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

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

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

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

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

Survival And Mitosis Of Myelinating Oligodendrocytes In Experimental Autoimmune Encephalomyelitis: An Immunocytochemical Study With Rip Antibody

The fate of myelin-forming oligodendrocytes in the spinal cord of Lewis rats with acute and chronic relapsing experimental autoimmune encephalomyelitis (EAE) was studied using the pre-embedding immunolabelling technique with the Rip monoclonal antibody which specifically labels the cytoplasm of the cell body and processes of the mature oligodendrocyte. Morphologically normal Rip-positive (Rip+) cells were found in close contact with demyelinated axons at the onset of demyelination and during the course of disease, indicating that oligodendrocytes survive the acute demyelinating insult. Occasional Rip+ oligodendrocytes were undergoing mitosis at the time of onset of neurological signs. These mitotic oligodendrocytes were present in both the grey and white matter. The majority of the mitotic oligodendrocytes had processes in direct contact with myelin sheaths for considerable lengths, indicating that they were myelinating cells. This study indicates that oligodendrocytes survive the acute demyelinating insult in EAE and that mature myelinating oligodendrocytes are able to undergo mitosis

Multiple Sclerosis with Idiopathic Dilated Cardiomyopathy: A Case Report

Multiple sclerosis and idiopathic dilated cardiomyopathy are two conditions in which an autoimmune process is implicated in the pathogenesis. There is evidence to support clustering of autoimmune diseases in patients with multiple sclerosis and their families. To our knowledge, this is the first report of idiopathic dilated cardiomyopathy occurring in a patient with multiple sclerosis

Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). The lesions of MS were first depicted in 1835. In 1940, pathological similarities were noted between experimental autoimmune encephalomyelitis (EAE) and acute cases of MS. These similarities gave rise to the theory that MS is an autoimmune disease, a theory further supported by the similarities between MS and chronic relapsing EAE

Experimental Autoimmune Encephalomyelitis

Experimental Autoimmune Encephalomyelitis (EAE) is the prototype for cell-mediated autoimmune disease in general, and is the best animal model of human CNS inflammatory demyelinating disease. It has three forms, which vary in clinical course and neuropathology: acute EAE, hyperacute EAE and chronic relapsing EAE. Acute EAE and hyperacute EAE are monophasic diseases which resemble the human diseases, acute disseminated encephalomyelitis and acute haemhorrhagic leukoencephalitis, respectively. Chronic relapsing EAE has a chronic relapsing course and resmebles the human disease multiple sclerosis