Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis

Dimitrijević, Mirjana; Arsenović-Ranin, Nevena; Kosec, Duško; Bufan, Biljana; Nacka-Aleksić, Mirjana; Pilipović, Ivan; Leposavić, Gordana

doi:10.1016/j.bbi.2018.11.311

Cited by 19 publications

(24 citation statements)

References 101 publications

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“…Our findings also revealed the enhanced expression of IL-21 and IL-27, the cytokines supporting Tfh-cell differentiation 45 , in female compared with male rat dLN cells. Given that IL-12p/35 stimulates IL-21 expression 45 , the upregulated expression of IL-21 in dLN cells from females compared with males was consistent with the greater IL-12p/35 expression in their dLNs 10 . It should be emphasized that IL-21, as IL-27 62 , supports not only Tfh-cell differentiation and thereby GC B-cell formation and function, but also directly acts on B cells supporting their growth, survival, and antibody secretion 33 .…”

Section: Discussionmentioning

confidence: 62%

“…A more prominent increase in the number of Tfh cells in female rat dLNs following immunization with CII leading to sex bias in their number in immunized rats (greater number in females) was consistent with data indicating that Th cells from adult women and female mice have greater proliferative capacity than those from age-matched men and male mice, respectively 60,61 . Additionally, we have recently shown the greater activation/proliferation of Th cells from dLNs of female CII-immunized DA rats compared with their male counterparts 10 . Our findings also revealed the enhanced expression of IL-21 and IL-27, the cytokines supporting Tfh-cell differentiation 45 , in female compared with male rat dLN cells.…”

Section: Discussionmentioning

confidence: 88%

“…were performed as previously described 10 . In brief, for surface immunolabeling, dLN cells were incubated with either fluorochrome-conjugated or unconjugated/biotin-conjugated monoclonal antibodies, followed by incubation with a second step reagent.…”

Section: Immunolabeling and Flow Cytometry Analysis (Fca) Immunostaimentioning

confidence: 99%

“…RT-qPCR reactions were set up in triplicate (25 μl final volume) using TaqMan Gene Expression Master Mix and premade TaqMan Gene Expression Assays, according to supplier's protocols (Applied Biosystems). Both reverse transcription and RT-qPCR were performed using Applied Biosystems 7500 Real-Time PCR System, as previously described in detail 10 . TaqMan Gene Expression Assays used in the study: IL-2 (Il2; Rn00587673_m1), IL-21 (Il21; Rn01755623_m1), IL-7 (Il7; Rn00681900_m1), IL-27-subunit p28 (Il27; Rn01510484_m1), T-bet (Tbx21; Rn01461633_m1) and β-actin (Actb; Rn00667869_m1).…”

Section: Rt-qpcrmentioning

confidence: 99%

“…more severe CIA) compared with their male counterparts and pointed out to some underlying mechanisms 9,10 . However, although CD4+ T cells are of essential significance for the induction and maintenance of inflammation in CIA and RA, the activation of self-antigen-specific B cells is thought to be extremely important for the target tissue damage 16 .…”

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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: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 88%

Section: Immunolabeling and Flow Cytometry Analysis (Fca) Immunostaimentioning

confidence: 99%

Section: Rt-qpcrmentioning

confidence: 99%

mentioning

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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Immature neutrophil signature associated with the sexual dimorphism of systemic juvenile idiopathic arthritis

Prada-Medina

Peron

Nakaya

2020

Journal of Leukocyte Biology

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Juvenile idiopathic arthritis (JIA) is a group of inflammatory conditions of unknown etiology whose incidence is sex dependent. Although several studies have attempted to identify JIArelated gene signatures, none have systematically assessed the impact of sex on the whole blood transcriptomes of JIA patients. By analyzing over 400 unique pediatric gene expression profiles, we characterized the sexual differences in leukocyte composition of systemic JIA patients and identified sex-specific gene signatures that were related to immature neutrophils. Female systemic JIA patients presented higher activation of immature neutrophil-related genes compared to males, and these genes were associated with the response to IL-1 receptor blockade treatment. Also, we found that this immature neutrophil signature is sexually dimorphic across human lifespan and in adults with rheumatoid arthritis and asthma. These results suggest that neutrophil maturation is sexually dimorphic in rheumatic inflammation, and that this may impact disease progression and treatment.

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Sex-Based Differences in Monocytic Lineage Cells Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats

et al. 2020

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Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis

Cited by 19 publications

References 101 publications

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

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

Immature neutrophil signature associated with the sexual dimorphism of systemic juvenile idiopathic arthritis

Sex-Based Differences in Monocytic Lineage Cells Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats

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