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ABSTRACT: Rat models are useful for the genetic dissection of the biology of innate immunity. Inbred rat strains were evaluated for carrageenan-induced innate inflammatory responses. Results indicated that the genetic control of innate immune responses is polygenic and influenced by gender, and may not necessarily be consistent with the genetics of experimental arthritis. The newly identified susceptible strains, in order of decreasing susceptibility, include Dahl salt-sensitive (S), Dahl salt-resistant (R), Milan normotensive strain (MNS) and Wistar Kyoto (WKY) rats. Similarly, the newly identified relatively resistant strains, in decreasing order of resistance, include DA rats, spontaneously hypertensive rats (SHRs) and Brown Norway (BN) rats. Linkage analyses using combinations of these susceptible and resistant strains are proposed.
European Journal of Immunogenetics 09/2003; 30(4):243-7.
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ABSTRACT: Collagen-induced arthritis (CIA) is a useful model for dissecting the genetic patterns underlying susceptibility to rheumatoid arthritis (RA) and related chronic/inflammatory autoimmune diseases. CIA exhibits three phenotypes characteristic of autoimmune disease pathogenesis: abnormal levels of immune reactivity to self antigens; chronic inflammation of target organs expressing that specific autoantigen; activation and direct participation of invading mononuclear cells and resident tissue fibroblasts in organ damage. Over 25 different quantitative trait loci (QTL) regulating arthritis severity and autoantibody in rats with CIA are mapped. QTL-congenic strains show that certain CIA-QTLs can modulate arthritis independently These monogenic models are proving to be highly informative for fine mapping and function studies, revealing gender effects and evidence of gene clusters. Recent genome scans of RA populations identified RA-susceptibility loci in chromosome regions homologous to rat chromosomal segments housing CIA-QTLs. Also, CIA-QTLs frequently co-localize with susceptibility QTLs mapped in other rat arthritis models induced with non-immunogenic adjuvant oils and/or in rat autoimmune models of multiple sclerosis and diabetes. Common autoimmunity genes and inflammation genes important to several human diseases are likely being detected in the various rat disease models. Continued dissection of the genetic underpinnings of rat arthritis models should provide candidate genes for investigation in human patients and lead to a clearer understanding of the complex genetics of RA.
Immunological Reviews 01/2002; 184:172-83. · 11.15 Impact Factor
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Immunogenetics 08/2001; 53(5):427-9. · 2.93 Impact Factor
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ABSTRACT: Inbred rat strains manifest remarkable differences in susceptibility/severity to autoimmune disease. MHC alleles strongly influence the pathogenesis of autoimmune disease in rats, but the precise mechanism(s) remain inadequately defined. The TNFalpha gene is located in the class III region of the MHC. Polymorphisms, influencing either the structure or expression of the TNF protein, might contribute to differences in autoimmune disease susceptibility/severity. We therefore sequenced the Tnf locus using genomic DNA from ACI, BB(DR), BN, DA, F344, and LEW rats that vary in susceptibility/severity to autoimmune diseases. We found 42 polymorphisms among these six strains. Although none of these polymorphisms are predicted to change the amino acid sequence of the TNF protein, several reside in potential non-coding regulatory regions and may influence expression levels. These polymorphisms may serve as good candidates for analysis of TNF expression to elucidate the mechanism(s) by which the MHC regulates susceptibility and/or severity of autoimmune diseases.
Genes and Immunity 07/2001; 2(4):229-32. · 3.87 Impact Factor
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ABSTRACT: Analysis of several inbred rat strains has led us to hypothesize that HPA axis abnormalities may contribute, in part, to susceptibility to both autoimmune disease and addiction. In this article we review the evidence for this hypothesis and describe our ongoing efforts to genetically characterize these traits. We have mapped the locations of 23 loci that regulate autoimmune disease in rats, and are currently constructing QTL congenic lines in which a genomic region from the resistant strain is transferred to the susceptible strain or vice versa. These QTL congenic lines will be valuable to test whether genes encoding autoimmune regulation also control neuroendocrine traits. Further genetic dissection and identification of the underlying genes will be necessary to infer a mechanistic link between autoimmune and neuroendocrine traits.
Advances in experimental medicine and biology 02/2001; 493:59-67. · 1.09 Impact Factor
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ABSTRACT: Rheumatoid arthritis (RA) is a common, chronic, autoimmune, inflammatory disease that is influenced by genetic factors including gender. Many studies suggest that the genetic risk for RA is determined by the MHC, in particular class II alleles with a 'shared epitope' (SE), and multiple non-MHC loci. Other studies indicate that RA and other autoimmune diseases, in particular insulin-dependent diabetes mellitus (IDDM) and autoimmune thyroid disease (ATD), share genetic risk factors. Rat collagen-induced arthritis (CIA) is an experimental model with many features that resemble RA. The spontaneous diabetes-resistant bio-breeding rat, BB(DR), is of interest because it is susceptible to experimentally induced CIA, IDDM and ATD, and it has an SE in its MHC class II allele. To explore the genetics of CIA, including potential gender influences and the genetic relationships between CIA and other autoimmune diseases, we conducted a genome-wide scan for CIA regulatory loci in the F(2) progeny of BB(DR) and CIA-resistant BN rats. We identified 10 quantitative trait loci (QTLs), including 5 new ones (Cia15, Cia16*, Cia17, Cia18* and Cia19 on chromosomes 9, 10, 18 and two on the X chromosome, respectively), that regulated CIA severity. We also identified four QTLs, including two new ones (Ciaa4* and Ciaa5* on chromosomes 4 and 5, respectively), that regulated autoantibody titer to rat type II collagen. Many of these loci appeared to be gender influenced, and most co-localized with several other autoimmune trait loci. Our data support the view that multiple autoimmune diseases may share genetic risk factors, and suggest that many of these loci are gender influenced.
Human Molecular Genetics 10/2000; 9(15):2241-50. · 7.64 Impact Factor
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M M Griffiths,
J Wang,
B Joe,
S Dracheva,
Y Kawahito,
J S Shepard,
V R Reese,
S McCall-Vining,
A Hashiramoto,
G W Cannon, E F Remmers,
R L Wilder
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ABSTRACT: Collagen-induced arthritis (CIA) is a polygenic model of experimentally induced autoimmunity and chronic joint inflammation. This study maps genetic loci that regulate CIA susceptibility in DA/Bkl (DA) and BN/SsNHsd (BN) rats.
Genome scans covering chromosomes 1-20 and interval mapping techniques using 159 simple sequence-length polymorphism markers were used to identify quantitative trait loci (QTLs) that regulate CIA in (DA x BN)F2 hybrids. Serum antibody titers to type II collagen were determined by enzyme-linked immunosorbent assay.
DA rats were high responders to porcine type II collagen (PII) and developed severe CIA (100%). BN rats were low responders to PII and resistant to CIA (0%). BN genes strongly repressed PII-induced CIA. Only 12% of (DA x BN)F1 rats (7 of 60) and 31% of (DA x BN)F2 rats (307 of 1,004) developed CIA. Three new QTLs (Cia11, Cia12, and Cia13) with significant logarithm of odds (LOD) scores of 5.6, 4.6, and 4.5, respectively, plus a suggestive QTL (Cia14*, LOD 3.0) regulating arthritis severity were identified on chromosomes 3, 12, 4, and 19. A new QTL, Ciaa3, associating with anticollagen antibody titer (antibody to PII LOD 6.5; antibody to rat type II collagen LOD 5.2) mapped to chromosome 9. Of 10 CIA QTLs previously identified in (DA x F344) and (DA x ACI) rats, only Cia1 in the major histocompatibility complex and a region coincident to Cia5 on chromosome 10 (LOD >8.0) influenced CIA severity in (DA x BN)F2 rats.
Since CIA exhibits many of the pathologic features of rheumatoid arthritis, the data indicate that the variety of genetic elements regulating human autoimmune and rheumatic diseases may be much larger and more varied than originally envisioned.
Arthritis & Rheumatism 06/2000; 43(6):1278-89. · 7.87 Impact Factor
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ABSTRACT: DA and LEW inbred rats are extraordinarily susceptible to a wide range of experimental autoimmune diseases. These diseases include rheumatoid arthritis models such as collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA), multiple sclerosis models such as myelin-basic-protein (MBP)-induced experimental autoimmune encephalomyelitis (MBP-EAE), and autoimmune uveitis models such as retinal S antigen (SAG) and interphotoreceptor-retinoid-binding-protein (IRBP)-induced experimental autoimmune uveitis (SAG-EAU and IRBP-EAU, respectively). DA and LEW rats are also addiction-prone to various drugs of abuse, such as cocaine. Moreover, they exhibit a variety of behavioral and biochemical characteristics that appear to be related to their susceptibility to addiction. By contrast, F344 and BN rats show quite different phenotypes. They are relatively resistant to CIA, AIA, MBP-EAE, SAG-EAU, and IRBP-EAU, and they are relatively resistant to addiction. Interestingly, both DA and LEW rats, in contrast to F344 and BN rats, have abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function. For example, circadian production of corticosteroids is very abnormal in DA and LEW rats; that is, they exhibit minimal circadian variation in corticosterone levels. Since corticosteroids potentially have significant influences on immune function and autoimmune disease susceptibility and may also influence sensitivity to drugs of abuse, we have begun to dissect genetic control of these various phenotypic differences, focusing initially on the regulation of autoimmune disease expression. Using genomewide scanning techniques involving F2 crosses of DA x F344 (CIA and AIA), DA x BN (CIA), and LEW x F344 [IRBP-EAU and streptococcal-cell-wall arthritis (SCWA)], we have identified, to date, 14 genomic regions [quantitative trait loci (QTL)] that regulate disease expression in these crosses. Development and analysis of QTL-congenic rats involving these loci are in progress and should permit us to address the relationships among autoimmune disease susceptibility, drug addiction, and HPA axis and stress response function. These initial data, however, indicate that the genetic control of the autoimmune disease traits is highly complex.
Annals of the New York Academy of Sciences 02/2000; 917:784-96. · 3.15 Impact Factor
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S V Dracheva, E F Remmers,
S Chen,
L Chang,
P S Gulko,
Y Kawahito,
R E Longman,
J Wang,
Y Du,
J Shepard,
L Ge,
B Joe,
S Kotake,
J L Salstrom,
T Furuya,
J Hoffman,
G W Cannon,
M M Griffiths,
R L Wilder
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ABSTRACT: The rat (Rattus norvegicus) is an important experimental model for many human diseases including arthritis, diabetes, and other autoimmune and chronic inflammatory diseases. The rat genetic linkage map, however, is less well developed than those of mouse and human. Integrated rat genetic linkage maps have been previously reported by Pravenec et al. (1996, Mamm. Genome 7: 117-127) (500 markers mapped in one cross), Bihoreau et al. (1997, Genome Res. 7: 434-440) (767 markers mapped in three crosses), Wei et al. (1998, Mamm. Genome 9: 1002-1007) (562 markers mapped in two crosses), Brown et al. (1998, Mamm. Genome 9: 521-530) (678 markers mapped in four crosses), and Nordquist et al. (1999, Rat Genome 5: 15-20) (330 markers mapped in two crosses). The densest linkage map combined with a radiation hybrid map, reported by Steen et al. (1999, Genome Res. 9: AP1-AP8), includes 4736 markers mapped in two crosses. Here, we present an integrated linkage map with 1137 markers. We have constructed this map by genotyping F2 progeny of five crosses: F344/NHsd x LEW/NHsd (673 markers), DA/Bkl x F344/NHsd (531 markers), BN/SsN x LEW/N (714 markers), DA/Bkl x BN/SsNHsd (194 markers), and DA/Bkl x ACI/SegHsd (245 markers). These inbred rat strains vary in susceptibility/resistance to multiple autoimmune diseases and are used extensively for many types of investigation. The integrated map includes 360 loci mapped in three or more crosses. The map contains 196 new SSLP markers developed by our group, as well as many SSLP markers developed by other groups. Two hundred forty genes are incorporated in the map. This integrated map should allow comparison of rat genetic maps from different groups and thereby facilitate genetic studies of rat autoimmune and related disease models.
Genomics 02/2000; 63(2):202-26. · 3.02 Impact Factor
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ABSTRACT: Rat and mouse models for the major human autoimmune/inflammatory diseases are under intense genetic scrutiny. Genome-wide linkage studies reveal that each model is regulated by multiple genetic loci. Many of these loci colocalize to homologous genomic regions associated with several different autoimmune diseases of mice, rats and humans. Candidate genes are being identified. Polymorphic alleles associated with these chromosomal segments may represent predisposing genetic elements common to a number of human diseases with very different clinical presentations.
Current Opinion in Immunology 01/2000; 11(6):689-700. · 9.52 Impact Factor
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Transplantation Proceedings 06/1999; 31(3):1589. · 1.00 Impact Factor
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E F Remmers,
M M Griffiths,
R E Longman,
P S Gulko,
Y Kawahito,
S Chen,
L Chang,
J Shepard,
L Ge,
S Dracheva,
J P Wang,
B Joe,
G W Cannon,
R L Wilder
Transplantation Proceedings 06/1999; 31(3):1549-54. · 1.00 Impact Factor
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R L Wilder,
M M Griffiths, E F Remmers,
G W Cannon,
R R Caspi,
Y Kawahito,
P S Gulko,
R E Longman,
S V Dracheva,
Y Du,
S H Sun,
J Wang,
J S Shepard,
B Joe,
L Ge,
S Chen,
L Chang,
J Hoffman,
P B Silver,
V R Reese
Transplantation Proceedings 06/1999; 31(3):1585-8. · 1.00 Impact Factor
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ABSTRACT: The present study attempts to identify specific genetic loci contributing to experimental autoimmune uveoretinitis (EAU) susceptibility in F2 progeny of resistant Fischer (F344/N) and susceptible Lewis (LEW/N) inbred rats. F2 progeny of F344/N x LEW/N inbred rats were immunized with the R16 peptide of interphotoreceptor retinoid-binding protein (IRBP). A genome-wide scan was conducted using 125 simple sequence length polymorphism markers in selected F2 animals that developed severe eye disease or remained unaffected to identify phenotype:genotype co-segregation. The F2 population (n = 1287) demonstrated a wide range of histologically assessed EAU scores (assessed on a scale of 0-4). The disease incidence and severity were not consistent with a simple Mendelian inheritance model. Of the F2 hybrid rats, 60% developed EAU, implying the existence of a potent susceptibility locus with incomplete penetrance associated with the LEW genome or a more complex polygenic model of inheritance. Two genomic regions, on chromosomes 4 and 12, showed strong genetic linkage to the EAU phenotype (P < 0.0016), suggesting the presence of susceptibility loci in these chromosomal regions. In conclusion, we have identified two genomic candidate intervals from D4Arb8 to D4Mit17 on chromosome 4 and from the chromosome end to D12Arb8 on chromosome 12, that appear to influence EAU susceptibility in LEW/F344 rats. Further analysis of these genomic regions may lead to identification of the susceptibility genes and to characterization of their function.
International Immunology 04/1999; 11(4):529-34. · 3.41 Impact Factor
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Current directions in autoimmunity 02/1999; 1:121-65.
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P S Gulko,
Y Kawahito, E F Remmers,
V R Reese,
J Wang,
S V Dracheva,
L Ge,
R E Longman,
J S Shepard,
G W Cannon,
A D Sawitzke,
R L Wilder,
M M Griffiths
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ABSTRACT: To identify novel non-major histocompatibility complex (non-MHC) genetic loci controlling the severity of homologous rat type II collagen-induced arthritis (CIA).
We conducted a genome-wide scan to identify CIA regulatory quantitative trait loci (QTL) in an F2 cross between DA (CIA highly susceptible) and ACI (CIA resistant) inbred rats immunized with homologous rat type II collagen (RII). These strains share the MHC/RT1av1 haplotype required for susceptibility to RII-induced CIA.
F2 females had higher median arthritis scores than did males. Relative resistance in the males was determined by inheriting either a DA or an ACI Y chromosome and was independent of the source of the X chromosome. In addition, a major QTL was localized on chromosome 2 (Cia7, logarithm of odds score 4.6). Cia7 is in a region that shows linkage conservation with chromosomal regions that regulate autoimmune diabetes and experimental autoimmune encephalomyelitis in mice and multiple sclerosis in humans.
Sex chromosomes and Cia7 play an important role in regulating CIA in response to RII. This rat model should facilitate positional cloning and functional characterization of regulatory genes that may play a role in several forms of autoimmune disease, including rheumatoid arthritis.
Arthritis & Rheumatism 01/1999; 41(12):2122-31. · 7.87 Impact Factor
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ABSTRACT: Adjuvant-induced arthritis (AIA) in rats is a widely used autoimmune experimental model with many features similar to rheumatoid arthritis (RA). To identify potential genetic regulatory mechanisms in RA, we conducted genome-wide linkage analysis in F2 progeny of arthritis-susceptible Dark Agouti (DA) and relatively resistant Fischer 344 (F344) inbred rats. We compared the data with our previously reported investigation of collagen-induced arthritis (CIA), which was expanded in the follow-up study reported in this work. We found two quantitative trait loci (QTLs) in common, i.e., Aia1/Cia1 on chromosome 20, which includes the MHC, and Aia3/Cia3 on chromosome 4. We also identified a second unique QTL in AIA, Aia2, on chromosome 4. Interestingly, the QTL region on chromosome 4 (Aia3/Cia3), like the MHC, appears to be involved in several other autoimmune diseases in rats, including insulin-dependent diabetes, thyroiditis, and experimental autoimmune uveitis. Moreover, an analysis of conserved synteny among rats, mice, and humans suggested that Aia2 and Aia3/Cia3, like Aia1/Cia1, contain candidate genes for several autoimmune/inflammatory diseases in mice and humans, including diabetes, systemic lupus erythematosus, inflammatory bowel disease, asthma/atopy, multiple sclerosis, and RA. The rat models appear to provide a powerful complementary approach to identify and characterize candidate genes that may contribute to autoimmune diseases in several species.
The Journal of Immunology 11/1998; 161(8):4411-9. · 5.79 Impact Factor
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ABSTRACT: Osteopetrosis, a skeletal disorder of inadequate bone resorption with an abnormal increase in skeletal mass, results from a variety of independent single gene mutations that affect osteoclast differentiation and/or function. The osteopetrotic defect, op, is one of four spontaneous, nonallelic mutations in rats that result in osteopetrosis. In intercross progeny of (BN/SsN x LEW/SsN. +/op) F1 carriers, we mapped this locus by linkage analysis with microsatellite markers to rat chromosome 10. The linkage group contained, as well as op, 15 anonymous DNA loci and 9 DNA loci associated with genes (interleukin-3, myosin heavy chain [skeletal, embryonic], asialoglycoprotein receptor [hepatic lectin]-1, vesicle-associated membrane protein [synaptobrevin-2], sex hormone binding globulin, aldolase C, nitric oxide synthase [inducible], erythroblastic leukemia avian viral oncogene homolog-2, and proline-rich protein). The markers for these loci include nine not previously reported. The op locus mapped to the end of the chromosome 10 linkage group, within 1 cM of the anonymous DNA locus, D10Mit6. Based on its location, the op gene is likely to be distinct from seven described mutations in mice as well as three other mutations in rats. These results may permit a positional cloning strategy to be undertaken to identify the gene and mutation underlying the op defect.
Journal of Bone and Mineral Research 01/1997; 11(12):1856-61. · 6.37 Impact Factor
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ABSTRACT: A genomic DNA fragment containing the rat epimorphin gene sequence was cloned from a rat DNA cosmid library using a mouse epimorphin cDNA probe. Within the cosmid insert, nine epimorphin exons were identified and sequenced. The predicted amino acid sequence of the rat epimorphin protein exhibited 96 and 86% identity with the mouse and human epimorphin proteins, respectively. Consistent with the developmentally related expression pattern of the mouse epimorphin gene, transcripts of the rat epimorphin gene were detected in 17-day postfertilization rat embryos. The gene, designated Epim, was assigned to rat chromosome 12 by somatic cell hybrid analysis and localized to 12q16 by fluorescence in situ hybridization. The mouse and human homologs of this gene were localized on mouse chromosome 5 and human chromosome 7 by linkage analysis and chromosomal in situ hybridization, respectively.
Genomics 12/1996; 37(3):386-9. · 3.02 Impact Factor
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Mammalian Genome 12/1996; 7(11):856-7. · 2.89 Impact Factor
