Arbeitgruppe: Arbeitsgruppe Breloer (Helminthen-Immunologie)
Arbeitsgruppe Breloer (Helminthen-Immunologie)

Open PhD Position

In new research project HYBRIDS - chances and challenges of novel genetic combinations

The specific task of the PhD student will be the analysis of immune competence as a putative driving force in the preservation  of  primate  diversity  using  the  species-rich genus Microcebus in  Madagascar  and supporting laboratory mouse models.

For further information see the  BNITM job advertisement

and the webpage of HYBRIDS.

Overview

One-third of the world population is infected with parasitic worms, called helminths. To avoid being eliminated these parasites actively dampen the immune response of their hosts. This helminth-induced immune modulation also suppresses immune responses to third-party antigens. As a consequence, helminth-infected people may not mount successful immune responses to concomitant infections or to vaccinations. We employ the nematodes Strongyloides ratti and Litomosoides sigmodontis to investigate helminth-induced immune modulation in the mouse system. We are interested in the mechanisms of helminth-induced immune evasion and the impact of pre-existing helminth infections on vaccination efficiency.

Research Projects

Regulatory receptors in helminth-induced immune evasion

The mammalian immune system is a complex network of activating and inhibiting regulatory circuits that allow the rapid induction of immune responses to pathogens while facilitating homeostasis in the absence of infection. B and T-lymphocyte attenuator (BTLA, CD272) is an Ig domain superfamily protein that delivers inhibitory signals via an intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM) upon engagement by its ligand, herpes virus entry mediator (HVEM). Helminths exploit these regulatory pathways to dampen the immune response directed against them.

Infection with the parasitic nematode Strongyloides ratti induced up-regulation of the co-inhibitory receptor BTLA predominantly on CD4+ T cells but also on a small fraction of innate leukocytes. Deficiency of either BTLA or its ligand HVEM resulted in reduced numbers of parasitic adults in the small intestine and reduced larval output throughout infection. Reduced parasite burden in BTLA- and HVEM-deficient mice was accompanied by accelerated degranulation of mucosal mast cells and increased antigen-specific production of the mast cell activating cytokine IL-9. Our combined results support a model where BTLA on CD4+ T cells and additional innate leukocytes is triggered by HVEM and delivers negative signals into BTLA+ cells, thereby interfering with the protective immune response to this intestinal parasite (Breloer 2015).

Regulatory T cells and IL-10 in helminth-induced immune evasion

We observe a transient expansion of Foxp3+ regulatory T cell (Treg) numbers in mice during infection with the nematode Strongyloides ratti (Blankenhaus 2011, 2014). Treg expandend with similar kinetics and suppressed most features of the nematode-specific immune response in two different mouse strains, BALB/c and C57BL/6. One central factor of this immune response i.e. IL-9 driven rapid degranulation of mast cells was suppressed by parasite-induced Treg in BALB/c mice non-redundantly. Consequently Treg depletion elevated IL-9 production, accelerated mast cell degranulation and led to rapid expulsion of S. ratti in BALB/c mice. Interestingly, S. ratti-infected C57BL/6 mice still displayed low IL-9 production and delayed mast cell degranulation in the absence of Treg. Thus S. ratti was able to complete its life cycle in Treg-depleted C57BL/6 mice. This study shows that parasitic worms delay their expulsion by overactivating regulatory elements of their host`s immune system such as Treg. The importance of individual regulatory elements depends on their degree of redundancy within the host that is variable in different genetic backgrounds.

Infection with Litomosoides sigmodontis induced production of the regulatory cytokine Interleukin-10 by several leukocyte subsets. Using cell type-specific IL-10-deficient mice we disected the different functions of IL-10 derived from different sources. Selectively T-cell-derived but not B-cell-derived IL-10 suppressed the parasite-specific T cell response during infection (Haben 2013). These findings add another layer of complexity to the network of immune regulation by demonstrating that the function of a cytokine partly depends on its source.

Interference with vaccination efficiency

Chronic helminth infections induce immune suppresssion that can impair responses to vaccines or seccondary infections. Nematode-infected mice still controlled co-infections with Plasmodium or Leishmania although the respective immune responses interfered with each other (Kolbaum 2011; Kolbaum 2012a).

The antibody response to experimental vaccinations, in contrast, was drastically reduced in nematode-infected mice (Hartmann 2011; Hartmann 2012; Haben 2014). The nematode did not target the antibody-producing B cells directly but interfered with the expansion of accessory T helper cells. Although host Tregs did not mediate the parasite-induced inhibition of T helper cell proliferation, host-derived IL-10 was critical for suppression of proliferation in transferred T helper cells. Using a reductionist system of adoptive T cell transfer, we show that presence of parastic worms are tranlated to suppression of T helper cells via a two-staged process. Parasite productes first engage TGFß receptor on host derived T cells that are central for suppression. In a seccond step host-derived T cells produce IL-10 that subsequently suppress proliferation of adoptively transferred ovalbumin-specific T cells (Hartmann 2015). These data provide insight into the impaired vaccine efficiency observed in individuals hosting nematodes. This was also relevant in clinical settings. An experimental vaccination against malaria induced reduced numbers of Plasmodium-specific cytotoxic T cells and reduced protection against the liver phase of Plasmodium berghei infection in mice with pre-existing nematode infection compared to non-infected mice (Kolbaum 2012b).

Heat shock protein based vaccinations against the Strongyloides ratti infection itself elicited a type 1 immune response and did not confer any protection. Either diversion of the vaccination response towards a type-2 immune response or passive immunisation using heat shock protein-specific monoclonal antibodies reduced the worm burden during challenge infection (Nouir 2012a; Nouir 2012b).

Publication Highlights

Arbeitsgruppe Breloer (Helminthen-Immunologie)

Mucosal mast cells are indispensable for the timely termination of Strongyloides ratti infection
Reitz M, Brunn ML, Rodewald HR, Feyerabend TB, Roers A, Dudeck A, Voehringer D, Jönsson F, Kühl AA, Breloer M
Mucosal Immunol. 2016 Jul 6. doi: 10.1038/mi.2016.56. [Epub ahead of print]

Litomosoides sigmodontis induces TGF-beta receptor responsive, IL-10-producing T cells that suppress bystander T-cell proliferation in mice
Hartmann, W., Schramm, C. and Breloer, M
European Journal of Immunology 2015, 45: 2568-2581

Cutting Edge: The BTLA-HVEM Regulatory Pathway Interferes with Protective Immunity to Intestinal Helminth Infection
Breloer, M., W. Hartmann, B. Blankenhaus, M. L. Eschbach, K. Pfeffer, and T. Jacobs
Journal of Immunology 2015: 194: 1413-1416.

Foxp3+ regulatory T cells delay expulsion of intestinal nematodes by suppression of IL-9-driven mast cell activation in BALB/c but not in C57BL/6 mice
Blankenhaus B, Reitz M, Brenz Y, Eschbach ML, Hartmann W, Haben I, Sparwasser T, Huehn J, Kühl A, Feyerabend T, Rodewald H-R and Breloer M
Plos Pathogens 2014 DOI: 10.1371/journal.ppat.1003913

T-cell-derived, but not B-cell-derived, IL-10 suppresses antigen-specific T-cell responses in Litomosoides sigmodontis-infected mice
Haben I, Hartmann W, Specht S, Hoerauf A, Roers A, Müller W, Breloer M.
Eur J Immunol. 2013 Jul;43(7):1799-805. doi: 10.1002/eji.201242929

Nematode-induced interference with the anti-Plasmodium CD8+ T-cell response can be overcome by optimizing antigen administration
Kolbaum J, Tartz S, Hartmann W, Helm S, Nagel A, Heussler V, Sebo P, Fleischer B, Jacobs T, Breloer M
Eur J Immunol. 2012 Apr;42(4):890-900. doi: 10.1002/eji.201141955.

Pathogenic nematodes suppress humoral responses to third-party antigens in vivo by IL-10-mediated interference with Th cell function
Hartmann, W., I. Haben, B. Fleischer, and M. Breloer
J Immunol. 2011 Oct 15;187(8):4088-99. doi: 10.4049/jimmunol.1004136



All Publications

2016

Filariae-retrovirus co-infection in mice is associated with suppressed virus-specific IgG immune response and higher viral loads
Dietze KK, Dittmer U, Koudaimi DK, Schimmer S, Reitz M, Breloer M* and Hartmann W*
PLoS Neglected Tropical Diseases 2016; 10(12): e0005170

Mucosal mast cells are indispensable for the timely termination of Strongyloides ratti infection
Reitz M, Brunn ML, Rodewald HR, Feyerabend TB, Roers A, Dudeck A, Voehringer D, Jönsson F, Kühl AA, Breloer M
Mucosal Immunol. 2016 Jul 6. doi: 10.1038/mi.2016.56. [Epub ahead of print]

Strongyloides infection in rodents: immune response and immune regulation
Breloer M and Abraham D
Parasitology. 2016 Feb 24:1-21. [Epub ahead of print]

Functional characterization and immune recognition of the extracellular superoxide dismutase from the human pathogenic parasite Onchocerca volvulus (OvEC-SOD)
Ajonina-Ekoti I, Ndjonka D, Tanyi MK, Wilbertz M, Younis AE, Boursou D, Kurosinski MA, Eberle R, Lüersen K, Perbandt M, Breloer M, Brattig NW, Liebau E
Acta Trop. 2016 Sep;161:114. doi: 10.1016/j.actatropica.2016.05.019. Epub 2016 Jun 20

2015

Litomosoides sigmodontis induces TGF-beta receptor responsive, IL-10-producing T cells that suppress bystander T-cell proliferation in mice
Hartmann, W., Schramm, C. and Breloer, M.
European Journal of Immunology 2015 Sep;45(9):2568-81. doi: 10.1002/eji.201545503.

Cutting Edge: The BTLA-HVEM Regulatory Pathway Interferes with Protective Immunity to Intestinal Helminth Infection
Breloer, M., W. Hartmann, B. Blankenhaus, M. L. Eschbach, K. Pfeffer, and T. Jacobs.
Journal of Immunology 2015: 194: 1413-1416

Protein kinase CK2 enables regulatory T cells to suppress excessive T2 responses in vivo
Ulges, A., M. Klein, S. Reuter, B. Gerlitzki, M. Hoffmann, N. Grebe, V. Staudt, N. Stergiou, T. Bohn, T. J. Bruhl, S. Muth, H. Yurugi, K. Rajalingam, I. Bellinghausen, A. Tuettenberg, S. Hahn, S. Reissig, I. Haben, F. Zipp, A. Waisman, H. C. Probst, A. Beilhack, T. Buchou, O. Filhol-Cochet, B. Boldyreff, M. Breloer, H. Jonuleit, H. Schild, E. Schmitt, and T. Bopp.
Nature immunology 2015: 16: 267-275

Anti-CD83 promotes IgG1 isotype switch in marginal zone B cells in response to TI-2 antigen
Kretschmer, B., Weber, J., Hutloff, A., Fleischer, B., Breloer, M. and Osterloh, A.
Immunobiology 2015 Aug;220(8):964-75. doi: 10.1016/j.imbio.2015.02.008.

Arbeitsgruppe Breloer
2014

Nematode-Induced Interference with Vaccination Efficacy Targets Follicular T Helper Cell Induction and is Preserved after Termination of Infection
Irma Haben, Wiebke Hartmann and Minka Breloer
PLoS Negl Trop Dis. 2014 Sep 25;8(9):e3170. doi: 10.1371/journal.pntd.0003170.

Foxp3+ regulatory T cells delay expulsion of intestinal nematodes by suppression of IL-9-driven mast cell activation in BALB/c but not in C57BL/6 mice
Blankenhaus, B., M. Reitz, Y. Brenz, M. L. Eschbach, W. Hartmann, I. Haben, T. Sparwasser, J. Huehn, A. Kuhl, T. B. Feyerabend, H. R. Rodewald, and M. Breloer
PLoS pathogens 2014. 10: e1003913.

Immunization with Brugia malayi Hsp70 protects mice against Litomosoides sigmodontis challenge infection.
Hartmann W, Singh N, Rathaur S, Brenz Y, Liebau E, Fleischer B, Breloer M.
Parasite Immunol. 2014. 36: 141-149. doi: 10.1111/pim.12093

Immune recognition of Onchocerca volvulus proteins in the human host and animal models of onchocerciasis
Manchang TK, Ajonina-Ekoti I, Ndjonka D, Eisenbarth A, Achukwi MD, Renz A, Brattig NW, Liebau E, Breloer M
J Helminthol. 2014 Apr 10:1-12

Heat shock protein 60: an endogenous inducer of dopaminergic cell death in Parkinson disease Journal of Neuroinflammation 2014, 11:86 doi:10.1186/1742-2094-11-86
Noelker C , More L, Osterloh A, Alvarez-Fischer D, Lescot T, Breloer M, Gold M, Oertel W H, Henze C, Michel P P, Dodel R C, Lu L, Hirsch E C, Hunot E and Hartmann A
Journal of Neuroinflammation 2014, 11:86 doi:10.1186/1742-2094-11-86

Arbeitsgruppe Breloer
2013

T-cell-derived, but not B-cell-derived, IL-10 suppresses antigen-specific T-cell responses in Litomosoides sigmodontis-infected mice.
Haben, I., W. Hartmann, S. Specht, A. Hoerauf, A. Roers, W. Muller
European Journal of Immunology 2013. 43: 1799-1805.

Nematode-derived proteins suppress proliferation and cytokine production of antigen-specific T cells via induction of cell death
Hartmann W, Brenz Y, Kingsley MT, Ajonina-Ekoti I, Brattig NW, Liebau E, Breloer M.
PLoS One. 2013 Jun 21;8(6):e68380. doi: 10.1371/journal.pone.0068380. Print 2013.

Comparative analysis of macrophage migration inhibitory factors (MIFs) from the parasitic nematode Onchocerca volvulus and the free-living nematode Caenorhabditis elegans.
Ajonina-Ekoti I, Kurosinski MA, Younis AE, Ndjonka D, Tanyi MK, Achukwi M, Eisenbarth A, Ajonina C, Lüersen K, Breloer M, Brattig NW, Liebau E.
Parasitol Res. 2013 Sep;112(9):3335-46. doi: 10.1007/s00436-013-3513-1. Epub 2013 Jul 3.

Toll like receptor 4 mediates cell death in a mouse MPTP model of Parkinson disease
Noelker C, Morel L, Lescot T, Osterloh A, Alvarez-Fischer D, Breloer M, Henze C, Depboylu C, Skrzydelski D, Michel PP, Dodel RC, Lu L, Hirsch EC, Hunot S, Hartmann A
Sci Rep. 2013;3:1393. doi: 10.1038/srep01393.

Arbeitsgruppe Breloer
2012

Passive immunization with a monoclonal IgM antibody specific for Strongyloides ratti HSP60 protects mice against challenge infection
Ben Nouir N, Piédavent M, Osterloh A, Breloer M.
Vaccine. 2012 Jul 13;30(33):4971-6. doi: 10.1016/j.vaccine.2012.05.046.

Vaccination with Strongyloides ratti heat shock protein 60 increases susceptibility to challenge infection by induction of Th1 response.
Ben Nouir N, Eschbach ML, Piédavent M, Osterloh A, Kingsley MT, Erttmann K, Brattig N, Liebau E, Fleischer B, Breloer M.
Vaccine. 2012 Jan 20;30(5):862-71. doi: 10.1016/j.vaccine.2011.11.110. Epub 2011 Dec 13.

Efficient control of Plasmodium yoelii infection in BALB/c and C57BL/6 mice with pre-existing Strongyloides ratti infection.
Kolbaum J, Eschbach ML, Steeg C, Jacobs T, Fleischer B, Breloer M.
Parasite Immunol. 2012 Jul;34(7):388-93. doi: 10.1111/j.1365-3024.2012.01369.x.

Strongyloides ratti infection modulates B and T cell responses to third party antigens.
Hartmann W, Eschbach ML, Breloer M.
Exp Parasitol. 2012 Sep;132(1):69-75. doi: 10.1016/j.exppara.2011.06.001. Epub 2011 Jun 23.

Nematode-induced interference with the anti-Plasmodium CD8+ T-cell response can be overcome by optimizing antigen administration
Kolbaum, J., S. Tartz, W. Hartmann, S. Helm, A. Nagel, V. Heussler, P. Sebo, B. Fleischer, T. Jacobs, and M. Breloer
European Journal of Immunology. 2012. 42: 890-900.

Functional characterization and immune recognition of the extracellular superoxide dismutase from the human pathogenic parasite Onchocerca volvulus (OvEC-SOD)
Ajonina-Ekoti I, Ndjonka D, Tanyi MK, Wilbertz M, Younis AE, Boursou D, Kurosinski MA, Eberle R, Lüersen K, Perbandt M, Breloer M, Brattig NW, Liebau E.
Acta Trop. 2012 Oct;124(1):15-26. doi: 10.1016/j.actatropica.2012.05.013

Arbeitsgruppe Breloer
2011

Strongyloides ratti infection induces expansion of Foxp3+ regulatory T cells that interfere with immune response and parasite clearance in BALB/c mice.
Blankenhaus, B., U. Klemm, M. L. Eschbach, T. Sparwasser, J. Huehn, A. A. Kuhl, C. Loddenkemper, T. Jacobs, and M. Breloer
Journal of Immunology (2011) 186: 4295-4305.

Pathogenic nematodes suppress humoral responses to third-party antigens in vivo by IL-10-mediated interference with Th cell function
Hartmann, W., I. Haben, B. Fleischer, and M. Breloer.
Journal of Immunology (2011) 187: 4088-4099

Efficient control of Leishmania and Strongyloides despite partial suppression of nematode-induced Th2 response in co-infected mice.
Kolbaum J, Ritter U, Zimara N, Brewig N, Eschbach ML, Breloer M.
Parasite Immunol. 2011 Apr;33(4):226-35. doi: 10.1111/j.1365-3024.2010.01273.x.

Strongyloides ratti infection induces transient nematode-specific Th2 response and reciprocal suppression of IFN-gamma production in mice.
Eschbach ML, Klemm U, Kolbaum J, Blankenhaus B, Brattig N, Breloer M
Parasite Immunol. 2011 Apr;33(4):226-35. doi: 10.1111/j.1365-3024.2010.01273.x

Activated T cells induce rapid CD83 expression on B cells by engagement of CD40.
Kretschmer B, Kühl S, Fleischer B, Breloer M.
Immunol Lett. 2011 May;136(2):221-7. doi: 10.1016/j.imlet.2011.01.013. Epub 2011 Jan 28.

Arbeitsgruppe Breloer
2009

Engagement of CD83 on B cells modulates B cell function in vivo.
Kretschmer B, Lüthje K, Schneider S, Fleischer B, Breloer M.
J Immunol. 2009 Mar 1;182(5):2827-34. doi: 10.4049/jimmunol.0803153.

Heat shock protein 60 (HSP60) stimulates neutrophil effector functions.
Osterloh A, Geisinger F, Piédavent M, Fleischer B, Brattig N, Breloer M
J Leukoc Biol. 2009 Aug;86(2):423-34. doi: 10.1189/jlb.0109011. Epub 2009 May 15.

Arbeitsgruppe Breloer
2008

CD83 on murine APC does not function as a costimulatory receptor for T cells.
Kretschmer B, Lüthje K, Ehrlich S, Osterloh A, Piedavent M, Fleischer B, Breloer M.
Immunol Lett. 2008 Oct 30;120(1-2):87-95. doi: 10.1016/j.imlet.2008.07.004. Epub 2008 Aug 20.

CD83 regulates splenic B cell maturation and peripheral B cell homeostasis.
Lüthje K, Kretschmer B, Fleischer B, Breloer M.
Int Immunol. 2008 Aug;20(8):949-60. doi: 10.1093/intimm/dxn054. Epub 2008 Jun 10.

CD83 regulates lymphocyte maturation, activation and homeostasis
Breloer M, Fleischer B.
Trends Immunol. 2008 Apr;29(4):186-94. doi: 10.1016/j.it.2008.01.009.

CD83 expression in CD4+ T cells modulates inflammation and autoimmunity
Reinwald S, Wiethe C, Westendorf AM, Breloer M, Probst-Kepper M, Fleischer B, Steinkasserer A, Buer J, Hansen W.
J Immunol. 2008 May 1;180(9):5890-7.

Hsp60-mediated T cell stimulation is independent of TLR4 and IL-12.
Osterloh A, Veit A, Gessner A, Fleischer B, Breloer M.
Int Immunol. 2008 Mar;20(3):433-43. doi: 10.1093/intimm/dxn003

Heat shock proteins: linking danger and pathogen recognition.
Osterloh A, Breloer M.
Med Microbiol Immunol. 2008 Mar;197(1):1-8

Arbeitsgruppe Breloer
2007

CD83 modulates B cell function in vitro: increased IL-10 and reduced Ig secretion by CD83Tg B cells.
Kretschmer B, Lüthje K, Guse AH, Ehrlich S, Koch-Nolte F, Haag F, Fleischer B, Breloer M.
PLoS One. 2007 Aug 15;2(8):e755.

CD83 is a regulator of murine B cell function in vivo.
Breloer M, Kretschmer B, Lüthje K, Ehrlich S, Ritter U, Bickert T, Steeg C, Fillatreau S, Hoehlig K, Lampropoulou V, Fleischer B.
Eur J Immunol. 2007 Mar;37(3):634-48.

Synergistic and differential modulation of immune responses by Hsp60 and lipopolysaccharide.
Osterloh A, Kalinke U, Weiss S, Fleischer B, Breloer M.
J Biol Chem. 2007 Feb 16;282(7):4669-80

Arbeitsgruppe Breloer
2006

Transgenic expression of a CD83-immunoglobulin fusion protein impairs the development of immune-competent CD4-positive T cells.
Lüthje K, Cramer SO, Ehrlich S, Veit A, Steeg C, Fleischer B, Bonin Av, Breloer M.
Eur J Immunol. 2006 Aug;36(8):2035-45.

Arbeitsgruppe Breloer
2005

Heat shock protein 60 is released in immune-mediated glomerulonephritis and aggravates disease: in vivo evidence for an immunologic danger signal
Lang A, Benke D, Eitner F, Engel D, Ehrlich S, Breloer M, Hamilton-Williams E, Specht S, Hoerauf A, Floege J, von Bonin A, Kurts C.
J Am Soc Nephrol. 2005 Feb;16(2):383-91.

Arbeitsgruppe Breloer
2004

Lipopolysaccharide-free heat shock protein 60 activates T cells.
Osterloh A, Meier-Stiegen F, Veit A, Fleischer B, von Bonin A, Breloer M.
J Biol Chem. 2004 Nov 12;279(46):47906-11

Arbeitsgruppe Breloer
2001

Heat shock proteins as "danger signals": eukaryotic Hsp60 enhances and accelerates antigen-specific IFN-gamma production in T cells.
Breloer M, Dorner B, Moré SH, Roderian T, Fleischer B, von Bonin A.
Eur J Immunol. 2001 Jul;31(7):2051-9.

Alumni

Doctoral Thesis

Dr. Manchang Tanyi Kingsley (2009-2012; Promotion 2015) : Onchocerca ochengi derived excretory/secretory products: immune response and immune modulation

Dr. Irma Haben (2011-2014) : Einfluss einer chronischen Wurminfektion auf die Impfantwort der Maus (Mus musculus, Linneaus, 1758) D