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1.
Arthritis Rheum ; 48(6): 1708-20, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12794840

ABSTRACT

OBJECTIVE: To explore the effect of sex on clinical and immunologic traits in major histocompatibility complex-matched (H-2d) F(2) hybrid mice with proteoglycan (PG)-induced arthritis and to identify how the quantitative trait locus (QTL) on the X chromosome influences the onset QTL of another chromosome. METHODS: (BALB/c x DBA/2)F(2) hybrid mice were immunized with cartilage PG, and a genome-wide linkage analysis was performed using >200 simple sequence-length polymorphic markers. The major clinical traits (susceptibility, onset, and severity) were assessed, and PG-specific T and B cell responses, and the production of proinflammatory and antiinflammatory cytokines (tumor necrosis factor alpha, interleukin-1 [IL-1], IL-6, interferon-gamma, IL-4, IL-10, and IL-12) were measured in 133 arthritic and 426 nonarthritic female and male F(2) hybrid mice. The major clinical and immunologic traits were linked to genetic loci, and potential linkages among these QTLs and the effect of sex were analyzed. RESULTS: Thirteen QTLs reported in previous studies were confirmed. Binary traits (susceptibility to arthritis) and disease onset were female specific and were identified on chromosomes 3, 7, 10, 11, 13, and X. QTLs for disease severity were mostly male specific and were located on chromosomes 1, 4, 5, 8, 14, 15, and 19. In addition, we identified 4 new QTLs for the onset of arthritis on chromosomes 3, 4, and 11, and 1 new QTL for severity on chromosome 14; all showed a strong gender association. A locus on the X chromosome interacted with a QTL on chromosome 10, and these 2 loci together seemed to control disease incidence and onset. Most of the clinical traits (QTLs) shared common regions with the immunologic traits and frequently showed a locus-locus interaction. CONCLUSION: Numerous immunologic QTLs overlap with clinical QTLs, thus providing information about possible mechanisms underlying QTL function. Disease susceptibility and onset showed predominant linkage with the female sex, under the control of a QTL on the X chromosome, while the severity QTLs were more strongly linked to the male sex.


Subject(s)
Arthritis, Experimental/genetics , Arthritis, Experimental/immunology , Genetic Predisposition to Disease , Quantitative Trait Loci/immunology , Animals , Arthritis, Experimental/metabolism , Arthritis, Experimental/pathology , Cytokines/metabolism , Disease Models, Animal , Female , Gene Expression Profiling , Hindlimb , Joints/pathology , Lod Score , Male , Mice , Mice, Inbred BALB C , Mice, Inbred DBA , Polymorphism, Genetic , Sex Factors , X Chromosome
2.
Cancer Res ; 62(7): 1939-43, 2002 Apr 01.
Article in English | MEDLINE | ID: mdl-11929806

ABSTRACT

Loss of heterozygosity within the short arm of chromosome 3 is a common molecular event in several types of solid tumors. In breast cancer, 3p loss of heterozygosity occurs in invasive tumor cells as well as in morphologically normal terminal ductal lobular units adjacent to carcinoma in some cases [G. Deng et al., Science (Wash. DC), 274: 2057-2059, 1996.]. The most frequent region of allelic loss at 3p24.3 in morphologically normal terminal ductal lobular units encompasses the thyroid hormone receptor beta1 (TRbeta1) gene. Here we have observed a variable degree of TRbeta1 promoter hypermethylation in all 11 cases of primary breast cancer examined. Moreover, hypermethylation occurred at the same CpG sites in nonmalignant tissue peripheral to carcinoma in 4 of 11 cases. The lack of TRbeta1 nuclear staining, a likely result of biallelic gene inactivation, was observed in 25% (22 of 85) of primary tumors. This is a first demonstration of promoter hypermethylation and a concurrent reduction of TRbeta1 transcripts in breast cancer cell lines, although specific CpG sites targeted for gene silencing remain to be determined. Gene expression was restored by treatment with 5-aza-deoxycytidine in such cases. The observation of early, frequent, and multiple mechanisms of TRbeta1 inactivation suggests a potential role for this gene in the suppression of breast tumorigenesis.


Subject(s)
Alleles , Breast Neoplasms/genetics , Carcinoma, Ductal, Breast/genetics , Gene Silencing , Receptors, Thyroid Hormone/genetics , Thyroid Hormone Receptors beta , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Ductal, Breast/pathology , DNA Methylation , Gene Dosage , Gene Expression Regulation, Neoplastic , Humans , Loss of Heterozygosity , Neoplasm Staging , Promoter Regions, Genetic , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptors, Thyroid Hormone/biosynthesis , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured
3.
Arthritis Res ; 4(1): 54-8, 2002.
Article in English | MEDLINE | ID: mdl-11879537

ABSTRACT

BALB/c mice immunized with human cartilage proteoglycan (PG) develop arthritis accompanied by the production of autoantibodies to mouse cartilage PG. To determine whether the autoantibody isotype contributes to the onset and severity of arthritis, PG-specific serum IgG1 (Th2, IL-4-cytokine-supporting) and IgG2a (Th1, IFN-gamma-controlling) concentrations were monitored during immunization with PG in IL-4-deficient and IFN-gamma-deficient mice. Paradoxically, despite elevated IFN-gamma, the PG-specific IgG1 isotype was significantly higher than the PG-specific IgG2a response, and the PG-specific IgG1 isotype was independent of IL-4. In contrast, the serum concentration of PG-specific IgG2a isotype was six times higher in IL-4-deficient mice than in wild-type controls. Moreover, the high concentration of PG-specific IgG2a isotype in IL-4-deficient mice corresponded to an increased severity of arthritis. The concentration of PG-specific IgG2a isotype was lower in IFN-gamma-deficient mice than in wild-type mice, and the incidence and severity of arthritis also were significantly lower. Concentrations of PG-specific IgG2a isotype autoantibody correlated with the onset and severity of arthritis, suggesting a pathological role of this isotype, probably locally in the joint.


Subject(s)
Arthritis, Experimental/immunology , Extracellular Matrix Proteins , Proteoglycans/immunology , Th1 Cells/immunology , Th2 Cells/immunology , Aggrecans , Animals , Arthritis, Experimental/metabolism , Arthritis, Experimental/pathology , Autoantibodies , Cartilage, Articular/drug effects , Cartilage, Articular/immunology , Cartilage, Articular/metabolism , Female , Humans , Immunization , Immunoglobulin G/metabolism , Immunoglobulin Isotypes/immunology , Immunoglobulin Isotypes/metabolism , Interferon-gamma/deficiency , Interferon-gamma/genetics , Interleukin-4/deficiency , Interleukin-4/genetics , Lectins, C-Type , Mice , Mice, Inbred BALB C , Mice, Knockout , Proteoglycans/administration & dosage , Rats , Th1 Cells/metabolism , Th2 Cells/metabolism
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