| Objective: Chronic inflammatory demyelinating polyneuropathy(CIDP)is a kind of acquired immune mediated peripheral neuropathy.It is hard to make accurate and specific diagnostic criteria since CIDP is heterogeneous and lack of biomarker.Neurofascin(NF)155 is an adhension molecular that located at paranode.NF155 interacts with contactin-1 and contactin-associated protein-1 playing a key role to the stability node and paranode.Immunoglobulin(IgG)4 anti-NF155 antibody has been detected in a fraction of CIDP patients and the antibody was involved in the pathogenic mechanism.Compared with anti-NF155 negative patients,IgG4anti-NF155 antibody-positive patients showed differet characteristics.However,IgG4 can not active complements and recruit associated inflammatory cells.The IgG4anti-NF155 antibody can not explain all the differences between positive and negative patients,especially hypertrophy of spinal roots and higher protein level in cerebrospinal fluid(CSF)that suggest inflammation.In addition,the inflammation suggests that T cells might also be involved in the disease.In this study,we try to clarify the CSF cytokine profile and human leukocyte antigen(HLA)association in Japanese patients with IgG4 anti-NF155 antibody-positive polyneuropathy presenting root hypertrophy and explore the mechanism of T cells.Methods: Twenty-eight CSF cytokines/chemokines/growth factors were measured by multiplexed fluorescence bead-based immunoassay,and HLA alleles were genotyped using 42 IgG4 anti-NF155 antibody-positive polyneuropathy and 37 CIDP patients.As controls,CSF and HLA studies used 28 patients with other non-inflammatory neurological diseases(OND)and 394 healthy controls(HCs),respectively.Results: CSF CXCL8/IL-8,IL-13,TNF-?,CCL11/eotaxin,CCL2/MCP-1,and IFN-glevels were significantly higher,while IL-1b,IL-1ra,and G-CSF were lower,in IgG4anti-NF155 antibody-positive polyneuropathy versus OND.Even compared with seronegative CIDP,CXCL8/IL-8 and IL-13 levels were significantly higher,and IL-1 b and IL-1ra levels were lower,in IgG4 anti-NF155 antibody-positive polyneuropathy.CXCL8/IL-8,IL-13,and CCL11/eotaxin levels were positively correlated with markedly elevated CSF protein,while CCL11/eotaxin levels were significantly positively correlated with increased CSF cell counts.CXCL8/IL-8,CCL2/MCP-1,and CCL4/MIP-1b were significantly decreased by immunotherapies.By contrast,anti-NF155 antibody-negative CIDP patients had significantly increased IFN-g compared with OND patients,and a positive correlation of CXCL10/IP-10 with CSF protein.The results of cluster analysis also suggested different pattern of cytokines/chemokines/growth factors between IgG4 anti-NF155 antibody-positive patients and anti-NF155 antibody-negative patients.Besides,the cluster analysis also suggested that type 2 helper T cell(Th2)cytokines play an important role in IgG4anti-NF155 antibody-positive patients.All IgG4 anti-NF155 antibody-positive polyneuropathy patients carried either DRB1*15:01-DRB5*01:01-DQA1*01:02-DQB1*06:02 or(A*24:02)-B*52:01-C*12:02-DRB1*15:02-DRB5*01:02-DQA1*01:03-DQB1*06:01,resulting in significantly increased DRB1*15,DRB1*15:01 and DQB1*06:02 frequencies compared with HCs.Interpretation:1.The level of CXCL8/IL-8,IL-13,TNF-?,CCL11/eotaxin,CCL2/MCP-1,and IFN-g in CSF were significantly higher,while IL-1 b,IL-1ra,and G-CSF were significantly lower in IgG4 anti-NF155 antibody-positive polyneuropathy compared with OND.Even compared with seronegative CIDP,the level of CXCL8/IL-8 and IL-13 were significantly higher in patients with IgG4 anti-NF155 antibody-positive polyneuropathy.The cluster analysis also suggested similar results.In contrast to a type 1 helper T cell(Th1)shift in seronegative CIDP,intrathecal up-regulation of both Th2 and Th1 cytokines is the characteristic of the patients with IgG4 anti-NF155antibody-positive polyneuropathy.2.The levels of CXCL8/IL-8,IL-13,and CCL11/eotaxin were positively correlated with markedly elevated CSF protein,while the levels of CCL11/eotaxin were significantly positively correlated with increased CSF cell counts.CXCL8/IL-8,CCL2/MCP-1,and CCL4/MIP-1b were significantly decreased by immunotherapies.Th2 cells might be involved in the hypertrophy of spinal nerve roots.The significantly higher CSF cell counts and CSF protein levels revealed more sever inflammation of spinal nerve roots in IgG4 anti-NF155 antibody-positive polyneuropathy patients than anti-NF155 antibody-negative CIDP patients.3.All IgG4 anti-NF155 antibody-positive polyneuropathy patients carried either DRB1*15:01-DRB5*01:01-DQA1*01:02-DQB1*06:02 or(A*24:02)-B*52:01-C*12:02-DRB1*15:02-DRB5*01:02-DQA1*01:03-DQB1*06:01,resulting in significa ntly increased DRB1*15,DRB1*15:01 and DQB1*06:02 frequencies compared with HCs.Together with a strong DRB1*15 association,these data suggest Th2/Th1 involvement in spinal root inflammation. |
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