Immunopathogenesis of Guillain-Barré syndrome and chronic inflammatory demyelinating polyradoculoneuropathy

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Clinical Neuroscience, Occupational Therapy and Elderly Care Research (NEUROTEC)

Sammanfattning: Guillain-Barre syndrome (GBS) is an inflammatory polyradiculoneuropathy with acute onset and usually a spontaneous recovery. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic progressive inflammatory neuropathy. GBS and CIDP are associated with high morbidity despite treatment with immunomodulatory drugs. Both conditions are associated with inflammation of spinal nerve roots and/or distal nerves of the peripheral nervous system (PNS). GBS is assumed to be induced by infection + abnormal autoimmunity, whereas the immunopathogenesis of CIDP remains obscure. Previous studies have shown up-regulation of myelin-reactive T cells, and of levels of blood cytokines, indicative of T cell auto-reactivity in GBS. Few studies have addressed the balance between Th1 and Th2 cytokines over the course of GBS. GBS, but not CIDP, is associated with anti-GM1 and anti-GD1a anti-ganglioside serum antibodies (abs), but the temporal profile of anti-ganglioside abs over the course of GBS is not known. Despite the presumed importance of the role of prior infections in GBS pathogenesis, the nature of the antigen-presenting cells involved in this putative process is unclear. Dendritic cells (DC) are believed to play an important role in the induction of adaptive and innate immune responses. The myeloid subset of DC activates T and B cells, and the plasmacytoid subset of DC may induce tolerance. The role of DC has not been examined in GBS and CIDP. The aims of the study were to explore the roles of cytokine-secreting cells, anti-ganglioside abs and DC in blood, CSF and PNS over the course of GBS and CIDP, in relation to clinical parameters and immuno-modulatory treatment. Patients examined in the acute phase of GBS prior to treatment with intravenous high dose immunoglobulin (IvIg), had elevated levels of IL-10, but not of IFN-gamma secreting blood mononuclear cells (MNC). Pre-treatment levels of IL-10 secreting MNC correlated with neurophysiological signs of axonal damage and with levels of anti-ganglioside serum IgM abs. The highest titers of anti-GM1 serum IgG abs were observed in GBS patients examined 40 days after onset of GBS, while peak anti-GD1a IgM antibody titers were measured in the recovery phase, i.e. 90 days after onset of GBS. Patients developing steadily increasing levels of serum anti-GM1 IgG- and anti- GD1a IgM abs over the course of GBS, followed by a drop in levels of abs (i.e. patients developing peak ab titers) had a worse clinical outcome. Patients examined in the acute phase of GBS prior to lvIg treatment had also high levels of IL-6 secreting blood MNC. Patients examined in the recovery phase of GBS had lower levels of TNF-alpha secreting MNC vs. controls. Levels of IL-12p70 secreting blood MNC were not altered. Percentages of freshly isolated blood DC expressing cell surface molecules CD1a (involved in antigen- presentation), CD80 and CD86 (co-stimulatory molecules), CD54 (adhesion molecule), CD11c (marker of myeloid DC) and CD 123 (marker of plasmacytoid DC) as well as the chemokine receptors CCR1, CCR2, CCR5, and CXCR4 were not altered in patients with GBS and CIDP compared to controls. In contrast, levels of CD11c+ DC were elevated in cerebrospinal fluid (CSF) of CIDP patients, and of CD123+ DC in CSF of GBS patients prior to immunomodulatory treatment. Small numbers of immature myeloid CD11 c+CD14-CD16- DC were detected in the perineurium of sural nerve biopsies of patients with CIDP as well as in controls. Chemokines released by nerve tissue or in CSF are assumed to be responsible for recruiting DC to sites of inflammation. The CSF levels of chemokines MCP-1 and IP-10 were elevated in GBS patients and of IP-10 and MIP-3 beta in CIDP prior to treatment. The absence of a clear systemic Th 1 cytokine secretion profile in GBS, as well as presence in CSF of plasmacytoid DC, may be one of the explanations for the self-limited course of the auto-aggressive attack against PNS in GBS. Myeloid DC, which may enter the CSF due to elevated levels of MCP-1, may be retained by MIP-3 beta and thus contribute to sustained PNS inflammation in CIDP. DC in the CSF and in peripheral nerves, may be responsible for uptake of antigen released from the inflamed PNS, whereby antigen may be presented to T and B cells locally and/or in draining lymph nodes. Further studies of the cause of differential recruitment of DC subsets to CSF as well as the role of CSF chemokines in GBS vs. CIDP are warranted.

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