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Thurman, Joshua M.,Kraus, Damian M.,Girardi, Guillermina,Hourcade, Dennis,Kang, Hee J.,Royer, Pamela A.,Mitchell, Lynne M.,Giclas, Patricia C.,Salmon, Jane,Gilkeson, Gary,Holers, V. Michael Elsevier 2005 Molecular immunology Vol.42 No.1
<P><B>Abstract</B></P><P>Studies in gene-targeted mice have demonstrated that factor B of the alternative complement pathway plays an important role in several disease models, but an exogenous inhibitor of factor B has not previously been available. We have developed an inhibitory monoclonal antibody directed against a critical epitope on mouse factor B and have tested it in a model of antiphospholipid (aPL) antibody (Ab)-induced fetal loss. Gene-targeted factor B-deficient mice (fB<SUP>−/−</SUP>) were injected with a fusion protein comprised of the second and third short consensus repeat (SCR) domains of mouse factor B linked to a mouse IgG<SUB>1</SUB> Fc domain. Hybridomas were made from splenocytes of the immunized mouse. One mAb, designated 1379, produced an IgG<SUB>1</SUB> antibody that inhibited alternative pathway activation in vitro and in vivo by preventing formation of the C3bBb complex. Strikingly, this mAb inhibited alternative pathway activation in serum from mice, rats, humans, monkeys, pigs and horses. Fab fragments made from this mAb also inhibited alternative pathway activation. Epitope mapping demonstrated that this antibody binds to factor B within the third SCR domain. When mAb 1379 was administered to mice that also received human IgG containing antiphospholipid antibodies, it provided significant protection from antiphospholipid antibody-induced complement activation and fetal loss. Thus, this mAb to factor B has broad species reactivity and effectively inhibits alternative pathway activation. The mAb protects mice in an in vivo model of antiphospholipid antibody syndrome, demonstrating the therapeutic potential for the inhibition of factor B in this disease.</P>
Genetic associations of LYN with systemic lupus erythematosus
Lu, R,Vidal, G S,Kelly, J A,Delgado-Vega, A M,Howard, X K,Macwana, S R,Dominguez, N,Klein, W,Burrell, C,Harley, I T,Kaufman, K M,Bruner, G R,Moser, K L,Gaffney, P M,Gilkeson, G S,Wakeland, E K,Li, Q-Z Macmillan Publishers Limited 2009 GENES AND IMMUNITY Vol.10 No.5
We targeted LYN, a src-tyosine kinase involved in B-cell activation, in case–control association studies using populations of European-American, African-American and Korean subjects. Our combined European-derived population, consisting of 2463 independent cases and 3131 unrelated controls, shows significant association with rs6983130 in a female-only analysis with 2254 cases and 2228 controls (P=1.1 × 10<SUP>−4</SUP>, odds ratio (OR)=0.81 (95% confidence interval: 0.73–0.90)). This single nucleotide polymorphism (SNP) is located in the 5′ untranslated region within the first intron near the transcription initiation site of LYN. In addition, SNPs upstream of the first exon also show weak and sporadic association in subsets of the total European-American population. Multivariate logistic regression analysis implicates rs6983130 as a protective factor for systemic lupus erythematosus (SLE) susceptibility when anti-dsDNA, anti-chromatin, anti-52 kDa Ro or anti-Sm autoantibody status were used as covariates. Subset analysis of the European-American female cases by American College of Rheumatology classification criteria shows a reduction in the risk of hematological disorder with rs6983130 compared with cases without hematological disorders (P=1.5 × 10<SUP>−3</SUP>, OR=0.75 (95% CI: 0.62−0.89)). None of the 90 SNPs tested show significant association with SLE in the African American or Korean populations. These results support an association of LYN with European-derived individuals with SLE, especially within autoantibody or clinical subsets.Genes and Immunity (2009) 10, 397–403; doi:10.1038/gene.2009.19; published online 16 April 2009