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1.
Genes Immun ; 7(7): 592-9, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16943797

ABSTRACT

Systemic lupus erythematosus is an autoimmune disease in which complex interactions between genes and environmental factors determine the disease phenotype. We have shown that genes from the non-autoimmune strains 129 and C57BL/6 (B6), commonly used for generating gene-targeted animals, can induce a lupus-like disease. Here, we conducted a genome-wide scan analysis of a cohort of (129 x B6)F2 C1q-deficient mice to identify loci outside the C1qa locus contributing to the autoimmune phenotype described in these mice. The results were then confirmed in a larger dataset obtained by combining the data from the C1q-deficient mice with data from previously reported wild-type mice. Both analyses showed that a 129-derived interval on distal chromosome 1 is strongly linked to autoantibody production. The B6 genome contributed to anti-nuclear autoantibody production with an interval on chromosome 3. Two regions were linked to glomerulonephritis: a 129 interval on proximal chromosome 7 and a B6 interval on chromosome 13. These findings demonstrate that interacting loci between 129 and B6 mice can cause the expression of an autoimmune phenotype in gene-targeted animals in the absence of any disrupted gene. They also indicate that some susceptibility genes can be inherited from the genome of non-autoimmune parental strains.


Subject(s)
Lupus Erythematosus, Systemic/genetics , Animals , Antibodies, Antinuclear/biosynthesis , Chromosome Mapping , Complement C1q/deficiency , Complement C1q/genetics , Female , Lupus Erythematosus, Systemic/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Quantitative Trait Loci , Species Specificity
2.
Blood ; 98(2): 442-9, 2001 Jul 15.
Article in English | MEDLINE | ID: mdl-11435315

ABSTRACT

The glycolipid-anchored glycoprotein CD59 inhibits assembly of the lytic membrane attack complex of complement by incorporation into the forming complex. Absence of CD59 and other glycolipid-anchored molecules on circulating cells in the human hemolytic disorder paroxysmal nocturnal hemoglobinuria is associated with intravascular hemolysis and thrombosis. To examine the role of CD59 in protecting host tissues in health and disease, CD59-deficient (CD59(-/-)) mice were produced by gene targeting in embryonic stem cells. Absence of CD59 was confirmed by staining cells and tissues with specific antibody. Despite the complete absence of CD59, mice were healthy and fertile. Erythrocytes in vitro displayed increased susceptibility to complement and were positive in an acidified serum lysis test. Despite this, CD59(-/-) mice were not anemic but had elevated reticulocyte counts, indicating accelerated erythrocyte turnover. Fresh plasma and urine from CD59(-/-) mice contained increased amounts of hemoglobin when compared with littermate controls, providing further evidence for spontaneous intravascular hemolysis. Intravascular hemolysis was increased following administration of cobra venom factor to trigger complement activation. CD59(-/-) mice will provide a tool for characterizing the importance of CD59 in protection of self tissues from membrane attack complex damage in health and during diseases in which complement is activated.


Subject(s)
CD59 Antigens/genetics , Gene Deletion , Hemoglobinuria/genetics , Hemolysis/genetics , Animals , Blood Platelets/chemistry , CD59 Antigens/physiology , Complement Activation , Elapid Venoms/pharmacology , Erythrocytes/chemistry , Female , Flow Cytometry , Heterozygote , Homozygote , Leukocytes/chemistry , Male , Mice , Mice, Knockout , Reticulocyte Count , Sex Characteristics
3.
Eur J Immunol ; 30(10): 2871-80, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11069069

ABSTRACT

The biosynthesis of MHC class II/peptide complexes involves classical, cell surface MHC products as well as the intracellular component H2-M, required for the removal of invariant chain-derived CLIP and for peptide loading. The function of another intracellular class II heterodimer, H2-O, is the matter of some controversy. The physical association of H2-O with H2-M and co-localization in class II+ vesicles suggest a related function in peptide exchange. Furthermore, the distinctive thymic distribution of H2-O raises the possibility of a specialized role in T cell thymic selection. To investigate the role of H2-O in vivo we generated mice carrying a targeted disruption in the H2-Oa gene. No evidence was obtained for a defect in removal of CLIP. However, the array of endogenous peptides bound by class II was altered and a defect in antigen presentation through H2-A to T cells was seen on the 129/Sv/ C57BL/6 mixed strain background but not in 129/Sv pure strain mice. Furthermore, H2-O-null mice showed enhanced selection of CD4+ single positive thymocytes. The findings indicate that H2-O interacts with H2-M in peptide editing but that the genetic background in which H2-O deficiency is manifest is also important. Overall, the experiments indicate that H2-O/HLA-DO should be regarded as neither up-regulating nor down-regulating the DM-dependent release of CLIP, but as a modulator of peptide editing, determining the presenting cell type specific peptide profile able to retain stability in the class II groove.


Subject(s)
Antigen Presentation , Histocompatibility Antigens Class II/immunology , Peptide Fragments/metabolism , Animals , Antigens/immunology , Antigens/metabolism , Antigens, Differentiation, B-Lymphocyte/metabolism , CD4 Antigens/immunology , CD8 Antigens/immunology , Dimerization , Female , Genes, MHC Class II , Genotype , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class II/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Peptide Fragments/immunology , Protein Binding , Receptors, Antigen, T-Cell, alpha-beta/genetics , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , T-Lymphocyte Subsets/immunology
5.
J Immunol ; 162(10): 5676-9, 1999 May 15.
Article in English | MEDLINE | ID: mdl-10229798

ABSTRACT

C1q-deficient (C1qa-/-) mice develop antinuclear Abs and glomerulonephritis (GN) characterized by multiple apoptotic bodies. To explore the contribution of C3 activation to the induction of spontaneous GN, C1qa-/- mice were crossed with factor B- and C2-deficient (H2-Bf/C2-/-) mice. GN was present in 64% of the 45 C1qa/H2-Bf/C2-/- mice compared with 8% of the 65 H2-Bf/C2-/- mice and none of the 24 wild-type controls. IgG was detected in the glomeruli of diseased C1qa/H2-Bf/C2-/- kidneys. However, glomerular staining for C3 was absent. Increased numbers of glomerular apoptotic bodies were detected in undiseased C1qa/H2-Bf/C2-/- kidneys. These findings support the hypothesis that C1q may play a role in the clearance of apoptotic cells without the necessity for C3 activation and demonstrate that the activation of C3 is not essential for the development of GN in this spontaneous model of lupus-like disease.


Subject(s)
Complement Activation/genetics , Complement C1q/deficiency , Complement C3/immunology , Glomerulonephritis/immunology , Animals , Antibodies, Antinuclear/blood , Complement C1q/genetics , Complement C2/deficiency , Complement C2/genetics , Complement Pathway, Alternative/genetics , Complement Pathway, Classical/genetics , Glomerulonephritis/etiology , Kidney/pathology , Mice , Mice, Mutant Strains
6.
Nat Genet ; 19(1): 56-9, 1998 May.
Article in English | MEDLINE | ID: mdl-9590289

ABSTRACT

The complement system plays a paradoxical role in the development and expression of autoimmunity in humans. The activation of complement in systemic lupus erythematosus (SLE) contributes to tissue injury. In contrast, inherited deficiency of classical pathway components, particularly C1q (ref. 1), is powerfully associated with the development of SLE. This leads to the hypothesis that a physiological action of the early part of the classical pathway protects against the development of SLE (ref. 2) and implies that C1q may play a key role in this respect. C1q-deficient (C1qa-/-) mice were generated by gene targeting and monitored for eight months. C1qa-/- mice had increased mortality and higher titres of autoantibodies, compared with strain-matched controls. Of the C1qa-/- mice, 25% had glomerulonephritis with immune deposits and multiple apoptotic cell bodies. Among mice without glomerulonephritis, there were significantly greater numbers of glomerular apoptotic bodies in C1q-deficient mice compared with controls. The phenotype associated with C1q deficiency was modified by background genes. These findings are compatible with the hypothesis that C1q deficiency causes autoimmunity by impairment of the clearance of apoptotic cells.


Subject(s)
Complement C1q/deficiency , Glomerulonephritis/genetics , Homozygote , Animals , Antibodies, Antinuclear/immunology , Autoantigens/immunology , Complement C1q/genetics , Crosses, Genetic , Glomerulonephritis/immunology , Kidney Glomerulus/metabolism , Kidney Glomerulus/pathology , Kidney Glomerulus/ultrastructure , Mice , Microscopy, Electron
7.
J Biol Chem ; 273(3): 1699-704, 1998 Jan 16.
Article in English | MEDLINE | ID: mdl-9430715

ABSTRACT

Factor B is a serine protease, essential for the function of the alternative pathway of complement activation. To study further the importance of the alternative pathway of complement activation in vivo and to help elucidate any additional functions of factor B or its activation fragments we developed, by homologous recombination in embryonic stem cells, mice with a disrupted factor B gene. Factor B-deficient mice produced no detectable factor B mRNA or protein and had no detectable factor B enzymatic activity or alternative pathway function in their serum. Further studies revealed that the two adjacent genes, complement component C2 and D17H6S45, had been down regulated as a result of the disruption. The down-regulation of C2 gene expression was sufficient to cause a complete loss of classical pathway function as determined by the failure of sera from the deficient mice to opsonize antibody-sensitized sheep erythrocytes and by impairment of immune complex processing in vivo. The resulting mouse is deficient in both factor B and C2, and hence the alternative and classical pathways of complement activation, and adds to the repertoire of models for studying the in vivo role of complement in the immune system.


Subject(s)
Complement C2/genetics , Complement Factor B/genetics , Complement Pathway, Alternative , Gene Expression , Nuclear Proteins/genetics , RNA-Binding Proteins/genetics , Animals , Complement Activation , Down-Regulation , Mice , Mice, Inbred C57BL , RNA, Messenger/metabolism , RNA-Binding Proteins/metabolism
8.
Nat Med ; 3(8): 855-9, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9256275

ABSTRACT

The tissue amyloid deposits that characterize systemic amyloidosis, Alzheimer's disease and the transmissible spongiform encephalopathies always contain serum amyloid P component (SAP) bound to the amyloid fibrils. We have previously proposed that this normal plasma protein may contribute to amyloidogenesis by stabilizing the deposits. Here we show that the induction of reactive amyloidosis is retarded in mice with targeted deletion of the SAP gene. This first demonstration of the participation of SAP in pathogenesis of amyloidosis in vivo confirms that inhibition of SAP binding to amyloid fibrils is an attractive therapeutic target in a range of serious human diseases.


Subject(s)
Amyloid/metabolism , Gene Deletion , Serum Amyloid P-Component/genetics , Amyloidosis/chemically induced , Amyloidosis/genetics , Animals , Caseins/toxicity , Disease Models, Animal , Glycoproteins/toxicity , Humans , Male , Mice , Mice, Inbred C57BL , Silver Nitrate/toxicity
9.
Genes Dev ; 1(2): 161-71, 1987 Apr.
Article in English | MEDLINE | ID: mdl-3500093

ABSTRACT

alpha 1-Antitrypsin (alpha 1AT) is an abundant serum protein whose major site of synthesis is in the hepatocyte. alpha 1AT transcripts are also present, albeit at a lower level, in a variety of other human tissues. This pattern of expression is partly related to initiation of transcription at sites with distinct tissue specificities. The mouse alpha 1AT gene, in contrast, is more strictly liver specific in its expression. To explore the regulation of the alpha 1AT gene we have microinjected a cosmid insert carrying the human gene into fertilized mouse eggs. In three lines obtained from transgenic mice, inheritance of copies of the human gene is accompanied by a high serum concentration of the human protein. Human alpha 1AT RNA accumulates to the highest level in liver of transgenic animals. The presence of transcripts in other tissues indicates that the human pattern of expression is maintained, whereas the temporal activity of the introduced gene parallels that of the endogenous one during mouse embryogenesis.


Subject(s)
Genes , Transcription, Genetic , alpha 1-Antitrypsin/genetics , Animals , Gene Expression Regulation , Humans , Mice , Mice, Transgenic , Organ Specificity , Species Specificity
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