{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T17:48:58Z","timestamp":1759772938373,"version":"3.38.0"},"reference-count":127,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2020,5,1]],"date-time":"2020-05-01T00:00:00Z","timestamp":1588291200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000066","name":"National Institutes of Health (NIH)\/National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["P30ES007033"],"award-info":[{"award-number":["P30ES007033"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the NIH","doi-asserted-by":"publisher","award":["5T32AR007108-40"],"award-info":[{"award-number":["5T32AR007108-40"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012051","name":"Lupus Research Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012051","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Lupus nephritis (LN) is a major contributor to morbidity and mortality in lupus patients, but the mechanisms of kidney damage remain unclear. In this study, we introduce, to our knowledge, novel models of LN designed to resemble the polygenic nature of human lupus by embodying three key genetic alterations: the Sle1 interval leading to anti-chromatin autoantibodies; Mfge8\u2212\/\u2212, leading to defective clearance of apoptotic cells; and either C1q\u2212\/\u2212 or C3\u2212\/\u2212, leading to low complement levels. We report that proliferative glomerulonephritis arose only in the presence of all three abnormalities (i.e., in Sle1.Mfge8\u2212\/\u2212C1q\u2212\/\u2212 and Sle1.Mfge8\u2212\/\u2212C3\u2212\/\u2212 triple-mutant [TM] strains [C1q\u2212\/\u2212TM and C3\u2212\/\u2212TM, respectively]), with structural kidney changes resembling those in LN patients. Unexpectedly, both TM strains had significant increases in autoantibody titers, Ag spread, and IgG deposition in the kidneys. Despite the early complement component deficiencies, we observed assembly of the pathogenic terminal complement membrane attack complex in both TM strains. In C1q\u2212\/\u2212TM mice, colocalization of MASP-2 and C3 in both the glomeruli and tubules indicated that the lectin pathway likely contributed to complement activation and tissue injury in this strain. Interestingly, enhanced thrombin activation in C3\u2212\/\u2212TM mice and reduction of kidney injury following attenuation of thrombin generation by argatroban in a serum-transfer nephrotoxic model identified thrombin as a surrogate pathway for complement activation in C3-deficient mice. These novel mouse models of human lupus inform the requirements for nephritis and provide targets for intervention.<\/jats:p>","DOI":"10.4049\/jimmunol.1901473","type":"journal-article","created":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T20:24:29Z","timestamp":1585772669000},"page":"2627-2640","source":"Crossref","is-referenced-by-count":4,"title":["Complement Deficiencies Result in Surrogate Pathways of Complement Activation in Novel Polygenic Lupus-like Models of Kidney Injury"],"prefix":"10.1093","volume":"204","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6350-9582","authenticated-orcid":false,"given":"Sladjana","family":"Skopelja-Gardner","sequence":"first","affiliation":[{"name":"Division of Rheumatology, University of Washington , Seattle, WA 98109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucrezia","family":"Colonna","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, University of Washington , Seattle, WA 98109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Payton","family":"Hermanson","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, University of Washington , Seattle, WA 98109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xizhang","family":"Sun","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, University of Washington , Seattle, WA 98109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lena","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, University of Washington , Seattle, WA 98109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joyce","family":"Tai","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, University of Washington , Seattle, WA 98109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yenly","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, University of Washington , Seattle, WA 98109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica M","family":"Snyder","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, University of Washington , Seattle, WA 98109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1859-1772","authenticated-orcid":false,"given":"Charles E","family":"Alpers","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University of Washington , Seattle, WA 98109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly L","family":"Hudkins","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University of Washington , Seattle, WA 98109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J","family":"Salant","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Boston University , Boston, MA 02215"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"YuFeng","family":"Peng","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, University of Washington , Seattle, WA 98109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keith B","family":"Elkon","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, University of Washington , Seattle, WA 98109"},{"name":"Department of Immunology, University of Washington , Seattle, WA 98109"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,5,15]]},"reference":[{"key":"2025030417511777300_r1","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/jhg.2015.94","article-title":"Genetics of autoimmune diseases: insights from population genetics","volume":"60","author":"Ramos","year":"2015","journal-title":"J. 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