The neonatal CNS is not conducive for encephalitogenic Th1 T cells and B cells during experimental autoimmune encephalomyelitis

Petra D Cravens,Olaf Stüve,Rehana Hussain,Scott S Zamvil,Emily Herndon,Brenda C Timmons,Benjamine Arellano,Li-Hong Ben,Bernhard Hemmer,Hans-Peter Hartung,Bernd C Kieseier,Martin S Weber,Cyd Castro-Rojas

doi:10.1186/1742-2094-10-67

Abstract

Multiple sclerosis (MS) is thought to be a CD4+ T cell mediated autoimmune demyelinating disease of the central nervous system (CNS) that is rarely diagnosed during infancy. Cellular and molecular mechanisms that confer disease resistance in this age group are unknown. We tested the hypothesis that a differential composition of immune cells within the CNS modulates age-associated susceptibility to CNS autoimmune disease. C57BL/6 mice younger than eight weeks were resistant to experimental autoimmune encephalomyelitis (EAE) following active immunization with myelin oligodendrocyte glycoprotein (MOG) peptide (p) 35–55. Neonates also developed milder EAE after transfer of adult encephalitogenic T cells primed by adult or neonate antigen presenting cells (APC). There was a significant increase in CD45+ hematopoietic immune cells and CD45+ high side scatter granulocytes in the CNS of adults, but not in neonates. Within the CD45+ immune cell compartment of adults, the accumulation of CD4+ T cells, Gr-1+ and Gr-1- monocytes and CD11c+ dendritic cells (DC) was identified. A significantly greater percentage of CD19+ B cells in the adult CNS expressed MHC II than neonate CNS B cells. Only in the adult CNS could IFNγ transcripts be detected 10 days post immunization for EAE. IFNγ is highly expressed by adult donor CD4+ T cells that are adoptively transferred but not by transferred neonate donor cells. In contrast, IL-17 transcripts could not be detected in adult or neonate CNS in this EAE model, and neither adult nor neonate donor CD4+ T cells expressed IL-17 at the time of adoptive transfer.

Highlights

Multiple sclerosis (MS) is the most common inflammatory demyelinating disorder of the central nervous system (CNS) in humans with a presumed autoimmune pathogenesis [1]
Susceptibility to experimental autoimmune encephalitis is age-associated To examine age-associated susceptibility to CNS autoimmune disease, EAE was induced in C57BL/6 mice between the ages of 4 days and 20 weeks by immunization with MOGp35-55
The age of antigen presenting cells (APC) contributes to recall proliferative responses in vitro Since Ag-specific CD4+ T cell responses depend on interaction with major histocompatibility complex (MHC) II molecules expressed on APC, T cell responses were initially assessed with primary proliferation assays

Summary

Introduction

Multiple sclerosis (MS) is the most common inflammatory demyelinating disorder of the central nervous system (CNS) in humans with a presumed autoimmune pathogenesis [1]. Activated myelin-reactive CD4+ Th1 cells are thought to have a central role in the pathogenesis of MS, and its prototypic animal model experimental autoimmune encephalomyelitis (EAE) [6]. Ag presentation in the context of MHC II appears to be required at different stages of EAE and MS pathogenesis. Studies suggested that the activation of T cells in secondary lymphoid organs facilitated their entry into the brain and spinal cord [9,10] but more recently, it was shown that CNSspecific T cells can enter the CNS without the requirement for antigen priming in peripheral lymphoid tissues [11]. After CNS injury, astrocytes [12,13] and microglial cells [14,15] can upregulate MHC II in response to inflammatory mediators, including IFNγ, the signature cytokine of T helper 1 (Th1) cells [16]. The regulation and expression of MHC II genes are considered critical in MS and its animal model, EAE

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