ABSTRACT
Objectives: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated neuropathy defined by clinical progression for more than 2 months. 16-20% of CIDP patients may present with rapidly progressive weakness that resembles GBS, known as acute-onset CIDP (A-CIDP). However, it is challenging to distinguish from GBS-TRF because of their similar clinical symptom and features. In this case review, we report a patient with A-CIDP with the detection of anti-GM3 and anti-sulfatides antibodies, which rarely have been in A-CIDP and may account for her progressive and recurrent symptoms. Methods: We analyzed existing medical literature and described a clinical case of A-CIDP with antibodies positive. Results: We reported a 56-year-old female presented with bilateral lower extremity weakness and distal numbness. She experienced similar symptoms four times and responded well to the IVIg therapy. Lumbar puncture demonstrated albumin-cytologic dissociation and EDX examination revealed multiple peripheral nerve damage. After ruling out other demyelination diseases, a diagnosis of A-CIDP was made. Discussion: The antiganglioside and anti-sulfatide antibodies are involved in CIDP pathogenesis and can help to distinguish A-CIDP and other variants. To prevent secondary damage, it is important to monitor relapse and remission symptoms along the treatment line. A rare case of A-CIDP is discussed concerning the detection of anti-GM3 and anti-sulfatides antibodies, thus making a retrospective comparison of antibodies in some literature to understand A-CIDP better.
Subject(s)
Autoantibodies , G(M3) Ganglioside , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating , Humans , Female , Middle Aged , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/immunology , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/blood , Autoantibodies/blood , Autoantibodies/immunology , G(M3) Ganglioside/immunology , G(M3) Ganglioside/analogs & derivatives , Sulfoglycosphingolipids/immunology , Immunoglobulins, Intravenous/therapeutic use , Diagnosis, DifferentialABSTRACT
Background: Contactin-1 (CNTN1) antibody-positive nodopathy is rare and exhibits distinct clinical symptoms such as tremors and ataxia. However, the mechanisms of these symptoms and the characteristics of the cerebral spinal fluid (CSF) remain unknown. Case presentation: Here, we report a case of recurrent CNTN1 antibody-positive nodopathy. Initially, a 45-year-old woman experiencing numbness in the upper limbs and weakness in the lower limbs was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Eleven years later, her symptoms worsened, and she began to experience tremors and ataxia. Tests for serum CNTN1, GT1a, and GQ1b antibodies returned positive. Subsequently, she was diagnosed with CNTN1 antibody-positive nodopathy and underwent plasmapheresis therapy, although the treatment's efficacy was limited. To gain a deeper understanding of the disease, we conducted a comprehensive literature review, identifying 52 cases of CNTN1 antibody-positive nodopathy to date, with a tremor prevalence of 26.9%. Additionally, we found that the average CSF protein level in CNTN1 antibody-positive nodopathy was 2.57 g/L, with 87% of patients exhibiting a CSF protein level above 1.5 g/L. Conclusion: We present a rare case of recurrent CNTN1 antibody-positive nodopathy. Our findings indicate a high prevalence of tremor (26.9%) and elevated CSF protein levels among patients with CNTN1 antibody-positive nodopathy.
Subject(s)
Autoantibodies , Contactin 1 , Humans , Female , Middle Aged , Autoantibodies/blood , Autoantibodies/immunology , Contactin 1/immunology , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/immunology , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/therapy , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/blood , Recurrence , Tremor/immunology , Tremor/etiology , PlasmapheresisABSTRACT
BACKGROUND: To investigate Ranvier's autoantibodies prevalence and isotypes in various peripheral neuropathy variants, compare clinical features between seronegative and seropositive patients, and elucidate immune mechanisms underlying antibody generation. METHODS: Antibodies against anti-neurofascin-155 (NF155), NF186, contactin-1 (CNTN1), CNTN2, contactin-associated protein 1 (CASPR1), and CASPR2 were identified through cell-based assays. Plasma cytokines were analyzed in anti-NF155 antibody-positive chronic inflammatory demyelinating polyneuropathy (NF155+ CIDP) and Ranvier's antibodies-negative CIDP (Ab- CIDP) patients using a multiplexed fluorescent immunoassay, validated in vitro in a cell culture model. RESULTS: In 368 plasma samples, 50 Ranvier's autoantibodies were found in 45 individuals, primarily in CIDP cases (25 out of 69 patients) and in 10 out of 122 Guillain-Barré syndrome patients. Anti-NF155 and CNTN1-IgG were exclusive to CIDP. Fourteen samples were NF155-IgG, primarily IgG4 subclass, linked to CIDP features including early onset, tremor, sensory disturbance, elevated CSF protein, prolonged motor latency, conduction block, and poor treatment response. NF155-IgG had low sensitivity (20.28%) but high specificity (100%) for CIDP, rising to 88.88% with tremor and prolonged motor latency. Cytokine profiling in NF155+ CIDP revealed distinct immune responses involving helper T cells, toll-like receptor pathways. Some NF155+ CIDP patients had circulating NF155-specific B cells producing NF155-IgG without antigen presence, suggesting therapeutic potential. CONCLUSION: The study emphasizes the high specificity and sensitivity of NF155-IgG for diagnosing CIDP characterized by distinctive features. Further investigation into circulating NF155-specific B cell phenotypes may pave the way for B cell directed therapy.
Subject(s)
Autoantibodies , Cell Adhesion Molecules , Nerve Growth Factors , Phenotype , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating , Humans , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/blood , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/immunology , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis , Male , Female , Cell Adhesion Molecules/blood , Cell Adhesion Molecules/immunology , Nerve Growth Factors/immunology , Nerve Growth Factors/blood , Middle Aged , Autoantibodies/blood , Aged , Adult , Cytokines/blood , Ranvier's Nodes/immunology , Contactin 1/immunologyABSTRACT
Advances in the understanding of cytokines have revolutionized mechanistic treatments for chronic inflammatory and autoimmune diseases, as exemplified by rheumatoid arthritis. We conducted a systematic literature review on the role of cytokines and chemokines in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN). Ovid Medline, EMBASE and Web of Science were searched until August 31, 2022 for human studies investigating cytokines levels in CIDP or MMN. Fifty-five articles on 1061 CIDP patients and 86 MMN patients were included, with a median of 18 patients per study (range 3-71). Studies differed in the inclusion criteria, type of assay, manufacturer, control subjects, and tested biological material. Only a minority of studies reported data on disease activity. Interleukin (IL)-6, IL-17, CXCL10, and tumor necrosis factor alpha (TNF-α), were elevated in CIDP compared to controls in most of the studies. IL-6 and TNF-α levels are also correlated with disability. In MMN patients, IL-1Ra was elevated in the majority of the reports. While acknowledging the challenges in comparing studies and the various limitations of the studies, including small patient numbers, particularly in MMN, our review suggests that IL-6, IL-17, CXCL10, and TNF-α might play a role in CIDP pathogenesis. Larger studies are needed in MMN.
Subject(s)
Cytokines , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating , Humans , Chemokines/blood , Cytokines/blood , Polyneuropathies/physiopathology , Polyneuropathies/blood , Polyneuropathies/immunology , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/physiopathology , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/bloodSubject(s)
Autoantibodies , Contactin 1 , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating , Humans , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/drug therapy , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/immunology , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/blood , Autoantibodies/blood , Autoantibodies/immunology , Contactin 1/immunology , Male , Female , Middle Aged , Adrenal Cortex Hormones/therapeutic use , AdultABSTRACT
B-cell activating factor (BAFF) is a crucial cytokine for differentiation and survival of B-cells and correlates to disease activity in some auto-immune diseases. To evaluate BAFF as a biomarker for disease activity in chronic inflammatory demyelinating polyneuropathy (CIDP), serum BAFF levels were measured at varying disease stages: patients starting treatment, patients starting treatment withdrawal, patients in remission and healthy controls. Serum BAFF levels were elevated in patients compared to healthy controls, but did not differ between patients starting treatment and patients in remission. Serum BAFF levels did not change with or predict treatment response or relapse. Serum BAFF is not a responsive biomarker reflecting disease activity in CIDP.
Subject(s)
B-Cell Activating Factor , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating , Humans , B-Cell Activating Factor/blood , Biomarkers/blood , Cytokines , Interleukin-4 , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/blood , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/immunologySubject(s)
Immunoglobulin G4-Related Disease/immunology , Methylprednisolone/therapeutic use , Optic Nerve/pathology , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/drug therapy , Humans , Male , Middle Aged , Muscle Weakness/etiology , Neural Conduction , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/blood , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/immunologyABSTRACT
OBJECTIVE: To investigate whether serum levels of contactin-1, a paranodal protein, correlate with paranodal injury as seen in patients with CIDP with antibodies targeting the paranodal region. METHODS: Serum contactin-1 levels were measured in 187 patients with CIDP and 222 healthy controls. Paranodal antibodies were investigated in all patients. RESULTS: Serum contactin-1 levels were lower in patients (N = 41) with paranodal antibodies compared with patients (N = 146) without paranodal antibodies (p < 0.01) and showed good discrimination between these groups (area under the curve 0.84; 95% CI: 0.76-0.93). CONCLUSIONS: These findings suggest that serum contactin-1 levels have the potential to serve as a possible diagnostic biomarker of paranodal injury in CIDP. CLASSIFICATION OF EVIDENCE: This study provides class II evidence that serum contactin-1 levels can discriminate between patients with CIDP with or without paranodal antibodies with a sensitivity of 71% (95% CI: 56%-85%) and a specificity of 97% (95% CI: 83%-100%).
Subject(s)
Contactin 1/blood , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/blood , Aged , Biomarkers/blood , Cross-Sectional Studies , Female , Humans , Male , Middle AgedABSTRACT
OBJECTIVE: To discover systemic characteristics in the repertoires of targeted autoantigens in chronic inflammatory demyelinating polyneuropathy (CIDP), we detected the entire autoantigen repertoire of patients and controls and analyzed them systematically. METHODS: We screened 43 human serum samples, of which 22 were from patients with CIDP, 12 from patients with other neuropathies, and 9 from healthy controls via HuProt Human Proteome microarrays testing about 16,000 distinct human bait proteins. Autoantigen repertoires were analyzed via bioinformatical autoantigenomic approaches: principal component analysis, analysis of the repertoire sizes in disease groups and clinical subgroups, and overrepresentation analyses using Gene Ontology and PantherDB. RESULTS: The autoantigen repertoires enabled the identification of a subgroup of 10/22 patients with CIDP with a younger age at onset and a higher frequency of mixed motor and sensory CIDP. IV immunoglobulin therapy responders targeted 3 times more autoantigens than nonresponders. No CIDP-specific autoantibody is present in all patients; however, anchoring junction components were significantly targeted by 86.4% of patients with CIDP. There are potential novel CIDP-specific autoantigens such as the myelination- or axo-glial structure-related proteins actin-related protein 2/3 complex subunit 1B, band 4.1-like protein 2, cadherin-15, cytohesin-1, epidermal growth factor receptor, ezrin, and radixin. CONCLUSIONS: The repertoire of targeted autoantigens of patients with CIDP differs in a systematic degree from those of controls. Systematic autoantigenomic approaches can help to understand the disease and to discover novel bioinformatical tools and novel autoantigen panels to improve diagnosis, treatment, prognosis, or patient stratification.
Subject(s)
Autoantibodies/genetics , Autoantigens/genetics , Genomics/methods , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/genetics , Aged , Autoantibodies/blood , Autoantigens/blood , Case-Control Studies , Female , Humans , Male , Middle Aged , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/blood , Retrospective StudiesABSTRACT
Autoimmune diseases are frequently associated with autoantibodies. Recently, large sets of autoantibody-targeted antigens ("autoantigen-omes") of patient and control sera have been revealed, enabling autoantigen-omic approaches. However, statistical standards for defining such autoantigen-omes are lacking. The z-score indicates how many standard deviations an antigen reactivity of a given sample is from the mean reactivity of the corresponding antigen in a reference group. Hence, it is a common measure to define significantly positive reactivity in autoantigen profiling approaches. Here, we address the risk of biased analyses resulting from unbalanced selection of the reference group. Three study groups were selected. Patients-of-interest were chronic inflammatory demyelinating polyneuropathy (CIDP); controls were other neuropathies (ONP); and healthy controls (HC). Each serum was screened for significant autoantigen reactivity using HuProt™ protein arrays. We compared three possible selections of reference groups for statistical z-score calculations: method#1, the control groups (ONPâ¯+â¯HC); method #2, all groups together; method #3, the respective other groups (e.g., CIDPâ¯+â¯HC for the ONP autoantigen-ome). The method selection seriously affected the size of the autoantigen-omes. Method #1 introduced a bias favoring significantly more antigens per patient in the CIDP group (for z >4: 19⯱â¯3 antigens) than in the control groups (ONP: 2⯱â¯1; HC: 0⯱â¯0). The more balanced methods #2 and #3 did not result in significant differences. This contribution may help to avoid interpretation biases and to develop guidelines for population studies revealing autoantigen-omes via high throughput studies such as protein microarrays, immunoprecipitation with mass spectrometry, or phage display assays.
Subject(s)
Antigen-Antibody Complex/blood , Antigens/blood , Autoantibodies/blood , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/blood , Protein Array Analysis , Aged , Antigen-Antibody Complex/immunology , Antigens/immunology , Autoantibodies/immunology , Female , Humans , Male , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/immunologyABSTRACT
Interleukin (IL)-34 is ligand for the colony-stimulating factor (CSF)-1 receptor. This cytokine has fundamental roles the pathogenesis of a number of autoimmune and neurologic disorders. However, its role in the pathogenesis of acute and chronic inflammatory demyelinating polyneuropathies (AIDP and CIDP) has not been assessed yet. We measured serum levels of IL-34 33 CIDP cases, 16 AIDP cases, and 33 control subjects using commercial ELISA kits. IL-34 levels were significantly higher in both AIDP (44.87 ± 4.38) and CIDP (44.87 ± 4.38) groups compared with healthy subjects (30.10 ± 1.05) (P = 0.046 and P = 0.01, respectively). Differences between female subgroups were insignificant. However, levels of this cytokine were significantly higher in male subjects with CIDP compared with male controls (P = 0.042). Thus, levels of this cytokine might be regarded as biomarkers for these kinds of autoimmune disorders. Future studies are needed to verify these results and find the molecular mechanism of participation of IL-34 in the pathogenesis of AIDP/CIDP.
Subject(s)
Guillain-Barre Syndrome/blood , Interleukins/blood , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/blood , Biomarkers , Case-Control Studies , Female , Guillain-Barre Syndrome/immunology , Humans , Interleukins/physiology , Male , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/immunology , Sex CharacteristicsABSTRACT
OBJECTIVE: To assess whether IV immunoglobulins (IVIgs) as a first-line treatment for chronic inflammatory demyelinating polyneuropathy (CIDP) have a regulative effect on natural killer (NK) cells that is related to clinical responsiveness to IVIg. METHODS: In a prospective longitudinal study, we collected blood samples of 29 patients with CIDP before and after initiation of IVIg treatment for up to 6 months. We used semiquantitative PCR and flow cytometry in the peripheral blood to analyze the effects of IVIg on the NK cells. The results were correlated with clinical aspects encompassing responsiveness. RESULTS: We found a reduction in the expression of several typical NK cell genes 1 day after IVIg administration. Flow cytometry furthermore revealed a reduced cytotoxic CD56dim NK cell population, whereas regulatory CD56bright NK cells remained mostly unaffected or were even increased after IVIg treatment. Surprisingly, the observed effects on NK cells almost exclusively occurred in IVIg-responsive patients with CIDP. CONCLUSIONS: The correlation between the altered NK cell population and treatment efficiency suggests a crucial role for NK cells in the still speculative mode of action of IVIg treatment. Analyzing NK cell subsets after 24 hours of treatment initiation appeared as a predictive marker for IVIg responsiveness. Further studies are warranted investigating the potential of NK cell status as a routine parameter in patients with CIDP before IVIg therapy. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that NK cell markers predict clinical response to IVIg in patients with CIDP.
Subject(s)
Immunoglobulins, Intravenous/pharmacology , Immunologic Factors/pharmacology , Killer Cells, Natural/drug effects , Outcome Assessment, Health Care , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/blood , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/drug therapy , Adult , Aged , Biomarkers , CD56 Antigen , Female , Humans , Killer Cells, Natural/metabolism , Longitudinal Studies , Male , Middle AgedABSTRACT
OBJECTIVE: Subcutaneous immunoglobulin (SCIg) administered through infusion pump has been reported as effective in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients. In this study we evaluate an alternative technique of SCIg administration, based on the delivery of lower volumes administered daily using manual push technique (MPT) in 10 CIDP patients. METHODS: In this randomized, controlled, two-arm, crossover clinical trial, CIDP patients were randomly assigned 1:1 to receive SCIg either by MPT or pumps for 4 consecutive months with crossover to the other. The primary objective was to assess whether MPT had the same effectiveness as pumps. The secondary objectives were to assess whether MPT resulted in greater plasma IgG levels and improved quality of life (QoL). RESULTS: Ten patients (mean ageâ¯=â¯48.3) were enrolled. No significant changes were observed in the efficacy parameters (INCAT, MRC, R-ODS, and GS scales). A positive mean variation of 5.4 % in plasma IgG levels in the group treated with MPT was observed at the end of MPT periods. Treatment interference, which is one of the dimensions of the Life Quality Index, showed a significant improvement in the MPT periods. CONCLUSION: In CIDP patients, the MPT technique was as effective as pump infusion, allowed comparable, slightly increases plasma IgG levels, and also improved the QoL.
Subject(s)
Immunoglobulin G/administration & dosage , Immunoglobulin G/blood , Infusion Pumps , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/blood , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/drug therapy , Proof of Concept Study , Adult , Aged , Cross-Over Studies , Drug Administration Routes , Female , Humans , Injections, Subcutaneous , Male , Middle Aged , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosisABSTRACT
OBJECTIVE: To determine whether IgG subclasses of antiparanodal autoantibodies are related to disease course and treatment response in acute- to subacute-onset neuropathies, we retrospectively screened 161 baseline serum/CSF samples and 66 follow-up serum/CSF samples. METHODS: We used ELISA and immunofluorescence assays to detect antiparanodal IgG and their subclasses and titers in serum/CSF of patients with Guillain-Barré syndrome (GBS), recurrent GBS (R-GBS), Miller-Fisher syndrome, and acute- to subacute-onset chronic inflammatory demyelinating polyradiculoneuropathy (A-CIDP). We evaluated clinical data retrospectively. RESULTS: We detected antiparanodal autoantibodies with a prevalence of 4.3% (7/161), more often in A-CIDP (4/23, 17.4%) compared with GBS (3/114, 2.6%). Longitudinal subclass analysis in the patients with GBS revealed IgG2/3 autoantibodies against Caspr-1 and against anti-contactin-1/Caspr-1, which disappeared at remission. At disease onset, patients with A-CIDP had IgG2/3 anti-Caspr-1 and anti-contactin-1/Caspr-1 or IgG4 anti-contactin-1 antibodies, IgG3 being associated with good response to IV immunoglobulins (IVIg). In the chronic phase of disease, IgG subclass of one patient with A-CIDP switched from IgG3 to IgG4. CONCLUSION: Our data (1) confirm and extend previous observations that antiparanodal IgG2/3 but not IgG4 antibodies can occur in acute-onset neuropathies manifesting as monophasic GBS, (2) suggest association of IgG3 to a favorable response to IVIg, and (3) lend support to the hypothesis that in some patients, an IgG subclass switch from IgG3 to IgG4 may be the correlate of a secondary progressive or relapsing course following a GBS-like onset.
Subject(s)
Autoantibodies , Cell Adhesion Molecules, Neuronal/immunology , Contactin 1/immunology , Guillain-Barre Syndrome , Immunoglobulin G , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating , Adult , Autoantibodies/blood , Autoantibodies/cerebrospinal fluid , Autoantibodies/immunology , Follow-Up Studies , Guillain-Barre Syndrome/blood , Guillain-Barre Syndrome/cerebrospinal fluid , Guillain-Barre Syndrome/immunology , Humans , Immunoglobulin G/blood , Immunoglobulin G/cerebrospinal fluid , Immunoglobulin G/immunology , Miller Fisher Syndrome/blood , Miller Fisher Syndrome/cerebrospinal fluid , Miller Fisher Syndrome/immunology , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/blood , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/cerebrospinal fluid , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/immunology , Retrospective StudiesABSTRACT
We herein to describe the response and the potential treatment mechanism of low dose rituximab in patients with treatment-resistant chronic inflammatory demyelinating polyneuropathy (CIDP) with antibodies against neurofascin-155 (NF-155). Patients received 100 mg rituximab once weekly for 4 weeks followed by 100 mg per month for 2 additional doses. Clinical function scores, Fahn- Tolosa-Marin Tremor Rating Scale (FTMTRS) and flow cytometry of peripheral blood were scheduled before and at 1, 3, 6 months after rituximab treatment. All clinical function score including MRC, INCAT, Hughes, mRS, ODSS and FTMTRS scores showed obvious improvement at the post-treatment follow-up 1,3,6 months in comparison with baseline values. The proportion of CD19 + CD27+, CD19 + CD38+ and CD138 in lymphocytes of all patients declined at 1,3,6 month and the proportion of CD19 + CD24hiCD38hi in one patient was increased at 6 months after rituximab treatment. Low dose rituximab can significant improve disease severity and disabling tremor of CIDP patients with anti-NF155 antibody by the powerful role of B cell depletion within six months and subsequent reestablishment of B-cell subsets including increasing regulatory B cells, inhibiting memory B cells and reducing plasmablasts.
Subject(s)
Autoantibodies/blood , Cell Adhesion Molecules/blood , Immunologic Factors/administration & dosage , Nerve Growth Factors/blood , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/blood , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/drug therapy , Rituximab/administration & dosage , Adolescent , Adult , Dose-Response Relationship, Drug , Female , Follow-Up Studies , HEK293 Cells , Humans , Male , Middle Aged , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis , Treatment OutcomeABSTRACT
Immune-mediated neuropathies include some specific types such as acute and chronic inflammatory demyelinating polyneuropathy (AIDP and CIDP). Previous studies have demonstrated abnormal cellular or humoral immune responses in these conditions. Although aberrant regulation of several cytokines have been reported in AIDP and CIDP, the significance of interleukin 19 (IL-19) in these conditions have not been elucidated yet. In the current study, we assessed serum levels of IL-19 in 12 CIDP patients (female/male ratio, 4/8), 9 AIDP patients (female/male ratio, 3/6), and 27 normal subjects (female/male ratio. 8/19) using commercial ELISA kits. Notably, we detected higher levels of this cytokine in CIDP patients (136.4 ± 8.57 ng/l) compared with both AIDP patients (93.89 ± 2.26 ng/l) and controls (83.78 ± 1.72 ng/l). However, the differences between AIDP patients and controls were not significant. The current study demonstrates the role of IL-19 in the pathogenesis of CIDP and potentiates this cytokine as a biomarker for this condition.
Subject(s)
Interleukins/blood , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/blood , Biomarkers/blood , Female , Humans , MaleABSTRACT
To clarify the immunogenetic background of patients with immunoglobulin G (IgG)4 anti-neurofascin 155 (NF155) antibody-positive chronic inflammatory demyelinating polyneuropathy (CIDP), we genotyped the extended human leukocyte antigen (HLA) haplotypes in 22 Japanese patients with this disorder and compared them with those of healthy Japanese controls. All IgG4 anti-NF155 antibody-positive CIDP patients exclusively carried either HLA-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 HLA-DRB1*15, -DRB1*15:01, -DQB1*06:01/06:02, -DQB1*06:02, and -DRB1*15:01-DQB1*06:02 frequencies compared with healthy Japanese controls. These findings indicate the involvement of specific HLA class II molecules in the pathomechanisms of IgG4 anti-NF155 antibody-positive CIDP.
Subject(s)
Autoantibodies/genetics , Cell Adhesion Molecules/genetics , HLA Antigens/genetics , Haplotypes/genetics , Immunoglobulin G/genetics , Nerve Growth Factors/genetics , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/genetics , Adolescent , Adult , Aged , Asian People/genetics , Autoantibodies/blood , Cell Adhesion Molecules/blood , Female , HLA Antigens/blood , Humans , Immunoglobulin G/blood , Male , Middle Aged , Nerve Growth Factors/blood , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/blood , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis , Young AdultABSTRACT
OBJECTIVE: To assess the prevalence and isotypes of anti-nodal/paranodal antibodies to nodal/paranodal proteins in a large chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cohort, compare clinical features in seronegative vs seropositive patients, and gather evidence of their isotype-specific pathogenic role. METHODS: Antibodies to neurofascin-155 (Nfasc155), neurofascin-140/186 (Nfasc140/186), contactin-1 (CNTN1), and contactin-associated protein 1 (Caspr1) were detected with ELISA and/or cell-based assay. Antibody pathogenicity was tested by immunohistochemistry on skin biopsy, intraneural injection, and cell aggregation assay. RESULTS: Of 342 patients with CIDP, 19 (5.5%) had antibodies against Nfasc155 (n = 9), Nfasc140/186 and Nfasc155 (n = 1), CNTN1 (n = 3), and Caspr1 (n = 6). Antibodies were absent from healthy and disease controls, including neuropathies of different causes, and were mostly detected in patients with European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite CIDP (n = 18). Predominant antibody isotypes were immunoglobulin G (IgG)4 (n = 13), IgG3 (n = 2), IgG1 (n = 2), or undetectable (n = 2). IgG4 antibody-associated phenotypes included onset before 30 years, severe neuropathy, subacute onset, tremor, sensory ataxia, and poor response to intravenous immunoglobulin (IVIG). Immunosuppressive treatments, including rituximab, cyclophosphamide, and methotrexate, proved effective if started early in IVIG-resistant IgG4-seropositive cases. Five patients with an IgG1, IgG3, or undetectable isotype showed clinical features indistinguishable from seronegative patients, including good response to IVIG. IgG4 autoantibodies were associated with morphological changes at paranodes in patients' skin biopsies. We also provided preliminary evidence from a single patient about the pathogenicity of anti-Caspr1 IgG4, showing their ability to penetrate paranodal regions and disrupt the integrity of the Nfasc155/CNTN1/Caspr1 complex. CONCLUSIONS: Our findings confirm previous data on the tight clinico-serological correlation between antibodies to nodal/paranodal proteins and CIDP. Despite the low prevalence, testing for their presence and isotype could ultimately be part of the diagnostic workup in suspected inflammatory demyelinating neuropathy to improve diagnostic accuracy and guide treatment. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that antibodies to nodal/paranodal proteins identify patients with CIDP (sensitivity 6%, specificity 100%).
Subject(s)
Autoantibodies/blood , Cell Adhesion Molecules, Neuronal/immunology , Cell Adhesion Molecules/immunology , Contactin 1/immunology , Immunoglobulin G/classification , Nerve Growth Factors/immunology , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/blood , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/immunology , Adult , Female , Humans , MaleSubject(s)
Autoantibodies/blood , Complement System Proteins/metabolism , Gangliosides/blood , Macrophages/metabolism , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/blood , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis , Complement System Proteins/ultrastructure , Humans , Macrophages/ultrastructure , Male , Middle AgedABSTRACT
BACKGROUND: Pre-treatment screening for IgA deficiency and close monitoring of full blood count(FBC) and renal function is recommended with intravenous immunoglobulin(IVIg) therapy in neurological diseases. AIMS: To examine the frequency of biochemically defined and clinically significant episodes of treatment associated haemolysis, neutropenia, thrombocytopenia and acute kidney injury(AKI) in a cohort of patients on maintenance Immunoglobulin(Ig) therapy for inflammatory neuropathy. METHODS: A retrospective review of routine blood monitoring in patients from two UK specialist peripheral nerve centres. Accepted definitions for clinically and biochemically significant haemolysis, neutropenia, thrombocytopenia and AKI were used. RESULTS: 1919 infusion episodes in 90 patients were analysed. Age(mean(S.D))â¯=â¯58.09(14.4)years, 63% male, 72% CIDP(28% MMN), 97% IVIg(3% SCIg). Doseâ¯=â¯1.57(0.79)g/kg/month or 97.1(37.3)g/infusion, frequency:3.9(1.4) weeks. Relative IgA deficiency was noted in 2 individuals (prevalence:2.2%, 95%C.I.:0-5.2) who received a combined total of 38 infusions(3800â¯g IVIg) without adverse event. No clinically significant episodes of haemolysis, neutropenia, thrombocytopenia or AKI occurred in relation to treatment. An asymptomatic drop>10â¯g/L haemoglobin(Hb) occurred in 3.5%(95%CI:2.7-4.3) of treatment episodes in 38 individuals, mean reduction:17.7(7.4)g/L; lowest Hb:86â¯g/L. Lower pre-treatment haemoglobin correlated with risk of recurrent Ig-related drop(p:0.007). Two patients with chronic renal failure(stage 1 and 3) received 28(IV) and 104(SC) infusions respectively(6416â¯g) without impact on estimated glomerular filtration rate(eGFR). CONCLUSIONS: No clinically significant Ig-related episodes of haemolysis or AKI were identified in this representative cohort. This suggests that routine monitoring is not essential in long-term Ig use but should be considered when clinically indicated.