TY  - JOUR
AU  - Dimitrijević, Mirjana
AU  - Arsenović-Ranin, Nevena
AU  - Kosec, Duško
AU  - Bufan, Biljana
AU  - Nacka-Aleksić, Mirjana
AU  - Pilipović, Ivan
AU  - Leposavić, Gordana
PY  - 2020
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC6985112
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3604
AB  - 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 higher Tfh 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.
T2  - Scientific Reports
T1  - Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis.
IS  - 1
VL  - 10
DO  - 10.1038/s41598-020-58127-y
SP  - 1214
ER  - 

@article{
author = "Dimitrijević, Mirjana and Arsenović-Ranin, Nevena and Kosec, Duško and Bufan, Biljana and Nacka-Aleksić, Mirjana and Pilipović, Ivan and Leposavić, Gordana",
year = "2020",
abstract = "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 higher Tfh 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.",
journal = "Scientific Reports",
title = "Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis.",
number = "1",
volume = "10",
doi = "10.1038/s41598-020-58127-y",
pages = "1214"
}

Dimitrijević, M., Arsenović-Ranin, N., Kosec, D., Bufan, B., Nacka-Aleksić, M., Pilipović, I.,& Leposavić, G.. (2020). Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis.. in Scientific Reports, 10(1), 1214.
https://doi.org/10.1038/s41598-020-58127-y

Dimitrijević M, Arsenović-Ranin N, Kosec D, Bufan B, Nacka-Aleksić M, Pilipović I, Leposavić G. Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis.. in Scientific Reports. 2020;10(1):1214.
doi:10.1038/s41598-020-58127-y .

Dimitrijević, Mirjana, Arsenović-Ranin, Nevena, Kosec, Duško, Bufan, Biljana, Nacka-Aleksić, Mirjana, Pilipović, Ivan, Leposavić, Gordana, "Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis." in Scientific Reports, 10, no. 1 (2020):1214,
https://doi.org/10.1038/s41598-020-58127-y . .

TY  - JOUR
AU  - Dimitrijević, Mirjana
AU  - Arsenović-Ranin, Nevena
AU  - Kosec, Duško
AU  - Bufan, Biljana
AU  - Nacka-Aleksić, Mirjana
AU  - Pilipović, Ivan
AU  - Leposavić, Gordana
PY  - 2019
UR  - https://www.sciencedirect.com/science/article/pii/S0889159118304574?via%3Dihub
UR  - http://www.ncbi.nlm.nih.gov/pubmed/30476564
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3300
AB  - Collagen type II-induced arthritis (CIA) in Dark Agouti rats, a model of rheumatoid arthritis (RA), reproduces sexual dimorphism in the incidence and severity of the human disease. Th17 cells are central in the induction/propagation of autoimmune inflammation in CIA and RA. To assess mechanisms underlying this dimorphism in CIA rats, in lymph nodes draining inflamed joints and adjacent tissues (dLNs) from CIA rats of both sexes Th17/CD25+Foxp3+CD4+ T-regulatory cell (Treg) ratio, Th17 cell redifferentiation in functionally distinct subsets and Treg transdifferentiation into IL-17-producing cells (exTregs) were examined. In female rats (developing more severe CIA than their male counterparts) the higher frequency of all Th17 cells (reflecting partly their greater proliferation), followed by the higher frequency of highly pathogenic IFN-γ/GM-CSF-co-producing cells, but lower frequency of less pathogenic/immunoregulatory IL-10-producing cells among them was found. Additionally, compared with male rats, in female rats the lower frequency of Tregs was observed. Moreover, Tregs from female rats exhibited diminished proliferative and suppressive capacity (judging by PD-1 expression) and enhanced conversion into IL-17-producing cells. Given that TGF-β concentration was comparable in collagen-type II-stimulated dLN cell cultures from female and male rats, the shift in Th17/Treg ratio followed by augmented Th17 cell redifferentiation into IFN-γ/GM-CSF-co-producing cells and Treg transdifferentiation into IL-17-producing cells in female rats was associated with increased concentration of IL-6 in female rat dLN cell cultures, and the higher frequency of IL-1β- and IL-23-producing cells among their dLN cells. The lower frequency of IL-10-producing B cells, presumably B regulatory cells (Bregs) could also contribute to the shift in Th17/Treg ratio in female rat compared with male rat dLNs. Consistently, the lower expression of IL-35 (the cytokine promoting Treg expansion directly and indirectly, by favoring Breg expansion and conversion into IL-10/IL-35-producing cells) in female rat dLN cells was detected. Thus, the study identified putative cellular and molecular substrates of the sexual dimorphism in the immunopathogenesis and clinical outcome of CIA and suggested mechanisms to be targeted in females to improve control of Th17 response, and consequently clinical outcome of CIA, and possibly RA.
T2  - Brain, Behavior, and Immunity
T1  - Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis.
VL  - 76
DO  - 10.1016/j.bbi.2018.11.311
SP  - 198
EP  - 214
ER  - 

@article{
author = "Dimitrijević, Mirjana and Arsenović-Ranin, Nevena and Kosec, Duško and Bufan, Biljana and Nacka-Aleksić, Mirjana and Pilipović, Ivan and Leposavić, Gordana",
year = "2019",
abstract = "Collagen type II-induced arthritis (CIA) in Dark Agouti rats, a model of rheumatoid arthritis (RA), reproduces sexual dimorphism in the incidence and severity of the human disease. Th17 cells are central in the induction/propagation of autoimmune inflammation in CIA and RA. To assess mechanisms underlying this dimorphism in CIA rats, in lymph nodes draining inflamed joints and adjacent tissues (dLNs) from CIA rats of both sexes Th17/CD25+Foxp3+CD4+ T-regulatory cell (Treg) ratio, Th17 cell redifferentiation in functionally distinct subsets and Treg transdifferentiation into IL-17-producing cells (exTregs) were examined. In female rats (developing more severe CIA than their male counterparts) the higher frequency of all Th17 cells (reflecting partly their greater proliferation), followed by the higher frequency of highly pathogenic IFN-γ/GM-CSF-co-producing cells, but lower frequency of less pathogenic/immunoregulatory IL-10-producing cells among them was found. Additionally, compared with male rats, in female rats the lower frequency of Tregs was observed. Moreover, Tregs from female rats exhibited diminished proliferative and suppressive capacity (judging by PD-1 expression) and enhanced conversion into IL-17-producing cells. Given that TGF-β concentration was comparable in collagen-type II-stimulated dLN cell cultures from female and male rats, the shift in Th17/Treg ratio followed by augmented Th17 cell redifferentiation into IFN-γ/GM-CSF-co-producing cells and Treg transdifferentiation into IL-17-producing cells in female rats was associated with increased concentration of IL-6 in female rat dLN cell cultures, and the higher frequency of IL-1β- and IL-23-producing cells among their dLN cells. The lower frequency of IL-10-producing B cells, presumably B regulatory cells (Bregs) could also contribute to the shift in Th17/Treg ratio in female rat compared with male rat dLNs. Consistently, the lower expression of IL-35 (the cytokine promoting Treg expansion directly and indirectly, by favoring Breg expansion and conversion into IL-10/IL-35-producing cells) in female rat dLN cells was detected. Thus, the study identified putative cellular and molecular substrates of the sexual dimorphism in the immunopathogenesis and clinical outcome of CIA and suggested mechanisms to be targeted in females to improve control of Th17 response, and consequently clinical outcome of CIA, and possibly RA.",
journal = "Brain, Behavior, and Immunity",
title = "Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis.",
volume = "76",
doi = "10.1016/j.bbi.2018.11.311",
pages = "198-214"
}

Dimitrijević, M., Arsenović-Ranin, N., Kosec, D., Bufan, B., Nacka-Aleksić, M., Pilipović, I.,& Leposavić, G.. (2019). Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis.. in Brain, Behavior, and Immunity, 76, 198-214.
https://doi.org/10.1016/j.bbi.2018.11.311

Dimitrijević M, Arsenović-Ranin N, Kosec D, Bufan B, Nacka-Aleksić M, Pilipović I, Leposavić G. Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis.. in Brain, Behavior, and Immunity. 2019;76:198-214.
doi:10.1016/j.bbi.2018.11.311 .

Dimitrijević, Mirjana, Arsenović-Ranin, Nevena, Kosec, Duško, Bufan, Biljana, Nacka-Aleksić, Mirjana, Pilipović, Ivan, Leposavić, Gordana, "Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis." in Brain, Behavior, and Immunity, 76 (2019):198-214,
https://doi.org/10.1016/j.bbi.2018.11.311 . .

TY  - JOUR
AU  - Dimitrijević, Mirjana
AU  - Arsenović-Ranin, Nevena
AU  - Bufan, Biljana
AU  - Nacka-Aleksić, Mirjana
AU  - Lazarević Macanović, Mirjana
AU  - Milovanović, Petar
AU  - Đurić, Marija
AU  - Sopta, Jelena
AU  - Leposavić, Gordana
PY  - 2018
UR  - https://www.sciencedirect.com/science/article/pii/S0014480017305646?via%3Dihub
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3076
AB  - Collagen-induced arthritis (CIA) is a frequently used animal model of rheumatoid arthritis, human autoimmune disease that exhibits clear sex bias in incidence and clinical course. Female Dark Agouti rats immunized for CIA showed also greater incidence and higher arthritic score than their male counterparts. The study investigated sex differences in mechanisms controlling the primary immune responses in draining lymph nodes (dLNs), as a factor contributing to this dimorphism. The higher frequencies of CD4 + CD25 + Foxp3- cells, presumably activated effector T (Teff) cells, and IL-17+, IFN-γ + and IL-17 + IFN-γ + T cells were found in female compared with male rat dLNs. However, the frequency of CD4 + CD25 + Foxp3+ T regulatory cells (Treg) did not differ between sexes. Thus, CD4+ Teff cells/Treg ratio, and IL-17+ T cells/Treg and IFN-γ + T cells/Treg ratios were higher in female than in male rats, and among them was found lower frequency of PD-1+ cells. This suggested less efficient control of (auto)immune Th1/Th17 cell responses in female rat dLNs. On the contrary, the frequency of IL-4+ T cells was lower in female than in male rat dLNs. Consistently, the ratio of serum levels of collagen-specific IgG2a (IFN-γ-dependent, with an important pathogenic role in CIA) and IgG1 (IL-4-dependent) was shifted towards IgG2a in female compared with male rats. As a whole, the study suggests that sexual dimorphism in the control of T cell activation/polarization could contribute to sex bias in the susceptibility to CIA. Moreover, the study advises the use of animals of both sexes in the preclinical testing of new drugs for rheumatoid arthritis.
T2  - Experimental and Molecular Pathology
T1  - Collagen-induced arthritis in Dark Agouti rats as a model for study of immunological sexual dimorphisms in the human disease.
IS  - 1
VL  - 105
DO  - 10.1016/j.yexmp.2018.05.007
SP  - 10
EP  - 22
ER  - 

@article{
author = "Dimitrijević, Mirjana and Arsenović-Ranin, Nevena and Bufan, Biljana and Nacka-Aleksić, Mirjana and Lazarević Macanović, Mirjana and Milovanović, Petar and Đurić, Marija and Sopta, Jelena and Leposavić, Gordana",
year = "2018",
abstract = "Collagen-induced arthritis (CIA) is a frequently used animal model of rheumatoid arthritis, human autoimmune disease that exhibits clear sex bias in incidence and clinical course. Female Dark Agouti rats immunized for CIA showed also greater incidence and higher arthritic score than their male counterparts. The study investigated sex differences in mechanisms controlling the primary immune responses in draining lymph nodes (dLNs), as a factor contributing to this dimorphism. The higher frequencies of CD4 + CD25 + Foxp3- cells, presumably activated effector T (Teff) cells, and IL-17+, IFN-γ + and IL-17 + IFN-γ + T cells were found in female compared with male rat dLNs. However, the frequency of CD4 + CD25 + Foxp3+ T regulatory cells (Treg) did not differ between sexes. Thus, CD4+ Teff cells/Treg ratio, and IL-17+ T cells/Treg and IFN-γ + T cells/Treg ratios were higher in female than in male rats, and among them was found lower frequency of PD-1+ cells. This suggested less efficient control of (auto)immune Th1/Th17 cell responses in female rat dLNs. On the contrary, the frequency of IL-4+ T cells was lower in female than in male rat dLNs. Consistently, the ratio of serum levels of collagen-specific IgG2a (IFN-γ-dependent, with an important pathogenic role in CIA) and IgG1 (IL-4-dependent) was shifted towards IgG2a in female compared with male rats. As a whole, the study suggests that sexual dimorphism in the control of T cell activation/polarization could contribute to sex bias in the susceptibility to CIA. Moreover, the study advises the use of animals of both sexes in the preclinical testing of new drugs for rheumatoid arthritis.",
journal = "Experimental and Molecular Pathology",
title = "Collagen-induced arthritis in Dark Agouti rats as a model for study of immunological sexual dimorphisms in the human disease.",
number = "1",
volume = "105",
doi = "10.1016/j.yexmp.2018.05.007",
pages = "10-22"
}

Dimitrijević, M., Arsenović-Ranin, N., Bufan, B., Nacka-Aleksić, M., Lazarević Macanović, M., Milovanović, P., Đurić, M., Sopta, J.,& Leposavić, G.. (2018). Collagen-induced arthritis in Dark Agouti rats as a model for study of immunological sexual dimorphisms in the human disease.. in Experimental and Molecular Pathology, 105(1), 10-22.
https://doi.org/10.1016/j.yexmp.2018.05.007

Dimitrijević M, Arsenović-Ranin N, Bufan B, Nacka-Aleksić M, Lazarević Macanović M, Milovanović P, Đurić M, Sopta J, Leposavić G. Collagen-induced arthritis in Dark Agouti rats as a model for study of immunological sexual dimorphisms in the human disease.. in Experimental and Molecular Pathology. 2018;105(1):10-22.
doi:10.1016/j.yexmp.2018.05.007 .

Dimitrijević, Mirjana, Arsenović-Ranin, Nevena, Bufan, Biljana, Nacka-Aleksić, Mirjana, Lazarević Macanović, Mirjana, Milovanović, Petar, Đurić, Marija, Sopta, Jelena, Leposavić, Gordana, "Collagen-induced arthritis in Dark Agouti rats as a model for study of immunological sexual dimorphisms in the human disease." in Experimental and Molecular Pathology, 105, no. 1 (2018):10-22,
https://doi.org/10.1016/j.yexmp.2018.05.007 . .

TY  - JOUR
AU  - Dimitrijević, Mirjana
AU  - Arsenović-Ranin, Nevena
AU  - Kosec, Duško
AU  - Bufan, Biljana
AU  - Nacka-Aleksić, Mirjana
AU  - Pilipović, Ivan
AU  - Leposavić, Gordana
PY  - 2018
UR  - https://www.sciencedirect.com/science/article/pii/S0889159118304574?via%3Dihub
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3195
AB  - Collagen type II-induced arthritis (CIA) in Dark Agouti rats, a model of rheumatoid arthritis (RA), reproduces sexual dimorphism in incidence and severity of the human disease. Th17 cells are central in the induction/propagation of autoimmune inflammation in CIA and RA. To assess mechanisms underlying this dimorphism in CIA rats, in lymph nodes draining inflamed joints and adjacent tissues (dLNs) from CIA rats of both sexes Th17/CD25+Foxp3+CD4+ T-regulatory cell (Treg) ratio, Th17 cell redifferentiation in functionally distinct subsets and Treg transdifferentiation into IL-17-producing cells (exTregs) were examined. In female rats (developing more severe CIA than their male counterparts) the higher frequency of all Th17 cells (reflecting partly their greater proliferation), followed by the higher frequency of highly pathogenic IFN-γ/GM-CSF-co-producing cells, but lower frequency of less pathogenic/immunoregulatory IL-10-producing cells among them was found. Additionally, compared with male rats, in female rats the lower frequency of Tregs was observed. Moreover, Tregs from female rats exhibited diminished proliferative and suppressive capacity (judging by PD-1 expression) and enhanced conversion into IL-17-producing cells. Given that TGF-β concentration was comparable in collagen-type II-stimulated dLN cell cultures from female and male rats, the shift in Th17/Treg ratio followed by augmented Th17 cell redifferentiation into IFN-γ/GM-CSF-co-producing cells and Treg transdifferentiation into IL-17-producing cells in female rats was associated with increased concentration of IL-6 in female rat dLN cell cultures, and the higher frequency of IL-1β- and IL-23-producing cells among their dLN cells. The lower frequency of IL-10-producing B cells, presumably B regulatory cells (Bregs) could also contribute to the shift in Th17/Treg ratio in female rat compared with male rat dLNs. Consistently, the lower expression of IL-35 (the cytokine promoting Treg expansion directly and indirectly, by favouring Breg expansion and conversion into IL-10/IL-35-producing cells) in female rat dLN cells was detected. Thus, the study identified putative cellular and molecular substrates of the sexual dimorphism in the immunopathogenesis and clinical outcome of CIA and suggested mechanisms to be targeted in females to improve control of Th17 response, and consequently clinical outcome of CIA, and possibly RA.
T2  - Brain, Behavior, and Immunity
T1  - Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis.
DO  - 10.1016/j.bbi.2018.11.311
ER  - 

@article{
author = "Dimitrijević, Mirjana and Arsenović-Ranin, Nevena and Kosec, Duško and Bufan, Biljana and Nacka-Aleksić, Mirjana and Pilipović, Ivan and Leposavić, Gordana",
year = "2018",
abstract = "Collagen type II-induced arthritis (CIA) in Dark Agouti rats, a model of rheumatoid arthritis (RA), reproduces sexual dimorphism in incidence and severity of the human disease. Th17 cells are central in the induction/propagation of autoimmune inflammation in CIA and RA. To assess mechanisms underlying this dimorphism in CIA rats, in lymph nodes draining inflamed joints and adjacent tissues (dLNs) from CIA rats of both sexes Th17/CD25+Foxp3+CD4+ T-regulatory cell (Treg) ratio, Th17 cell redifferentiation in functionally distinct subsets and Treg transdifferentiation into IL-17-producing cells (exTregs) were examined. In female rats (developing more severe CIA than their male counterparts) the higher frequency of all Th17 cells (reflecting partly their greater proliferation), followed by the higher frequency of highly pathogenic IFN-γ/GM-CSF-co-producing cells, but lower frequency of less pathogenic/immunoregulatory IL-10-producing cells among them was found. Additionally, compared with male rats, in female rats the lower frequency of Tregs was observed. Moreover, Tregs from female rats exhibited diminished proliferative and suppressive capacity (judging by PD-1 expression) and enhanced conversion into IL-17-producing cells. Given that TGF-β concentration was comparable in collagen-type II-stimulated dLN cell cultures from female and male rats, the shift in Th17/Treg ratio followed by augmented Th17 cell redifferentiation into IFN-γ/GM-CSF-co-producing cells and Treg transdifferentiation into IL-17-producing cells in female rats was associated with increased concentration of IL-6 in female rat dLN cell cultures, and the higher frequency of IL-1β- and IL-23-producing cells among their dLN cells. The lower frequency of IL-10-producing B cells, presumably B regulatory cells (Bregs) could also contribute to the shift in Th17/Treg ratio in female rat compared with male rat dLNs. Consistently, the lower expression of IL-35 (the cytokine promoting Treg expansion directly and indirectly, by favouring Breg expansion and conversion into IL-10/IL-35-producing cells) in female rat dLN cells was detected. Thus, the study identified putative cellular and molecular substrates of the sexual dimorphism in the immunopathogenesis and clinical outcome of CIA and suggested mechanisms to be targeted in females to improve control of Th17 response, and consequently clinical outcome of CIA, and possibly RA.",
journal = "Brain, Behavior, and Immunity",
title = "Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis.",
doi = "10.1016/j.bbi.2018.11.311"
}

Dimitrijević, M., Arsenović-Ranin, N., Kosec, D., Bufan, B., Nacka-Aleksić, M., Pilipović, I.,& Leposavić, G.. (2018). Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis.. in Brain, Behavior, and Immunity.
https://doi.org/10.1016/j.bbi.2018.11.311

Dimitrijević M, Arsenović-Ranin N, Kosec D, Bufan B, Nacka-Aleksić M, Pilipović I, Leposavić G. Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis.. in Brain, Behavior, and Immunity. 2018;.
doi:10.1016/j.bbi.2018.11.311 .

Dimitrijević, Mirjana, Arsenović-Ranin, Nevena, Kosec, Duško, Bufan, Biljana, Nacka-Aleksić, Mirjana, Pilipović, Ivan, Leposavić, Gordana, "Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis." in Brain, Behavior, and Immunity (2018),
https://doi.org/10.1016/j.bbi.2018.11.311 . .

TY  - JOUR
AU  - Nacka-Aleksić, Mirjana
AU  - Stojanović, Marija
AU  - Simić, Lidija
AU  - Bufan, Biljana
AU  - Kotur-Stevuljević, Jelena
AU  - Stojić-Vukanić, Zorica
AU  - Dimitrijević, Mirjana
AU  - Ražić, Slavica
AU  - Leposavić, Gordana
PY  - 2017
UR  - http://link.springer.com/10.1007/s10522-017-9726-4
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2838
AB  - To close the gap in our knowledge of sex influence on age-related changes in inflammation-oxidation state in spinal cord (SC) relevant to inflammation/oxidative-stress associated neuropathologies, 2–3 month-old (young) and 18–20 month-old (old) rats, exhibiting increased level of IL-6, a commonly used marker of inflamm-aging, were examined for inflammatory/redox status, and the underlying regulatory networks’ molecules expression. With age, rat SC microglia became sensitized (“primed”), while SC tissue shifted towards mild inflammatory state, with increased levels of proinflammatory IL-1β (key marker of microglial systemic inflammation-induced neurotoxicity), which was more prominent in males. This, most likely, reflected age- and sex-related impairment in the expression of CX3CR1, the receptor for fractalkine (CX3CL1), the soluble factor which regulates microglial activation and diminishes production of IL-1β (central for fractalkine neuroprotection). Considering that (i) age-related changes in SC IL-1β expression were not followed by complementary changes in SC IL-6 expression, and (ii) the reversal in the direction of the sex bias in circulating IL-6 level and SC IL-1β expression, it seems obvious that there are tissue-specific differences in the proinflammatory cytokine profile. Additionally, old male rat SC exhibited greater oxidative damage than female, reflecting, most likely, their lower capacity to maintain the pro-oxidant-antioxidant balance. In conclusion, these findings, apart from highlighting the significance of sex for age-associated changes in SC inflammation-oxidation, may be relevant for understating sex differences in human inflammation/oxidative-stress related SC diseases, and consequently, for optimizing their prevention/therapy.
T2  - Biogerontology
T1  - Sex as a determinant of age-related changes in rat spinal cord inflammation-oxidation state
DO  - 10.1007/s10522-017-9726-4
ER  - 

@article{
author = "Nacka-Aleksić, Mirjana and Stojanović, Marija and Simić, Lidija and Bufan, Biljana and Kotur-Stevuljević, Jelena and Stojić-Vukanić, Zorica and Dimitrijević, Mirjana and Ražić, Slavica and Leposavić, Gordana",
year = "2017",
abstract = "To close the gap in our knowledge of sex influence on age-related changes in inflammation-oxidation state in spinal cord (SC) relevant to inflammation/oxidative-stress associated neuropathologies, 2–3 month-old (young) and 18–20 month-old (old) rats, exhibiting increased level of IL-6, a commonly used marker of inflamm-aging, were examined for inflammatory/redox status, and the underlying regulatory networks’ molecules expression. With age, rat SC microglia became sensitized (“primed”), while SC tissue shifted towards mild inflammatory state, with increased levels of proinflammatory IL-1β (key marker of microglial systemic inflammation-induced neurotoxicity), which was more prominent in males. This, most likely, reflected age- and sex-related impairment in the expression of CX3CR1, the receptor for fractalkine (CX3CL1), the soluble factor which regulates microglial activation and diminishes production of IL-1β (central for fractalkine neuroprotection). Considering that (i) age-related changes in SC IL-1β expression were not followed by complementary changes in SC IL-6 expression, and (ii) the reversal in the direction of the sex bias in circulating IL-6 level and SC IL-1β expression, it seems obvious that there are tissue-specific differences in the proinflammatory cytokine profile. Additionally, old male rat SC exhibited greater oxidative damage than female, reflecting, most likely, their lower capacity to maintain the pro-oxidant-antioxidant balance. In conclusion, these findings, apart from highlighting the significance of sex for age-associated changes in SC inflammation-oxidation, may be relevant for understating sex differences in human inflammation/oxidative-stress related SC diseases, and consequently, for optimizing their prevention/therapy.",
journal = "Biogerontology",
title = "Sex as a determinant of age-related changes in rat spinal cord inflammation-oxidation state",
doi = "10.1007/s10522-017-9726-4"
}

Nacka-Aleksić, M., Stojanović, M., Simić, L., Bufan, B., Kotur-Stevuljević, J., Stojić-Vukanić, Z., Dimitrijević, M., Ražić, S.,& Leposavić, G.. (2017). Sex as a determinant of age-related changes in rat spinal cord inflammation-oxidation state. in Biogerontology.
https://doi.org/10.1007/s10522-017-9726-4

Nacka-Aleksić M, Stojanović M, Simić L, Bufan B, Kotur-Stevuljević J, Stojić-Vukanić Z, Dimitrijević M, Ražić S, Leposavić G. Sex as a determinant of age-related changes in rat spinal cord inflammation-oxidation state. in Biogerontology. 2017;.
doi:10.1007/s10522-017-9726-4 .

Nacka-Aleksić, Mirjana, Stojanović, Marija, Simić, Lidija, Bufan, Biljana, Kotur-Stevuljević, Jelena, Stojić-Vukanić, Zorica, Dimitrijević, Mirjana, Ražić, Slavica, Leposavić, Gordana, "Sex as a determinant of age-related changes in rat spinal cord inflammation-oxidation state" in Biogerontology (2017),
https://doi.org/10.1007/s10522-017-9726-4 . .

TY  - JOUR
AU  - Ćuruvija, Ivana
AU  - Stanojević, Stanislava
AU  - Arsenović-Ranin, Nevena
AU  - Blagojević, Veljko
AU  - Dimitrijević, Mirjana
AU  - Vidić-Danković, Biljana
AU  - Vujić, Vesna
PY  - 2017
UR  - http://link.springer.com/10.1007/s10753-017-0551-3
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2726
AB  - The aim of this study was to examine the influence of sex on age-related changes in phenotype and functional capacity of rat macrophages. The potential role of estradiol as a contributing factor to a sex difference in macrophage function with age was also examined. Thioglycollate-elicited peritoneal macrophages derived from the young (2 months old) and the naturally senescent intact middle-aged (16 months old) male and female rats were tested for cytokine secretion and antimicrobial activity (NO and H2O2 production and myeloperoxidase activity). Serum concentration of estradiol and the expression of estrogen receptor (ER)α and ERβ on freshly isolated peritoneal macrophages were also examined. Decreased secretion of IL-1β and IL-6 by macrophages from middle-aged compared to the young females was accompanied with the lesser density of macrophage ERα expression and the lower systemic level of estradiol, whereas the opposite was true for middle-aged male rats. Macrophages in the middle-aged females, even with the diminished circulating estradiol levels, produce increased amount of IL-6, and comparable amounts of IL-1β, TNF-α, and NO to that measured in macrophages from the middle-aged males. Age-related changes in macrophage phenotype and the antimicrobial activity were independent of macrophage ERα/ERβ expression and estradiol level in both male and female rats. Although our study suggests that the sex difference in the level of circulating estradiol may to some extent contribute to sex difference in macrophage function of middle-aged rats, it also points to more complex hormonal regulation of peritoneal macrophage activity in females.
T2  - Inflammation
T1  - Sex Differences in Macrophage Functions in Middle-Aged Rats: Relevance of Estradiol Level and Macrophage Estrogen Receptor Expression
DO  - 10.1007/s10753-017-0551-3
ER  - 

@article{
author = "Ćuruvija, Ivana and Stanojević, Stanislava and Arsenović-Ranin, Nevena and Blagojević, Veljko and Dimitrijević, Mirjana and Vidić-Danković, Biljana and Vujić, Vesna",
year = "2017",
abstract = "The aim of this study was to examine the influence of sex on age-related changes in phenotype and functional capacity of rat macrophages. The potential role of estradiol as a contributing factor to a sex difference in macrophage function with age was also examined. Thioglycollate-elicited peritoneal macrophages derived from the young (2 months old) and the naturally senescent intact middle-aged (16 months old) male and female rats were tested for cytokine secretion and antimicrobial activity (NO and H2O2 production and myeloperoxidase activity). Serum concentration of estradiol and the expression of estrogen receptor (ER)α and ERβ on freshly isolated peritoneal macrophages were also examined. Decreased secretion of IL-1β and IL-6 by macrophages from middle-aged compared to the young females was accompanied with the lesser density of macrophage ERα expression and the lower systemic level of estradiol, whereas the opposite was true for middle-aged male rats. Macrophages in the middle-aged females, even with the diminished circulating estradiol levels, produce increased amount of IL-6, and comparable amounts of IL-1β, TNF-α, and NO to that measured in macrophages from the middle-aged males. Age-related changes in macrophage phenotype and the antimicrobial activity were independent of macrophage ERα/ERβ expression and estradiol level in both male and female rats. Although our study suggests that the sex difference in the level of circulating estradiol may to some extent contribute to sex difference in macrophage function of middle-aged rats, it also points to more complex hormonal regulation of peritoneal macrophage activity in females.",
journal = "Inflammation",
title = "Sex Differences in Macrophage Functions in Middle-Aged Rats: Relevance of Estradiol Level and Macrophage Estrogen Receptor Expression",
doi = "10.1007/s10753-017-0551-3"
}

Ćuruvija, I., Stanojević, S., Arsenović-Ranin, N., Blagojević, V., Dimitrijević, M., Vidić-Danković, B.,& Vujić, V.. (2017). Sex Differences in Macrophage Functions in Middle-Aged Rats: Relevance of Estradiol Level and Macrophage Estrogen Receptor Expression. in Inflammation.
https://doi.org/10.1007/s10753-017-0551-3

Ćuruvija I, Stanojević S, Arsenović-Ranin N, Blagojević V, Dimitrijević M, Vidić-Danković B, Vujić V. Sex Differences in Macrophage Functions in Middle-Aged Rats: Relevance of Estradiol Level and Macrophage Estrogen Receptor Expression. in Inflammation. 2017;.
doi:10.1007/s10753-017-0551-3 .

Ćuruvija, Ivana, Stanojević, Stanislava, Arsenović-Ranin, Nevena, Blagojević, Veljko, Dimitrijević, Mirjana, Vidić-Danković, Biljana, Vujić, Vesna, "Sex Differences in Macrophage Functions in Middle-Aged Rats: Relevance of Estradiol Level and Macrophage Estrogen Receptor Expression" in Inflammation (2017),
https://doi.org/10.1007/s10753-017-0551-3 . .

TY  - JOUR
AU  - Dimitrijević, Mirjana
AU  - Kotur-Stevuljević, Jelena
AU  - Stojić-Vukanić, Zorica
AU  - Vujnović, Ivana
AU  - Pilipović, Ivan
AU  - Nacka-Aleksić, Mirjana
AU  - Leposavić, Gordana
PY  - 2017
UR  - http://link.springer.com/10.1007/s11064-016-2094-7
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2685
AB  - The study examined (a) whether there is sex difference in spinal cord and plasma oxidative stress profiles in Dark Agouti rats immunised for experimental autoimmune encephalomyelitis (EAE), the principal experimental model of multiple sclerosis, and (b) whether there is correlation between the oxidative stress in spinal cord and neurological deficit. Regardless of rat sex, with the disease development xanthine oxidase (XO) activity and inducible nitric oxide synthase (iNOS) mRNA expression increased in spinal cord, whereas glutathione levels decreased. This was accompanied by the rise in spinal cord malondialdehyde level. On the other hand, with EAE development superoxide dismutase (SOD) activity decreased, while O2− concentration increased only in spinal cord of male rats. Consequently, SOD activity was lower, whereas O2− concentration was higher in spinal cord of male rats with clinically manifested EAE. XO activity and iNOS mRNA expression were also elevated in their spinal cord. Consistently, in the effector phase of EAE the concentration of advanced oxidation protein product (AOPP) was higher in spinal cord of male rats, which exhibit more severe neurological deficit than their female counterparts. In as much as data obtained in the experimental models could be translated to humans, the findings may be relevant for designing sex-specific antioxidant therapeutic strategies. Furthermore, the study indicated that the increased pro-oxidant–antioxidant balance in plasma may be an early indicator of EAE development. Moreover, it showed that plasma AOPP level may indicate not only actual activity of the disease, but also serve to predict severity of its course.
T2  - Neurochemical Research
T1  - Sex Difference in Oxidative Stress Parameters in Spinal Cord of Rats with Experimental Autoimmune Encephalomyelitis: Relation to Neurological Deficit
IS  - 2
VL  - 42
DO  - 10.1007/s11064-016-2094-7
SP  - 481
EP  - 492
ER  - 

@article{
author = "Dimitrijević, Mirjana and Kotur-Stevuljević, Jelena and Stojić-Vukanić, Zorica and Vujnović, Ivana and Pilipović, Ivan and Nacka-Aleksić, Mirjana and Leposavić, Gordana",
year = "2017",
abstract = "The study examined (a) whether there is sex difference in spinal cord and plasma oxidative stress profiles in Dark Agouti rats immunised for experimental autoimmune encephalomyelitis (EAE), the principal experimental model of multiple sclerosis, and (b) whether there is correlation between the oxidative stress in spinal cord and neurological deficit. Regardless of rat sex, with the disease development xanthine oxidase (XO) activity and inducible nitric oxide synthase (iNOS) mRNA expression increased in spinal cord, whereas glutathione levels decreased. This was accompanied by the rise in spinal cord malondialdehyde level. On the other hand, with EAE development superoxide dismutase (SOD) activity decreased, while O2− concentration increased only in spinal cord of male rats. Consequently, SOD activity was lower, whereas O2− concentration was higher in spinal cord of male rats with clinically manifested EAE. XO activity and iNOS mRNA expression were also elevated in their spinal cord. Consistently, in the effector phase of EAE the concentration of advanced oxidation protein product (AOPP) was higher in spinal cord of male rats, which exhibit more severe neurological deficit than their female counterparts. In as much as data obtained in the experimental models could be translated to humans, the findings may be relevant for designing sex-specific antioxidant therapeutic strategies. Furthermore, the study indicated that the increased pro-oxidant–antioxidant balance in plasma may be an early indicator of EAE development. Moreover, it showed that plasma AOPP level may indicate not only actual activity of the disease, but also serve to predict severity of its course.",
journal = "Neurochemical Research",
title = "Sex Difference in Oxidative Stress Parameters in Spinal Cord of Rats with Experimental Autoimmune Encephalomyelitis: Relation to Neurological Deficit",
number = "2",
volume = "42",
doi = "10.1007/s11064-016-2094-7",
pages = "481-492"
}

Dimitrijević, M., Kotur-Stevuljević, J., Stojić-Vukanić, Z., Vujnović, I., Pilipović, I., Nacka-Aleksić, M.,& Leposavić, G.. (2017). Sex Difference in Oxidative Stress Parameters in Spinal Cord of Rats with Experimental Autoimmune Encephalomyelitis: Relation to Neurological Deficit. in Neurochemical Research, 42(2), 481-492.
https://doi.org/10.1007/s11064-016-2094-7

Dimitrijević M, Kotur-Stevuljević J, Stojić-Vukanić Z, Vujnović I, Pilipović I, Nacka-Aleksić M, Leposavić G. Sex Difference in Oxidative Stress Parameters in Spinal Cord of Rats with Experimental Autoimmune Encephalomyelitis: Relation to Neurological Deficit. in Neurochemical Research. 2017;42(2):481-492.
doi:10.1007/s11064-016-2094-7 .

Dimitrijević, Mirjana, Kotur-Stevuljević, Jelena, Stojić-Vukanić, Zorica, Vujnović, Ivana, Pilipović, Ivan, Nacka-Aleksić, Mirjana, Leposavić, Gordana, "Sex Difference in Oxidative Stress Parameters in Spinal Cord of Rats with Experimental Autoimmune Encephalomyelitis: Relation to Neurological Deficit" in Neurochemical Research, 42, no. 2 (2017):481-492,
https://doi.org/10.1007/s11064-016-2094-7 . .

TY  - GEN
AU  - Stojić-Vukanić, Zorica
AU  - Kotur-Stevuljević, Jelena
AU  - Nacka-Aleksić, Mirjana
AU  - Kosec, Duško
AU  - Vujnović, Ivana
AU  - Pilipović, Ivan
AU  - Dimitrijević, Mirjana
AU  - Leposavić, Gordana
PY  - 2017
UR  - http://link.springer.com/10.1007/s12035-017-0595-2
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2763
AB  - In the present study, upon showing sexual dimorphism in dimethyl fumarate (DMF) efficacy to moderate the clinical severity of experimental autoimmune encephalomyelitis (EAE) in Dark Agouti rats, cellular and molecular substrate of this dimorphism was explored. In rats of both sexes, DMF administration from the day of immunization attenuated EAE severity, but this effect was more prominent in males leading to loss of the sexual dimorphism observed in vehicle-administered controls. Consistently, in male rats, DMF was more efficient in diminishing the number of CD4+ T lymphocytes infiltrating spinal cord (SC) and their reactivation, the number of IL-17+ T lymphocytes and particularly cellularity of their highly pathogenic IFN-γ+GM-CSF+IL-17+ subset. This was linked with changes in SC CD11b+CD45+TCRαβ− microglia/proinflammatory monocyte progeny, substantiated in a more prominent increase in the frequency of anti-inflammatory phygocyting CD163+ cells and the cells expressing high surface levels of immunoregulatory CD83 molecule (associated with apoptotic cells phagocytosis and implicated in downregulation of CD4+ T lymphocyte reactivation) among CD11b+CD45+TCRαβ– cells in male rat SC. These changes were associated with greater increase in the nuclear factor (erythroid-derived 2)-like 2 expression in male rats administered with DMF. In accordance with the previous findings, DMF diminished reactive nitrogen and oxygen species generation and consistently, SC level of advanced oxidation protein products, to the greater extent in male rats. Overall, our study indicates sex-specificity in the sensitivity of DMF cellular and molecular targets and encourages sex-based clinical research to define significance of sex for action of therapeutic agents moderating autoimmune neuroinflammation-/oxidative stress-related nervous tissue damage.
T2  - Molecular Neurobiology
T1  - Sex Bias in Pathogenesis of Autoimmune Neuroinflammation: Relevance for Dimethyl Fumarate Immunomodulatory/Anti-oxidant Action
DO  - 10.1007/s12035-017-0595-2
ER  - 

@misc{
author = "Stojić-Vukanić, Zorica and Kotur-Stevuljević, Jelena and Nacka-Aleksić, Mirjana and Kosec, Duško and Vujnović, Ivana and Pilipović, Ivan and Dimitrijević, Mirjana and Leposavić, Gordana",
year = "2017",
abstract = "In the present study, upon showing sexual dimorphism in dimethyl fumarate (DMF) efficacy to moderate the clinical severity of experimental autoimmune encephalomyelitis (EAE) in Dark Agouti rats, cellular and molecular substrate of this dimorphism was explored. In rats of both sexes, DMF administration from the day of immunization attenuated EAE severity, but this effect was more prominent in males leading to loss of the sexual dimorphism observed in vehicle-administered controls. Consistently, in male rats, DMF was more efficient in diminishing the number of CD4+ T lymphocytes infiltrating spinal cord (SC) and their reactivation, the number of IL-17+ T lymphocytes and particularly cellularity of their highly pathogenic IFN-γ+GM-CSF+IL-17+ subset. This was linked with changes in SC CD11b+CD45+TCRαβ− microglia/proinflammatory monocyte progeny, substantiated in a more prominent increase in the frequency of anti-inflammatory phygocyting CD163+ cells and the cells expressing high surface levels of immunoregulatory CD83 molecule (associated with apoptotic cells phagocytosis and implicated in downregulation of CD4+ T lymphocyte reactivation) among CD11b+CD45+TCRαβ– cells in male rat SC. These changes were associated with greater increase in the nuclear factor (erythroid-derived 2)-like 2 expression in male rats administered with DMF. In accordance with the previous findings, DMF diminished reactive nitrogen and oxygen species generation and consistently, SC level of advanced oxidation protein products, to the greater extent in male rats. Overall, our study indicates sex-specificity in the sensitivity of DMF cellular and molecular targets and encourages sex-based clinical research to define significance of sex for action of therapeutic agents moderating autoimmune neuroinflammation-/oxidative stress-related nervous tissue damage.",
journal = "Molecular Neurobiology",
title = "Sex Bias in Pathogenesis of Autoimmune Neuroinflammation: Relevance for Dimethyl Fumarate Immunomodulatory/Anti-oxidant Action",
doi = "10.1007/s12035-017-0595-2"
}

Stojić-Vukanić, Z., Kotur-Stevuljević, J., Nacka-Aleksić, M., Kosec, D., Vujnović, I., Pilipović, I., Dimitrijević, M.,& Leposavić, G.. (2017). Sex Bias in Pathogenesis of Autoimmune Neuroinflammation: Relevance for Dimethyl Fumarate Immunomodulatory/Anti-oxidant Action. in Molecular Neurobiology.
https://doi.org/10.1007/s12035-017-0595-2

Stojić-Vukanić Z, Kotur-Stevuljević J, Nacka-Aleksić M, Kosec D, Vujnović I, Pilipović I, Dimitrijević M, Leposavić G. Sex Bias in Pathogenesis of Autoimmune Neuroinflammation: Relevance for Dimethyl Fumarate Immunomodulatory/Anti-oxidant Action. in Molecular Neurobiology. 2017;.
doi:10.1007/s12035-017-0595-2 .

Stojić-Vukanić, Zorica, Kotur-Stevuljević, Jelena, Nacka-Aleksić, Mirjana, Kosec, Duško, Vujnović, Ivana, Pilipović, Ivan, Dimitrijević, Mirjana, Leposavić, Gordana, "Sex Bias in Pathogenesis of Autoimmune Neuroinflammation: Relevance for Dimethyl Fumarate Immunomodulatory/Anti-oxidant Action" in Molecular Neurobiology (2017),
https://doi.org/10.1007/s12035-017-0595-2 . .