DNC News

 

MS Update: Siblings, Epstein-Barr virus and other links.

Subject: MS risk is linked to lack of younger siblings and later exposure to EBV.

In the last few months several new bits of information have been added to our understanding of the development of multiple sclerosis. Perhaps we can use this knowledge to lower risk of development and possibly think of new methods of treatment.

 

A week ago on January 27, JAMA published a study authored by Anne-Louise Ponsonby from Canberra , Australia that suggests the risk of developing MS varies with the number of younger sibling a person has. As peculiar as this may sound on first hearing, it is part of a growing hypothesis called the Hygiene Hypothesis, which is beginning to explain many of the auto-immune diseases and atopic disease. The theory is that early, frequent exposures to infectious agents prepare the immune system to fight off diseases rather than to turn against a person's own tissues. Getting sick as a kid trains the immune system to function and to do a better job later in life. Without the training provided by routine infections, the immune system doesn't know how to decide who is bad and who is good. Out of ignorance it attacks its own body.

 

These days most researchers consider MS to be an auto immune disease. The disease appears when the fatty sheaths that insulate nerve fibers are damaged by what is assumed to be a misled immune system. The symptoms of tremors, pain, loss of muscle control, and slurred speech all result from this nerve damage.

 

This new study suggests that childhood exposure to infants and the infections they spread could reduce the risk of developing MS. Ponsonby and her buds identified 136 people with MS in Tasmania and 272 matched controls. The number of preschool years up to age 6 were calculated when a person hung out with a sibling 2 years or younger. Once all the numbers were sorted out, the results were interesting. People who had less than one year of close contact with a young sibling had the highest risk of getting MS later in life, almost 8 times the risk of people who had spent more than 5 years with young siblings at home. The sibling-less folks were twice as likely to get MS as people who had young siblings around for 1 to 5 years. [1] [i]

 

This information comes in the wake of a number of studies published over the last few years linking MS to exposure to the Epstein-Barr virus. [2] [ii] When contacted early in childhood, this virus causes only mild, flu-like symptoms. But if a person gets an Epstein-Barr infection after adolescence, the virus can cause infectious mononucleosis. Nearly all of the study participants in the JAMA study had been exposed to the virus at some point. But the MS patients were more than twice as likely to have had full blown mononucleosis, suggesting they had caught the infection later in life. This same link between EBV and MS has been shown in children. [3] [iii] . Nor is this the first study to link later onset of EBV infection with MS, earlier ones had reported a similar association to age of infection. [4] [iv]

 

Similar hygiene theories of the relationship between infectious disease exposure have been put forward for other autoimmune disease. A French paper on the relationship with Type I diabetes was published last fall. [5] [v] At least in mice, it appears that the development of diabetes can actually be halted by giving the mice a Salmonella infection. [6] [vi]

The same story seems valid with inflammatory bowel diseases. The hygiene hypothesis has been used to explain Crohn's disease and a February, 2005 study showed that a therapeutically administered parasitic infections could rebalance the gut immune function and be used clinically to treat Crohn's disease. [7] [vii] The balance of bacteria living in the gut is associated with risk of developing airways diseases such as asthma; the question being asked now is how much they affect general immune function. [8] [viii] We've been working on the assumption that this is true for years. Our clinical practices are gaining support from published papers pointing at the role gut bacteria have in moderating the balance of the immune system in general. [9] [ix]

 

Of course all of you remember my earlier letter on the relationship between latitude, sun exposure and vitamin D levels with MS development. The obvious question then is whether vitamin D status changes Epstein Barr development? So far I haven't found a paper on this topic and I don't know whether anyone has asked the question.

 

Stay tuned, we'll let you know.

 

References:

[1] JAMA. 2005 Jan 26;293(4):463-9.

Exposure to infant siblings during early life and risk of multiple sclerosis.

Ponsonby AL, van der Mei I, Dwyer T, Blizzard L, Taylor B, Kemp A, Simmons R, Kilpatrick T.

 

[2] JAMA. 2003 Mar 26;289(12):1533-6.

Multiple sclerosis and Epstein-Barr virus.

Levin LI, Munger KL, Rubertone MV, Peck CA, Lennette ET, Spiegelman D, Ascherio A.

[3] JAMA. 2004 Apr 21;291(15):1875-9.

Epstein-Barr virus in pediatric multiple sclerosis.

Alotaibi S, Kennedy J, Tellier R, Stephens D, Banwell B.

[4] Acta Neurol Scand. 2004 Apr;109(4):270-5.

A role of late Epstein-Barr virus infection in multiple sclerosis.

Haahr S, Plesner AM, Vestergaard BF, Hollsberg P.

  

[5] Clin Dev Immunol. 2004 Sep-Dec;11(3-4):191-4.

On the mechanisms of the protective effect of infections on type 1 diabetes.

Feillet H, Bach JF.

 

[6] Eur J Immunol. 2004 Nov;34(11):3246-56. Related Articles, Links

Salmonella typhimurium infection halts development of type 1 diabetes in NOD mice.

Zaccone P, Raine T, Sidobre S, Kronenberg M, Mastroeni P, Cooke A.

 

[7] [7] Inflamm Bowel Dis. 2005 Feb;11(2):178-84.

Gastrointestinal parasites: potential therapy for refractory inflammatory bowel diseases.

Moreels TG, Pelckmans PA.

 

[8] Trends Microbiol. 2004 Dec;12(12):562-8.

Does the microbiota regulate immune responses outside the gut?

Noverr MC, Huffnagle GB.

 

[9] Can J Gastroenterol. 2004 Aug;18(8):493-500.

Bacterial colonization and the development of intestinal defences.

Shi HN, Walker A.

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Abstracts of References:

[i] JAMA. 2005 Jan 26;293(4):463-9.

Exposure to infant siblings during early life and risk of multiple sclerosis.

Ponsonby AL, van der Mei I, Dwyer T, Blizzard L, Taylor B, Kemp A, Simmons R, Kilpatrick T.

 

National Centre for Epidemiology and Population Health, The Australian National University , Canberra ACT, Australia . anne-louise.ponsonby@anu.edu.au

 

CONTEXT: The "hygiene hypothesis" has implicated sibship as a marker of infection load during early life and suggests that exposure or reexposure to infections can influence the developing immune system. Viral infection has also been implicated in the pathogenesis of multiple sclerosis (MS). OBJECTIVES: 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. DESIGN, SETTING, AND PATIENTS: Population-based case-control study in Tasmania , Australia , from 1999 to 2001 based on 136 cases of magnetic resonance imaging-confirmed MS and 272 community controls, matched on sex and year of birth. MAIN OUTCOME MEASURE: Risk of MS by duration of contact with younger siblings aged less than 2 years in the first 6 years of life. RESULTS: Increasing duration of contact with a younger sibling aged less than 2 years in the first 6 years of life was associated with reduced MS risk (adjusted odds ratios [AORs]: <1 infant-year, 1.00 [reference]; 1 to <3 infant-years, 0.57 [95% confidence interval {CI}, 0.33-0.98]; 3 to <5 infant-years, 0.40 [95% CI, 0.19-0.92]; > or =5 infant-years, 0.12 [95% CI, 0.02-0.88]; test for trend, P = .002). A history of exposure to infant siblings was associated with a reduced IgG response to EBV among controls. Controls with at least 1 infant-year contact had a reduced risk of infectious mononucleosis and a reduced risk of very high composite EBV IgG titers (AOR, 0.33; 95% CI, 0.11-0.98) compared with other controls. The inverse association between higher infant contact and MS was independent of EBV IgG titer. CONCLUSION: Higher infant sibling exposure in the first 6 years of life was associated with a reduced risk of MS, possibly by altering childhood infection patterns and related immune responses.

 

PMID: 15671431 [PubMed - indexed for MEDLINE]

[ii] JAMA. 2003 Mar 26;289(12):1533-6.

Comment in:

JAMA. 2003 Jul 9;290(2):192-3; author reply 193.

JAMA. 2003 Jul 9;290(2):192; author reply 193.

Multiple sclerosis and Epstein-Barr virus.

 

Levin LI, Munger KL, Rubertone MV, Peck CA, Lennette ET, Spiegelman D, Ascherio A.

 

Division of Preventive Medicine, Walter Reed Army Institute of Research, Washington , DC , USA .

 

CONTEXT: Infection with Epstein-Barr virus (EBV) has been associated with an increased risk of multiple sclerosis (MS), but the temporal relationship remains unclear. OBJECTIVE: To determine whether antibodies to EBV are elevated before the onset of MS. DESIGN, SETTING, AND POPULATION: Nested case-control study conducted among more than 3 million US military personnel with blood samples collected between 1988 and 2000 and stored in the Department of Defense Serum Repository. Cases were identified as individuals granted temporary or permanent disability because of MS. For each case (n = 83), 2 controls matched by age, sex, race/ethnicity, and dates of blood sample collection were selected. MAIN OUTCOME MEASURES: Antibodies including IgA against EBV viral capsid antigen (VCA) and IgG against VCA, nuclear antigens (EBNA complex, EBNA-1, and EBNA-2), diffuse and restricted early antigens, and cytomegalovirus. RESULTS: The average time between blood collection and MS onset was 4 years. The strongest predictors of MS were serum levels of IgG antibodies to VCA or EBNA complex. The risk of MS increased monotonically with these antibody titers; relative risk (RR) in persons in the highest category of VCA (> or =2560) compared with those in the lowest (< or =160) was 19.7 (95% confidence interval [CI], 2.2-174; P for trend =.004). For EBNA complex titers, the RR for those in the highest category (> or =1280) was 33.9 (95% CI, 4.1-283; P for trend <.001) vs those in the lowest category (< or =40). Similarly strong positive associations between EBV antibodies and risk of MS were already present in samples collected 5 or more years before MS onset. No association was found between cytomegalovirus antibodies and MS. CONCLUSION: These results suggest a relationship between EBV infection and development of MS.

 

PMID: 12672770 [PubMed - indexed for MEDLINE]

[iii] JAMA. 2004 Apr 21;291(15):1875-9.

Epstein-Barr virus in pediatric multiple sclerosis.

Alotaibi S, Kennedy J, Tellier R, Stephens D, Banwell B.

 

Department of Pediatrics(Neurology), Al-Sabah Hospital , Shuwaikh , Kuwait

 

CONTEXT: Infection with common viruses, particularly Epstein-Barr virus (EBV), has been postulated to contribute to the pathobiology of multiple sclerosis (MS). Detailed virological studies in pediatric MS have not been previously reported. OBJECTIVE: To evaluate whether children with MS are more likely to be seropositive for EBV or other common viruses than their healthy age-matched peers. DESIGN, SETTING, AND PATIENTS: Case-control study of viral samples collected from March 1994 to February 2003 from 30 pediatric MS patients, 90 emergency department controls matched 3:1 with the MS patients by year of birth, and 53 healthy control children. MAIN OUTCOME MEASURES: Archived serum samples were analyzed for the presence of IgG antibodies directed against EBV viral capsid antigens, nuclear antigens, and early antigens, cytomegalovirus, parvovirus B19, herpes simplex virus, and varicella zoster. RESULTS: Serological evidence for remote EBV infection was present in 83% of pediatric MS patients compared with 42% of emergency department and healthy controls (P<.001). Five pediatric MS patients were negative for all 3 EBV antigens. Pediatric MS patients were less likely than controls to have been exposed to herpes simplex virus (P =.003), while seropositivity for cytomegalovirus, parvovirus B19, and varicella zoster did not differ between MS patients and controls. CONCLUSION: These results suggest an association between EBV infection and pediatric MS.

 

PMID: 15100207 [PubMed - indexed for MEDLINE]

[iv] Acta Neurol Scand. 2004 Apr;109(4):270-5.

A role of late Epstein-Barr virus infection in multiple sclerosis.

Haahr S, Plesner AM, Vestergaard BF, Hollsberg P.

 

Department of Medical Microbiology and Immunology, University of Aarhus , Aarhus , Denmark . sven.haahr@stofanet.dk

 

OBJECTIVE: To assess Epstein-Barr virus (EBV) seroconversion in a high multiple sclerosis (MS) prevalence area and to evaluate the recall of diagnosed infectious mononucleosis in MS patients. METHODS: The study was based on information or blood samples, or both, from schoolchildren, young MS patients and matched controls. EBV serology was performed on 1154 blood samples. RESULTS : We demonstrate that more than one third of the population in a high MS prevalence area is seronegative to EBV at puberty. This is in contrast to the virtually complete seroconversion to EBV early in life in individuals from areas with a low prevalence of MS. Furthermore, we demonstrate that recall of diagnosed infectious mononucleosis (IM), but not recall of common childhood diseases, is significantly more frequent among MS patients than healthy controls. All MS patients, including patients without prior immunosuppressive treatment, were EBV seropositive. CONCLUSION: During or after puberty, EBV is transmitted to a major proportion of the population in an MS high-prevalence area. Together with our previous documentation of an association between late infection with EBV and an increased risk of developing MS, these data support a role of EBV infection in MS.

 

PMID: 15016009 [PubMed - indexed for MEDLINE]

[v] Clin Dev Immunol. 2004 Sep-Dec;11(3-4):191-4.

On the mechanisms of the protective effect of infections on type 1 diabetes.

Feillet H, Bach JF.

Necker Hospital , INSERM U580, 161 rue de Sevres , 75015 Paris , France .

 

The incidence of type 1 diabetes (T1D) shows a worrying tendency for a steady increase in Western countries. Along the line of the hygiene hypothesis, evidence accumulates to suggest that this increase is explained by the decrease of infections due to improved hygiene and medical care. This article presents a review of epidemiological data and of the main putative underlying cellular and molecular mechanisms.

 

PMID: 15559363 [PubMed - indexed for MEDLINE]

 

[vi] Eur J Immunol. 2004 Nov;34(11):3246-56. Related Articles, Links

Salmonella typhimurium infection halts development of type 1 diabetes in NOD mice.

Zaccone P, Raine T, Sidobre S, Kronenberg M, Mastroeni P, Cooke A.

 

Immunology Division, Department of Pathology, University of Cambridge , Cambridge , UK .

 

Infectious disease has been proposed as an environmental modifier of autoimmunity in both human populations and the NOD mouse. We found that infection of NOD mice with attenuated, but not killed, Salmonella typhimurium can reduce the incidence of type 1 diabetes (T1D), even if infection occurs after the development of a peri-islet pancreatic infiltrate. Functional diabetogenic effector T cells are still present, as demonstrated by the initiation of diabetes in NOD-scid recipients of transferred splenocytes. High levels of IFN-gamma are secreted by splenocytes of infected mice, but there is no evidence of involvement of IL-10 in the protective effect of the infection. Finally, prolonged changes in cell subsets are observed in infected mice involving invariant Valpha14Jalpha281 NuKappaTau and dendritic cells. These data reinforce the idea that prevention of T1D in the NOD mouse cannot be reduced to the simple Th1/Th2 paradigm and that different infections may involve different protective mechanisms.

 

PMID: 15376194 [PubMed - indexed for MEDLINE]

[vii] Inflamm Bowel Dis. 2005 Feb;11(2):178-84.

Gastrointestinal parasites: potential therapy for refractory inflammatory bowel diseases.

Moreels TG, Pelckmans PA.

From the Department of Gastroenterology and Hepatology, University Hospital Antwerp , Antwerp , Belgium .

 

Crohn's disease and ulcerative colitis are chronic relapsing inflammatory bowel diseases (IBDs). Different pharmacological agents are currently used in several combinations to control the inflammatory process. Recently, antibodies against the proinflammatory cytokine tumor necrosis factor-alpha appeared to be very effective in treating patients with Crohn's disease. However, due to the fact that the pathogen causing IBD is still unknown, no causative treatment is currently available that is able to make the disease disappear. Recently, the hygiene hypothesis of the development of immunological diseases was proposed, stating that raising children in extremely hygienic environments with less exposure to parasite infections may negatively affect the development of the immune system, predisposing them to immunologic diseases such as IBD. This hypothesis is supported by experimental data showing that helminthic parasites protect against T helper (TH) type 1 cell-mediated gastrointestinal inflammations like Crohn's disease. Both TH-2 cells and regulatory T cells may be involved in this immunomodulatory mechanism. Here, we review the experimental and clinical studies in favor of the hygiene hypothesis, opening perspectives on new therapies for IBD.

 

PMID: 15677912 [PubMed - in process]

[viii] Trends Microbiol. 2004 Dec;12(12):562-8.

Does the microbiota regulate immune responses outside the gut?

Noverr MC, Huffnagle GB.

 

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-0642, USA.

 

Perturbations in the gastrointestinal (GI) microbiota composition that occur as a result of antibiotics and diet in "westernized" countries are strongly associated with allergies and asthma ("hygiene hypothesis"). The microbiota ("microflora") plays a crucial role in the development of mucosal tolerance, including the airways. Significant attention has been focused on the role of the microbiota in GI development, immune adaptation and initiation of GI inflammatory diseases. This review covers the post-developmental functions that the microbiota plays in regulating immunological tolerance to allergen exposure outside the GI tract and proposes the question: is the microbiota a major regulator of the immune system?

 

PMID: 15539116 [PubMed - in process]

[ix] Can J Gastroenterol. 2004 Aug;18(8):493-500. Bacterial colonization and the development of intestinal defences.

Shi HN, Walker A.

 

Mucosal Immunology Laboratory, Combined Program in Pediatric Gatroenterology , Massachusetts General Hospital and Harvard Medical School , Charlestown , Massachusetts 02129 , USA .

 

In humans, intestinal defences develop during gestation and, at full term, have the capacity to respond in an appropriate manner to infectious agents and foreign antigens. Before an active protective response can occur, however, the gut must first be exposed to colonizing bacteria. Colonization with diverse intestinal microbes is necessary for the development of important gut defenses such as the synthesis and secretion of polymeric immunoglobulin A and the generation of a balanced T helper (Th) cell response. Insights into normal immune physiological development of the gut have been made by studying the germ-free animal and intestinal defenses. These studies have provided insights into the physiology of immune responses. Two important immunological functions are the secretion of polymeric immunoglobulin A to protect the intestinal surface against harmful stimuli and inhibition of the systemic response to commensal bacteria and food proteins (eg, oral tolerance) to prevent chronic inflammation. Neither function exists in the germ-free state, but rapidly develops after conventionalization (colonization) of the germ-free animal. In the present review, the importance of bacterial colonization on the appearance of normal mucosal immune function and to the clinical consequences of inadequate colonization to the development of disease will be discussed. For example, excessive Th2 activity can lead to atopy, whereas Th1 predominance is found in conditions such as Helicobacter pylori gastritis and Crohn's disease. With the eradication of infectious diseases in developed countries in the past three decades, the incidence of atopic and autoimmune diseases has increased. This epidemiological observation has been explained by the 'hygiene hypothesis', which suggests that a reduction in microbial burden by public health measures has contributed to an immunological imbalance in the intestine. A family of pattern recognition receptors (Toll-like receptors) on gut lymphoid and epithelial cells mediates innate immune responses to bacterial molecular patterns and, thereby, orchestrates acquired immunity. As the role of bacterial communication within the gut (bacterial-epithelial cross-talk) is clarified, physicians should be able to modulate gut immune responses, for example, by the use of probiotics.


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