Altered Th1/Th2 balance associated with non‐major histocompatibility complex genes in collagen‐induced arthritis in resistant and non‐resistant rat strains

Müssener, Å; Lorentzen, Johnny C.; Kleinau, Sandra; Klareskog, Lars

doi:10.1002/eji.1830270318

Cited by 29 publications

(24 citation statements)

References 21 publications

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“…Indeed, BN rats congenic for the LEW MHC (BN-1L rats) responded in a similar way as the BN rats, and LEW rats congenic for the BN MHC (LEW-1N rats) exhibited the same cytokine response as the LEW rats. In agreement with our study it has been shown that the MHC genes are not involved in the regulation of the type 1/type 2 cytokine balance and therefore do not play a dominant role in determining susceptibility to several experimental autoimmune diseases (11,55,56).…”

Section: Discussionsupporting

confidence: 93%

The CD8 T Cell Compartment Plays a Dominant Role in the Deficiency of Brown-Norway Rats to Mount a Proper Type 1 Immune Response

Cautain

Damoiseaux

Bernard

et al. 2002

The Journal of Immunology

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Differential cytokine production by T cells plays an important role in regulating the nature of an immune response. In the rat, Brown-Norway (BN) and Lewis (LEW) strains differ markedly in their susceptibility to develop either type 1 or type 2-mediated autoimmune manifestations. BN rats are susceptible to type 2-dependent systemic autoimmunity, while LEW rats are resistant. Conversely, type 1-mediated, organ-specific autoimmune disease can be easily induced in LEW, but not in BN, rats. The mechanisms involved in the differential development of type 1 and type 2 immune responses by these two strains are still unknown. In the present study we analyzed the contributions of APC, CD4 and CD8 T cells, and MHC molecules in the difference between LEW and BN rats to develop a type 1 immune response. First, we show that the defect of BN T cells to produce type 1 cytokines in vitro does not require the presence of APC and, by using an APC-independent stimulation assay, we have localized the defect within the T cell compartment. Both CD4 and CD8 T cells are involved in the defect of BN rats to develop a type 1 immune response with a major contribution of the CD8 T cell compartment. This defect is associated with an increase in the type 2 cytokine IL-4 in both BN T cell populations, but neutralization of this cytokine does not restore this defect. Finally, by using MHC congenic rats, we show that the MHC haplotype is not involved in the defect of BN T cells to mount a proper type 1 cytokine response.

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Section: Discussionsupporting

confidence: 93%

The CD8 T Cell Compartment Plays a Dominant Role in the Deficiency of Brown-Norway Rats to Mount a Proper Type 1 Immune Response

Cautain

Damoiseaux

Bernard

et al. 2002

The Journal of Immunology

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“…In addition, the secretion of IL-12 by macrophages is inhibited [26]. Our data of a decreased responsiveness to the T cell mitogen Con A suggest that the down-regulation of arthritis may be due to an inhibition of T cell-induced proinflammatory pathways participating in the pathogenesis of the disease, and may also correspond to the finding of an increase of IL-4 expression in the lymph nodes day 7 p.i., which is associated with a decreased arthritis susceptibility in certain inbred rat strains [27] or in rats given antigen, i.e. CII, with the Th2 adjuvant alum [21].…”

Section: Discussionmentioning

confidence: 99%

A vitamin D analogue (MC 1288) has immunomodulatory properties and suppresses collagen-induced arthritis (CIA) without causing hypercalcaemia

Larsson

Mattsson

Klareskog

et al. 1998

Clinical and Experimental Immunology

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SUMMARYThe immunomodulatory properties of the vitamin D analogue MC 1288 (20-epi-1a,25-dihydroxycholecalciferol) were investigated in CIA in rats. The analogue was administered systemically at three different time points; (i) for 10 consecutive days before collagen (CII) immunization; (ii) for 10 consecutive days after CII immunization; or (iii) for 7 consecutive days from disease onset. Treatment initiated either 10 days before CII immunization or at the day of collagen immunization effectively suppressed the development of arthritis. Treatment initiated at the day of the onset of arthritis reduced the severity of joint inflammation. Significantly, doses which did not induce hypercalcaemia decreased the incidence and severity of arthritis. In vivo treatment with the 20-epi analogue of 1a,25-dihydroxycholecalciferol diminished the serum levels of antibodies to rat CII. Similarly, mitogen-induced proliferation of lymph node cells from rat CII-immunized animals was reduced. The experiments demonstrate that the vitamin D analogue MC 1288 has the ability to prevent, and furthermore to suppress, already established CIA by its immunomodulatory properties without inducing hypercalcaemia.

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“…In addition, we measured anti-MOG IgG isotypes, which could potentially discriminate between a T1/T2 bias in the immune response. IgG2b and IgG2c are associated with T1 and IgG1 is associated with T2 responses in the rat (36) (37). We compared the anti-MOG Ab levels in BN (n ϭ 30) and BN.DA-Eae5 (n ϭ 28) rats.…”

Section: Eae5 Is Associated With Total Serum Ab Levels and Anti-mogspmentioning

confidence: 99%

Advanced Intercross Line Mapping of Eae5 Reveals Ncf-1 and CLDN4 as Candidate Genes for Experimental Autoimmune Encephalomyelitis

Bečanović

Jagodic

Sheng

et al. 2006

The Journal of Immunology

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Eae5 in rats was originally identified in two F2 intercrosses, (DA × BN) and (E3 × DA), displaying linkage to CNS inflammation and disease severity in experimental autoimmune encephalomyelitis (EAE), respectively. This region overlaps with an arthritis locus, Pia4, which was also identified in the (E3 × DA) cross. Two congenic strains, BN.DA-Eae5 and BN.DA-Eae5.R1, encompassing the previously described Eae5 and Pia4, were established. DA alleles within the chromosome 12 fragment conferred an increase in disease susceptibility as well as increased inflammation and demyelination in the CNS as compared with BN alleles. To enable a more precise fine mapping of EAE regulatory genes, we used a rat advanced intercross line between the EAE-susceptible DA strain and the EAE-resistant PVG.1AV1 strain. Linkage analysis performed in the advanced intercross line considerably narrowed down the myelin oligodendrocyte glycoprotein-EAE regulatory locus (Eae5) to a ∼1.3-megabase region with a defined number of candidate genes. In this study we demonstrate a regulatory effect of Eae5 on MOG-EAE by using both congenic strains as well as fine mapping these effects to a region containing Ncf-1, a gene associated with arthritis. In addition to structural polymorphisms in Ncf-1, both sequence polymorphisms and expression differences were identified in CLDN4. CLDN4 is a tight junction protein involved in blood-brain barrier integrity. In conclusion, our data strongly suggests Ncf-1 to be a gene shared between two organ-specific inflammatory diseases with a possible contribution by CLDN4 in encephalomyelitis.

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Altered Th1/Th2 balance associated with non‐major histocompatibility complex genes in collagen‐induced arthritis in resistant and non‐resistant rat strains

Cited by 29 publications

References 21 publications

The CD8 T Cell Compartment Plays a Dominant Role in the Deficiency of Brown-Norway Rats to Mount a Proper Type 1 Immune Response

The CD8 T Cell Compartment Plays a Dominant Role in the Deficiency of Brown-Norway Rats to Mount a Proper Type 1 Immune Response

A vitamin D analogue (MC 1288) has immunomodulatory properties and suppresses collagen-induced arthritis (CIA) without causing hypercalcaemia

Advanced Intercross Line Mapping of Eae5 Reveals Ncf-1 and CLDN4 as Candidate Genes for Experimental Autoimmune Encephalomyelitis

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