal-title":"Rheumatology (Oxford)"},{"key":"2022101210064048200_CIT0108","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.jaci.2015.08.017","article-title":"Clinical characteristics and genotype-phenotype correlations in C3 deficiency.","volume":"137","author":"Okura","year":"2016","journal-title":"J Allergy Clin Immunol"}],"container-title":["Clinical and Experimental Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/cei\/advance-article-pdf\/doi\/10.1093\/cei\/uxac056\/44264141\/uxac056.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/209\/2\/151\/46454457\/uxac056.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/209\/2\/151\/46454457\/uxac056.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T11:03:59Z","timestamp":1665572639000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cei\/article\/209\/2\/151\/6596890"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,1]]},"references-count":108,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,6,1]]},"published-print":{"date-parts":[[2022,8,19]]}},"URL":"https:\/\/doi.org\/10.1093\/cei\/uxac056","relation":{},"ISSN":["0009-9104","1365-2249"],"issn-type":[{"value":"0009-9104","type":"print"},{"value":"1365-2249","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,8,1]]},"published":{"date-parts":[[2022,6,1]]}}}