14 research outputs found
Posttranslational modification of collagen type II : effects on antigen-specific T-cell tolerance and autoreactivity in collagen-induced arthritis
No full textRheumatoid arthritis (RA) is a common chronic inflammatory disease affecting peripheral joints in approximately 1% of the world population. Immunization of susceptible strains with CII, leads to development of collagen-induced arthritis (CIA), an animal model for RA. The aim of this thesis was to investigate mechanisms involved in regulation of immunological T-cell tolerance in CIA by studying availability of joint-specific CII for presentation to autoreactive T cells in healthy as well as pathological settings.This work shows that transgenic expression of heterologous CII can inhibit expansion and Th1/Th17-skewing of antigen-specific T cells upon immunization with heterologous CII. The strength of tolerance induction was found to be dependent on the abundance of the selfantigen, the genetic background of the mice, as well as the presence or absence of posttranslational modifications on CII. Data indicate that joint-specific antigens are readily available for presentation in draining lymph nodes to induce immunological tolerance. Furthermore, a defect in thymic tolerance induction suggests that certain CII modifications are presented differentially depending on the location in the organism (Paper IV).To obtain these results, established mouse systems were refined by generating a T-cell receptor specific antibody (Paper I) or by breeding diverse mouse and human transgenes on genetic backgrounds with different susceptibilities (Paper II & III).Even though it is accepted that T cells play an important role in arthritis development, it remains controversial where and how they contribute to pathogenic mechanisms after loss of tolerance. In summary, this thesis describes a series of new mouse models that will aid to further elucidate the arthritogenic action of T cells in disease relevant sites. This will hopefully enlarge the mechanistic framework for further investigation of human disease pathogenesis, which might lead to new therapeutic strategies to promote self-tolerance in diseased individuals.List of scientific papersI. Merky, P., Batsalova, T., Bockermann, R., Dzhambazov, B., Sehnert, B., Burkhardt, H., and Bäcklund, J. Visualization and phenotyping of pro-inflammatory antigen-specific T cells during collagen-induced arthritis in a mouse with a fixed collagen type II specific transgenic TCR beta chain. Arthritis research & therapy. 2010, 12(4):R155. https://doi.org/10.1186/ar3108 II. Batsalova, T., Dzhambazov, B., Merky, P., Bäcklund, A., and Bäcklund, J. Breaking T cell tolerance against self type II collagen in HLA-DR4-transgenic mice and development of autoimmune arthritis. Arthritis Rheum. 2010, 62(7):1911-1920. https://doi.org/10.1002/art.27460 III. Merky, P., Batsalova, T., Dzhambazov, B., Förster, M., Yamada, H., Holmdahl, R., and Bäcklund, J. Tolerance to glycosylated self-collagen type II is regulated in the periphery and leads to protection from collagen-induced arthritis. [Manuscript]IV. Merky, P., Holmdahl, R., and Bäcklund, J. AIRE-expression is specifically associated with controlling tolerance to non-glycosylated collagen type II in collagen-induced arthritis. [Manuscript]</p
Polyclonal and specific antibodies mediate protective immunity against enteric helminth infection
No full textAnti-helminth immunity involves CD4+ T cells, yet the precise effector mechanisms responsible for parasite killing or expulsion remain elusive. We now report an essential role for antibodies in mediating immunity against the enteric helminth Heligmosomoides polygyrus (Hp), a natural murine parasite that establishes chronic infection. Polyclonal IgG antibodies, present in naive mice and produced following Hp infection, functioned to limit egg production by adult parasites. Comparatively, affinity-matured parasite-specific IgG and IgA antibodies that developed only after multiple infections were required to prevent adult worm development. These data reveal complementary roles for polyclonal and affinity-matured parasite-specific antibodies in preventing enteric helminth infection by limiting parasite fecundity and providing immune protection against reinfection, respectively. We propose that parasite-induced polyclonal antibodies play a dual role, whereby the parasite is allowed to establish chronicity, while parasite load and spread are limited, likely reflecting the long coevolution of helminth parasites with their hosts.UPHARRISMcCoy, Kathy D Stoel, Maaike Stettler, Rebecca Merky, Patrick Fink, Katja Senn, Beatrice M Schaer, Corinne Massacand, Joanna Odermatt, Bernhard Oettgen, Hans C Zinkernagel, Rolf M Bos, Nicolaas A Hengartner, Hans Macpherson, Andrew J Harris, Nicola L AI054471/AI/NIAID NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States Cell host & microbe Cell Host Microbe. 2008 Oct 16;4(4):362-73
Aire-mediated central tolerance includes na�ve but not post-translational modified self-antigens
No full textVisualization and phenotyping of proinflammatory antigen-specific T cells during collagen-induced arthritis in a mouse with a fixed collagen type II-specific transgenic T-cell receptor beta-chain
No full textIntroduction: The Vbeta12-transgenic mouse was previously generated to investigate the role of antigen-specific T cells in collagen-induced arthritis (CIA), an animal model for rheumatoid arthritis. This mouse expresses a transgenic collagen type II (CII)-specific T-cell receptor (TCR) beta-chain and consequently displays an increased immunity to CII and increased susceptibility to CIA. However, while the transgenic Vbeta12 chain recombines with endogenous alpha-chains, the frequency and distribution of CII-specific T cells in the Vbeta12-transgenic mouse has not been determined. The aim of the present report was to establish a system enabling identification of CII-specific T cells in the Vbeta12-transgenic mouse in order to determine to what extent the transgenic expression of the CII-specific beta-chain would skew the response towards the immunodominant galactosylated T-cell epitope and to use this system to monitor these cells throughout development of CIA. Methods: We have generated and thoroughly characterized a clonotypic antibody, which recognizes a TCR specific for the galactosylated CII(260-270) peptide in the Vbeta12-transgenic mouse. Hereby, CII-specific T cells could be quantified and followed throughout development of CIA, and their phenotype was determined by combinatorial analysis with the early activation marker CD154 (CD40L) and production of cytokines. Results: The Vbeta12-transgenic mouse expresses several related but distinct T-cell clones specific for the galactosylated CII peptide. The clonotypic antibody could specifically recognize the majority (80%) of these. Clonotypic T cells occurred at low levels in the naïve mouse, but rapidly expanded to around 4% of the CD4+ T cells, whereupon the frequency declined with developing disease. Analysis of the cytokine profile revealed an early Th1-biased response in the draining lymph nodes that would shift to also include Th17 around the onset of arthritis. Data showed that Th1 and Th17 constitute a minority among the CII-specific population, however, indicating that additional subpopulations of antigen-specific T cells regulate the development of CIA. Conclusions: The established system enables the detection and detailed phenotyping of T cells specific for the galactosylated CII peptide and constitutes a powerful tool for analysis of the importance of these cells and their effector functions throughout the different phases of arthritis
Breaking T cell tolerance against self type II collagen in HLA–DR4–transgenic mice and development of autoimmune arthritis
No full textBreaking T cell tolerance against self type II collagen in HLA-DR4-transgenic mice and development of autoimmune arthritis. Arthritis Rheum62:1911-1920
No full textepitope is clearly immunodominant in both tolerized and nontolerized DR4 mice
NIH/3T3 Fibroblasts Selectively Activate T Cells Specific for Posttranslationally Modified Collagen Type II
No full textIt has been shown that synovial fibroblasts (SF) play a key role in the initiation of inflammation and joint destruction, leading to arthritis progression. Fibroblasts may express major histocompatibility complex class II region (MHCII) molecules, and thus, they could be able to process and present antigens to immunocompetent cells. Here we examine whether different types of fibroblasts (synovial, dermal, and thymic murine fibroblasts, destructive LS48 fibroblasts, and noninvasive NIH/3T3 fibroblasts) may be involved in the initiation of rheumatoid arthritis (RA) pathogenesis and can process and present type II collagen (COL2)—an autoantigen associated with RA. Using a panel of MHCII/Aq-restricted T-cell hybridoma lines that specifically recognize an immunodominant COL2 epitope (COL2259–273), we found that NIH/3T3 fibroblasts activate several T-cell clones that recognize the posttranslationally glycosylated or hydroxylated COL2259–273 epitope. The HCQ.3 hybridoma, which is specific for the glycosylated immunodominant COL2 epitope 259–273 (Gal264), showed the strongest response. Interestingly, NIH/3T3 cells, but not destructive LS48 fibroblasts, synovial, dermal, or thymic fibroblasts, were able to stimulate the HCQ.3 hybridoma and other COL2-specific T-cell hybridomas. Our experiments revealed that NIH/3T3 fibroblasts are able to activate COL2-specific T-cell hybridomas even in the absence of COL2 or a posttranslationally modified COL2 peptide. The mechanism of this unusual activation is contact-dependent and involves the T-cell receptor (TCR) complex
Ncf1-Associated Reduced Oxidative Burst Promotes IL-33R+ T Cell-Mediated Adjuvant-Free Arthritis in Mice.
No full textReactive oxygen species (ROS) are important in the immune defense against invading pathogens, but they are also key molecules in the regulation of inflammatory reactions. Low levels of ROS production due to a polymorphism in the neutrophil cytosolic factor 1 (Ncf1) gene are associated with autoimmunity and arthritis severity in mouse models induced with adjuvant. We established an adjuvant-free arthritis model in which disease is induced by injection of the autoantigen collagen type II (CII) and depends on IL-5-producing T cells and eosinophils. In addition, the transgenic expression of mutated mouse CII allowed us to investigate an autoreactive immune response to an autologous Ag and by that natural tolerance mechanism. We show that a deficient ROS production, due to a spontaneous mutation in Ncf1, leads to increased autoantibody production and expansion of IL-33R-expressing T cells, impaired T cell tolerance toward tissue-specific CII, and severe arthritis in this unique model without disturbing adjuvant effects. These results demonstrate that the insufficient production of ROS promotes the breakdown of immune tolerance and development of autoimmune and adjuvant-free arthritis through an IL-5- and IL33R-dependent T cell activation pathway
Polyclonal and specific antibodies mediate protective immunity against enteric helminth infection
No full textAnti-helminth immunity involves CD4+ T cells, yet the precise effector mechanisms responsible for parasite killing or expulsion remain elusive. We now report an essential role for antibodies in mediating immunity against the enteric helminth Heligmosomoides polygyrus (Hp), a natural murine parasite that establishes chronic infection. Polyclonal IgG antibodies, present in naive mice and produced following Hp infection, functioned to limit egg production by adult parasites. Comparatively, affinity-matured parasite-specific IgG and IgA antibodies that developed only after multiple infections were required to prevent adult worm development. These data reveal complementary roles for polyclonal and affinity-matured parasite-specific antibodies in preventing enteric helminth infection by limiting parasite fecundity and providing immune protection against reinfection, respectively. We propose that parasite-induced polyclonal antibodies play a dual role, whereby the parasite is allowed to establish chronicity, while parasite load and spread are limited, likely reflecting the long coevolution of helminth parasites with their hosts
T cells specific for post-translational modifications escape intrathymic tolerance induction
No full textEstablishing effective central tolerance requires the promiscuous expression of tissue-restricted antigens by medullary thymic epithelial cells. However, whether central tolerance also extends to post-translationally modified proteins is not clear. Here we show a mouse model of autoimmunity in which disease development is dependent on post-translational modification (PTM) of the tissue-restricted self-antigen collagen type II. T cells specific for the non-modified antigen undergo efficient central tolerance. By contrast, PTM-reactive T cells escape thymic selection, though the PTM variant constitutes the dominant form in the periphery. This finding implies that the PTM protein is absent in the thymus, or present at concentrations insufficient to induce negative selection of developing thymocytes and explains the lower level of tolerance induction against the PTM antigen. As the majority of self-antigens are post-translationally modified, these data raise the possibility that T cells specific for other self-antigens naturally subjected to PTM may escape central tolerance induction by a similar mechanism
