Autoreactive T cells target peripheral nerves in Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is a rare heterogenous disorder of the peripheral nervous system, which is usually triggered by a preceding infection, and causes a potentially life-threatening progressive muscle weakness1. Although GBS is considered an autoimmune disease, the mechanisms that underlie its distinct clinical subtypes remain largely unknown. Here, by combining in vitro T cell screening, single-cell RNA sequencing and T cell receptor (TCR) sequencing, we identify autoreactive memory CD4+ cells, that show a cytotoxic T helper 1 (TH1)-like phenotype, and rare CD8+ T cells that target myelin antigens of the peripheral nerves in patients with the demyelinating disease variant. We characterized more than 1,000 autoreactive single T cell clones, which revealed a polyclonal TCR repertoire, short CDR3ß lengths, preferential HLA-DR restrictions and recognition of immunodominant epitopes. We found that autoreactive TCRß clonotypes were expanded in the blood of the same patient at distinct disease stages and, notably, that they were shared in the blood and the cerebrospinal fluid across different patients with GBS, but not in control individuals. Finally, we identified myelin-reactive T cells in the nerve biopsy from one patient, which indicates that these cells contribute directly to disease pathophysiology. Collectively, our data provide clear evidence of autoreactive T cell immunity in a subset of patients with GBS, and open new perspectives in the field of inflammatory peripheral neuropathies, with potential impact for biomedical applications.

Variations of the perforin gene in patients with chronic inflammatory demyelinating polyradiculoneuropathy.

Perforin (PRF) has a key role in the function of cytotoxic T and natural killer cells. Rare variations of PRF1 predispose to autoimmunity. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system, involving defective lymphocyte apoptosis. The aim of this study was to investigate the role of PRF1 in CIDP. The entire coding region of PRF1 was sequenced in 94 patients and 158 controls. We found three missense variations leading to amino acid substitutions and one nonsense variation resulting in a premature stop codon. All variations would decrease PRF activity. Their overall frequency was significantly higher in patients than in controls (odds ratio (OR)=4.47). The most frequent variation was p.Ala91Val (OR=3.92) previously associated with other autoimmune diseases. Clinical analysis showed that PRF1 variations were more frequent in relapsing patients and in patients displaying axonal damage. These data suggest that PRF1 variations may influence CIDP development and course.

Progressive multifocal leucoencephalopathy after autologous bone marrow transplantation: a treatment option.

A patient with multiple myeloma was treated with high-dose chemotherapy followed by two autologous bone marrow transplantations (ABMTs). Nine months after the second ABMT the patient complained of severe left hemiparesis, paraesthesias, left homonymous visual field defects and gait ataxia. She was diagnosed with progressive multifocal leucoencephalopathy (PML) confirmed by detection of JC virus (JCV) DNA and prescribed cidofovir every other week and mirtazapine daily. Her symptoms and signs remained stable and after 6 months the JCV DNA was undetectable in the cerebrospinal fluid. Repeated MRI scans demonstrated the stabilisation of demyelinating lesion volume; after more than 2 years of follow-up the patient's neurological examination does not show significant variations. Combination of cidofovir and mirtazapine may be helpful in the treatment of PML in HIV-negative patients.

Neutralizing antibodies in multiple sclerosis patients treated with 375 micrograms interferon-beta-1b.

BACKGROUND: Neutralizing antibodies (NAbs) to IFN-beta may have a detrimental effect on treatment response, but increasing IFN-beta dose could reduce their occurrence. The OPTimization of Interferon for MS (OPTIMS) study was a multicenter trial investigating clinical and MRI outcomes with the approved IFN-beta-1b dose (250 microg) and a higher dose (375 microg), s.c. every other day. OBJECTIVE: To analyze the occurrence of NAbs and their effect on clinical and MRI response over a long-term (4-year) follow-up using cross-sectional and longitudinal statistical analysis. METHODS: Relapses or disease progression was assessed open-label and MRI scans were performed serially during the first year of the study. Neutralizing antibodies were measured using the MxA protein production neutralization assay. RESULTS: A total of 145 patients with relapsing-remitting multiple sclerosis from 14 centers participated in the study. Neutralizing antibody frequency was negatively associated with MRI treatment response, but no detrimental effect of NAbs on the clinical response was observed. Results obtained using cross-sectional or longitudinal statistical approaches were similar. Over the 4-year period, NAb-positive patients treated with 375 microg had a significantly greater probability of NAb disappearance (hazard ratio: 3.41; 95% confidence interval: 1.78 - 6.43; p < 0.01). CONCLUSION: Use of an IFN-beta-1b dose higher than the currently approved 250-microg dose is associated with an increased probability of NAb disappearance. The OPTIMS study was registered at ClinicalTrials.gov: NCT00473213.

MRI activity and neutralising antibody as predictors of response to interferon beta treatment in multiple sclerosis.

OBJECTIVE: To prospectively validate MRI activity and neutralising anti-interferon antibody (NAb) during the first 6 months of interferon beta treatment as response indicators in multiple sclerosis (MS). METHODS: Patients with relapsing-remitting MS were followed during the first 2 years of treatment. Neurological assessments were performed every 3 months or when a relapse was suspected. MRI scans performed at baseline and at 3, 4, 5 and 6 months after the start of treatment were assessed centrally for disease activity: new T2 or gadolinium enhancing T1 lesions. NAb were assessed using the MxA protein assay; positivity was defined as two consecutive titres >or=20 NU/ml. We evaluated the predictivity of an active scan, NAb positivity, or both, during the first 6 months of treatment, on the occurrence of clinical disease activity in the following 18 months. RESULTS: 147 patients were assessed at 16 centres. Predictivity parameters (with confidence intervals) were as follows: active scan, sensitivity (SN) 52% (34-69%), specificity (SP) 80% (65-91%), negative predictive value (NPV) 73% (58-77%), positive predictive value (PPV) 62% (42-79%), p = 0.002; NAb positivity, SN 71% (45-88%), SP 66% (55-76%), NPV 92% (82-97%), PPV 29% (16-45%), p = 0.01; active scan and NAb positivity, SN 71% (38-91%), SP 86% (73-94%), NPV 94% (86-98%), PPV 50% (29-70%), p = 0.0003. CONCLUSIONS: MRI activity and NAb occurrence during the first 6 months of interferon beta treatment were reliable predictors of long term clinical response, particularly when combined. Patients with negative predictors showed a less than 10% risk of developing clinical activity. Patients with positive predictors showed a 50% risk of further clinical activity. These patients need to be followed carefully with further MRI and NAb tests.