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

• Published in: The Journal of pathology Vol. 217; no. 4; pp. 543 - 551
• Main Authors: van Zwam, Marloes, Huizinga, Ruth, Heijmans, Nicole, van Meurs, Marjan, Wierenga-Wolf, Annet F, Melief, Marie-José, Hintzen, Rogier Q, 't Hart, Bert A, Amor, Sandra, Boven, Leonie A, Laman, Jon D
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.03.2009; Wiley
• Subjects: Animals; Autoimmunity; Biological and medical sciences; blood-brain barrier; Brain - immunology; Cell Proliferation; Central Nervous System - immunology; Central Nervous System - pathology; Central Nervous System - surgery; Encephalomyelitis, Autoimmune, Experimental; epitope speading; Epitopes - analysis; Epitopes - immunology; Female; Immunohistochemistry; Investigative techniques, diagnostic techniques (general aspects); lymph node excision; Lymph Nodes - immunology; Lymph Nodes - pathology; Lymph Nodes - surgery; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; mucosal tolerance; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Multiple Sclerosis, Relapsing-Remitting - immunology; Multiple Sclerosis, Relapsing-Remitting - pathology; Multiple Sclerosis, Relapsing-Remitting - surgery; Myelin Sheath - immunology; nasal lymphatics; Neurology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Spinal Cord - immunology; Spleen - immunology; Treatment Outcome; Autoimmunity; Animal model; Relapse; Multiple sclerosis; Antigenic determinant; Mucosa; Central nervous system; Autoimmune disease; Blood brain barrier; Encephalon; Inflammatory disease; nasal lymphatics; Surgery; Nose; mucosal tolerance; blood-brain barrier; Immunopathology; Nervous system diseases; Lymphatic system; Excision; Lymph node; Tolerance; Lymphatic; Experimental allergic encephalomyelitis; Anatomic pathology; Chronic; lymph node excision; Treatment; Central nervous system disease; epitope speading
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2476

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.