C1q regulatory region polymorphism down-regulating murine c1q protein levels with linkage to lupus nephritis.
Much of the pathology of systemic lupus erythematosus (SLE) is caused by deposition of immune complexes (ICs) into various tissues, including renal glomeruli. Because clearance of ICs depends largely on early complement component C1q, homozygous C1q deficiency is a strong genetic risk factor in SLE, although it is rare in SLE patients overall. In this work we addressed the issue of whether genetic polymorphisms affecting C1q levels may predispose to SLE, using the (NZB x NZW)F(1) model. C1q genes are composed of three genes, C1qa, C1qc, and C1qb, arranged in this order, and each gene consists of two exons separated by one intron. Sequence analysis of the C1q gene in New Zealand Black (NZB), New Zealand White (NZW), and BALB/c mice showed no polymorphisms in exons and introns of three genes. However, Southern blot analysis revealed unique insertion polymorphism of a total of approximately 3.5 kb in the C1qa upstream region of NZB mice. C1q levels in sera and culture supernatants of LPS-stimulated peritoneal macrophages and C1q messages in spleen cells were all lower in disease-free young NZB and (NZB x NZW)F(1) mice than in age-matched non-autoimmune NZW and BALB/c mice. Quantitative trait loci analysis using (NZB x NZW)F(1) x NZW backcrosses showed that NZB microsatellites in the vicinity of the C1q allele on chromosome 4 were significantly linked to low serum C1q levels and the development of nephritis. These data imply that not only C1q deficiency but also regulatory region polymorphisms down-regulating C1q levels may confer the risk for lupus nephritis by reducing IC clearance and thus promoting IC deposition in glomeruli.
Department of Pathology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Yuko
Y
Miura-Shimura
Kazuhiro
K
Nakamura
Mareki
M
Ohtsuji
Hideaki
H
Tomita
Yi
Y
Jiang
Masaaki
M
Abe
Danqing
D
Zhang
Yoshitomo
Y
Hamano
Hiroshi
H
Tsuda
Hiroshi
H
Hashimoto
Hiroyuki
H
Nishimura
Shinsuke
S
Taki
Toshikazu
T
Shirai
Sachiko
S
Hirose
D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001323:Autoantibodies / Q000096:biosynthesis; D015922:Complement C1q / Q000096:biosynthesis / Q000235:genetics*; D015536:Down-Regulation; D020022:Genetic Predisposition to Disease; D008181:Lupus Nephritis / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB; D011110:Polymorphism, Genetic
D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D015922:Complement C1q