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- Muhallab, Saad
(författare)
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T cell production of cytokines, neurotrophins and MHC regulation in autoimmune neuroinflammation
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Multiple Sclerosis (MS) is a common disabling disease of the central nervous system (CNS). A role for the major histocompatibility complex (MHC) in disease susceptibility is established but not completely understood. Autoreactive T cells are believed to mediate the CNS lesion formation, but recently emerging data points towards a possible beneficial role for autoimmune inflammation. This thesis, employing the animal model experimental autoimmune encephalomyelitis (EAE), attempts to further the understanding of the role of MHC in disease susceptibility and to characterize the neuroprotective potential of autoimmune T cells with respect to neurotrophin production and cellular distribution. We used a well-characterized rat EAE model in which encephalitogenic T cells use the TCRBV8S2 chain. Production of IFN-gamma selectively occurred in this TCRBV8S2+subset derived from both the CNS and the periphery. Furthermore, encephalitogenic TCRBV8S2+ T cells infiltrating the CNS produced higher amounts of IFN-gamma upon antigen stimulation and displayed significantly increased in vivo proliferation compared with peripheral lymphocytes. The methodology is thus useful for detection of cellular responses to peptides (epitopes) among CNS- infiltrating cells. In a study designed to investigate the neuroprotective potential of autoimmune neuroinflammation, we employed the same rat model. Messenger RNA expression for brain-derived neurotrophic factor (BDNF) neurotrophin-3 (NT-3), as well as the proinflammatory cytokines IFN- gamma and TNF-alpha, were quantified. Infiltrating inflammatory cells isolated from the CNS were sorted into encephalitogenic alpha-beta+/TCRBV8S2+ and nonencephalitogenic alpha- beta+/TCRBV8S2- cells. These two populations displayed contrasting expression pattems of nerve growth factors and proinflammatory cytokines, with higher inflammatory cytokine mRNA levels in encephalitogenic cells at all time intervals, whereas the levels of BDNF and NT3 were higher in non- encephalitogenic cells. We conclude that a potentially important neuroprotective facet of CNS inflammation dominantly prevails within other non-MBP peptide-specific lymphoid cells and that there are independent regulatory mechanisms for neurotrophin and inflammatory cytokine expression during EAE. In humans, mRNA for BDNF but not NT-3 or nerve growth factor was readily detectable in PBMC and levels in MS were significantly increased compared to patients with other neurological diseases or healthy subjects. This finding suggests a possible neuroprotective role for BDNF in MS To study the MHC regulation of MOG- and MBP-induced EAE, four new intraMHC recombinant rat strains were established between two parental strains with reciprocal susceptibilities to MOG- and MBP- induced EAE. The congenic rats were immunized and immunologically assayed for T and B cell responses. Major regulatory influences mapped to the MHC class H in both disease models with no influence from other regions within the MHC.
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| 2. |
- Salomonsson, Stina, et al.
(författare)
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Ro/SSA autoantibodies directly bind cardiomyocytes, disturb calcium homeostasis, and mediate congenital heart block
- 2005
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 201:1, s. 11-17
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Tidskriftsartikel (refereegranskat)abstract
- Congenital heart block develops in fetuses after placental transfer of Ro/SSA autoantibodies from rheumatic mothers. The condition is often fatal and the majority of live-born children require a pacemaker at an early age. The specific antibody that induces the heart block and the mechanism by which it mediates the pathogenic effect have not been elucidated. In this study, we define the cellular mechanism leading to the disease and show that maternal autoantibodies directed to a specific epitope within the leucine zipper amino acid sequence 200–239 (p200) of the Ro52 protein correlate with prolongation of fetal atrioventricular (AV) time and heart block. This finding was further confirmed experimentally in that pups born to rats immunized with p200 peptide developed AV block. p200-specific autoantibodies cloned from patients bound cultured cardiomyocytes and severely affected Ca2+ oscillations, leading to accumulating levels and overload of intracellular Ca2+ levels with subsequent loss of contractility and ultimately apoptosis. These findings suggest that passive transfer of maternal p200 autoantibodies causes congenital heart block by dysregulating Ca2+ homeostasis and inducing death in affected cells.
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