Gestational Attenuation of Lyme Arthritis Is Mediated by Progesterone and IL-41
Infection of different strains of laboratory mice with the agent of Lyme disease, Borrelia burgdorferi, results in arthritis, the severity of which has been correlated with the dominance of Th1 cytokines. In this study, we demonstrate that changes in B. burgdorferi-specific immunologic responses associated with pregnancy can alter the outcome of Lyme arthritis in mice. Whereas nonpregnant female C3H mice consistently developed severe Lyme arthritis, pregnant mice had a marked reduction in arthritis severity that was associated with a slight reduction in IFN- and markedly increased levels of IL-4 production by B. burgdorferi-specific T cells. Similar reductions in arthritis severity and patterns of cytokine production were observed in nonpregnant, progesterone-implanted mice. Ab neutralization of IL-4 in progesterone-implanted mice resulted in severe arthritis. Our results are consistent with the known shift toward Th2 cytokine expression at the maternal-fetal interface, and are the first to show a pregnancy-related therapeutic effect in an infectious model
During pregnancy, a series of profound immunologic changes occurs, including changes associated with altered tryptophan metabolism and progesterone-mediated alterations in the balance of cytokine elaboration (12, 13). One of the generally observed effects on immune responses during pregnancy has been a bias toward humoral responses, often at the expense of cell-mediated immunity and associated inflammatory sequelae (14, 15, 16, 17, 18, 19). Pregnant mice mount higher Ab levels to heterologous Ags compared with nonpregnant mice and display concomitant reductions in delayed-type hypersensitivity responses against paternal MHC and other nonself-Ags (20, 21). On the basis of these and other observations, it has been proposed that Th2 cytokines (IL-4, 5, 6, 10, and 13) produced at murine fetal-maternal interface down-regulate Th1 responses responsible for acute allograft rejection, thus along with other mechanisms, promoting fetal survival (18, 22, 23). However, this Th2 bias during pregnancy may have a deleterious effect on the outcome of certain infectious processes. In mice and in some instances in humans, pregnancy may increase susceptibility to certain intracellular pathogens such as Leishmania major (mice only), Listeria monocytogenes, Mycobacterium leprae, Mycobacterium tuberculosis, and Toxoplasma gondii (mice only), in which protective immunity is associated with Th1 responses (15, 16, 24, 25, 26).
In this study, we show that during pregnancy in a murine model, the severity of pathogenic inflammatory responses associated with Lyme arthritis is significantly attenuated. The pregnancy-associated reduction in disease severity was associated with modestly reduced production of IFN- and significantly higher relative production levels of the Th2 cytokine IL-4 compared with nonpregnant infected controls. This gestational therapeutic effect was reproduced in nonpregnant mice by progesterone treatment
Pregnancy, in general, is associated with a general decline in production of Th1- associated cytokines and an increase in Th2-associated cytokines (33). Administration of Th1 cell-associated cytokines (IFN- or IL-2) or TNF- is associated with immunologic rejection of fetal tissues, and can result in abortion (34, 35). Pregnancy also increases susceptibility to many diseases caused by helminths, protozoa, and bacteria, although this heightened susceptibility is most evident for infections with intracellular protozoa and bacteria (24, 25, 26). NK cells, Th1 T lymphocyte subsets, cytotoxic CD8+ T cell activities, and the production of IFN-, IL-2, and TNF- are all decreased during pregnancy and all contribute to the protective immune response against these pathogens (36). IL-4, IL-5, and IL-10, which down-regulate and antagonize the effects of IFN-, IL-2, and TNF-, are produced locally at the maternal-fetal interface during pregnancy. This may explain the decreased production of IFN- observed in pregnant mice infected with L. major and T. gondii compared with nonpregnant mice (16, 37). Administration of IL-2 or IFN- to pregnant mice can significantly increase their resistance to T. gondii infection, but also increases the risk of abortion (38).
Ours is the first conclusive study showing decreased tissue pathology associated with an infectious process during pregnancy, and is consistent with what is known about the pathogenesis of Lyme arthritis in inbred mouse models. We found little evidence of a stochastic effect leading to Th2-dominant responses during pregnancy, but rather an attenuation of the Th1 response and a corresponding decrease in inflammatory cytokine production.
Ag-stimulated lymphocytes from pregnant mice secreted higher IL-4 and lower levels of IFN- than nonpregnant controls. This differential cytokine secretion was noted in vivo, with the marked decrease in the IgG2a subclass of B. burgdorferi Abs in pregnant mice compared with nonpregnant mice. We also examined regional (popliteal) lymph nodes in footpad-inoculated pregnant mice. The arthritis results as well as IFN- and IL-4 values were similar to animals infected by the suprascapular route (data not shown).
Interestingly, clinical observations in humans suggest that the severity of rheumatoid arthritis is ameliorated during pregnancy, whereas systemic lupus erythematosus, in which the principal pathology is associated with autoantibody production, may become exacerbated during gestation (39, 40). The delicate cytokine balance between the host response to infection and maintenance of pregnancy may also work against the fetus in some cases; host responses to certain pathogens, even if the site of infection is distant from the fetal-placental interface, may overwhelm fetal tolerance mechanisms and impair successful pregnancy (12).
Experimental infection of inbred mice with B. burgdorferi results in arthritis, the severity of which appears to be genetically determined by pathogen/host interactions that control the spirochete burden and/or the host inflammatory response (27, 28). B. burgdorferi-infected C3H mice characteristically mount a Th1-dominant response in the postacute phase, as evidenced by high levels of IFN- and low or undetectable levels of IL-4 in lymphocytes restimulated by B. burgdorferi Ags (3, 6). Consistent with this, B. burgdorferi-specific IgG2a serum levels exhibited a marked increase (6, 41). The arthritis-modulating effects of IL-4 have been shown by depletion of IL-4 with mAb and by experiments in which this cytokine has been administered exogenously during the course of B. burgdorferi infection of mice (3, 5, 6). The precise mechanism by which this cytokine is associated with joint inflammation has not been elucidated, but the known inhibitory effects of IL-4 on Th1-specific inflammatory cytokines could lead to a decrease in joint inflammation independent of direct effects on pathogen burden (42). Indeed, we did not detect significant differences in spirochetal tissue burden between pregnant and
nonpregnant controls. In one study in which T cell cytokine secretion was monitored at different time intervals after initial inoculation during the development of murine Lyme arthritis, the evolution of a Th2-type immune response developed after an initial Th1-dominant response in a disease-resistant mouse (43), suggesting modulation of proinflammatory effects over time.
We used progesterone treatment of C3H mice to test the hypothesis that this hormone was responsible for the therapeutic effect of pregnancy (44, 45). In comparing pregnant mice with nonpregnant, progesterone-treated mice, our results showed similar degrees of reduced arthritis severity, differential cytokine secretion, and predominance of the IgG2a Ab subclass. We then observed a significant increase in arthritic activity when progesterone-treated animals were treated with anti-IL-4 Abs, indicating that the anti-inflammatory effects of progesterone were mediated by IL-4 in Borrelia-infected mice.
In conclusion, our study demonstrates that pregnancy alters the equilibrium of cytokine elaboration toward reduction of a pathogenic inflammatory response to an infectious challenge in pregnant mice. This down-regulation of Th1 responses, most likely via progesterone-mediated up-regulation of Th2 cytokine production, provides a plausible explanation for the significant reduction of Lyme arthritis in pregnant mice. Further clarification in the dynamics of the immune response in pregnant mice may in this, and in other infectious models, be useful for understanding the basis of the profound immunologic changes associated with pregnancy
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Lyme arthritis alleviated by pregnancy
S. H. Keenihan
Available online 24 August 2001