Antibodies and IL-3 support helminth-induced basophil expansion

Basophils are powerful mediators of Th2 immunity and are present in increased numbers during allergic inflammation and helminth infection. Despite their ability to potentiate Th2 immunity the mechanisms regulating basophil development remain largely unknown. We have found a unique role for isotype-switched antibodies in promoting helminth-induced basophil production following infection of mice with Heligmosomoides polygyrus bakeri or Nippostrongylus brasiliensis. H. polygyrus bakeri-induced basophil expansion was found to occur within the bone marrow, and to a lesser extent the spleen, and was IL-3 dependent. IL-3 was largely produced by CD4+CD49b+NK1.1− effector T cells at these sites, and required the IL-4Rα chain. However, antibody-deficient mice exhibited defective basophil mobilization despite intact T-cell IL-3 production, and supplementation of mice with immune serum could promote basophilia independently of required IL-4Rα signaling. Helminth-induced eosinophilia was not affected by the deficiency in isotype-switched antibodies, suggesting a direct effect on basophils rather than through priming of Th2 responses. Although normal type 2 immunity occurred in the basopenic mice following primary infection with H. polygyrus bakeri, parasite rejection following challenge infection was impaired. These data reveal a role for isotype-switched antibodies in promoting basophil expansion and effector function following helminth infection

Polyclonal and specific antibodies mediate protective immunity against enteric helminth infection

Anti-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

Posttranslational modification of collagen type II : effects on antigen-specific T-cell tolerance and autoreactivity in collagen-induced arthritis [Elektronisk resurs]

Rheumatoid 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

Mechanisms of neonatal mucosal antibody protection

Following an abrupt transition at birth from the sterile uterus to an environment with abundant commensal and pathogenic microbes, neonatal mammals are protected by maternal Abs at mucosal surfaces. We show in mice that different Ab isotypes work in distinct ways to protect the neonatal mucosal surface. Secretory IgA acts to limit penetration of commensal intestinal bacteria through the neonatal intestinal epithelium: an apparently primitive process that does not require diversification of the primary natural Ab repertoire. In contrast, neonatal protection against the exclusively luminal parasite Heligmosomoides polygyrus required IgG from primed females. This immune IgG could either be delivered directly in milk or retrotransported via neonatal Fc receptor from the neonatal serum into the intestinal lumen to exert its protective effect