Multifocal motor neuropathy is not associated with genetic variation in PTPN22, BANK1, Blk, FCGR2B, CD1A/E, and TAG-1 genes

The contribution of genetic heterogeneity to the pathogenesis of multifocal motor neuropathy (MMN) has not been elucidated. We investigated frequencies of single nucleotide polymorphisms (SNPs) in the candidate genes protein tyrosine phosphatase, non-receptor type 22 (PTPN22), B-cell scaffold protein with ankyrin repeats (BANK1), B lymphocyte kinase (Blk), and Fc gamma receptor class IIB (FCGR2B), which have been found to be associated with other autoimmune diseases, CD1A and CD1E, important for antigen presentation of glycolipids, and transient axonal glycoprotein 1 (TAG-1), which is associated with responsiveness to intravenous immunoglobulin in patients with chronic inflammatory demyelinating polyneuropathy. SNP frequencies were determined by means of TaqMan SNP genotyping assay and direct sequencing of candidate genes in 92 Dutch patients with MMN and 1152 healthy controls. SNP frequencies did not differ between patients and controls (all p-values >0.15) and disease characteristics were not associated with SNP genotypes. Our results suggest that allelic variation in these genes does not play a major role in determining MMN susceptibility.     

Dendritic cells in the cerebrospinal fluid and peripheral nerves in Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy

The role of antigen-presenting cells (APC) involved in induction of T and B cell mediated autoaggressive immunity in Guillain-Barre syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is poorly understood. We studied the numbers and phenotype of dendritic cells (DC) in blood and cerebrospinal fluid (CSF) over the course of GBS and CIDP before and after immunomodulatory treatment. Four out of seven GBS patients examined prior to treatment with high-dose intravenous immunoglobulins (IvIg) had elevated numbers of CD123(+) plasmacytoid DC in the CSF, while both GBS and CIDP patients examined prior to treatment had elevated numbers of CD11c(+) myeloid DC in the CSF, as compared to patients with noninflammatory neurological diseases (OND). The percentages of blood DC expressing the cell surface marker CD1a, co-stimulatory molecules CD80 and CD86, adhesion molecule CD54, and chemokine receptors CCR1, CCR2, CCR5, and CXCR4 were not affected in GBS or CIDP. The immunohistochemistry of sural nerve biopsies revealed CD11c(+)CD83(-)CD14(-)CD16(-) immature myeloid DC at low numbers, mostly in the perineurium, without difference between CIDP patients and controls. In contrast, the numbers of CD11c(+)CD14(+)/CD16(+) macrophages were higher within the endoneurium in CIDP patients compared with the controls. The recruitment of DC to CSF in GBS and CIDP may be important in capturing antigens released from inflamed spinal nerve roots into CSF and in transferring these antigens from CSF to local lymph nodes, where naive T and B cells may be activated.     

Differential gene expression in nerve biopsies of inflammatory neuropathies

DNA microarray analysis is a powerful tool for simultaneous analysis and comparison of gene products expressed in normal and diseased tissues. We used this technique to identify differentially expressed genes (DEGs) in nerve biopsy samples of chronic inflammatory demyelinating polyneuropathy (CIDP) and vasculitic neuropathy (VAS) patients. We found novel previously uncharacterized genes of relevance to CIDP or VAS pathogenesis. Of particular interest in CIDP were tachykinin precursor 1, which may be involved in pain mediation, stearoyl-co-enzyme A (CoA) desaturase, which may be a marker for remyelination, HLA-DQB1, CD69, an early T-cell activation gene, MSR1, a macrophage scavenger receptor, and PDZ and LIM domain 5 (PDLIM5), a factor regulating nuclear factor (NF)-kappa B activity. Genes upregulated in VAS included IGLJ3, IGHG3, IGKC, and IGL, which all function in B-cell selection or antigen recognition of B cells. Other upregulated genes included chemokines, such as CXCL9 and CCR2, as well as CPA3, a mast cell carboxypeptidase. Allograft inflammatory factor-1 (AIF-1), a modulator of immune response was upregulated both in CIDP and VAS. Microarray-based analysis of human sural nerve biopsies showed distinct gene expression patterns in CIDP and VAS. DEGs might provide clues to the pathogenesis of the diseases and be potential targets for therapeutics.     

Susceptibility to Guillain-Barré syndrome is not associated with CD1A and CD1E gene polymorphisms

Immune responses to microbial glycolipids that cross-react to neural epitopes may trigger the Guillain-Barré syndrome (GBS). CD1 molecules are involved in antigen presentation of glycolipids and variation in CD1 genes was recently reported to confer susceptibility to develop GBS. This hypothesis was tested by comparing single nucleotide polymorphisms (SNPs) of CD1A and CD1E in 312 well defined GBS patients and 212 healthy controls. SNPs in CD1A and CD1E were not associated with GBS susceptibility, specific clinical subgroups, anti-ganglioside antibodies, antecedent infections and prognosis. Based on this study, CD1 polymorphisms are not a susceptibility or disease modifying factor in GBS.     

慢性炎性脱髓鞘性周围神经病样表现的腓骨肌萎缩症二例

目的观察亚急性病程的慢性炎性脱髓鞘性周围神经病（CIDP）样表现的腓骨肌萎缩症（CMT）的临床、病理和电生理特点。方法报道2例亚急性的CIDP样表现的CMT患者的临床、神经电生理及周围神经活检的病理特点。结果2例证实为17p12重复突变的CMTIA患者，慢性病程中亚急性加重，临床表现类似于CIDP。肌电图示运动神经传导速度（MNCV）减慢、阻滞；神经活检见洋葱头样改变，髓鞘脱失，有炎性细胞的浸润，证明有炎性脱髓鞘的CMT1A存在，且免疫治疗有效。结论慢性病程的CMT1A可有类似于CIDP的病程和临床表现，免疫治疗可改善症状。     

Susceptibility to Guillain-Barré syndrome is associated to polymorphisms of CD1 genes

Guillain-Barré syndrome (GBS) is the prototype of a postinfectious autoimmune neuropathy. Molecular mimicry between glycolipid antigens expressed by an infective antigen such as Campylobacter jejuni and the human peripheral nerve has been hypothesized to be the causative mechanism of GBS. However, only 1/1000 of C. jejuni enteritis develops GBS. This emphasizes the importance of host-related factors in the development of the disease. HLA studies in GBS failed to show an association or gave conflicting results but MHC class I and II process and present peptides to T lymphocytes making unlikely that the HLA system plays a role in GBS with autoantibodies against self-gangliosides. CD1 molecules are MCH-like glycoproteins specialized in capturing and presenting a variety of glycolipid to antigen-specific T cells. There are five closely linked CD1 genes in humans located in chromosome 1 (named CD1A, B, C, D, and E) all showing limited polymorphism in exon 2 which codifies for the alpha1 domain of CD1 molecules. The nucleotide substitutions in CD1B and CD1C are rare and reported to be silent. In 100 controls and 65 GBS patients (21 with a recent C. jejuni infection and 35 with anti-glycolipid antibodies) we used direct sequencing by polymerase chain reaction to genotype exon 2 of CD1A, CD1D and CD1E genes. CD1D is monomorphic in both controls and patients whereas CD1A and CD1E are biallelic in exon 2. Subjects with CD1E*01/01 genotype are 2.5 times more likely to develop GBS, whereas subjects with CD1A*01/02 or CD1E*01/02 have a reduced relative risk by 3.6 and 2.3 times respectively. The combination of CD1A*01/02 and CD1E*01/02 reduces by 5 times the risk of developing GBS. Although a correlation between CD1E*01/01 genotype and recent C. jejuni infection or presence of antiganglioside antibodies was not found the overall findings indicate that susceptibility to develop GBS is associated with polymorphisms of CD1E and CD1A genes.     

Th1 shift in CIDP versus Th2 shift in vasculitic neuropathy in CSF

To investigate the intra- and extracellular levels of various cytokines and chemokines in CSF in chronic inflammatory demyelinating polyneuropathy (CIDP) and vasculitic neuropathy (VN), 16 cytokines, IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, IFN-gamma, TNF-alpha, G-CSF, MCP-1 and MIP-1beta, were measured in CSF supernatant by a multiplexed fluorescent bead-based immunoassay and intracellular production of IFN-gamma and IL-4 in CSF CD4+ T cells were simultaneously measured by flow cytometry in 14 patients with CIDP, 8 patients with VN and 25 patients with other noninflammatory neurologic diseases (OND). In the CSF supernatant, a significant increase of IL-17, IL-8 and IL-6, and a significant decrease of IL-4, IL-5 and IL-7 levels were detected in pretreated CIDP as compared with OND. A significant increase of IL-6, IL-8 and IL-10 levels was found in pretreated VN. Both IL-17 and IL-8 levels correlated strongly with CSF protein levels in CIDP, although the correlation of IL-6 levels was weak. In CSF CD4+ T cells, IFN-gamma+ IL-4- cell percentages were markedly elevated in CIDP compared with OND, but not in VN, resulting in a significant increase of intracellular IFN-gamma/IL-4 ratio in CIDP, even in the absence of CSF pleocytosis. The nonresponders to intravenous immunoglobulins (IVIGs) showed a significantly lower IFN-gamma- IL-4+ CD4+ T cell percentage, and tended to have a higher intracellular IFN-gamma/IL-4 ratio than the responders in CSF. Marked upregulation of Th1 cytokine, IL-17, and downregulation of Th2 cytokines, together with infiltration of IFN-gamma-producing CD4+ T cells are useful markers for CIDP, while several Th2 cytokines are upregulated in VN in CSF.     

Polymorphism of transient axonal glycoprotein-1 in chronic inflammatory demyelinating polyneuropathy

Chronic inflammatory demyelinating polyneuropathy (CIDP) is characterized by immune-mediated peripheral demyelination. Although corticosteroid, intravenous immunoglobulin (IVIg), and plasma exchange have been established as the most effective therapeutics, sub-populations of patients show little or no response to either of these therapies. We identified the clinical, electrophysiological, and genetic features related to IVIg responsiveness in CIDP by conducting a multi-center study. Muscle atrophy and decreased compound muscle action potential (CMAP) were pronounced in IVIg non-responders, that is, features suggesting axonal dysfunction in peripheral nerves indicated IVIg unresponsiveness in CIDP. We then performed an association analysis using single nucleotide polymorphisms (SNPs) and haplotype studies between the IVIg responders and non-responders. We assessed SNPs of candidate genes that are particularly related to the function of Ranvier's node, paranode, or juxtaparanode. Two separate SNPs, corresponding to transient axonal glycoprotein-1 (TAG-1) and C-type lectin domain family 10, member A (CLEC10A), showed significant differences between responders and non-responders. Haplotype analysis of a series of expanded SNPs, from TAG-1 or CLEC10A, showed that only TAG-1 included a significant haplotype within one linkage disequilibrium block that accommodates IVIg responsiveness. Diplotype analysis of TAG-1 also supported this observation. In conclusion, SNPs in TAG-1, which is a key molecule for axon-Schwann cell interactions and is distributed at the juxtaparanode, are related to the IVIg responsiveness of CIDP patients.     

慢性炎性脱髓鞘性多发性神经根神经病周围神经细胞免疫与临床研究

目的研究慢性炎性脱髓鞘性多发性神经根神经病（chronic inflammatory demyelinating polyradic—uloneuropathy，CIDP）细胞免疫染色结果与临床、电生理和病理的关系。方法经周围神经活检确诊的12例CIDP神经活检标本和10例其它神经系统疾病患者的周围神经标本，用免疫组织化学染色的方法标记神经内膜的淋巴细胞、巨噬细胞和表达鼠抗人白细胞DR抗原（HLA-DR）的细胞，并分别计数，比较2组患者阳性细胞数量；分析CIDP患者3种阳性细胞数与临床、电生理和病理的关系。结果CIDP组与对照组比较，鼠抗人白细胞共同抗原（LCA）单克隆抗体、鼠抗人巨细胞（CD68）单克隆抗体、HDL-DR单克隆抗体的计数均有明显差异，P值分别为0．001、0．006和0．002；CIDP组HLA-DR阳性计数与CD68阳性计数之间有明显差异，P值为0．04，神经内膜水肿的LCA计数和无水肿的LCA计数比较有明显差异，P值为0．03，CD68阳性细胞在感觉神经传导速度减慢、神经纤维中重度减少的患者较相应的亚组有明显增高，且有显著差异，P值均为0．01，HLA-DR阳性计数在神经纤维中重度减少的患者也较相应的亚组有明显增高，有统计学差异，P值为0．01。结论CIDP患者神经内膜的炎性细胞浸润是较多见的病理特点，并与神经内膜水肿有关，巨噬细胞的浸润与感觉神经传导速度减慢以及神经纤维数量减少有关，病程较长时巨噬细胞和雪旺氏细胞都可能为HLA-II类抗原的抗原提呈细胞，雪旺氏细胞可能不仅为抗原提呈细胞，还可能同时参与对髓鞘的吞噬与破坏。     

Association of CD1 and FcγR gene polymorphisms with Guillain–Barré syndrome susceptibility: a meta-analysis

CD1 and immunoglobulin G Fc receptor (FcγR) genes have been proposed to be involved in the pathogenesis of Guillain–Barré syndrome (GBS). However, results of different studies are conflicting. This meta-analysis aimed to systematically examine the association between CD1 and FcγR gene polymorphisms and GBS. A comprehensive literature search through PubMed, EmBase, ScienceDirect, and Cochrane Library was performed to identify all eligible studies. The strength of association was assessed by pooled odds ratios (ORs) and corresponding 95% confidence intervals (95% CI) in allelic, dominant, recessive, homozygous and heterozygous genetic models. Four case–control studies about polymorphisms of exon 2 in CD1A and CD1E genes and GBS risk and five studies (six cohorts) about FcγR gene polymorphisms and GBS risk were included in this meta-analysis. The association between exon 2 of CD1E gene polymorphism and GBS was marginally significant in Caucasians in allelic model (OR?=?1.193, 95% CI?=?1.001–1.423, P?=?0.049). FcγRIIA gene polymorphism was significantly associated with GBS risk in Caucasians under allelic model (OR?=?1.553, 95% CI?=?1.018–2.368, P?=?0.041) and dominant model (OR?=?1.320, 95% CI?=?1.027–1.697, P?=?0.030). However, no significant association was found between polymorphisms in exon 2 of CD1A, FcγRIIIA and FcγRIIIB genes and GBS susceptibility. This meta-analysis suggested that FcγRIIA gene polymorphism may contribute to GBS risk in Caucasians and revealed a certain trend toward significance in the association of exon 2 of CD1E gene with GBS in Caucasians. Further studies with larger sample size are required to validate these results.     

Genetics of Guillain‐Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): current knowledge and future directions

Guillain‐Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are thought to be autoimmune diseases. There have been many attempts to find a human leukocyte antigen (HLA) association with GBS and CIDP with little success. There have been studies of other plausible genes in GBS and CIDP and the role of these genes in GBS and CIDP and the data from these genetic studies is reviewed. Some of the genes that have been studied are immune related and some others have nervous system effects. The studies are limited by small numbers. Some of the genes show association with disease severity rather than disease susceptibility. The need for more detailed molecular studies of the role of HLA molecules and the need for modern genetic approaches to GBS and CIDP are explained.     

What’s new in chronic inflammatory demyelinating polyradiculoneuropathy in 2007–2008?

Abstract Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)–related research has made progress in the field of pathogenesis, genetics, and treatment. The number of circulating CD4⁺ CD25⁺ T‐regulatory cells was shown to be reduced in CIDP patients. Increased frequency of genotype GA13‐16 of the SH2D2A gene encoding for a T‐cell‐specific adapter protein in CIDP patients may result in a defective control and elimination of autoreactive T cells. IVIg treatment has been shown to increase numbers and function of peripheral CD4⁺ CD25⁺ T‐regulatory cell in a mouse model. These findings shed new light on the understanding of why peripheral tolerance is breached in CIDP patients and why the disease becomes chronic and adds another possible mechanism of action of intravenous immunoglobulin to the already long list. Long‐term effectiveness of IVIg has now been proven. Subcutaneous immunoglobulin could be an alternative for IVIg, but this has to be explored further in well‐designed trials. Autologous stem cell transplantation has been tried in refractory patients, but larger trials are necessary to assess safety and effect of this treatment.     

Proposed revised electrophysiological criteria for chronic inflammatory demyelinating polyradiculoneuropathy.

Electrophysiological criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) were proposed by an Ad Hoc Subcommittee of the American Academy of Neurology (AAN) in 1991. Only 60% of CIDP patients fulfilled these criteria, which therefore appear poorly sensitive. We therefore sought to revise the electrophysiological criteria. We selected 40 CIDP patients and compared them with 35 patients with axonal polyneuropathy, 116 patients with Charcot-Marie-Tooth type 1A (CMT1A) disease, and 66 patients with immunoglobulin M (IgM) monoclonal gammopathy. The proposed electrophysiological criteria identified 90% of the CIDP patients, although 3% of patients with axonal polyneuropathy were falsely identified. For the CIDP patients, sensitivity and specificity were 90% and 97%, respectively. Of the patients with IgM monoclonal gammaglobulin of undetermined significance (MGUS) and CMT1A, 100% fulfilled these new criteria, whereas 90% and 97%, respectively, fulfilled the AAN criteria. These results suggest that the AAN criteria are more appropriate for IgM MGUS and CMT1A patients than for CIDP patients. We therefore propose new electrophysiological criteria for CIDP that appear to have better sensitivity.     

Blink R1 latency utility in diagnosis and treatment assessment of polyradiculoneuropathy‐organomegaly‐endocrinopathy‐monoclonal protein‐skin changes and chronic inflammatory demyelinating polyradiculoneuropathy

Introduction: In polyradiculoneuropathy‐organomegaly‐endocrinopathy‐monoclonal protein‐skin changes (POEMS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), limb nerve conduction studies (NCSs) are limited in identifying demyelination and in detecting treatment effects in severely affected patients. Blink R1 latency may improve these assessments. Methods: POEMS and CIDP patients who had undergone NCS and blink reflex were identified. Correlations among R1 latency, limb NCS, and neuropathy impairment scores (NIS) were compared. Results: Among 182 patients (124 POEMS, 58 CIDP) who were identified, R1 prolongation (>13 ms) occurred in 64.3% (65.3% POEMS, 62.1% CIDP). R1 prolongation correlated with more severely affected NCS in both POEMS (ulnar CMAP 2.6 mV vs. 4.5 mV, P = 0.001) and CIDP (2.0 mV vs. 6.1 mV, P < 0.001). In severely affected patients (ulnar CMAP ≤0.5 mV [10%:18/182]), R1 (>13 ms) helped establish demyelination. In 31 patients (16 POEMS, 15 CIDP), the R1 latency changes were concordant with NIS changes in 94% of patients with POEMS and 60% of patients with CIDP. Discussion: Blink R1 latencies are valuable in defining demyelination and detecting improvement in severely affected POEMS and CIDP patients. Muscle Nerve 57 : E8–E13, 2018     

Dysregulated Epstein-Barr virus infection in patients with CIDP

Ubiquitous viruses have frequently been proposed as a cause or trigger of chronic immune-mediated diseases. Infections are reported to be temporally associated with clinical exacerbations in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We examined immunological parameters of herpesvirus infections in untreated patients with CIDP compared to demographically matched controls. Patients with CIDP were uniformly seropositive for EBV-specific IgG and the disease was associated with a moderately enhanced IgG reactivity to EBV-encoded antigens expressed during both B cell transformation and productive viral replication. Moreover, cellular EBV copy numbers were 3-fold increased in patients with CIDP. In contrast, humoral immune responses to other herpesviruses (HCMV, HSV) as well as virus-specific IgM responses were unchanged in CIDP. These data indicate that host–pathogen interactions during chronic EBV infection are dysregulated in treatment-naïve patients with CIDP.     

The effect of IgG levels on the number of natural killer cells and their Fc receptors in chronic inflammatory demyelinating polyradiculoneuropathy

Background and purpose: High‐dose intravenous immunoglobulin (IVIg) is an established treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Although Fc receptors on natural killer cells have been suggested as a target for IVIg, the pharmacological effects are not yet clarified. We hypothesize that IVIg therapy, dependent on the plasma IgG level, suppresses the cytotoxic capacity by a reduction in numbers of NK cells and their Fc receptor CD16. Patients and methods: Ten consecutive patients with CIDP in maintenance therapy with IVIg were studied before and immediately after the infusion of 0.7–2.0 g/kg IVIg. Peripheral blood mononuclear cell samples from these patients were analyzed immediately after isolation using flow cytometry and cytotoxicity assays. Results: We found that following IVIg treatment, the cytotoxic activity of NK cells in CIDP patients was suppressed, partly caused by a dose‐dependent decline in the number of circulating NK cells. In addition, a dose‐dependent blockage of CD16 occurred. Conclusions: The study implies that IVIg infusion induces a substantial decline in the number of peripheral NK cells and a suppression of NK‐cell‐mediated cytotoxicity. We propose that these impairments of the NK cells contribute to the therapeutic effect of IVIg in CIDP.     

Antibodies to LM1 and LM1-containing ganglioside complexes in Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy

LM1 is localized in human peripheral nerve myelin. Antibodies to ganglioside complexes (GSCs) have been reported in Guillain-Barré syndrome (GBS). We investigated IgG antibodies to LM1 and two GSCs (GM1 and LMI, or GD1b and LM1) in the sera of each 40 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and GBS, using ELISA. We detected anti-LM1 antibody in five with GBS and seven with CIDP; anti-GM1/LM1 antibody in three with GBS and one with CIDP; and anti-GD1b/LM1 antibody in two with CIDP. Antibodies to LM1 and LM1-containing GSCs may be among the targets for autoimmunity in GBS and CIDP.     

Intravenous immunoglobulin modulates lymphocyte CD54 and monocyte FcgammaRII expression in patients with chronic inflammatory neuropathies

We studied the expression of different lymphocyte and monocyte cellular determinants involved in leukodiapedesis and antigen presentation in 10 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) with persistent conduction blocks before intravenous immunoglobulin (IVIg), immediately after infusion of IVIg and 1 week after infusion. We observed a decrease of T lymphocytes expressing ICAM-1 (CD54) immediately after infusion in 8 out of 10 patients (p<0.04) with a return to pretreatment values after 1 week. The monocytes showed an increase in CD14(+) cells and CD14(+) FcgammaRII inhibitory receptor positive cells, no change in the number of CD14(+) FcgammaRIII activation receptor cells, and an increase in the FcgammaRII/FcgammaRIII ratio on monocytes 1 week after IVIg. Thus, the mechanism of action of IVIg in both CIDP and MMN may involve inhibition of T cell transmigration and modulation of antigen presentation capacities through FcgammaR expression.     

MRI of the cauda equina in CIDP: clinical correlations.

Isolated reports have documented enhancement and/or enlargement of spinal nerve roots on magnetic resonance imaging (MRI) in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). This work examines those findings in a consecutive series of 16 patients with CIDP, with blinded comparison to MRI in 13 disease controls, including five patients with Charcot-Marie-Tooth disease type 1A. MRI sequences consisted of T1 weighted sagittal and axial views, before and after administration of gadolinium. Blinded MRI interpretation was performed independently by two neuroradiologists. MRI results were correlated with data collected from chart review. Enhancement of the cauda equina was seen in 11 of 16 CIDP patients (69%), and in none of 13 control subjects. Nerve roots were enlarged, most significantly in the extraforaminal region, in three CIDP patients, and in one patient with Charcot-Marie-Tooth type 1A. MRI findings did not correlate with disease activity and severity, nor with any clinical or laboratory features in patients with CIDP.