T cell production of cytokines, neurotrophins and MHC regulation in autoimmune neuroinflammation
Author: Muhallab, Saad
Date: 2002-06-14
Location: Hörsalen vid Centrum för Molekylär Medicin, Karolinska Sjukhuset
Time: 9.00
Department: Institutionen för medicin / Department of Medicine
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.
List of papers:
I. Muhallab S, Lidman O, Weissert R, Olsson T, Svenningsson A (2001). "Intra-CNS activation by antigen-specific T lymphocytes in experimental autoimmune encephalomyelitis. " J Neuroimmunol 113(2): 202-11
Pubmed
II. Muhallab S, Lundberg C, Gielen AW, Lidman O, Svenningsson A, Piehl F, Olsson T (2002). "Differential expression of neurotrophic factors and inflammatory cytokines by myelin basic protein-specific and other recruited T cells infiltrating the central nervous system during experimental autoimmune encephalomyelitis. " Scand J Immunol 55(3): 264-73
Pubmed
III. Gielen A, Khademi M, Muhallab S, Olsson T, Piehl F (2002). "Increased BDNF expression in white blood cells of multiple sclerosis patients." Neuroreport (Submitted)
IV. Muhallab S, Olsson T, Dahlman I, Wallstrom E (2002). "Myelin oligodendrocyte glycoprotein and myelin basic protein-induced neuroinflammation is controlled by dispartate MHC haplotypes and by genes within the class II region." (Manuscript)
I. Muhallab S, Lidman O, Weissert R, Olsson T, Svenningsson A (2001). "Intra-CNS activation by antigen-specific T lymphocytes in experimental autoimmune encephalomyelitis. " J Neuroimmunol 113(2): 202-11
Pubmed
II. Muhallab S, Lundberg C, Gielen AW, Lidman O, Svenningsson A, Piehl F, Olsson T (2002). "Differential expression of neurotrophic factors and inflammatory cytokines by myelin basic protein-specific and other recruited T cells infiltrating the central nervous system during experimental autoimmune encephalomyelitis. " Scand J Immunol 55(3): 264-73
Pubmed
III. Gielen A, Khademi M, Muhallab S, Olsson T, Piehl F (2002). "Increased BDNF expression in white blood cells of multiple sclerosis patients." Neuroreport (Submitted)
IV. Muhallab S, Olsson T, Dahlman I, Wallstrom E (2002). "Myelin oligodendrocyte glycoprotein and myelin basic protein-induced neuroinflammation is controlled by dispartate MHC haplotypes and by genes within the class II region." (Manuscript)
Issue date: 2002-05-24
Publication year: 2002
ISBN: 91-7349-260-4
Statistics
Total Visits
Views | |
---|---|
T ... | 318 |
T ...(legacy) | 189 |
Total Visits Per Month
September 2023 | October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | |
---|---|---|---|---|---|---|---|
T ... | 10 | 14 | 11 | 10 | 9 | 21 | 14 |
Top country views
Views | |
---|---|
Ireland | 82 |
Sweden | 81 |
United States | 77 |
Germany | 47 |
China | 38 |
United Arab Emirates | 14 |
South Korea | 12 |
Finland | 6 |
Canada | 5 |
United Kingdom | 5 |
Top cities views
Views | |
---|---|
Dublin | 82 |
Kiez | 16 |
Al Ain City | 11 |
Seoul | 11 |
Ashburn | 9 |
Sunnyvale | 8 |
Shenzhen | 5 |
Beijing | 4 |
Ludwigshafen am Rhein | 4 |
Mountain View | 4 |