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ScienceWeek
MEDICAL BIOLOGY: MULTIPLE SCLEROSIS AND THE HYGIENE HYPOTHESIS
The following points are made by A-L. Ponsonby et al (J. Am. Med. Assoc. 2005 293:463):
1) The "hygiene hypothesis" proposes that early life infections may down-regulate allergic and autoimmune disorders.[1] Having siblings may increase the number of early life infections. In fact, lack of contact with siblings has been associated with TH2-related immune disorders and some TH1-related disorders. For multiple sclerosis (MS), a TH1-related autoimmune disease, the association with birth order has been inconsistent across studies[2-4] and absent in others.[5] However, birth order provides clearer information on the number of older siblings, and the independent influence of younger siblings has not been evaluated. Younger siblings may be important because infants provide a source of common viral infections. Reexposure to active viral infection is known to cause immune boosting with rising IgG titers in seropositive individuals. Also, repeated antigenic stimulation induces affinity maturation of the B-cell line and influences T-cell phenotype and T-cell receptor diversity. This may be advantageous if the acquisition of a highly developed immune response to putative viral triggers is required to prevent MS development in later life.
2) A protective role for early life infection in the development of MS is consistent with several features of MS, including the apparent recent increase in incidence that has accompanied a decline in childhood infection rates over time.[1] The suggestion that MS may result from the postponement of early life infection was first made in 1966. Since then, several studies have shown MS to be associated with childhood infection of later onset, especially Epstein-Barr virus (EBV) infection. A Danish historical cohort reported infectious mononucleosis, a marker of late EBV infection, to be associated with subsequent MS, and two recent cohort studies have reported strong associations between elevated EBV IgG antibodies and subsequent MS.
3) In addition to early life infection, other risk factors for MS have been identified. In prospective studies, cigarette smoking has been associated with higher MS risk and vitamin D supplementation with reduced risk. Higher levels of sunlight exposure have been associated with reduced MS risk, with an adjusted odds ratio (AOR) for higher sun exposure at ages 6 to 15 years and MS in a previous study of 0.31. Sun exposure may modify the host immune response. For example, antigen-specific T-suppressor cells are induced by exposure to UV radiation.19
4) The authors report a study to evaluate whether exposure to infant siblings in early life is associated with the risk of MS, and to explore the possible mechanism for any apparent protective effect, including altered Epstein-Barr virus (EBV) infection patterns.
5) The authors conclude: Higher infant sibling exposure in the first 6 years of life is associated with a reduced risk of MS, possibly by altering childhood infection patterns and related immune responses.
References (abridged):
1. Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med. 2002;347:911-920
2. Isager H, Andersen E, Hyllested K. Risk of multiple sclerosis inversely associated with birth order position. Acta Neurol Scand. 1980;61:393-396
3. Visscher BR, Liu KS, Sullivan C, Valdiviezo NL, Detels R. Birth order and multiple sclerosis. Acta Neurol Scand. 1982;66:209-215
4. Zilber N, Kutai-Berman M, Kahana E, Korczyn AD. Multiple sclerosis and birth order. Acta Neurol Scand. 1988;78:313-317
5. Hernan MA, Zhang SM, Lipworth L, Olek MJ, Ascherio A. Multiple sclerosis and age at infection with common viruses. Epidemiology. 2001;12:301-306
J. Am. Med. Assoc. http://www.jama.com
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Related Material:
EPSTEIN-BARR VIRUS AND MULTIPLE SCLEROSIS
The following points are made by A. Ascherio et al (J. Am. Med. Assoc. 2001 286:3083):
1) The etiology of multiple sclerosis is largely unknown, but evidence supports the idea of an autoimmune process triggered by infection or other environmental factors. Epstein-Barr virus, a herpesvirus, infects more than 90 percent of the human population, establishing a persistent and highly immunogenic infection of B lymphocytes. The population of antigen-specific cytotoxic T cells is massively expanded in response to primary infection and persists at high levels for several years. Autoimmunity could result if some of these cells carry T-cell receptors that recognize self-peptides. Epstein-Barr virus has been related to nasopharyngeal carcinoma, Burkitt lymphoma, and Hodgkin disease, and a relation to autoimmune diseases has been proposed by remains unproven.
2) Infection with Epstein-Barr virus is usually asymptomatic in childhood but frequently causes infectious mononucleosis in adolescents and adults. The similarity in the epidemiology of multiple sclerosis and infectious mononucleosis led to the proposition that multiple sclerosis could be caused by infection with Epstein-Barr virus during or after adolescence in genetically susceptible individuals. This hypothesis is supported by observations suggesting an increased risk of multiple sclerosis following infectious mononucleosis, the rarity of multiple sclerosis among individuals without serum anti-Epstein-Barr virus antibodies, and the higher serum titers of anti-Epstein-Barr virus antibodies in multiple sclerosis patients than in controls.
3) The authors report a prospective study of the role of Epstein-Barr virus in the etiology of multiple sclerosis, the study involving examination of the association between serum anti-Epstein-Barr virus antibody titers and risk of developing multiple sclerosis in 2 large cohorts of US women. The total number of women in the study was 62,439. The authors report that their results support a role of Epstein-Barr virus in the etiology of multiple sclerosis. A 4-fold difference in titers of antibodies to Epstein-Barr virus antigens was associated with a 4-fold increase in risk of multiple sclerosis.
J. Am. Med. Assoc. http://www.jama.com
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Related Material:
MEDICAL BIOLOGY: A POSSIBLE CAUSE OF MULTIPLE SCLEROSIS
Notes by ScienceWeek:
In the vertebrate central nervous system, the axons of nerve cells involved in physiological functions that require rapid signaling (for example, the neural control of voluntary muscle) are wrapped in a special sheath called myelin. The myelin sheath consists of concentric layers of electrically insulating lipid-protein material, but the sheath is periodically interrupted along the length of the axon, and at the points where the sheath is interrupted so is the electrical insulation interrupted. The result, predictable from the classical physics of electrical transmission lines and the electrical parameters of nerve fibers, is that the propagation of an electrical pulse along such nerve fibers occurs at a velocity much higher than that found in unmyelinated fibers.
Multiple sclerosis is a human disease characterized by the progressive loss of the myelin of the brain and spinal cord, with the physiological disruptions to be expected from such loss, considering the significance of myelin in the functioning of nerve cells. The cause of the disease is unknown, but an immunological abnormality is suspected. It has also been postulated that the cause is infection by a latent virus, with viral activation and expression triggering a secondary immune response. There is some evidence for genetic susceptibility, and there is also evidence that environment may be a factor, since the disease is 5 times more common in temperate climates than in the tropics.
The following points are made by D.C. Shields et al (Proc. Nat. Acad. Sci. 1999 96:11486):
1) In autoimmune demyelinating diseases such as multiple sclerosis, the degradation of myelin proteins results in the destabilization of the myelin sheath. Protein-degrading enzymes (proteases, proteinases) have been implicated in myelin protein degradation, and recent studies have demonstrated increased expression and activity of a calcium-activated neutral proteinase (calpain) in experimental allergic encephalomyelitis, the corresponding animal model of multiple sclerosis.
2) In the present study, calpain activity and expression were evaluated in white matter from human patients with multiple sclerosis and Parkinson's and Alzheimer's diseases and compared with that of white matter from normal controls. Analysis indicates that the active form of calpain and calpain-specific degradation products were increased by 90.1 percent and 52.7 percent, respectively, in multiple sclerosis plaques compared with normal white matter, and that calpain expression increased by more than a factor of 4 compared with normal white matter. Calpain activity and expression were not increased significantly in white matter from patients with Parkinson's or Alzheimer's diseases compared with that of normal controls.
3) The authors suggest that because calpain degrades all major myelin proteins, the increased activity and expression of this proteinase may play a critical role in the degradation of myelin in autoimmune demyelinating diseases such as multiple sclerosis.
Proc. Nat. Acad. Sci. http://www.pnas.org
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