Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

Drainage of central nervous system (CNS) antigens to the brain-draining cervical lymph nodes (CLN) is likely crucial in the initiation and control of autoimmune responses during multiple sclerosis (MS). We demonstrate neuronal antigens within CLN of MS patients. In monkeys and mice with experimental autoimmune encephalomyelitis (EAE) and in mouse models with non-inflammatory CNS damage, the type and extent of CNS damage was associated with the frequencies of CNS antigens within the cervical lymph nodes. In addition, CNS antigens drained to the spinal-cord-draining lumbar lymph nodes. In human MS CLN, neuronal antigens were present in pro-inflammatory antigen-presenting cells (APC), whereas the majority of myelin-containing cells were anti-inflammatory. This may reflect a different origin of the cells or different drainage mechanisms. Indeed, neuronal antigen-containing cells in human CLN did not express the lymph node homing receptor CCR7, whereas myelin antigen-containing cells in situ and in vitro did. Nevertheless, CLN from EAE-affected CCR7-deficient mice contained equal amounts of myelin and neuronal antigens as wild-type mice. We conclude that the type and frequencies of CNS antigens within the CLN are determined by the type and extent of CNS damage. Furthermore, the presence of myelin and neuronal antigens in functionally distinct APC populations within MS CLN suggests that differential immune responses can be evoked

Immunological Function of Draining Lymph Nodes in Multiple Sclerosis and Animal Models Multiple Sclerosis and Animal Models

Multiple sclerosis (MS) is characterized by demyelination and irreversible neuronal damage. Although the cause of this damage is not yet elucidated, autoreactive lymphocytes against myelin and neuronal antigens could be instrumental. In view of understanding MS pathogenesis and possible therapeutic interventions aiming to limit activation of autoreactive lymphocytes, it is crucial to know in what anatomical locations these lymphocytes are activated. We hypothesized that antigens from the central nervous system (CNS) drain to the CNS-draining lymph nodes, and that at this location autoreactive lymphocytes are activated, thereby contributing to infammation during MS and its animal model EAE. To test this hypothesis, we combined analysis of human MS lymph nodes with functional studies using distinct animal models for brain infammation and injury. In this thesis, the involvement of the distinct CNS-draining lymphoid organs in drainage of CNS antigens and immunity against these antigens during MS and EAE will be discussed

Myelin ingestion by macrophages promotes their motility and capacity to recruit myeloid cells

Myelin-laden macrophages reside within the CNS, the CSF and in the CNS-draining lymph nodes during MS and EAE, suggesting migration of these macrophages between these compartments and interaction with other cells. Since chemokines and their receptors are pivotal for leukocyte trafficking, we addressed whether myelin ingestion affects chemotaxis of mouse macrophages in vitro. Myelin ingestion enhanced expression of CCR7 and CXCR3 on macrophages and migration towards CCL21 and CXCL10. Furthermore, myelin-laden macrophages released chemoattractants resulting in enhanced migration of myeloid cells in vitro. Our data demonstrate that myelin-laden macrophages have increased motility and suggest trafficking between anatomical compartments in vivo. (C) 2010 Elsevier B.V. All rights reserved

Myelin-laden macrophages are anti-inflammatory, consistent with foam cells in multiple sclerosis

Multiple sclerosis lesion activity concurs with the extent of inflammation, demyelination and axonal suffering. Pro-inflammatory myeloid cells contribute to lesion development, but the self-limiting nature of lesions implies as yet unidentified anti-inflammatory mechanisms. We addressed the hypothesis that myelin ingestion by myeloid cells induces a foamy appearance and confers anti-inflammatory function. First, we show that myelin-containing foam cells in multiple sclerosis lesions consistently express a series of anti-inflammatory molecules while lacking pro-inflammatory cytokines. Second, unique location-dependent cytokine and membrane receptor expression profiles imply functional specialization allowing for differential responses to micro-environmental cues. A novel human in vitro model of foamy macrophages functionally confirmed that myelin ingestion induces an anti-inflammatory programme. Foamy macrophages are unable to respond to prototypical inflammatory stimuli but do express molecules involved in suppression of inflammation. These findings provide novel insights into the mechanisms of lesion control and may open new roads to interventio