Congenic strains displaying similar clinical phenotype of arthritis represent different immunologic models of inflammation

Adarichev, Vyacheslav A.; Végvári, Anikó; Szabó, Zoltán; Kis-Tóth, Katalin; Mikecz, Katalin; Glant, Tibor T.

doi:10.1038/gene.2008.54

Cited by 12 publications

(18 citation statements)

References 52 publications

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“…Naïve BALB/c mice rarely develop spontaneous inflammation in synovial joints (Adarichev et al, 2008; Farkas et al, 2009). BALB/c females infected with B. melitensis for 26 weeks exhibited multiple skeletal involvement with inflammatory and non-inflammatory features.…”

Section: Resultsmentioning

confidence: 99%

Osteoarticular tissue infection and development of skeletal pathology in murine brucellosis

Magnani

Lyons

Forde

et al. 2013

Disease Models &Amp; Mechanisms

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SUMMARYBrucellosis, a frequent bacterial zoonosis, can produce debilitating chronic disease with involvement of multiple organs in human patients. Whereas acute brucellosis is well studied using the murine animal model, long-term complications of host-pathogen interaction remain largely elusive. Human brucellosis frequently results in persistent, chronic osteoarticular system involvement, with complications such as arthritis, spondylitis and sacroiliitis. Here, we focused on identifying infectious sites in the mouse that parallel Brucella melitensis foci observed in patients. In vivo imaging showed rapid bacterial dispersal to multiple sites of the murine axial skeleton. In agreement with these findings, immunohistochemistry revealed the presence of bacteria in bones and limbs, and in the lower spine vertebrae of the axial skeleton where they were preferentially located in the bone marrow. Surprisingly, some animals developed arthritis in paws and spine after infection, but without obvious bacteria in these sites. The identification of Brucella in the bones of mice corroborates the findings in humans that these osteoarticular sites are important niches for the persistence of Brucella in the host, but the mechanisms that mediate pathological manifestations in these sites remain unclear. Future studies addressing the immune responses within osteoarticular tissue foci could elucidate important tissue injury mediators and Brucella survival strategies.

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Section: Resultsmentioning

confidence: 99%

Osteoarticular tissue infection and development of skeletal pathology in murine brucellosis

Magnani

Lyons

Forde

et al. 2013

Disease Models &Amp; Mechanisms

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“…26,27 Chromosomal positions of these loci were confirmed in congenic strains. 26 The initial size of the Pgia26 locus was 60 Mbp of the DBA/2-homozygous ‘core,’ and it could have been larger (up to 64 Mbp) if flanking BALB/c-homozygous areas were taken into consideration (Figure 1; Table 1). Similarly, the Pgia23/Pgia12 locus was 46 Mbp in size, 58 Mbp with the flanking regions.…”

Section: Resultsmentioning

confidence: 82%

“…Since Pgia26 was found initially to be a ‘female-specific’ locus, and the Pgia12 locus was ‘male-specific’ when linkage analysis of the F2 hybrid population was performed, 26,27 we immunized both females and males of the congenic/subcongenic strains along with wild-type (WT) BALB/c females ( n = 87) and males ( n = 54). When all of the data from the clinical phenotypes of all WT, congenic and subcongenic strains were analyzed together (389 total animals for chr3 and 357 for chr19), the gender effect of both loci was found to be negligible.…”

Section: Resultsmentioning

confidence: 99%

“…We generated a set of BALB/c.DBA/2-congenic strains in which the PGIA-resistant loci from the DBA/2 strain were transferred to the susceptible BALB/c background. 26 We then selected mice with recombinations flanking the target intervals in order to reduce the size of the original QTLs, and to map the arthritis-susceptibility loci at higher resolution. We narrowed each mouse chromosome region to 3–6 Mbp in size (up to 19 Mbp with the flanking regions), which is small enough for high-throughput sequencing of genomic DNAs from arthritis-resistant and -susceptible strains.…”

Section: Introductionmentioning

confidence: 99%

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Disease-promoting and -protective genomic loci on mouse chromosomes 3 and 19 control the incidence and severity of autoimmune arthritis

et al. 2012

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Proteoglycan (PG)-induced arthritis (PGIA) is a murine model of rheumatoid arthritis. Arthritis-prone BALB/c mice are 100% susceptible, whereas the major histocompatibility complex-matched DBA/2 strain is completely resistant to PGIA. To reduce the size of the disease-suppressive loci for sequencing and to find causative genes of arthritis, we created a set of BALB/c.DBA/ 2-congenic/subcongenic strains carrying DBA/2 genomic intervals overlapping the entire Pgia26 locus on chromosome 3 (chr3) and Pgia23/Pgia12 loci on chr19 in the arthritis-susceptible BALB/c background. Upon immunization of these subcongenic strains and their wild-type (BALB/c) littermates, we identified a major Pgia26a sublocus on chr3 that suppressed disease onset, incidence and severity via controlling the complex trait of T-cell responses. The region was reduced to 3 Mbp (11.8 Mbp with flanking regions) in size and contained gene(s) influencing the production of a number of proinflammatory cytokines. Additionally, two independent loci (Pgia26b and Pgia26c) suppressed the clinical scores of arthritis. The Pgia23 locus (~3 Mbp in size) on chr19 reduced arthritis susceptibility and onset, and the Pgia12 locus (6 Mbp) associated with low arthritis severity. Thus, we have reached the critical sizes of arthritis-associated genomic loci on mouse chr3 and chr19, which are ready for high-throughput sequencing of genomic DNA.

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“…Our group has performed extensive genetic studies in PGIA, elucidating the most critical factors of susceptibility to this rheumatoid arthritis-like disease [22]. Genome-wide screening studies, confirmed by testing congenic and interval-specific congenic BALB/c strains, have revealed that numerous chromosome regions (genes) are simultaneously involved in susceptibility to PGIA [22][23][24]. Similar to the conclusion of age-associated human autoimmune disease, while the major histocompatibility complex (MHC) is a critical genetic component, the MHC alone is insufficient to control disease susceptibility [18,25].…”

Section: Discussionmentioning

confidence: 98%

Immunosenescence and its potential modulation: lessons from mouse models

Boldizsár

Mikecz

Glant

2010

Expert Review of Clinical Immunology

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Evaluation of: Goldmann O, Lehne S, Medina E. Age-related susceptibility to Streptococcus pyogenes infection in mice: underlying immune dysfunction and strategy to enhance immunity. J. Pathol. 220(5), 521-529 (2010). Immunosenescence is a pathophysiological event in the aging process, which probably represents the greatest danger to an individual; diminished immune functions and altered immunoregulation lead to increased susceptibility to infections, autoimmunity and increased frequency of tumors in the elderly. Immunosenescence affects the functions of both innate immune cells (such as neutrophils, macrophages and dendritic cells) and cells involved in adaptive immunity (T and B lymphocytes). A number of methods have been developed to monitor age-related abnormalities in inbred murine strains, including physiologial and immunological tests, and a variety of genetic and epigenetic assays. Various animal models enable investigation of certain aspects of the aging process, and also allow for testing of immune-modulating agents that might 'rejuvenate' the cellular functions altered by aging. Although short-term experiments with targeted compounds to replenish certain cell types or restore cellular functions may present impressive results of 'rejuvenation' of innate immunity (reduced susceptibility to an infectious agent), to date, immunosenescence still remains a phenomenological term with limited etiologic information at the cellular and molecular levels.

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Congenic strains displaying similar clinical phenotype of arthritis represent different immunologic models of inflammation

Cited by 12 publications

References 52 publications

Osteoarticular tissue infection and development of skeletal pathology in murine brucellosis

Osteoarticular tissue infection and development of skeletal pathology in murine brucellosis

Disease-promoting and -protective genomic loci on mouse chromosomes 3 and 19 control the incidence and severity of autoimmune arthritis

Immunosenescence and its potential modulation: lessons from mouse models

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