Abhijit Chaudhuri

Cytomegalovirus in autoimmunity: T cell crossreactivity to viral antigen and autoantigen glutamic acid decarboxylase

Antigens of pathogenic microbes that mimic autoantigens are thought to be responsible for the activation of autoreactive T cells. Viral infections have been associated with the development of the neuroendocrine autoimmune diseases type 1 diabetes and stiff-man syndrome, but the mechanism is unknown. These diseases share glutamic acid decarboxylase (GAD65) as a major autoantigen. We screened synthetic peptide libraries dedicated to bind to HLA-DR3, which predisposes to both diseases, using clonal CD4+ T cells reactive to GAD65 isolated from a prediabetic stiff-man syndrome patient. Here we show that these GAD65-specific T cells crossreact with a peptide of the human cytomegalovirus (hCMV) major DNA-binding protein. This peptide was identified after database searching with a recognition pattern that had been deduced from the library studies. Furthermore, we showed that hCMV-derived epitope can be naturally processed by dendritic cells and recognized by GAD65 reactive T cells. Thus, hCMV may be involved in the loss of T cell tolerance to autoantigen GAD65 by a mechanism of molecular mimicry leading to autoimmunity.

The clinical spectrum, diagnosis, pathogenesis and treatment of Hashimoto's encephalopathy (recurrent acute disseminated encephalomyelitis).

Hashimotos encephalopathy may present with a wide variety of different neurological symptoms and signs. These include recurrent severe migrainous headache, psychoses, seizures, ataxia, dementia, stupor and coma. We present a personal series of 18 adult patients with Hashimotos encephalopathy and a review of the literature in this paper. The natural history, laboratory abnormalities and neuroimaging data in these cases favour an immunopathological basis for this syndrome similar to relapsing acute disseminated encephalomyelitis. We suggest that Hashimotos encephalomyelitis should be considered in the differential diagnosis of seizures, coma, atypical migraine and reversible dementia. Serological screening for anti-thyroid antibody should form part of the initial investigations in all relapsing and reversible encephalopathies.

Association of British Neurologists: revised (2015) guidelines for prescribing disease-modifying treatments in multiple sclerosis

In June 1999, the Association of British Neurologists (ABN) first published guidelines for the use of the licensed multiple sclerosis (MS) disease-modifying treatments (at that time β-interferon and glatiramer acetate). The guidelines were revised in 2001 and have been periodically updated since then. In 2002, following the negative assessment of these treatments by the National Institute for Health and Care Excellence (NICE), the MS risk-sharing scheme started, in which patients eligible according to the 2001 ABN guidelines were provided with treatment funded through the UK National Health Service (NHS), and monitored annually for up to 10 years.1 Recruitment to the risk-sharing scheme cohort is complete. Pending a future final evaluation, the UK Department of Healths instruction to NHS funders remains in place: that patients who fulfil the ABN criteria should continue to receive treatment funded through the NHS. The British neurological community has fully accepted the risk-sharing scheme for prescribing β-interferon and glatiramer acetate. Approximately 70 ‘treating centres’ have recruited >5000 patients between 2002 and 2005, and these have been monitored annually for 10 years; many more patients have received these treatments since 2005. The ABN published revised guidelines in 2007, and then again in 2009, following the licensing of natalizumab and mitoxantrone. This 2015 revised guideline replaces former versions. It includes all newly approved or licensed treatments for MS and represents a consensus concerning their use. These guidelines will require future revision as other treatments receive approval (eg, daclizumab and ocrelizumab): we suggest they are reviewed after an interval of no longer than 12 months. The guideline is not intended to provide a complete description of the possible complications and monitoring of disease-modifying treatments in MS; we refer prescribing neurologists to the relevant summaries of product characteristics. MS is a complex disease. Perhaps uniquely in neurology its clinical course is characterised …

A gene signature for post-infectious chronic fatigue syndrome

BackgroundAt present, there are no clinically reliable disease markers for chronic fatigue syndrome. DNA chip microarray technology provides a method for examining the differential expression of mRNA from a large number of genes. Our hypothesis was that a gene expression signature, generated by microarray assays, could help identify genes which are dysregulated in patients with post-infectious CFS and so help identify biomarkers for the condition.MethodsHuman genome-wide Affymetrix GeneChip arrays (39,000 transcripts derived from 33,000 gene sequences) were used to compare the levels of gene expression in the peripheral blood mononuclear cells of male patients with post-infectious chronic fatigue (n = 8) and male healthy control subjects (n = 7).ResultsPatients and healthy subjects differed significantly in the level of expression of 366 genes. Analysis of the differentially expressed genes indicated functional implications in immune modulation, oxidative stress and apoptosis. Prototype biomarkers were identified on the basis of differential levels of gene expression and possible biological significanceConclusionDifferential expression of key genes identified in this study offer an insight into the possible mechanism of chronic fatigue following infection. The representative biomarkers identified in this research appear promising as potential biomarkers for diagnosis and treatment.

The sad plight of multiple sclerosis research (low on fact, high on fiction): critical data to support it being a neurocristopathy

The literature for evidence of autoimmunity in multiple sclerosis (MS) is analysed critically. In contrast to the accepted theory, the human counterpart of the animal model experimental autoimmune demyelinating disease, experimental allergic encephalomyelitis (EAE), is not MS but a different demyelinating disorder, i.e. acute disseminated encephalomyelitis and acute haemorrhagic leucoencephalitis. Extrapolation of EAE research to MS has been guided largely by faith and a blind acceptance rather than sound, scientific rationale. No specific or sensitive immunological test exists that is diagnostic of MS despite the extensive application of modern technology. Immunosuppression has failed to have any consistent effect on prognosis or disease progression. The available data on MS immunotherapy are conflicting, at times contradictory and are based on findings in animals with EAE. They show predominantly a 30% effect in relapsing/remitting MS which suggests powerful placebo effect. Critical analysis of the epidemiological data shows no association with any specific autoimmune diseases, but does suggest that geographic factors and age at development posit an early onset possibly dependent on environmental influences. Certain neurological diseases are, however, found in association with MS, namely hypertrophic peripheral neuropathy, neurofibromatosis-1, cerebral glioma, glioblastoma multiforme and certain familial forms of narcolepsy. These share a common genetic influence possibly from genes on chromosome 17 affecting cell proliferation. A significant number of these disorders are of neural crest origin, the classical example being abnormalities of the Schwann cell. These and other data allow us to propose that MS is a developmental neural crest disorder, i.e. a cristopathy, implicating glial cell dysfunction with diffuse blood–brain barrier breakdown. The data on transcription factor SOX10 mutations in animals may explain these bizarre clinical associations with MS and the phenotypic variability of such alterations (Cossais et al. 2010). Research directed to the area of neural crest associations is likely to be rewarding.

Lessons for clinical trials from natalizumab in multiple sclerosis

The approval of natalizumab and its recall after three months raises questions about the fast tracking of new drugs by the Food and Drug Administration for commercial licensing

Multiple sclerosis is primarily a neurodegenerative disease

The precise pathogenesis of multiple sclerosis is unknown. The assumption of a primary immunopathogenesis of the disease is seriously flawed and has failed to deliver an effective therapy for most patients. The progressive degeneration of grey and white matter is integral to the natural history of the disease and is reflected in the atrophy of brain and spinal cord. Demyelination is an essential component of this primary neurodegenerative process rather than the target of a systemic immune response. The primary pathology of multiple sclerosis is a process of neurodegeneration based on the integrity of the blood–brain barrier. Primary progressive multiple sclerosis is the prototype neurodegenerative disease, and the relapsing-remitting form in younger population represents the modifying effect of steroids (vitamin D, sex and stress hormones) on metabolic functions of the central nervous system.

EAE is not a useful model for demyelinating disease

Experimental allergic encephalomyelitis (EAE) is the commonest, readily induced, organspecific, autoimmune disorder of laboratory animals of its kind. It is an artificial disorder brought about by the immunisation of susceptible animals with brain antigens in complete Freund׳s adjuvant (CFA). Variations can be induced by altering the nature of the antigen and the conditions involving immunisation. Whilst it is often described as a demyelinating disease, in strict terms it is not, since the primary pathologic process is not demyelination but rather an encephalomyelitis that is immunologically induced. Rather, the prototype demyelinating disease is multiple sclerosis and its variants. In this paper, the central question we ask is whether the data gleaned from the EAE model contributes to our understanding of the pathological events in MS. Towards answering this, we describe the historical development of EAE and its hyperacute form, and discuss the findings studied extensively in the non-human primate which show that ordinary EAE is an exact model for ADEM in the human, and that the hyperacute form of EAE is represented by AHLE in the human. Additionally, we shall comment on the latest research on new variants of EAE, and explain our opinion regarding the use of EAE models in research aiming to understand the pathogenesis of multiple sclerosis.

The UK patient experience of relapse in Multiple Sclerosis treated with first disease modifying therapies

BACKGROUND The fixed, progressive disability associated with late Multiple Sclerosis (MS) is known to have a major impact on patients and their families, but the impact of relapse earlier in the disease course is less well documented, particularly from the patient׳s perspective. This study aimed to understand the effects of relapse for people with MS (PwMS), focussing on the years immediately after starting disease modifying therapy (DMT) when experience of a relapse may particularly influence a patient׳s opinions of their disease and its therapy. METHODS This was a multi-centre, retrospective, observational research study, recruiting patients from 7 UK NHS Hospital Trusts. Consenting patients with relapsing-remitting MS (RRMS), who had started a DMT more than 36 months before screening, were sent a study questionnaire. Data on MS relapses and treatments over 3 years were collected simultaneously from medical records. RESULTS One hundred and three patients completed the questionnaires. Relapses were under-reported to health care professionals, with 28% of respondents failing to report their most recent attack and 46% declaring they had failed to report an attack in the past. During their most recent relapse, 67% of those in paid employment reported taking time off sick, 48% reduced working hours temporarily, and 41% worked reduced hours and took time off sick. Sixty-six percent required additional support to undertake routine daily tasks during their most recent relapse. A range of effects of relapse which cannot be measured in financial terms were also reported, including effects on physical abilities, mental health and family roles and relationships. CONCLUSION This contemporary UK-based study provides an insight into the experience of relapse early in the treatment of RRMS from the patient perspective. The comparison of documented patient reported relapses reveals some deficiencies in the recording of relapses which is important to address in view of the reported impact of individual relapses, and emphasises relapse reduction as a worthy treatment aim.

Arguments for a Role of Abnormal Ionophore Function in Chronic Fatigue Syndrome

Chronic fatigue syndrome (CFS) is a disorder that is now receiving world-wide attention from the scientific and medical communities. The precise incidence is unknown, but it has been estimated to have a prevalence of approximately one per thousand (The facts about chronic fatigue syndrome. Coordinating Committee. US Department of Health and Human Services. CDC/NCID, September 28, 1993). It affects individuals, women more than men at the most productive time in their lives. Until now, the syndrome has been poorly defined. Recently an attempt has been made to give a comprehensive definition that can be used in studies and research but essentially this definition, which is far from perfect, is one of exclusion (Fukuda et al, 1994). The authors “support changing the name when more is known about the underlying pathophysiological process” (Fukuda et al, 1994). The patients reported in our studies all fulfilled this recent CDC criteria and also the other definitions that have also been proposed (Majeed et al, 1995, Sharpe, 1991). All of our cases were admitted as in-patients and had an exhaustive, comprehensive study to rule out all other causes of fatigue.