RESUMEN
BACKGROUND: To evaluate the efficacy of rituximab in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients not responding to conventional immune therapies. METHODS: An open-label, prospective exploratory study was conducted with intravenous rituximab on 17 CIDP patients who had not responded to at least two first-line therapies. The primary endpoint was to determine the proportion of patients who showed improvement 6 months after rituximab therapy. The percentage of responders to rituximab, along with a 95% CI, was reported and compared with the 30% response rate after other immunosuppressive drugs previously documented in the literature. RESULTS: 13 of the 17 treated patients (76.5%) showed improvement at 6 months (95% CI 50.1 to 93.2). Among the 14 patients who completed the 12-month follow-up (2 were lost to follow-up after showing improvement at months 8 and 10, and 1 deteriorated at 6 months), 13 (92.9%) demonstrated improvement at 12 months (95% CI 66.1 to 99.8). Nerve conduction parameters improved by at least 20% in two nerves in 6 out of 15 (40%) patients at 6 months and in 7 out of 13 (53.9%) at 12 months. None of the treated patients withdrew from the study due to side effects. There was a significant reduction of circulating CD19+ cells 15 days, 2, 6 and 12 months after treatment. CONCLUSION: Rituximab seems to be a safe therapy in most patients with CIDP not responding to conventional immune therapies. The high percentage of patients who improved in this study suggests a possible positive effect of rituximab which is worth investigating in future randomised controlled clinical trials. TRIAL REGISTRATION NUMBER: NCT05877040.
Asunto(s)
Factores Inmunológicos , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Rituximab , Humanos , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/tratamiento farmacológico , Rituximab/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Estudios Prospectivos , Adulto , Anciano , Factores Inmunológicos/uso terapéutico , Resultado del Tratamiento , Conducción Nerviosa/efectos de los fármacosRESUMEN
BACKGROUND: To investigate the utility of regular serum VEGF (sVEGF) levels assessment in the monitoring of POEMS syndrome. METHODS: We retrospectively reviewed data of 30 patients with POEMS syndrome whose sVEGF was tested regularly every 6 months. sVEGF levels after treatment were measured and correlated with disability (Overall Neuropathy Limitations Scale, ONLS), clinical impairment (measured with the modified Clinical Response Evaluation Scale, mCRES), and relapse-free survival. The ability of sVEGF to predict disease flares during remission and refractory disease was also analysed. RESULTS: Patients with normalised serum VEGF levels (< 1000 pg/ml) at 6 months showed prolonged relapse-free survival (at 3-year 94% for complete VEGF response, 57% partial, 0% none, p < 0.001) and greater later clinical improvement (median ΔmCRES complete VEGF response -5 vs partial -4, p = 0.019, and vs no VEGF response -2, p = 0.006). After remission, the sensitivity of 6-month sVEGF monitoring in predicting clinical relapse was 58% with a specificity of 100%. In patients refractory to treatment, the sensitivity in predicting further clinical worsening was 15%. In addition, in 25% of the patients in remission and 16% of those refractory to therapy, sVEGF levels only increased at the time of relapse. CONCLUSIONS: Regular sVEGF assessment is a valid biomarker in the prediction of disease reactivation in POEMS syndrome and was particularly useful during the phase of remission.
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Síndrome POEMS , Factor A de Crecimiento Endotelial Vascular , Humanos , Síndrome POEMS/diagnóstico , Estudios Retrospectivos , RecurrenciaRESUMEN
BACKGROUND AND PURPOSE: A diagnostic score was developed to discriminate anti-myelin-associated-glycoprotein (MAG) neuropathy from chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and applied it to patients with atypical anti-MAG neuropathy. METHODS: The clinical and electrophysiological features of patients with a diagnosis of typical anti-MAG neuropathy were compared to those of patients with a diagnosis of CIDP. The association of each feature with the diagnosis was assessed in the two groups. Features showing a significant association with the diagnosis were included in a multivariable logistic regression model and adjusted odds ratios were estimated for each feature. A score ranging from 1 to 3 was applied to each feature based on the magnitude of the estimated odds ratios. The score was then applied to patients with a clinical diagnosis of CIDP who also had high anti-MAG antibody titers (CIDP-MAG). RESULTS: Thirty-one anti-MAG neuropathy patients, 45 typical CIDP patients and 16 CIDP-MAG patients were included. Scores in anti-MAG antibody patients ranged from 1 to 5 and in CIDP patients from -7 to -1. Using the score, 4/16 CIDP-MAG patients were diagnosed to have anti-MAG neuropathy and 12/16 patients to have CIDP. Response to intravenous immunoglobulin in the CIDP-MAG patients classified as CIDP was similar to that of definite CIDP patients and higher than that of anti-MAG neuropathy patients. CONCLUSIONS: Our score allowed an accurate discrimination to be made, amongst patients with anti-MAG antibodies, of those affected by CIDP and the patients with anti-MAG neuropathy. This score may help proper treatment to be chosen for patients with anti-MAG antibodies with a CIDP-like presentation.
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Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Polirradiculoneuropatía , Humanos , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/terapia , Inmunoglobulina M , Inmunoglobulinas Intravenosas/uso terapéutico , Autoanticuerpos , Glicoproteína Asociada a Mielina , Polirradiculoneuropatía/tratamiento farmacológicoRESUMEN
OBJECTIVE: To investigate the frequency and clinical correlates of anti-nerve autoantibodies in an unselected series of Italian patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) METHODS: Sera from 276 CIDP patients fulfilling the EFNS/PNS criteria and included in the Italian CIDP database were examined for the presence of anti-nerve autoantibodies. Results were correlated with the clinical data collected in the database. RESULTS: Anti-neurofascin155 (NF155) antibodies were found in 9/258 (3.5%) patients, anti-contactin1 (CNTN1) antibodies in 4/258 (1.6%) patients, and anti-contactin-associated protein1 (Caspr1) in 1/197 (0.5%) patients, while none had reactivity to gliomedin or neurofascin 186. Predominance of IgG4 isotype was present in 7of the 9 examined patients. Anti-NF155 patients more frequently had ataxia, tremor, and higher CSF protein levels than antibody-negative patients. Anti-CNTN1 patients more frequently had a GBS-like onset, pain, and ataxia and had more severe motor impairment at enrollment than antibody-negative patients. They more frequently received plasmapheresis, possibly reflecting a less satisfactory response to IVIg or steroids. IgM antibodies against one or more gangliosides were found in 6.5% of the patients (17/260) and were more frequently directed against GM1 (3.9%). They were frequently associated with a progressive course, with a multifocal sensorimotor phenotype and less frequent cranial nerve involvement and ataxia. CONCLUSIONS: Anti-paranodal and anti-ganglioside antibodies are infrequent in patients with CIDP but are associated with some typical clinical association supporting the hypothesis that CIDP might be a pathogenically heterogeneous syndrome possibly explaining the different clinical presentations.
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Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Ataxia , Autoanticuerpos , Moléculas de Adhesión Celular , Contactina 1 , Humanos , Factores de Crecimiento Nervioso , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/epidemiologíaRESUMEN
Background Anti-ganglioside antibodies are currently used in the differential diagnosis of suspected immune-mediated neuropathies. In-house and increasingly used commercial assays seem to perform suboptimally, and comparative information on their analytical performance are essentially lacking. Born within the frame of guidelines and standardization activities by the Italian Association of Neuroimmunology, this external quality assessment scheme (EQAS) is a real-life snapshot of the laboratory diagnostics in this field. Methods The EQAS consisted of five surplus, anonymized serum samples from patients with clinically-defined neuropathies and two serum samples from healthy blood donors. Eight laboratories used commercial line-/dot-blots, seven in-house/commercial ELISAs (in addition, 13 laboratories tested a recently released ELISA by Bühlmann). Only high anti-ganglioside antibody reactivities were considered, in accordance with consolidated recommendations. Results Large variations in anti-ganglioside antibody profiles were observed, even, although to a lesser extent, within homogeneous classes of assays. Concordance between the profiles and clinical phenotypes was also partial. Conclusions Although conducted on a relatively small, but representative number of Italian laboratories, this EQAS shows a critical between-laboratory disagreement in the test results of anti-ganglioside antibodies. Also considering the trend for using certified assays in generalist laboratories, strong efforts toward standardization and the identification of the best method(s) for their determinations are compellingly needed.
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Autoanticuerpos/sangre , Enfermedades Autoinmunes/diagnóstico , Ensayo de Inmunoadsorción Enzimática/métodos , Gangliósidos/inmunología , Ensayo de Inmunoadsorción Enzimática/normas , Humanos , Italia , Laboratorios/normas , Control de CalidadRESUMEN
This document presents the guidelines for onconeural antibody testing that have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on paraneoplastic neurological syndromes, indications and limits of onconeural antibody testing, instructions for result interpretation, and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.
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Síndromes Paraneoplásicos del Sistema Nervioso/diagnóstico , Autoanticuerpos/inmunología , Autoanticuerpos/metabolismo , Humanos , Síndromes Paraneoplásicos del Sistema Nervioso/inmunología , Síndromes Paraneoplásicos del Sistema Nervioso/metabolismoRESUMEN
This document presents the guidelines for testing antibodies against neuronal surface antigens that have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on autoimmune encephalitis associated with antibodies against neuronal surface antigens, indications and limits of testing for such antibodies, instructions for result interpretation, and an agreed laboratory protocol (Appendix A) are reported for the communicative community of neurologists and clinical pathologists.
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Anticuerpos/metabolismo , Antígenos de Superficie/inmunología , Encefalitis/diagnóstico , Enfermedad de Hashimoto/diagnóstico , Proteínas del Tejido Nervioso/inmunología , Humanos , Modelos MolecularesRESUMEN
This document presents the guidelines for anti-ganglioside antibody testing that have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Main clinical information on dysimmune peripheral neuropathies, indications and limits of anti-ganglioside antibody testing, instructions for result interpretation, and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.
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Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Anticuerpos/metabolismo , Enfermedades Autoinmunes del Sistema Nervioso/complicaciones , Gangliósidos/inmunología , Humanos , Enfermedades del Sistema Nervioso Periférico/complicacionesRESUMEN
This document presents the guidelines for anti-myelin-associated glycoprotein (MAG) antibody testing that have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of sponsoring Italian Association of Neuroimmunology (AINI) congresses. The main clinical information on anti-MAG antibody polyneuropathy, indications and limits of anti-MAG antibody testing, instructions for result interpretation, and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.
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Autoanticuerpos , Glicoproteína Asociada a Mielina/inmunología , Polineuropatías/diagnóstico , Humanos , Polineuropatías/inmunologíaRESUMEN
This document presents the guidelines for the cerebrospinal fluid (CSF) analysis and the determination of oligoclonal bands (OCBs) as pivotal tests in neuroinflammatory pathologies of the central nervous system. The guidelines have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on the pathologies in which the CSF analysis is indicated, and, particularly, on those characterized by the presence of OCBs in the intrathecal compartment, indications and limits of CSF analysis and OCB determination, instructions for result interpretation, and agreed laboratory protocols (Appendix) are reported for the communicative community of neurologists and clinical pathologists.
Asunto(s)
Enfermedades Autoinmunes Desmielinizantes SNC/líquido cefalorraquídeo , Enfermedades Autoinmunes Desmielinizantes SNC/inmunología , Bandas Oligoclonales/líquido cefalorraquídeo , Humanos , Bandas Oligoclonales/análisisRESUMEN
BACKGROUND: Increased titres of serum IgM antibodies to GM1 ganglioside are often associated with multifocal motor neuropathy (MMN). Testing for IgM antibodies to other antigens including GM2, the mixture of GM1 and galactocerebroside (GM1/GalC) and the disulfated heparin disaccharide NS6S were reported to increase the sensitivity of antibody testing in MMN even if it is unclear whether the specificity and positive (PPV) or negative predictive value (NPV) for MMN were also affected. METHODS: We measured IgM antibodies to GM1, GM2, galactocerebroside, GM1/GalC and NS6S in 40 consecutive patients with MMN and 142 controls with other neuropathies or related diseases and compared their sensitivity, specificity and PPV for MMN. RESULTS: With the only exception of anti-GM2 and, partially, anti-NS6S antibodies, IgM antibodies to the antigens tested were more frequent in MMN than in controls. Increased titres of anti-GM1 IgM were found in 48% of MMN patients with a specificity of 93% and PPV for MMN of 66%. Anti-GM1/GalC antibodies were present in all anti-GM1 positive MMN patients and in 11 additional patients (28%) with MMN raising the sensitivity of antibody testing to 75%. The specificity (85%) and PPV (59%) for MMN was, however, moderately reduced compared to anti-GM1 IgM, even if they rose with increasing anti-GM1/GalC titres. IgM antibodies to GM2, NS6S and galactocerebroside were found in 8%, 23% and 60% of MMN patients but had a low specificity and PPV for MMN. CONCLUSIONS: Testing for anti-GM1/GalC IgM significantly increased the sensitivity of antibody testing in MMN compared to anti-GM1 alone (p=0.021) and may represent a preferred option for GM1 reactivity testing in MMN.
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Autoanticuerpos/inmunología , Gangliósido G(M1)/inmunología , Galactosilceramidas/inmunología , Inmunoglobulina M/inmunología , Polineuropatías/inmunología , Humanos , Inmunoglobulina M/sangre , Polineuropatías/diagnóstico , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Sensibilidad y EspecificidadAsunto(s)
Factores Inmunológicos/uso terapéutico , Lenalidomida/uso terapéutico , Síndrome POEMS/sangre , Síndrome POEMS/terapia , Trasplante de Células Madre , Factor A de Crecimiento Endotelial Vascular/sangre , Potenciales de Acción/fisiología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Conducción Nerviosa/fisiología , Síndrome POEMS/fisiopatología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Targeted immunotherapy combinations, including the anti-CD38 monoclonal antibody (MoAb) daratumumab, have shown promising results in patients with relapsed/refractory multiple myeloma (RRMM), leading to a considerable increase in progression-free survival. However, a large fraction of patients inevitably relapse. To understand this, we investigated 32 relapsed MM patients treated with daratumumab, lenalidomide, and dexamethasone (Dara-Rd; NCT03848676). We conducted an integrated analysis using whole-genome sequencing (WGS) and flow cytometry in patients with RRMM. WGS before and after treatment pinpointed genomic drivers associated with early progression, including RPL5 loss, APOBEC mutagenesis, and gain of function structural variants involving MYC and chromothripsis. Flow cytometry on 202 blood samples, collected every 3 months until progression for 31 patients, revealed distinct immune changes significantly impacting clinical outcomes. Progressing patients exhibited significant depletion of CD38-positive NK cells, persistence of T-cell exhaustion, and reduced depletion of regulatory T cells over time. These findings underscore the influence of immune composition and daratumumab-induced immune changes in promoting MM resistance. Integrating genomics and flow cytometry unveiled associations between adverse genomic features and immune patterns. Overall, this study sheds light on the intricate interplay between genomic complexity and the immune microenvironment driving resistance to Dara-Rd in patients with RRMM.
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Anticuerpos Monoclonales , Resistencia a Antineoplásicos , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Mieloma Múltiple/inmunología , Anticuerpos Monoclonales/uso terapéutico , Femenino , Masculino , Dexametasona/uso terapéutico , Dexametasona/farmacología , Anciano , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Lenalidomida/uso terapéutico , Lenalidomida/farmacología , Genómica/métodosRESUMEN
In the last years, the tumor microenvironment (TME) has emerged as a promising target for therapeutic interventions in cancer. Cancer cells are highly dependent on the TME to growth and evade the immune system. Three major cell subpopulations are facing each other in the TME: cancer cells, immune suppressor cells, and immune effector cells. These interactions are influenced by the tumor stroma which is composed of extracellular matrix, bystander cells, cytokines, and soluble factors. The TME can be very different depending on the tissue where cancer arises as in solid tumors vs blood cancers. Several studies have shown correlations between the clinical outcome and specific patterns of TME immune cell infiltration. In the recent years, a growing body of evidence suggests that unconventional T cells like natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) cells, and γδ T cells are key players in the protumor or antitumor TME commitment in solid tumors and blood cancers. In this review, we will focus on γδ T cells, especially Vγ9Vδ2 T cells, to discuss their peculiarities, pros, and cons as potential targets of therapeutic interventions in blood cancers.
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Neoplasias Hematológicas , Neoplasias , Humanos , Receptores de Antígenos de Linfocitos T gamma-delta , Inmunoterapia , Linfocitos T CD8-positivos/patología , Microambiente TumoralRESUMEN
Anti-CD38 antibody therapies have transformed multiple myeloma (MM) treatment. However, a large fraction of patients inevitably relapses. To understand this, we investigated 32 relapsed MM patients treated with daratumumab, lenalidomide, and dexamethasone (Dara-Rd; NCT03848676 ). Whole genome sequencing (WGS) before and after treatment pinpointed genomic drivers associated with early progression, including RPL5 loss and APOBEC mutagenesis. Flow cytometry on 202 blood samples, collected every three months until progression for 31 patients, revealed distinct immune changes significantly impacting clinical outcomes. Progressing patients exhibited significant depletion of CD38+ NK cells, persistence of T cell exhaustion, and reduced depletion of T-reg cells over time. These findings underscore the influence of immune composition and daratumumab-induced immune changes in promoting MM resistance. Integrating genomics and flow cytometry unveiled associations between adverse genomic features and immune patterns. Overall, this study sheds light on the intricate interplay between genomic complexity and the immune microenvironment driving resistance to Dara-Rd.
RESUMEN
POEMS syndrome is a rare paraneoplastic condition associated to an underlying plasmacellular dyscrasia. The pathogenesis of POEMS is poorly understood, but overproduction of VEGF, probably secreted by clonal plasma cells, is thought to be responsible for the signs and symptoms of the syndrome, and it seems to be useful for the monitoring of the response to therapy. At present, an effective therapeutic option for the patients is represented by autologous peripheral blood stem-cell transplantation (aPBSCT), although relapses have been described, and there is an important morbidity associated with this procedure. Before the implementation of aPBSCT, the clinical course of POEMS syndrome was characterized by progressive polyneuropathy potentially leading to death for respiratory failure. Given the high serum and plasma levels of VEGF observed in POEMS patients, the use of anti-angiogenetic drugs such as thalidomide and lenalidomide and other drugs with anti-VEGF and anti-TNF effect such as bortezomib have been considered to treat this syndrome. There are evidences of lenalidomide benefit in both front-line and previously treated patients, but scanty data are available about its use for relapse after aPBSCT. Here, we report the successful use of lenalidomide in a patient who relapsed after aPBSCT.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Síndrome POEMS/tratamiento farmacológico , Trasplante de Células Madre de Sangre Periférica , Terapia Recuperativa , Inhibidores de la Angiogénesis/administración & dosificación , Biomarcadores de Tumor/sangre , Terapia Combinada , Ciclofosfamida/administración & dosificación , Dexametasona/administración & dosificación , Humanos , Húmero/patología , Húmero/efectos de la radiación , Factores Inmunológicos/administración & dosificación , Lenalidomida , Masculino , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Mieloma Múltiple/radioterapia , Mieloma Múltiple/cirugía , Osteosclerosis/etiología , Osteosclerosis/radioterapia , Síndrome POEMS/etiología , Síndrome POEMS/cirugía , Prednisolona/administración & dosificación , Recurrencia , Talidomida/administración & dosificación , Talidomida/análogos & derivados , Trasplante AutólogoRESUMEN
Myeloid derived suppressors cells (MDSC) play major roles in regulating immune homeostasis and immune responses in many conditions, including cancer. MDSC interact with cancer cells within the tumor microenvironment (TME) with direct and indirect mechanisms: production of soluble factors and cytokines, expression of surface inhibitory molecules, metabolic rewiring and exosome release. The two-way relationship between MDSC and tumor cells results in immune evasion and cancer outgrowth. In multiple myeloma (MM), MDSC play a major role in creating protumoral TME conditions. In this minireview, we will discuss the interplay between MDSC and MM TME and the possible strategies to target MDSC.
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Mieloma Múltiple , Células Supresoras de Origen Mieloide , Humanos , Microambiente Tumoral , Terapia de Inmunosupresión , Citocinas/metabolismoRESUMEN
Introduction: Bone marrow (BM) Vγ9Vδ2 T cells are intrinsically predisposed to sense the immune fitness of the tumor microenvironment (TME) in multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS). Methods: In this work, we have used BM Vγ9Vδ2 T cells to interrogate the role of the immune checkpoint/immune checkpoint-ligand (ICP/ICP-L) network in the immune suppressive TME of MM patients. Results: PD-1+ BM MM Vγ9Vδ2 T cells combine phenotypic, functional, and TCR-associated alterations consistent with chronic exhaustion and immune senescence. When challenged by zoledronic acid (ZA) as a surrogate assay to interrogate the reactivity to their natural ligands, BM MM Vγ9Vδ2 T cells further up-regulate PD-1 and TIM-3 and worsen TCR-associated alterations. BM MM Vγ9Vδ2 T cells up-regulate TIM-3 after stimulation with ZA in combination with αPD-1, whereas PD-1 is not up-regulated after ZA stimulation with αTIM-3, indicating a hierarchical regulation of inducible ICP expression. Dual αPD-1/αTIM-3 blockade improves the immune functions of BM Vγ9Vδ2 T cells in MM at diagnosis (MM-dia), whereas single PD-1 blockade is sufficient to rescue BM Vγ9Vδ2 T cells in MM in remission (MM-rem). By contrast, ZA stimulation induces LAG-3 up-regulation in BM Vγ9Vδ2 T cells from MM in relapse (MM-rel) and dual PD-1/LAG-3 blockade is the most effective combination in this setting. Discussion: These data indicate that: 1) inappropriate immune interventions can exacerbate Vγ9Vδ2 T-cell dysfunction 2) ICP blockade should be tailored to the disease status to get the most of its beneficial effect.
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Mieloma Múltiple , Humanos , Receptor 2 Celular del Virus de la Hepatitis A , Médula Ósea , Receptor de Muerte Celular Programada 1 , Recurrencia Local de Neoplasia , Ácido Zoledrónico/farmacología , Linfocitos T/patología , Receptores de Antígenos de Linfocitos T , Microambiente TumoralRESUMEN
Antibodies to several nerve antigens have been reported in patients with chronic immune-mediated demyelinating neuropathies including chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, and IgM paraproteinemic demyelinating polyneuropathy. The association of some reactivities with specific neuropathies, such as IgM antibodies to the myelin-associated glycoprotein in neuropathy associated with IgM monoclonal gammopathy, permitted to cast some light in their pathogenetic mechanisms and introduced new useful tools in their diagnosis. Other antibodies have been variably associated with other forms of neuropathy or with neuropathy itself, casting some doubts on their diagnostic relevance in the workout of these neuropathies. This is particularly true for IgM antibodies to glycolipids, including ganglioside and sulfatides, whose possible role in immune-mediated neuropathies is still debated and will be here reviewed.