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      Association between parasite infection and immune responses in multiple sclerosis.

      Author(s):
      Publication date:
      Journal: Annals of Neurology
      Keywords: Adult, Antibody Formation, CD4-Positive T-Lymphocytes, metabolism, Cohort Studies, Disability Evaluation, Eosinophilia, etiology, Female, Follow-Up Studies, Forkhead Transcription Factors, Humans, Interleukin-10, Interleukin-2 Receptor alpha Subunit, Magnetic Resonance Imaging, Male, Multiple Sclerosis, Relapsing-Remitting, complications, diagnosis, immunology, physiopathology, Parasitic Diseases, Prospective Studies, T-Lymphocytes, Regulatory, Transforming Growth Factor beta

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          Abstract

          To assess whether parasite infection is correlated with a reduced number of exacerbations and altered immune reactivity in multiple sclerosis (MS). 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)-beta, and interferon-gamma 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. 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-beta and a decrease in IL-12 and interferon-gamma-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-beta 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-beta. Increased production of IL-10 and TGF-beta, together with induction of CD25+CD4+ FoxP3+ T cells, suggests that regulatory T cells induced during parasite infections can alter the course of MS.

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          CD4+CD25high regulatory cells in human peripheral blood.

          Andrew Allan, David A. Hafler, Emery Brown … (2001)
          Thymectomy in mice on neonatal day 3 leads to the development of multiorgan autoimmune disease due to loss of a CD(+)CD25(+) T cell regulatory population in their peripheral lymphoid tissues. Here, we report the identification of a CD4(+) population of regulatory T cells in the circulation of humans expressing high levels of CD25 that exhibit in vitro characteristics identical with those of the CD4(+)CD25(+) regulatory cells isolated in mice. With TCR cross-linking, CD4(+)CD25(high) cells did not proliferate but instead totally inhibited proliferation and cytokine secretion by activated CD4(+)CD25(-) responder T cells in a contact-dependent manner. The CD4(+)CD25(high) regulatory T cells expressed high levels of CD45RO but not CD45RA, akin to the expression of CD45RB(low) on murine CD4(+)CD25(+) regulatory cells. Increasing the strength of signal by providing either costimulation with CD28 cross-linking or the addition of IL-2 to a maximal anti-CD3 stimulus resulted in a modest induction of proliferation and the loss of observable suppression in cocultures of CD4(+)CD25(high) regulatory cells and CD4(+)CD25(-) responder cells. Whereas higher ratios of CD4(+)CD25(high) T cells are required to suppress proliferation if the PD-L1 receptor is blocked, regulatory cell function is shown to persist in the absence of the PD-1/PD-L1 or CTLA-4/B7 pathway. Thus, regulatory CD4 T cells expressing high levels of the IL-2 receptor are present in humans, providing the opportunity to determine whether alterations of these populations of T cells are involved in the induction of human autoimmune disorders.
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            Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease.

            G Monteleone, Thomas MacDonald, B. C. McKENZIE … (2001)
            TGF-beta1 functions as a negative regulator of T cell immune responses, signaling to target cells using the Smad family of proteins. We show here that Smad7, an inhibitor of TGF-beta1 signaling, is overexpressed in inflammatory bowel disease (IBD) mucosa and purified mucosal T cells. Both whole tissue and isolated cells exhibit defective signaling through this pathway, as measured by phospho-Smad3 immunoreactivity. Specific antisense oligonucleotides for Smad7 reduce Smad7 protein expression in cells isolated from patients with IBD, permitting the cells to respond to exogenous TGF-beta1. TGF-beta1 cannot inhibit proinflammatory cytokine production in isolated lamina propria mononuclear cells from patients with Crohn disease (CD), but inhibition of Smad7 restores TGF-beta1 signaling and enables TGF-beta1 to inhibit cytokine production. In inflamed mucosal tissue explants from patients with CD, inhibition of Smad7 also restores p-Smad3 and decreases proinflammatory cytokine production, an effect that is partially blocked by anti-TGF-beta1. These results show that Smad7 blockade of TGF-beta1 signaling helps maintain the chronic production of proinflammatory cytokines that drives the inflammatory process in IBD and that inhibition of Smad7 enables endogenous TGF-beta to downregulate this response.
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              Exposure to schistosome eggs protects mice from TNBS-induced colitis.

              Jie Li, Charles A. Blum, Khurram Qadir … (2003)
              Crohn's disease results from dysregulated T helper (Th)1-type mucosal inflammation. Crohn's disease is rare in tropical countries but prevalent in developed countries with temperate climates, in which its incidence rose after 1940. In contrast, exposure to helminthic parasites is common in tropical countries but is rare in developed countries. Helminthic parasites induce immunomodulatory T cell responses in the host. We hypothesize that immunomodulatory responses due to helminths may attenuate excessive Th1-type inflammation. To test that hypothesis, mice were exposed to eggs of the helminth Schistosoma mansoni and then challenged rectally with trinitrobenzesulfonic acid (TNBS) to induce colitis. Schistosome egg exposure attenuated TNBS colitis and protected mice from lethal inflammation. Schistosome egg exposure diminished IFN-gamma and enhanced IL-4 production from alphaCD3-stimulated spleen and mesenteric lymph node cells of TNBS-treated mice. Schistosome egg exposure decreased colonic IFN-gamma but increased IL-10 mRNA expression in TNBS-treated mice. Intact signal transducer and activator of transcription 6 was required for attenuation of colitis. Exposure to helminths can decrease murine colonic inflammation.
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                Author and article information

                Journal
                PubMed ID:: 17230481
                DOI:: 10.1002/ana.21067

                ScienceOpen disciplines: Chemistry
                Keywords: Adult,Antibody Formation,CD4-Positive T-Lymphocytes,metabolism,Cohort Studies,Disability Evaluation,Eosinophilia,etiology,Female,Follow-Up Studies,Forkhead Transcription Factors,Humans,Interleukin-10,Interleukin-2 Receptor alpha Subunit,Magnetic Resonance Imaging,Male,Multiple Sclerosis, Relapsing-Remitting,complications,diagnosis,immunology,physiopathology,Parasitic Diseases,Prospective Studies,T-Lymphocytes, Regulatory,Transforming Growth Factor beta
                Data availability:
                ScienceOpen disciplines: Chemistry
                Keywords: Adult, Antibody Formation, CD4-Positive T-Lymphocytes, metabolism, Cohort Studies, Disability Evaluation, Eosinophilia, etiology, Female, Follow-Up Studies, Forkhead Transcription Factors, Humans, Interleukin-10, Interleukin-2 Receptor alpha Subunit, Magnetic Resonance Imaging, Male, Multiple Sclerosis, Relapsing-Remitting, complications, diagnosis, immunology, physiopathology, Parasitic Diseases, Prospective Studies, T-Lymphocytes, Regulatory, Transforming Growth Factor beta

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