Influence of aging on germinal centre reaction and antibody response to inactivated influenza virus antigens in mice: sex-based differences

Arsenović-Ranin, Nevena; Petrović, Raisa; Živković, Irena; Bufan, Biljana; Stoiljković, Vera; Leposavić, Gordana

doi:10.1007/s10522-019-09811-8

Cited by 19 publications

(22 citation statements)

References 91 publications

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“…On the other hand, despite the lower serum level of IgG1 in females, the frequency of T cells producing IL-4, the cytokine associated with regulation of IgG1 antibody production 23 , in dLNs was comparable between sexes, whereas IL-4 levels in CII-stimulated dLN cell cultures did not significantly differ between female and male rats. This was in line with previous data indicating that the ratio between production levels of cytokines driving IgG subclass switching rather than their absolute concentrations determines IgG subclass profile 50 . Additionally, given that Tfr cells acting on GC B cells either directly or indirectly, via Tfh-mediated mechanism, influence IgG switching 77 , it may be speculated that sex differences in Tfr-cell regulatory action also contributed to the sex bias in IgG subclass profile.…”

Section: Discussionsupporting

confidence: 93%

“…The higher serum level of IgG2a could be related to the greater expression of T-bet in B cells from female rats affected by CIA compared with their male counterparts, as it was shown T-bet has a crucial role in the switching antibody response toward IgG2a 74 . In favour of these findings was the sexual www.nature.com/scientificreports www.nature.com/scientificreports/ dimorphism in serum IgG subclass profile in response to stimulation with some other (auto)antigens in humans and mice 46,50 . The shift in IgG2a/IgG1 ratio in females compared with males was in accordance with the higher frequency of INF-γ-producing T cells in dLNs from female compared with male rats, and the higher INF-γ levels in CII-stimulated female rat dLN cell cultures 22 leading to the shift in INF-γ/IL-4 production ratio to the side of INF-γ.…”

Section: Discussionmentioning

confidence: 99%

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Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis

Dimitrijević

Arsenović-Ranin

Kosec

et al. 2020

Sci Rep

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The study examined germinal centre (GC) reaction in lymph nodes draining inflamed joints and adjacent tissues (dLNs) in male and female Dark Agouti rat collagen type II (CII)-induced arthritis (CIA) model of rheumatoid arthritis. Female rats exhibiting the greater susceptibility to CIA mounted stronger serum CII-specific IgG response than their male counterparts. This correlated with the higher frequency of GC B cells in female compared with male dLNs. Consistently, the frequency of activated/proliferating Ki- 67+ cells among dLN B cells was higher in females than in males. This correlated with the shift in dLN T follicular regulatory (Tfr)/T follicular helper (Tfh) cell ratio towards Tfh cells in females, and greater densities of CD40L and CD40 on their dLN T and B cells, respectively. The higherTfh cell frequency in females was consistent with the greater dLN expression of mRNA for IL-21/27, the key cytokines involved in Tfh cell generation and their help to B cells. Additionally, in CII-stimulated female rat dLN cell cultures IFN-γ/IL-4 production ratio was shifted towards IFN-γ. Consistently, the serum IgG2a(b)/ IgG1 CII-specific antibody ratio was shifted towards an IgG2a(b) response in females. Thus, targeting T-/B-cell interactions should be considered in putative further sex-based translational pharmacology research.Rheumatoid arthritis (RA) is a chronic autoimmune systemic inflammatory disease characterized by synovial inflammation and the progressive destruction of joint cartilage and bones significantly reducing health-related quality of life 1 . The prevalence of RA is approximately threefold higher in women than in men, and the disease in women exhibits a more severe course 2 . Thus, research focused on sex as a determinant of disease severity could be important for further personalized management of patients with this autoimmune disease 3 .Collagen-induced arthritis (CIA) is a well-established experimental model mimicking many aspects of RA immunopathogenesis 4 . Differently from most of the mouse models of experimentally induced arthritis 5,6 , in several studies, female rats exhibited greater susceptibility to CIA compared with their male counterparts 7-10 . Thus, these rat CIA models seem to be suitable for research aimed to elucidate cellular and molecular mechanisms underlying sex differences in pathogenesis and clinical outcome of RA, as a base for designing efficient sex-specific therapies.Sex differences in susceptibility to autoimmune diseases have been related to sex-based differences in immunopathogenesis and susceptibility of the target tissue to damage caused by autoimmune or inflammatory burden 11,12 . These differences most likely arise from intricate interactions between circulating sex steroids, microbiota, genetic and environmental factors 11,13 .CIA is shown to be T helper (Th)1/Th17 mediated disease 14 . The main function of Th cells is to activate macrophages and fibroblasts and transform them into tissue-destructive cells 15 . Our previous studies in Dark Agouti (DA) rat CIA mo...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis

Dimitrijević

Arsenović-Ranin

Kosec

et al. 2020

Sci Rep

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“…Both Tfr cells and Tfh cells expand with age in mice, and Tfr cells are more pronounced . However, male mice exhibit a higher percentage of Tfr cells than their female counterparts regardless of age . Aged and young Tfr cells exhibit identical suppressive capacity but a distinct phenotype with enhanced PD‐1 and decreased ICOS expression …”

Section: Tfr Cells In Human Diseases and Animal Modelsmentioning

confidence: 99%

“…Both cTfr cells and cTfh cells were observed to be expanded in mice infected with influenza. 16,99 Botta et al 41 found that Tfr cells in the lungdraining mediastinal LNs fail to accumulate at the peak of influenza infection, but after the immune response subsides, a fraction of Treg cells downregulates CD25 and then differentiates into Tfr cells. Tfr cell-deficient mice exhibit enhanced immunity to influenza viruses, indicating that Tfr cells may be targets in infectious disease.…”

Section: Tfr Cells In Infectionsmentioning

confidence: 99%

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Follicular regulatory T cells: a novel target for immunotherapy?

et al. 2020

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High‐affinity antibodies are produced during multiple processes in germinal centres (GCs), where follicular helper T (Tfh) cells interact closely with B cells to support B‐cell survival, differentiation and proliferation. Recent studies have revealed that a specialised subset of regulatory T cells, follicular regulatory T (Tfr) cells, especially fine‐tune Tfh cells and GC B cells, ultimately regulating GC reactions. Alterations in frequencies or function of Tfr cells may result in multiple autoantibody‐mediated or autoantibody‐associated diseases. This review discusses recent insights into the physiology and pathology of Tfr cells, with a special emphasis on their potential roles in human diseases. Discrepancies are common among studies, reflecting the limited understanding of Tfr cells. Further exploration of the mechanisms of Tfr cells in these diseases and thus targeting Tfr cells may help reinstate immune homeostasis and provide novel immunotherapy.

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