Association between parasite infection and immune responses in multiple sclerosis
Jorge Correale, MD , Mauricio Farez, MD.
Department of Neurology, Raúl Carrea Institute for Neurological Research (FLENI), Buenos Aires, Argentina
Publish: Annals of Neurology Volume 61 Issue 2, Pages 97 – 108
Objective: To assess whether parasite infection is correlated with a reduced number of exacerbations and altered immune reactivity in multiple sclerosis (MS).
Methods: A prospective, double-cohort study was performed to assess the clinical course and radiological findings in 12 MS patients presenting associated eosinophilia. All patients presented parasitic infections with positive stool specimens. In all parasite-infected MS patients, the eosinophilia was not present during the 2 previous years. Eosinophil counts were monitored at 3- to 6-month intervals. When counts became elevated, patients were enrolled in the study. Interleukin (IL)-4, IL-10, IL-12, transforming growth factor (TGF)-ß, and interferon-γ production by myelin basic protein–specific peripheral blood mononuclear cells were studied using enzyme-linked immunospot (ELISPOT). FoxP3 and Smad7 expression were studied by reverse transcriptase polymerase chain reaction.
Results: During a 4.6-year follow-up period, parasite-infected MS patients showed a significantly lower number of exacerbations, minimal variation in disability scores, as well as fewer magnetic resonance imaging changes when compared with uninfected MS patients. Furthermore, myelin basic protein–specific responses in peripheral blood showed a significant increase in IL-10 and TGF-ß and a decrease in IL-12 and interferon-γ–secreting cells in infected MS patients compared with noninfected patients. Myelin basic protein–specific T cells cloned from infected subjects were characterized by the absence of IL-2 and IL-4 production, but high IL-10 and/or TGF-ß secretion, showing a cytokine profile similar to the T-cell subsets Tr1 and Th3. Moreover, cloning frequency of CD4+ CD25+ FoxP3+ T cells was substantially increased in infected patients compared with uninfected MS subjects. Finally, Smad7 messenger RNA was not detected in T cells from infected MS patients secreting TGF-ß.
Interpretation: Increased production of IL-10 and TGF-ß, together with induction of CD25+ CD4+ FoxP3+ T cells, suggests that regulatory T cells induced during parasite infections can alter the course of MS.
Helminth Infections Associated with Multiple Sclerosis Induce Regulatory B Cells
Jorge Correale, MD,1 Mauricio Farez, MD,1 and Gabriela Razzitte, PhD2
Objective: To assess the importance of B-cell control during parasite infections in multiple sclerosis (MS) patients.
Methods: Peripheral blood CD19+ B cells from 12 helminth-infected MS patients, 12 MS patients without infection, 10 patients infected with Trypanosoma cruzi, 8 subjects infected with Paracoccidioides brasiliensis, and 12 healthy control subjects were purified using magnetic cell sorting. Interleukin (IL)-4, IL-6, IL-10, tumor necrosis factor-α, lymphotoxin, transforming growth factor-Β, brain-derived neurotrophic factor, and nerve growth factor secretion were evaluated after stimulation with CDw32 L cells and CD40 antibody using enzyme-linked immunosorbent assays. The production of anti–myelin oligodendro- cyte glycoprotein IgG and IgM antibodies was evaluated by enzyme-linked immunosorbent spot assays. Cell phenotype was assessed by flow cytometry.
Results: Helminth infections in MS patients created a B-cell population producing high levels of IL-10, dampening harmful immune responses through a mechanism mediated, at least in part, by the ICOS-B7RP-1 pathway. The IL-10 –producing B-cell phenotype detected expressed high levels of CD1d and was similar to the one observed in mature naive B2 cells (namely, CD11b-, CD5-, CD27-, and IgD+). Moreover, B cells isolated from helminth-infected MS patients also produced greater amounts of brain-derived neurotrophic factor and nerve growth factor compared with those of normal subjects, T. cruzi–infected subjects, P. brasiliensis–infected subjects, or uninfected MS patients, raising the possibility that these cells may exert a neuro-protective effect on the central nervous system.
Interpretation: Increased production of B-cell–derived IL-10 and of neurotrophic factors are part of the parasite’s regulation of host immunity and can alter the course of MS, potentially explaining environmental-related MS suppression observed in areas with low disease prevalence.
Multiple sclerosis and the hygiene hypothesis
John O. Fleming, MD; and Thomas D. Cook, PhD
University of Wisconsin Medical School, Madison.
In 1966 Leibowitz et al. 1 first suggested that the prevalence of MSwas correlated with a childhood environment characterized by ahigh level of sanitation. Similar observations have led to the for-mulation of the hygiene hypothesis, which holds that a relativelack of “evolutionarily normal” childhood infectious exposures maypredispose susceptible individuals to allergic and autoimmune dis-eases later in life. Recent findings that are consistent with thehygiene hypothesis have come from studies in epidemiology, im-munology, and animal models, as well as successful clinical trialsof probiotic treatment for allergic and autoimmune diseases….
Immunomodulation of experimental autoimmune encephalomyelitis by helminth ova immunization
Diane Sewell, Zhu Qing, Emily Reinke, David Elliot, Joel Weinstock,
Matyas Sandor1 and Zsuzsa Fabry11 Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53706, USA
2 Department of Internal Medicine, University of Iowa,Abstract
Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS) characterized by chronic in¯ammatory demyelination of the central nervous system (CNS). The pathology of EAE involves autoimmune CD4+ Th1 cells. There is a striking inverse correlation between the occurrence of parasitic and autoimmune diseases. We demonstrate that in mice with Schistosoma mansoni ova immunization, the severity of EAE is reduced as measured by decreased clinical scores and CNS cellular in®ltrates. Disease suppression is associated with immune deviation in the periphery and the CNS, demonstrated by decreased IFN-g and increased IL-4, transforming growth factor-b and IL-10 levels in the periphery, and increased frequency of IL-4 producing neuroantigen-speci®c T cells in the brain. S. mansoni helminth ova treatment in¯uence dthe course of EAE in wild-type mice, but not in STAT6-de®cient animals. This indicates that STAT6 plays a critical role in regulating the ameliorating effect of S. mansoni ova treatment on the autoimmune response, and provides the direct link between helminth treatment, Th2 environment and improved EAE. As some intestinal helminthic infections induce minimal pathology, they might offer a safe and inexpensive therapy to prevent and/or ameliorate MS.
Schistosomiasis Decreases Central Nervous System Inflammation and Alters the Progression of Experimental Autoimmune Encephalomyelitis
Anne Camille La Flamme,* Kate Ruddenklau,and B. Thomas Backstrom
Wellington School of Medicine, Wellington, New Zealand
Abstract
A preestablished infection with the parasitic helminth, Schistosoma mansoni, significantly reduced the incidence and delayed the onset of experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice immunized with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide. The altered disease progression was not solely due to the induction of a strong Th2 response, since intraperitoneal injection of schistosome eggs did not affect disease development. MOG-specific gamma interferon (IFN-
Parasitic worms may lead to treatment for multiple sclerosis
MS Society about Nottingham’s University Study
http://www.mssociety.org.uk/news_events/news/press_releases/wirms.html