Uniformed Services University of the Health Sciences
Department of Microbiology and Immunology
4301 Jones Bridge Road
Bethesda, Maryland 20814-4799
Phone: (301) 295-1958
Lab: (301) 295-3447
Fax: (301) 295-3773
Role of IgE in the Immune Response to Filariasis
M.D., Johns Hopkins University
Immune response to filariae
Our lab studies the immune response to filariae. Filariae are tissue-invasive roundworms which are transmitted by insects. Pathogenic human filariae include Wuchereria bancrofti and Brugia malayi, which cause lymphatic filariasis (elephantiasis), Onchocerca volvulus, the cause of river blindness, and Loa loa, which causes African eyeworm. Lymphatic filariasis alone affects approximately 120 million people world-wide and, after malaria, is the second-most burdensome parasitic disease as measured by disability-adjusted life years. Onchocerciasis affects 18 million people, causing blindness or severe visual impairment in 750,000 people, mostly in sub-Saharan Africa.
The immune response to filariae is markedly different than that to most viral, bacterial, and fungal infections. Like other helminths, filariae induce a type 2 immune response characterized by eosinophilia, elevated serum levels of Ag-specific and polyclonal IgE, and increases in T-cell production of IL-4, IL-5, and IL-13. Most interestingly, when a person is infected for a long time, the immune response to filarial worms diminishes, though the rest of the immune system continues to work well against other infections. While it is clear that IL-4 plays a central role in driving type 2 responses, the exact factors responsible for the initiation, maintenance, and eventual diminution of these responses in filarial infections remain unknown. The mission of our lab is to understand the mechanisms behind the development, maintenance, and cessation of IgE-mediated responses in filarial infections in order to ultimately develop new modalities of prevention and treatment for parasitic, allergic, and autoimmune diseases.
To accomplish this, our lab utilizes the Litomosoides sigmodontis model of filaria infection, the only mouse model of filariasis in which larvae fully complete their development from infective L3 stage larvae into mature, sexually reproducing adult filarial worms.
Protection against Type 1 diabetes by filariae
In addition to being advantageous for the survival of the parasite, immunomodulatory responses induced by parasitic worms may have beneficial effects for the host. Both animal and human studies have demonstrated that chronic parasitic worm infections are protective against autoimmune diseases. Recently, our laboratory has demonstrated that infection of non-obese diabeteic (NOD) mice with L. sigmodontis protects against the development of diabetes. This protection is associated with an increase in T-regulatory cell numbers and with an autoantigen-specific Th2 shift. Live infection is not required for protection, as injection of a crude homogenate of L. sigmodontis antigens also protects against diabetes. Currently, we are working to determine the mechanisms by which L. sigmodontis protects against the development of diabetes in NOD mice and to identify specific molecules of L. sigmodontis that can induce this protection.
In addition to mouse immunology, we also have ongoing collaborations for studies on human immunology. Specifically, we collaborate with Dr. Phil Cooper’s group in Ecuador to study the effects worm infections have on allergic responses and on the development of the immune system. Additionally, we have an ongoing collaboration with investigators at NIH evaluating the effects H2 receptor blockers have on the clinical course and immune function of patients with the hyper-IgE syndrome.
Larson, D., Cooper, P.J., Hübner, M.P., Reyes, J., Vaca, M., Chico, M., Kong, H.H., and Mitre, E. (2012) ?Helminth infection is associated with decreased basophil responsiveness in humans.? (in press, Journal of Allergy and Clinical Immunology)
Larson, D., Hübner, M.P., Torrero, M.N., Brankin, A., Swierczewski, B.E., Davies, S.J., Vonakis, B., and Mitre, E. (2012) ?Chronic helminth infection reduces basophil responsiveness in an IL-10 dependent manner.? Journal of Immunology [Epub ahead of print]
Santiago, H., LeeVan, E., Bennuru, S., Ribeiro-Gomes, F., Mueller, E., Wilson, M., Wynn, T., Garboczi, D., Urban, J., Mitre, E., and Nutman, T.B. (2012) ?Molecular mimicry between cockroach and helminth glutathione S-transferases promotes cross-reactivity and cross-sensitization in humans and mice.? (in press, Journal of Allergy and Clinical Immunology)
Larson, D. and Mitre, E. (2012) ?Histamine release and surface CD200R1 staining as sensitive methods for assessing murine mast cell activation.? Journal of Immunological Methods, 379 (1-2):15-22.
Hübner, M.P., Shi, Y., Torrero, M.N., Mueller, E., Larson, D., Soloviova, K., Gondorf, F., Hoerauf, A., Killoran, K.E., Stocker, J.T., Davies, S.J., Tarbell, K.V., and Mitre, E. (2012) ?Helminth protection against autoimmune diabetes in NOD mice is independent of a type 2 immune shift and requires TGFβ.? Journal of Immunology, 188:559-568.
Hübner, M.P., Larson, D., Mueller, E., Shi, Y., and Mitre, E. (2011) ?Anti-FcεR1 antibody injections activate basophils and mast cells and delay Type 1 diabetes in NOD mice.? Clinical Immunology, 141:205-17.
Cooper, P.J., Chico, M.E., Guadalupe, I., Sandoval, C.A., Mitre, E., Platts-Mills, T.A., Barreto, M.L., Rodrigues, L.C., Strachan, D.P., Griffin, G.E. (2011) ?Impact of early life exposures to geohelminth infections on the development of vaccine immunity, allergic sensitization, and allergic inflammatory diseases in children living in tropical Ecuador: the ECUAVIDA birth cohort study.? BMC Infectious Diseases, 11:184.
Teran, R., Mitre, E., Vaca, M., Erazo, S., Oviedo, G., Hubner, M.P., Chico, M.E., Mattapalil, J., Bickle, Q., Rodrigues, L.C., Cooper, P.J. (2011) ?Immune system development during early childhood in tropical Latin America: Evidence for the age-dependent down regulation of the innate immune response.? Clinical Immunology, 138(3):299-310.
Torrero, M.N., Hübner, M.P., Karasuyama, H., Larson, D., and Mitre, E. (2010) ?Basophils amplify type 2 immune responses, but do not serve a protective role, during chronic infection of mice with the filarial nematode Litomosoides sigmodontis.? Journal of Immunology, 185(12):7426-34.
de Oliveira Fraga LA, Torrero MN, Tocheva AS, Mitre, E, and Davies, SJ. (2010) “Induction of type 2 responses by schistosome worms during prepatent infection.” Journal of Infectious Diseases 201(3):464-72.
Hübner M.P., Torrero M.N., and Mitre, E. (2010) “Type 2 immune-inducing helminth vaccination maintains protective efficacy in the setting of repeated parasite exposures.” Vaccine 28(7):1746-1757.
Hübner, M.P., Torrero, M.N., McCall, J.W., and Mitre, E. (2009) “Litomosoides sigmodontis: A simple method to infect mice with L3 larvae obtained from the pleural space of recently infected jirds (Meriones unguiculatus).” Experimental Parasitology 123(1):95-8.
Hübner M.P., Stocker J., and Mitre, E. (2009) “Inhibition of Type I diabetes in filaria-infected NOD mice is associated with a Th2 shift and induction of FoxP3+ regulatory T cells.” Immunology 127(4):512-22.
Guadalupe I., Mitre, E., Benitez S., Chico M.E., Andrade L., Nutman T.B., and Cooper P.J. (2009) "Evidence for in utero sensitization to Ascaris lumbricoides in newborns of mothers infected with ascariasis." Journal of Infectious Diseases 199(12):1846-1850.
Torrero, M.N., Larson, D., Hübner, M.P., and Mitre, E. (2009) "CD200R surface expression as a marker of murine basophil activation. Clinical and Experimental Allergy 39(3):361-9.
Cooper P.J., Mitre, E., Moncayo, A.L., Chico M.E., Vaca, M.G., and Nutman, T.B. (<2008) "Ascaris lumbricoides-induced interleukin-10 is not associated with atopy in schoolchildren in a rural area of the tropics." Journal of Infectious Diseases 197(90):1333-1340.
Hübner M.P., Pasche B., Kalaydjiev S., Soboslay P.T., Lengeling A., Schulz-Key H., Mitre E., and Hoffmann, W.H. (2008) "Microfilariae of the filarial nematode Litomosoides sigmodontis exacerbate the course of LPS-induced sepsis in mice." Infection and Immunity 76(4):1668-77.
Mitre, E., Chien D., and Nutman, T.B.. (2008) "CD4+ (and not CD25+) T-cells are the predominant IL-10-producing cells in the circulation of filaria-infected patients." Journal of Infectious Diseases 197:94-101.
Mitre, E., Talaat K.R., Sperling M.R., Nash, T.E. (2007) "Methotrexate as a Corticosteroid-sparing Agent in Complicated Neurocysticercosis." Clinical Infectious Diseases 44:449-53.
Mitre, E. and Nutman, T.B. (2006) "IgE memory: persistence of antigen specific IgE responses years after treatment of human filarial infections." Journal of Allergy and Clinical Immunology 117(4):939-45.
Mitre, E. and Nutman, T.B. (2006). "Basophils, basophilia, and helminth infections."Chemical Immunology and Allergy 90:141-56.
Mitre, E., Norwood, S., and Nutman, T.B. (2005) "Saturation of IgE binding sites by polyclonal IgE does not explain the protective effect of helminth infections on atopy." Infection and Immunity 73:4106-4111.
Mitre, E. and Nutman, T.B. (2005). "Basophils and Eosinophils." in Microbiology and Microbial Infections. S. Kaufmann and M. Steward eds. Arnold, London, pp 56-78.
Mitre, E., Taylor, R.T., et al (2004). "Parasite antigen-driven basophils are a major source of IL-4 in human filarial infections." Journalof Immunology 172: 2439-2445.
Mitre, E., Thompson, R.W., et al (2003). "Majority of interferon-gamma-producing CD4+ cells in patients infected with human T cell lymphotropic virus do not express Tax protein." Journal of Infectious Diseases 188:428-32.
Mitre, E. and Nutman, T.B. (2003). "Lack of basophilia in human parasitic infections." AmericanJournal of Tropical Medicine and Hygiene 69 (1): 87-91.
Mitre, E. and Nutman, T.B. (2001). "Lymphatic Filariasis." Current Treatment Options in Infectious Diseases, 3: 337-344.
Sizemore, J. and Mitre, E. (2001). "Leg pain in a patient with chronic hepatitis C." Lancet, 357(9254): 440.