Surgical excision of CNS‐draining lymph nodes reduces relapse severity in chronic‐relapsing experimental autoimmune encephalomyelitis

Abstract

Despite lack of classical lymphatic vessels in the central nervous system (CNS), cells and antigens do reach the CNS-draining lymph nodes. These lymph nodes are specialized to mediate mucosal immune tolerance, but can also generate T- and B-cell immunity. Their role in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) therefore remains elusive. We hypothesized that drainage of CNS antigens to the CNS-draining lymph nodes is vital for the recurrent episodes of CNS inflammation. To test this, we surgically removed the superficial cervical lymph nodes, deep cervical lymph nodes, and the lumbar lymph nodes prior to disease induction in three mouse EAE models, representing acute, chronic, and chronic-relapsing EAE. Excision of the CNS-draining lymph nodes in chronic-relapsing EAE reduced and delayed the relapse burden and EAE pathology within the spinal cord, which suggests initiation of CNS antigen-specific immune responses within the CNS-draining lymph nodes. Indeed, superficial cervical lymph nodes from EAE-affected mice demonstrated proliferation against the immunizing peptide, and the deep cervical lymph nodes, lumbar lymph nodes, and spleen demonstrated additional proliferation against other myelin antigen epitopes. This indicates that intermolecular epitope spreading occurs and that CNS antigen-specific immune responses are differentially generated within the different CNS-draining lymphoid organs. Proliferation of splenocytes from lymphadenectomized and sham-operated mice against the immunizing peptide was similar. These data suggest a role for CNS-draining lymph nodes in the induction of detrimental immune responses in EAE relapses, and conclusively demonstrate that the tolerance-inducing capability of cervical lymph nodes is not involved in EAE.

Group 3 innate lymphoid cells accumulate and exhibit disease-induced activation in the meninges in EAE

“…Because LTis are important for lymph node development, RorcÀ/À mice lack these secondary lymphoid organs raising the possibility that Th17 cell induction is compromised in these mice. However, although one study showed slight diminution of disease during relapse after surgical excision of CNS draining lymph nodes [68], most data indicates that lymph nodes are dispensable for cell mediated immunity in EAE and only necessary for antibody affinity maturation and class switching [7,27,28]. Due to the normal splenic architecture of RorcÀ/À mice and our observation of normal cell proliferation and cytokine production of transferred T cells in these mice (Fig.…”

Commensal gut flora and brain autoimmunity: a love or hate affair?

“…The nominal myelin antigen, MOG, might be available to the MOG-specific B cells in the local draining LNs through specialised transport via lymphatic vessels. Indeed, deposits of myelin antigen were detected in the brain-draining cLNs during active EAE and surgical removal of these LNs ameliorated the severity of EAE [28,123]. Detailed analysis of the cLNs in RR mice found evidence of changes which preceded the onset of spontaneous EAE.…”

Understanding the functions and relationships of the glymphatic system and meningeal lymphatics

“…As discussed above, this connection is primarily due to the glymphatic system that connects ISF and CSF (15). In both rodent and primate models of multiple sclerosis, for example, brain antigens were increased in the cervical lymph nodes (80,81). After stroke, brain injury, or oligodendrocyte death induced by diphtheria toxin, myelin antigens have similarly been found to accumulate in the cervical lymph nodes (82)(83)(84).…”