Abstract
BackgroundAging influences immune response and susceptibility to EAE in a strain specific manner. The study was designed to examine influence of aging on EAE induction in Albino Oxford (AO) rats.ResultsDifferently from 3-month-old (young) rats, which were resistant to EAE induction, the majority of aged (24-26-month-old) rats developed mild chronic form of EAE. On 16th day post-immunization, when in aged rats the neurological deficit reached plateau, more mononuclear cells, including CD4+ T lymphocytes was retrieved from spinal cord of aged than young rats. The frequencies of IL-17+ and GM-CSF+ cells within spinal cord infiltrating CD4+ lymphocytes were greater in aged rats. To their increased frequency contributed the expansion of GM-CSF + IL-17 + IFN-γ+ cells, which are highly pathogenic in mice. The expression of the cytokines (IL-1β and IL-23/p19) driving GM-CSF + IL-17 + IFN-γ + cell differentiation in mice was also augmented in aged rat spinal cord mononuclear cells. Additionally, in aged rat spinal cord the expansion of GM-CSF + IL-17-IFN-γ- CD4+ T lymphocytes was found. Consistently, the expression of mRNAs for IL-3, the cytokine exhibiting the same expression pattern as GM-CSF, and IL-7, the cytokine driving differentiation of GM-CSF + IL-17-IFN-γ- CD4 + lymphocytes in mice, was upregulated in aged rat spinal cord mononuclear cells, and the tissue, respectively. This was in accordance with the enhanced generation of the brain antigen-specific GM-CSF+ CD4+ lymphocytes in aged rat draining lymph nodes, as suggested by (i) the higher frequency of GM-CSF+ cells (reflecting the expansion of IL-17-IFN-γ- cells) within their CD4+ lymphocytes and (ii) the upregulated GM-CSF and IL-3 mRNA expression in fresh CD4+ lymphocytes and MBP-stimulated draining lymph node cells and IL-7 mRNA in lymph node tissue from aged rats. In agreement with the upregulated GM-CSF expression in aged rats, strikingly more CD11b + CD45int (activated microglia) and CD45hi (mainly proinflammatory dendritic cells and macrophages) cells was retrieved from aged than young rat spinal cord. Besides, expression of mRNA for SOCS1, a negative regulator of proinflammatory cytokine expression in innate immunity cells, was downregulated in aged rat spinal cord mononuclear cells.ConclusionsThe study revealed that aging may overcome genetic resistance to EAE, and indicated the cellular and molecular mechanisms contributing to this phenomenon in AO rats.Electronic supplementary materialThe online version of this article (doi:10.1186/s12979-015-0044-x) contains supplementary material, which is available to authorized users.
Highlights
Aging influences immune response and susceptibility to EAE in a strain specific manner
Aged Albino Oxford (AO) rats immunized for EAE develop mild chronic disease Differently from young AO rats, which were resistant to the induction of clinical EAE, 14 animals out of 22 aged rats immunized for EAE (i.e. 6 rats from 9 rats sacrificed on the 16th d.p.i. and 8 rats from 13 rats, which were followed until 60th d.p.i.) exhibited mild signs of the disease (Fig. 1)
Aging increases the number of CD4+ TCRαβ + lymphocytes infiltrating the spinal cord of AO rats immunized for EAE The analysis of spinal cord mononuclear cells isolated on the 16th d.p.i. revealed slightly lower (p < 0.05) frequency of CD4+ TCRαβ + lymphocytes (Fig. 2)
Summary
Aging influences immune response and susceptibility to EAE in a strain specific manner. The etiology of MS is not well understood, but it is believed that myelin-specific CD4+ T cells play a central role in initiating and orchestrating CNS inflammation [1] Their role has been studied extensively, principally by using experimental autoimmune encephalomyelitis (EAE), an animal model of MS. EAE can be actively induced in susceptible strains of mice and rats by immunization with either whole spinal cord homogenate or encephalitogenic proteins or peptides in adjuvants Both Th1 and Th17 cells have been implicated in MS/EAE development [1, 2]. IL-7-STAT5 signalling axis-induced CD4+ T cells are suggested to be the major source of GM-CSF in T cell-mediated neuroinflammation [10] They are thought to represent a new Th subset with a distinct differentiation program and cytokine production profile [10]. GM-CSF accelerates the release of bone marrow precursors that differentiate into the CNS-infiltrating dendritic cells and macrophages [11], and provides activation/expansion of cells belonging to the myeloid lineage, which in turn promote (i) Th-GM cell activation/differentiation and (ii) tissue destruction through release of various bioactive molecules [8, 9, 12, 13]
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