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

Abstract

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 J Mol Med (2009) 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.

Brain-Derived Antigens in Lymphoid Tissue of Patients with Acute Stroke

“…The presence of brain-derived Ags in the CLN was previously shown in patients with multiple sclerosis (13,15,19) and in animals with neurologic autoimmune disease or brain ischemia (13)(14)(15). To our knowledge, this study is the first to describe increased immunoreactivity to brain-derived compounds in the CLN and PT of patients with acute stroke and that this immunologic trait was associated with the volume of infarction and with the functional outcome of patients at follow-up.…”

“…In addition, molecules can reach the CLN by bulk flow of the intracranial fluids (11,12). Indeed, brain-derived Ags or APCs carrying these Ags can reach the CLN under experimental conditions, (13)(14)(15)(16) and the presence of brain-derived Ags in the CLN is recognized in human anatomic studies (17,18) and in sporadic clinical descriptions (13,19,20) of patients with multiple sclerosis.…”

Phagocytosis of neuronal debris by microglia is associated with neuronal damage in multiple sclerosis

“…In MS and stroke in humans, and after EAE and neurological damage in experimental animals, CNS antigens released during damage drain to the local cervical lymph nodes (CLN; Bechmann and Nitsch, 1997;de Vos et al, 2002;van Zwam et al, 2009). How CNS antigens are transported to the CLN is unknown.…”

Chronic Cerebrospinal Venous Insufficiency in Multiple Sclerosis: The Hydrostatic-Immune Paradigm and the Flow Cytometry as a Diagnostic Tool

“…Altered neuronal microenvironment and changes in antigen presentation to regional lymph nodes may provide a theoretical framework combining hydrostatic and immune effects. Lymph nodes are a site of sensitive immune regulation where both immune suppression and immune activation take place [80,81] CCSVI and its treatment may act via tipping the balance towards one or the other side of the scales.…”