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Pathogenesis of endometriosis (EN) is still unknown, but growing evidence suggests that immune regulation may be important, and the pattern of peripheral immune changes in reproductive women with EN has yet to be fully explored. In this study, we conducted a comprehensive and systematic analysis of immune cell subsets within T cells, B cells, NK cells, and γδ T cells in peripheral blood (PB) samples from women with EN, women with uterine fibroids (UF) but without EN (UF-alone), and healthy controls using multi-parameter flow cytometry. Our findings revealed that UF, a common comorbidity of EN, exhibited similar peripheral immune features to EN, particularly in T cell and B cell immunity. Compared to healthy controls, we constructed the peripheral immune profile of EN. This profile highlighted that the immunopathogenic factors in EN predominantly relate to the immune disorder of B cells and their subsets, as well as the functional abnormalities within immune cell subsets of CD4+ T cells, CD8+ T cells, and γδ T cells. Moreover, using the random forest (RF) machine-learning method, we developed a diagnostic model that can effectively identify the patients with EN from healthy controls. The immune factors identified within this model could be pivotal for unraveling the immune pathogenic mechanisms of EN. Our study is the first to present a comprehensive depiction of the circulating immune features in EN, although the detailed roles and underlying mechanisms of these immune factors in the context of EN require further investigation.

Humans and a wide range of mammals are generally susceptible to Schistosoma infection, while some rodents such as Rattus rats and Microtus spp are not. We previously demonstrated that inherent high expression levels of nitric oxide (NO), produced by inducible nitric oxide synthase (iNOS), plays an important role in blocking the growth and development of Schistosoma japonicum in wild-type rats. However, the potential regulatory effects of NO on the immune system and immune response to S. japonicum infection in rats are still unknown. In this study, we used iNOS-knockout (KO) rats to determine the role of iNOS-derived NO in the immune system and immunopathological responses to S. japonicum infection in rats. Our data showed that iNOS deficiency led to weakened immune activity against S. japonicum infection. This was characterized by the impaired T cell responses and a significant decrease in S. japonicum-elicited Th2/Th1 responses and cytokine and chemokine-producing capability in the infected iNOS-KO rats. Unlike iNOS-KO mice, Th1-associated cytokines were also decreased in the absence of iNOS in rats. In addition, a profile of pro-inflammatory and pro-fibrogenic cytokines was detected in serum associated with iNOS deficiency. The alterations in immune responses and cytokine patterns were correlated with a slower clearance of parasites, exacerbated granuloma formation, and fibrosis following S. japonicum infection in iNOS-KO rats. Furthermore, we have provided direct evidence that high levels of NO in rats can promote the development of pulmonary fibrosis induced by egg antigens of S. japonicum, but not inflammation, which was negatively correlated with the expression of TGF-β3. These studies are the first description of the immunological and pathological profiles in iNOS-KO rats infected with S. japonicum and demonstrate key differences between the responses found in mice. Our results significantly enhance our understanding of the immunoregulatory effects of NO on defensive and immunopathological responses in rats and the broader nature of resistance to pathogens such as S. japonicum.

Leishmania infection causes diverse clinical manifestations in humans. The disease outcome is complicated by the combination of many host and parasite factors. Inbred mouse strains vary in resistance to Leishmania major but are highly susceptible to Leishmania amazonensis infection. However, rats are highly resistant to L. amazonensis infection due to unknown mechanisms. We use the inducible nitric oxide synthase (Nos2) gene knockout rat model (Nos2−/− rat) to investigate the role of NOS2 against leishmania infection in rats. Our results demonstrated that diversion toward the NOS2 pathway is the key factor explaining the resistance of rats against L. amazonensis infection. Rats deficient in NOS2 are susceptible to L. amazonensis infection even though their immune response to infection is still strong. Moreover, adoptive transfer of NOS2 competent macrophages into Nos2−/− rats significantly reduced disease development and parasite load. Thus, we conclude that the distinct L-arginine metabolism, observed in rat macrophages, is the basis of the strong innate resistance to Leishmania. These data highlight that macrophages from different hosts possess distinctive properties and produce different outcomes in innate immunity to Leishmania infections.

We found that after stimulation for a few hours, memory but not naive CD4+ T cells produced a large amount of IFN- γ; however, the mechanism of rapid response of memory CD4+ T cells remains undefined. We compared the expression of transcription factors in resting or activated naive and memory CD4+ T cells and found that T-bet, but not pSTAT-1 or pSTAT-4, was highly expressed in resting memory CD4+ T cells and that phenotypic characteristics of T-bet+CD4+ T cells were CD45RAlowCD62Llow CCR7low. After short-term stimulation, purified memory CD4+ T cells rapidly produced effector cytokines that were closely associated with the pre-existence of T-bet. By contrast, resting naive CD4+ T cells did not express T-bet, and they produced cytokines only after sustained stimulation. Our further studies indicated that T-bet was expressed in the nuclei of resting memory CD4+ T cells, which might have important implications for rapid IFN-γ production. Our results indicate that the pre-existence and nuclear mobilization of T-bet in resting memory CD4+ T cells might be a possible transcriptional mechanism for rapid production of cytokines by human memory CD4+ T cells. [ABSTRACT FROM AUTHOR]