Infection of Autoreactive B Lymphocytes with EBV, Causing Chronic Autoimmune Diseases

I hypothesize that human chronic autoimmune diseases are based on infection of autoreactive B lymphocytes by Epstein-Barr virus (EBV), in the following proposed scenario. During primary infection, autoreactive B cells are infected by EBV, proliferate and become latently infected memory B cells, which are resistant to the apoptosis that occurs during normal B-cell homeostasis because they express virus-encoded anti-apoptotic molecules. Genetic susceptibility to the effects of B-cell infection by EBV leads to an increased number of latently infected autoreactive memory B cells, which lodge in organs where their target antigen is expressed, and act there as antigen-presenting cells. When CD4+ T cells that recognize antigens within the target organ are activated in lymphoid organs by cross-reactivity with infectious agents, they migrate to the target organ but fail to undergo activation-induced apoptosis because they receive a co-stimulatory survival signal from the infected B cells. The autoreactive T cells proliferate and produce cytokines, which recruit other inflammatory cells, with resultant target organ damage and chronic autoimmune disease

Cyclosporine and Multiple Sclerosis

Recent studies have shown that the administration of low-dose cyclosporine can convert acute experimental allergic encephalomyelitis into chronic relapsing EAE with large plaques of spinal cord demyelination

CSF Testing for Multiple Sclerosis

New diagnostic criteria for multiple sclerosis (MS) were published in 2001 by McDonald and colleagues. These criteria take account of the clinical features, brain and spinal-cord MRI findings, CSF findings, and visual evoked-potential studies. The McDonald criteria define rigorous MRI requirements but do not define an optimum CSF test for the diagnosis of MS. CSF testing should be optimised, because, in the McDonald criteria, a positive CSF study is an essential diagnostic criterion in patients who have objective clinical evidence of only one lesion and only a few MRI lesions, and it is a mandatory criterion for the diagnosis of primary progressive MS

The Use of Interferon Beta at the Time of Initial Diagnosis of Multiple Sclerosis

Dr Hodgkinson points out the increasing evidence that damage to axons as well as to myelin can occur early in the clinical course of multiple sclerosis (MS) and accumulates over time. This indicates the need for a safe effective treatment for MS from its onset. The main question here is whether interferon beta meets this need. Dr Macdonell makes it clear that when considering this therapy one has to take into account the nature of the disease at the time of clinical presentation. Currently it is unclear whether interferon beta is beneficial in secondary progressive MS, and so its initiation at this stage of MS is probably best avoided. Certainly interferon beta should be avoided in primary progressive MS at present, as there is no evidence that it has a beneficial clinical effect and indeed there is one report that it actually worsens the clinical picture by increasing spasticity

The Pathogenesis Of Primary Progressive Multiple Sclerosis: Antibody-Mediated Attack And No Repair?

Primary progressive multiple sclerosis (MS) differs from the more common form of MS which has an initial relapsing-remitting course in a number of ways, including pathological features, clinical course, differential diagnosis and response to treatment. The lesions in primary progressive MS tend to be more diffuse, less inflammatory and less likely to remyelinate than those occurring in relapsing-remitting MS and secondary progressive MS; there are also fewer focal lesions in the brain in primary progressive MS. Recent evidence suggests that antibodies to central nervous system (CNS) antigens have an important role in disease progression. Such antibodies could cause demyelination, inhibit remyelination and cause axonal destruction. Ongoing immune attack by autoantibody and lack of CNS repair could be responsible for the gradually increasing disability in primary progressive MS. Further research on the B-cell and autoantibody response in primary progressive MS might lead to advances in diagnosis and treatment. Inhibition of autoantibody production by inducing B-cell apoptosis with rituximab is a potential new therapy for primary progressive MS

Recovery from Acute Experimental Allergic Encephalomyelitis in the Lewis Rat: Early Restoration of Nerve Conduction and Repair by Schwann Cells and Oligodendrocytes

Light and electron microscopic histological studies and electrophysiological studies were performed on Lewis rats with acute experimental allergic encephalomyelitis (EAE) induced by whole spinal cord or myelin basic protein to determine the mechanism of clinical recovery. In these animals, total clinical recovery from complete paraplegia may occur as early as 4 days after the onset of hindlimb weakness. These studies indicate that this recovery occurs at a time when there is restoration of nerve conduction in the peripheral nervous system (PNS) and central nervous system (CNS) and when most demyelinated fibres have been invested, and some partially remyelinated, by Schwann cells or oligodendrocytes in the PNS and CNS, respectively. These findings support the hypothesis that the neurological signs of acute EAE are due to demyelination in the PNS and CNS

CD8+ T-Cell Deficiency, Epstein-Barr Virus Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis

CD8+ T-cell deficiency is a feature of many chronic autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, dermatomyositis, primary biliary cirrhosis, primary sclerosing cholangitis, ulcerative colitis, Crohn's disease, psoriasis, vitiligo, bullous pemphigoid, alopecia areata, idiopathic dilated cardiomyopathy, type 1 diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, myasthenia gravis, IgA nephropathy, membranous nephropathy, and pernicious anaemia. It also occurs in healthy blood relatives of patients with autoimmune diseases, suggesting it is genetically determined. Here it is proposed that this CD8+ T-cell deficiency underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of Epstein-Barr virus (EBV) infection, with the result that EBV-infected autoreactive B cells accumulate in the target organ where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells which would otherwise die in the target organ by activation-induced apoptosis. Autoimmunity is postulated to evolve in the following steps: (1) CD8+ T-cell deficiency, (2) primary EBV infection, (3) decreased CD8+ T-cell control of EBV, (4) increased EBV load and increased anti-EBV antibodies, (5) EBV infection in the target organ, (6) clonal expansion of EBV-infected autoreactive B cells in the target organ, (7) infiltration of autoreactive T cells into the target organ, and (8) development of ectopic lymphoid follicles in the target organ. It is also proposed that deprivation of sunlight and vitamin D at higher latitudes facilitates the development of autoimmune diseases by aggravating the CD8+ T-cell deficiency and thereby further impairing control of EBV. The hypothesis makes predictions which can be tested, including the prevention and successful treatment of chronic autoimmune diseases by controlling EBV infection

The Pathophysiology of Chronic Relapsing Experimental Allergic Encephalomyelitis in the Lewis Rat

Electrophysiological studies were performed in Lewis rats with chronic relapsing experimental allergic encephalomyelitis (EAE) induced by inoculation with guinea-pig spinal cord and adjuvants and treatment with low dose cyclosporin A. During clinical episodes there was conduction failure in the central nervous system (CNS), namely the spinal cord dorsal columns, and in the afferent fibres in the peripheral nervous system (PNS). The following observations indicated that the conduction failure was mainly due to demyelination-induced conduction block: (1) rate-dependent conduction block in the CNS and PNS; (2) temporal dispersion due to slowing of PNS conduction; (3) restoration of PNS conduction by cooling; (4) restoration of CNS conduction by ouabain; (5) previously demonstrated histological evidence of primary demyelination in the dorsal columns, dorsal root ganglia and dorsal roots; and (6) the temporal association of restoration of conduction with remyelination. However, it is likely that CNS and PNS axonal degeneration, which occurs in this disease, also contributed to the conduction failure. In clinical remissions there was restoration of conduction in the CNS and PNS which can be explained by ensheathment/remyelination by oligodendrocytes and Schwann cells, respectively. In most rats during clinical episodes the cerebral somatosensory evoked potential was reduced in amplitude and prolonged in latency, which can be accounted for by demyelination and axonal degeneration in the CNS and PNS components of the afferent pathway. In 2 rats with episodes of EAE, however, this potential was markedly increased in amplitude, which might have been due to demyelination-induced conduction block of descending pathways that normally inhibit synaptic transmission in the afferent pathway. In well-established remission there was residual conduction failure in the CNS and PNS which can be mainly accounted for by axonal degeneration

Conduction Block in the Peripheral Nervous System in Experimental Allergic Encephalomyelitis

Experimental Allergic Encephalomyelitis (EAE) has been widely studied as a model of multiple sclerosis, a central nervous system (CNS) disease of unknown aetiology. The clinical features of both EAE and multiple sclerosis provide the only guide to the progress and severity of these diseases, and are used to assess the response to treatment. In such comparisons the clinical features of EAE are assumed to be due to lesions in the CNS, but in this disease there is also histological evidence of damage to the peripheral nervous system (1-8). However, the functional consequences of such peripheral lesions have been entirely ignored. To examine this, we have studied nerve conduction in rabbits with EAE. We report here that most of the large diameter afferent fibres are blocked in the region of the dorsal root ganglion and at the dorsal root entry zone, thus accounting for the loss of tendon jerks and also, through the severe loss of proprioceptive information, the ataxia of thse animals. We conclude that whenever clinical comparisons are made between EAE and multiple sclerosis, the pathophysiology associated with histological damage of the peripheral nervous system must be taken into account

Lower Motor Neuron Weakness After Diving-Related Decompression

We present a case of lower motor neuron upper limb weakness due to infarction of the anterior horn cells of the spinal cord following diving. To our knowledge, this is the first report of an isolated lower motor neuron syndrome following diving-related decompression