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The discovery that major histocompatibility complex (MHC) class I-related molecule 1 (MR1) presents microbial antigens to mucosal-associated invariant T (MAIT) cells was a significant scientific milestone in the last decade. Surveillance for foreign metabolically derived antigens added a new class of target structures for immune recognition. The recent identification of a second family of MR1-restricted T cells, called MR1T cells, which show self-reactivity suggests the microbial antigens characterized so far may only represent a handful of the potential structures presented by MR1. Furthermore, the reactivity of MR1T cells towards tumours and not healthy cells indicates tight regulation in the generation of self-antigens and in MR1 expression and antigen loading. These novel and exciting observations invite consideration of new perspectives of MR1-restricted antigen presentation and its wider role within immunity and disease.

SummaryMR1T lymphocytes are a recently identified population of T cells that recognize unknown self-antigens presented by the non-polymorphic MHC-I-related molecule, MR1. MR1T cells can kill tumor cells and modulate the functions of other immune cells with promising therapeutic applications. By integrating genetic, pharmacological and biochemical approaches we identified carbonyl stress and alterations of nucleobase metabolism in tumor target cells that promote recognition by MR1 T cells. We dissected these pathways and found that nucleobase adduct-containing metabolites are self-antigens stimulating MR1T cells. Several nucleobase adducts are presented by MR1 molecules and stimulate individual MR1T cells. Our data suggest that MR1T cells are surveyor of cellular metabolic alterations occurring in conditions of metabolic stress, such as cancer, and lay the groundwork for the development of novel HLA-unrestricted T cell-based therapies.

MR1 is an MHC class I-like molecule with unique structural and biological features that make it an important member among the molecules involved in antigen presentation to T cells. Distinctive features include ubiquitous expression of the MR1 gene and its monomorphism. Another relevant property is that the MR1 protein appears at very low levels on the plasma membrane and its surface expression is regulated by antigen binding. Finally, the nature of presented antigens differs from those that bind other presenting molecules and includes small metabolites of microbial and self-origin, small drugs and tumor-associated antigens. This opinion paper describes in detail some of those features and discusses recent literature in the field.

The family of non‐classical major histocompatibility complex (MHC) class‐I like CD1 molecules has an emerging role in human disease. Group 1 CD1 includes CD1a, CD1b and CD1c, which function to display lipids on the cell surface of antigen‐presenting cells for direct recognition by T‐cells. The recent advent of CD1 tetramers and the identification of novel lipid ligands has contributed towards the increasing number of CD1‐restricted T‐cell clones captured. These advances have helped to identify novel donor unrestricted and semi‐invariant T‐cell populations in humans and new mechanisms of T‐cell recognition. However, although there is an opportunity to design broadly acting lipids and harness the therapeutic potential of conserved T‐cells, knowledge of their role in health and disease is lacking. We briefly summarize the current evidence implicating group 1 CD1 molecules in infection, cancer and autoimmunity and show that although CD1 are not as diverse as MHC, recent discoveries highlight their versatility as they exhibit intricate mechanisms of antigen presentation.

BACKGROUND AND PURPOSE Sensory neuronopathy is a cardinal feature of cerebellar ataxia neuropathy vestibular areflexia syndrome (CANVAS). Having observed that two patients with CANVAS had small median and ulnar nerves on ultrasound, we set out to examine this finding systematically in a cohort of patients with CANVAS, and compare them with both healthy controls and a cohort of patients with axonal neuropathy. We have previously reported preliminary findings in seven of these patients with CANVAS and seven healthy controls. METHODS We compared the ultrasound cross-sectional area of median, ulnar, sural and tibial nerves of 14 patients with CANVAS with 14 healthy controls and 14 age- and gender-matched patients with acquired primarily axonal neuropathy. We also compared the individual nerve cross-sectional areas of patients with CANVAS and neuropathy with the reference values of our laboratory control population. RESULTS The nerve cross-sectional area of patients with CANVAS was smaller than that of both the healthy controls and the neuropathy controls, with highly significant differences at most sites (P < 0.001). Conversely, the nerve cross-sectional areas in the upper limb were larger in neuropathy controls than healthy controls (P < 0.05). On individual analysis, the ultrasound abnormality was sufficiently characteristic to be detected in all but one patient with CANVAS. DISCUSSION Small nerves in CANVAS probably reflect nerve thinning from loss of axons due to ganglion cell loss. This is distinct from the ultrasound findings in axonal neuropathy, in which nerve size was either normal or enlarged. Our findings indicate a diagnostic role for ultrasound in CANVAS sensory neuronopathy and in differentiating neuronopathy from neuropathy.

A 50-year-old female marine ecologist presented to the emergency department following 3 weeks of persistent headache, nausea, vomiting, disturbed vision, intermittent aural pulsations, unsteady gait and acroparesthesias. She had previously been healthy, specifically with no history of autoimmune disease. Mental status, vital signs and general medical examination were normal. Corrected visual acuity 6/60 right; 6/9 left. There were bilateral scotomata extending from the point of fixation towards the temporal field, worse on the right. She had a right afferent pupillary light defect. Funduscopy showed bilateral disc swelling with obscuration of vessels within the disc margins, without haemorrhage. Gait was slightly ataxic. There were no other abnormalities of the cranial nerves, motor or sensory examination. Haematology, chemistry and liver function tests were normal. Immunoglobulin (Ig)G 5.8 g/L (7.0–16.0) with IgA and IgM normal serum concentrations. Complement (C4) 0.18 g/L (0.2–0.6), with normal C3. Rheumatoid factor, anti-CCP IgG, antinuclear antibody, extractible nuclear antigen, anti-neutrophil cytoplasmic antibody (MPO+PR3), all normal. HIV and syphilis serology negative. Serum was negative for …

See Paisán-Ruiz and Jen (doi:10.1093/brain/awaa015) for a scientific commentary on this article. Cortese et al. describe the full disease phenotype, including progression of ataxia, in 100 confirmed carriers of RFC1 repeat expansions. RFC1 repeat expansion should be considered in all cases of sensory ataxic neuropathy, particularly if cerebellar dysfunction, vestibular involvement and cough coexist., Ataxia, causing imbalance, dizziness and falls, is a leading cause of neurological disability. We have recently identified a biallelic intronic AAGGG repeat expansion in replication factor complex subunit 1 (RFC1) as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and a major cause of late onset ataxia. Here we describe the full spectrum of the disease phenotype in our first 100 genetically confirmed carriers of biallelic repeat expansions in RFC1 and identify the sensory neuropathy as a common feature in all cases to date. All patients were Caucasian and half were sporadic. Patients typically reported progressive unsteadiness starting in the sixth decade. A dry spasmodic cough was also frequently associated and often preceded by decades the onset of walking difficulty. Sensory symptoms, oscillopsia, dysautonomia and dysarthria were also variably associated. The disease seems to follow a pattern of spatial progression from the early involvement of sensory neurons, to the later appearance of vestibular and cerebellar dysfunction. Half of the patients needed walking aids after 10 years of disease duration and a quarter were wheelchair dependent after 15 years. Overall, two-thirds of cases had full CANVAS. Sensory neuropathy was the only manifestation in 15 patients. Sixteen patients additionally showed cerebellar involvement, and six showed vestibular involvement. The disease is very likely to be underdiagnosed. Repeat expansion in RFC1 should be considered in all cases of sensory ataxic neuropathy, particularly, but not only, if cerebellar dysfunction, vestibular involvement and cough coexist.

Monocyte:lymphocyte ratio (M:L) has been identified as a risk factor in development of TB disease in children and those undergoing treatment for HIV in co-infected individuals. Retrospective analysis was performed using M:L data collected from TB modelling studies performed in Rhesus macaques of Indian genotype (RM), cynomolgus macaque of Chinese genotype (CCM) and cynomolgus macaque of Mauritian genotype (MCM), which found that the more susceptible populations (RM and MCM) had higher M:L ratios than the least susceptible population (CCM). Following Mycobacterium tuberculosis exposure, significant increases in M:L ratio were observed in susceptible RM and MCM within 12 weeks of TB infection, whereas M:L in CCM remained stable, suggesting that changes in M:L ratio may also act as a biomarker of TB disease progression. The frequency of PPD-specific interferon gamma (IFNγ) secreting cells (SFU) were compared, with the more susceptible macaque populations showing an association between M:L and IFNγ SFU frequency. Investigation of the genes associated with monocyte-derived antigen presenting cells revealed differences between RM and CCM, highlighting differences in their monocyte populations, as well as overall M:L ratio. Differences in M:L ratio between macaque populations could be used to explore immunological mechanisms in susceptible populations that would complement human population studies.

T lymphocytes expressing γδ T cell antigen receptors (TCRs) comprise evolutionarily conserved cells with paradoxical features. On the one hand, clonally expanded γδ T cells with unique specificities typify adaptive immunity. Conversely, large compartments of γδTCR+ intraepithelial lymphocytes (γδ IELs) exhibit limited TCR diversity and effect rapid, innate-like tissue surveillance. The development of several γδ IEL compartments depends on epithelial expression of genes encoding butyrophilin-like (Btnl (mouse) or BTNL (human)) members of the B7 superfamily of T cell co-stimulators. Here we found that responsiveness to Btnl or BTNL proteins was mediated by germline-encoded motifs within the cognate TCR variable γ-chains (Vγ chains) of mouse and human γδ IELs. This was in contrast to diverse antigen recognition by clonally restricted complementarity-determining regions CDR1–CDR3 of the same γδTCRs. Hence, the γδTCR intrinsically combines innate immunity and adaptive immunity by using spatially distinct regions to discriminate non-clonal agonist-selecting elements from clone-specific ligands. The broader implications for antigen-receptor biology are considered.

Background: We determined the mortality rates of motor neuron disease (MND) in New Zealand over 22 years from 1992 to 2013. Previous studies have found an unusually high and/or increasing incidence of MND in certain regions of New Zealand; however, no studies have examined MND rates nationwide to corroborate this. Methods: Death certificate data coded G12.2 by International Classification of Diseases (ICD)-10 coding, or 335.2 by ICD-9 coding were obtained. These codes specify amyotrophic lateral sclerosis, progressive bulbar palsy, or other motor neuron diseases as the underlying cause of death. Mortality rates for MND deaths in New Zealand were age-standardized to the European Standard Population and compared with rates from international studies that also examined death certificate data and were age-standardized to the same standard population. Results and Conclusion: The age-standardized mortality from MND in New Zealand was 2.3 per 100,000 per year from 1992–2007 and 2.8 per 100,000 per year from 2008–2013. These rates were 3.3 and 4.0 per 100,000 per year, respectively, for the population 20 years and older. The increase in rate between these two time periods was likely due to changes in MND death coding from 2008. Contrary to a previous regional study of MND incidence, nationwide mortality rates did not increase steadily over this time period once aging was accounted for. However, New Zealand MND mortality rate was higher than comparable studies we examined internationally (mean 1.67 per 100,000 per year), suggesting that further analysis of MND burden in New Zealand is warranted.

Correlates of immune protection that reliably predict vaccine efficacy against Mycobacterium tuberculosis (Mtb) infection are urgently needed. Invariant NKT cells (iNKTs) are CD1d-dependent innate T cells that augment host antimicrobial immunity through production of cytokines, including interferon (IFN)-γ and tumour necrosis factor (TNF)-α. We determined peripheral blood iNKT numbers, their proliferative responses and iNKT subset proportions after in vitro antigen expansion by α-galactosylceramide (αGC) in a large cohort of mycobacteria-naïve non-human primates, and macaques from Bacillus Calmette-Guerin (BCG) vaccine and Mtb challenge studies. Animals studied included four genetically distinct groups of macaques within cynomolgus and rhesus species that differ in their susceptibility to Mtb infection. We demonstrate significant differences in ex vivo iNKT frequency between groups, which trends towards an association with susceptibility to Mtb, but no significant difference in overall iNKT proliferative responses. Susceptible animals exhibited a skewed CD4+/CD8+ iNKT subset ratio in comparison to more Mtb-resistant groups. Correlation of iNKT subsets post BCG vaccination with clinical disease manifestations following Mtb challenge in the Chinese cynomolgus cynomolgus and Indian rhesus macaques identified a consistent trend linking increased CD8+ iNKTs with favourable disease outcome. Finally, a similar iNKT profile was conferred by BCG vaccination in rhesus macaques. Our study provides the first detailed characterisation of iNKT cells in macaque tuberculosis infection, suggesting that iNKT repertoire differences may impact on disease outcome, which warrants further investigation.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a recently recognized neurodegenerative ganglionopathy. Prompted by the presence of symptomatic postural hypotension in two patients with CANVAS, we hypothesized that autonomic dysfunction may be an associated feature of the syndrome. We assessed symptoms of autonomic dysfunction and performed autonomic nervous system testing among 26 patients from New Zealand. After excluding three patients with diabetes mellitus, 83% had evidence of autonomic dysfunction; all patients had at least one autonomic symptom and 91% had more than two symptoms. We also found a higher rate of downbeat nystagmus (65%) than previously described in CANVAS. We confirmed that sensory findings on nerve conduction tests were consistent with a sensory ganglionopathy and describe two patients with loss of trigeminal sensation consistent with previous pathological descriptions of trigeminal sensory ganglionopathy. Our results suggest that autonomic dysfunction is a major feature of CANVAS. This has implications for the management of patients with CANVAS as the autonomic symptoms may be amenable to treatment. The findings also provide an important differential diagnosis from multiple system atrophy for patients who present with ataxia and autonomic failure.

A previously well 46-year-old male doctor presented with a 10-week history of distressing vertiginousness with nausea, induced by rapid head movement, persisting for a few seconds, suggesting benign paroxysmal positional vertigo (BPPV). However, he could not reliably induce vertigo with any particular head positioning. Repeated treatments for BPPV with a physiotherapist over 3 weeks did not help. The patient thereafter sought neurological input, when he noticed mild but progressive lack of dexterity using the left, non-dominant hand. His positioning symptoms did not deteriorate further. On examination, there was mild ocular dysmetria but no primary position or gaze-evoked …

Cell biology differs between traditional cell culture and 3-dimensional (3-D) systems, and is modulated by the extracellular matrix. Experimentation in 3-D presents challenges, especially with virulent pathogens. Mycobacterium tuberculosis (Mtb) kills more humans than any other infection and is characterised by a spatially organised immune response and extracellular matrix remodelling. We developed a 3-D system incorporating virulent mycobacteria, primary human blood mononuclear cells and collagen–alginate matrix to dissect the host-pathogen interaction. Infection in 3-D led to greater cellular survival and permitted longitudinal analysis over 21 days. Key features of human tuberculosis develop, and extracellular matrix integrity favours the host over the pathogen. We optimised multiparameter readouts to study emerging therapeutic interventions: cytokine supplementation, host-directed therapy and immunoaugmentation. Each intervention modulates the host-pathogen interaction, but has both beneficial and harmful effects. This methodology has wide applicability to investigate infectious, inflammatory and neoplastic diseases and develop novel drug regimes and vaccination approaches.

Background:Déjà vu occurs both in normal experience and as a neuropsychiatric symptom. Its pathogenesis is partially understood. We describe an iatrogenic case with implications for the neuropharmacological basis of déjà vu.Case presentation:A 42-year-old woman received 5-hydroxytryptophan, in combination with carbidopa, as treatment for palatal tremor, on two occasions, separated by 1 week. On each occasion, she experienced intense, protracted déjà vu, lasting for several hours. We discuss her case in relation to the neuroanatomical and neuropharmacological basis of déjà vu.Conclusion:The serotonergic system is involved in the genesis of déjà vu.

Invariant NKT (iNKT) cells in healthy people express iNKT-TCRs with widely varying affinities for CD1d, suggesting different roles for high- and low-affinity iNKT clones in immune regulation. However, the functional implications of this heterogeneity have not yet been determined. Functionally aberrant iNKT responses have been previously demonstrated in different autoimmune diseases, including human type 1 diabetes, but their relationship to changes in the iNKT clonal repertoire have not been addressed. In this study, we directly compared the clonal iNKT repertoire of people with recent onset type 1 diabetes and age- and gender-matched healthy controls with regard to iNKT-TCR affinity and cytokine production. Our results demonstrate a selective loss of clones expressing high-affinity iNKT-TCRs from the iNKT repertoire of people with type 1 diabetes. Furthermore, this bias in the clonal iNKT repertoire in type 1 diabetes was associated with increased GM-CSF, IL-4, and IL-13 cytokine secretion among Ag-stimulated low-affinity iNKT clones. Thus, qualitative changes of the clonal iNKT repertoire with the potential to affect the regulatory function of this highly conserved T cell population are already established at the early stages in type 1 diabetes. These findings may inform future rationales for the development of iNKT-based therapies aiming to restore immune tolerance in type 1 diabetes.

A sporadic seasonal neurotoxic food poisoning, unique to northern parts of New Zealand, especially The Bay of Plenty, has recurred-with implications for our primary produce industry, as well as human health.

Eighty-five years ago Hans Berger, working in Jena, Germany, used silver wires inserted under the scalp of human subjects to record a mysterious 10 Hz wobble. Later, he acquired a valve amplifier to drive his galvanometer and reported his discoveries between 1929 and 1935, including the changes in cerebral activity after eye closure, in Archiv fur Psychiatrie und Nervenkrankheiten as “Uber das Electrenkephalogramm des Menschen”. To suggest that the brain’s electrical activity was detectable outside the skull sorely tested the credulity of his contemporaries. However, by the time unilateral spikes were correlated with clonic jerking of the contralateral extremities and 3 Hz spike and wave with absence attacks, the importance and potential of Berger’s original rhythms were realised. Would Hans be disappointed with the modern applications of his discovery? I think not. Admittedly, developments in EEG technology have been slow in comparison to the gargantuan, athletic strides made in structural imaging of the brain—but the EEG remains integral to clinical neurological practice,1 albeit with an intangible, even enigmatic, appeal to those of us who like to see our patients’ brain waves. Despite the limitations imposed by standard electrode placement, which preclude recording from basal or mesial cerebral regions, this “poor man’s functional imaging”, has matured to join a more sedate masters’ class. The EEG has the unique advantage in neurodiagnostics of not only spatial but also temporal resolution. On the other hand, Berger’s legacy has not fulfilled the hopes of subsequent generations of psychiatrists searching for an application in neurobehavioural disorders.2 Digital technology has replaced the paper, pen and ink machines which once spewed an impressively weighty ream of paper, later to lay dormant in vast musty corridors of hospital basements. Contemporary systems effortlessly record and store hours of EEG, with simultaneous …

Human resources kindly invited me to join a recent ceremony to acknowledge long serving staff members, as part of the local health board's ‘Staff Recognition Programme’. This moment of affirmation was tinged with regret when I was asked to fill out a form attached to the invitation which included: “…..who do you report to?” Apart from preferring “to whom do you report?”—grammatically and phonetically—this question says much about 21st century hospital medicine. Most of us would prefer to answer ‘my patient’, rather than the managerial chain of command. The organisation of healthcare delivery has never stood still but the reforms I have seen in the past 30 years have considerably reshaped our workplace landscape. In many cases physicians are less autonomous self-motivated individuals and more highly managed employees. We work to contractual volumes, answerable to multiple sources of internal and external monitoring. There is greater scrutiny by the traditional authorities of medical council and professional colleges, as well as exposure to public and patient advocate organisations and governmental agencies—for example, our Health and …

CASE PRESENTATION The patient, a right-handed 64-year-old pakeha man (New Zealand European), was referred to the neurology clinic in June 2000. His family doctor had discovered bilateral carotid bruits and arranged an ultrasound examination. He was feeling very well; specifically, there were no symptoms of any kind which could be attributed to these bruits – no focal neurological symptoms, or even dizziness or lightheadedness – and he took regular vigorous exercise without difficulty. Treatment of hypertension had begun more than a decade previously. In 1997 some recordings had been as high as 200/105 mmHg, but at the time of referral his blood pressure was controlled (150/80–90) with Atenolol 50 mg b.d. and Indapamide 2.5 mg daily. His family doctor had started treatment for a total plasma cholesterol of 7.1 mmol/L with Atorvastatin 40 mg daily, subsequently this improved to 5.8 mmol/L, with a total cholesterol/HDL ratio of 3.3. There was no

The paper “Eosinophilic myelitis, a souvenir from South East Asia” in the February issue,1 describes a patient with Gnathostoma spinigerum infection. Although, quite rightly, Dr Schmutzhard alerts physicians to this possibility in travellers returning …

In her article on Guillain-Barre syndrome (GBS) in the August issue, Jane Pritchard repeats the age-old neurological dogma that areflexia is part of the “essential diagnostic criteria”.1 But she does not mention that preserved or exaggerated reflexes do not exclude the diagnosis. I was unaware of this until I examined an exception to the rule last year. A 59 year old man was admitted with deteriorating weakness, 10 days after a meal of undercooked chicken, followed by diarrhoea, with two positive Clostridium jejuni stool samples. He …

1. (c) is false Overweight patients like this man with pain, are more likely than matched, non-neuropathy controls, to show impaired glucose tolerance (see Hughes et al. in Brain 2004, 127, 1723–30). This is less likely when the neuropathy is painless. Impaired glucose tolerance is usually defined by glucose levels of 7.8–11 mmol/L 2 hours after a 75g oral glucose load. The fasting insulin concentration is also likely to be elevated. After adjusting for body mass index, hypertriglyceridaemia not linked to diabetes mellitus, is more likely in patients than controls, suggesting a ‘metabolic’ basis to chronic axonal polyneuropathy, which is not a direct consequence of hyperglycaemia per se . 2. (a) and (d) are true Information on pergolide associated valvular heart disease is evolving. A high prevalence (> 40%) of ‘serious’ valve disease has recently been described in an echocardiographic case-control study ( Neurology 2004, 63, 301–4). It seems

1. Consider the following case. A 67-year-old man presents with at least 2 years of painful numb feet. His body mass index is 26. A 10 m walk takes 8 s, unaided. Routine inquiry and investigations for common causes of neuropathy, including random blood glucose are all negative. Electrophysiological examination reveals a chronic axonal polyneuropathy. Which of the following is false? An oral glucose load should be given to detect impaired glucose tolerance. Hypertriglyceridaemia, not linked to diabetes mellitus, is associated with chronic axonal polyneuropathy. Recent reports support a role for anti-ganglioside antibodies in chronic axonal polyneuropathy. Taking a detailed occupational history may reveal a relevant history of exposure to solvents or lead. Quality of life is significantly affected. 2. Concerning pergolide - which of the following are true? Nausea and hypotension are the most common adverse effects. Pergolide associated valvular heart disease

Edited by James M. Gilchrist . 1998. Pp. 473. Oxford: Butterworth Heinemann. Price £55. ISBN 0-7506-98888. One of the fundamental roles of a neurologist is counselling patients about their future, for both diseases for which treatment is available and those where none exists. Diagnostic skills are acquired early in training and, with time, can be delegated. However, depth of experience is a prerequisite for accurate, informed and sensitive advice about prognosis. The preface to this book claims that the success of modern medicine includes its scientific foundations and advances in treatment, but that the physician's role in prognosis, of great importance to our patients, has been `sadly neglected'. Whether you agree with this perception or not, the editor has assembled a multi-author volume of neurology with …