Age-related changes in arthritis susceptibility and severity in a murine model of rheumatoid arthritis.
Open accessAbstract
Background: Rheumatoid arthritis (RA) most often begins in females in the fourth-fifth decade of their life, suggesting that the aging of the immune system (immunosenescence) has a major role in this disease. Therefore, in the present study, we sought to investigate the effect of age on arthritis susceptibility in BALB/c mice using the proteoglycan (PG)-induced arthritis (PGIA) model of RA. Results: We have found that young, 1-month-old female BALB/c mice are resistant to the induction of PGIA, but with aging they become susceptible. PG-induced T cell responses decline with age, whereas there is a shift toward Th1 cytokines. An age-dependent decrease in T cell number is associated with an increased ratio of the memory phenotype, and lower CD28 expression. Antigen-presenting cells shifted from macrophages and myeloid dendritic cells in young mice toward B cells in older mice. The regulatory/activated T cell ratio decreases in older mice after PG injections indicating impaired regulation of the immune response. Conclusion: We conclude that immunosenescence could alter arthritis susceptibility in a very complex manner including both adaptive and innate immunities, and it cannot be determined by a single trait. Cumulative alterations in immunoregulatory functions closely resemble human disease, which makes this systemic autoimmune arthritis model of RA even more valuable.
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The aging of the immune system is accelerated in patients with rheumatoid arthritis.
“The process of immunosenescence is accelerated in rheumatoid arthritis.”
From T-cell aging in rheumatoid arthritis (2014) · cites this paper as [9]
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Cites
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Development of Proteoglycan-Induced Arthritis Is Independent of IL-17
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Self-citationUnchecked CD70 Expression on T Cells Lowers Threshold for T Cell Activation in Rheumatoid Arthritis
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“Arthritis severity and hyperemia were also evaluated semiquantitatively three times a week by visually scoring on a scale of 0–4 for each limb (0, no edema or redness; 1, mild edema of the distal paw or at least two digits; 2, moderate swelling of the paw joints distal to the ankle or wrist; 3, marked edema and hypere…”
BackgroundSelf-citationVázquez, N. M., Lisbona-Montañez, J. M., Redondo‐Rodríguez, R., Mucientes, A., Arija, S. M., Rioja, J., García-Studer, A., Ortiz-Marquez, F., Cano‐García, L., & Fernández‐Nebro, A. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.1016159 · Cited by 14 · see citing works
“Another potential explanation is that older patients had a more proinflammatory immune system, with higher levels of proinflammatory cytokines than patients with YORA, possibly owing to the more marked activation of CD4 T cells and M1 macrophages that is typical of older age and contributes to greater tissue damage an…”
BackgroundBesenyei, T., Kádár, A., Tryniszewska, B., Kurkó, J., Rauch, T. A., Glant, T. T., Mikecz, K., & Szekanecz, Z. (2012) · Clinical and Developmental Immunology · doi:10.1155/2012/284751 · Cited by 11 · see citing works
“It is important to note that all the previously mentioned experimental animal models of arthritis develop at a relatively young age (beginning at ∼4–6-weeks), except PGIA [48], and that arthritis develops in SKG and IRAPdeficient mice only in the BALB/c genetic background [40– 42].”
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“We used 4–5 months old [39] female Nkx2-3-deficient (Nkx2-3−/−) [29] and BALB/c mice.”
MethodTargeting senescence and inflammation in chronic destructive TNF-driven joint pathology
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Immunosenescence and its potential modulation: lessons from mouse models
Boldizsár, F., Mikecz, K., & Glant, T. T. (2010) · Expert Review of Clinical Immunology · doi:10.1586/eci.10.16 · Cited by 7 · see citing works
Self-citationBufan, B., Djikić, J., Nacka-Aleksić, M., Stojić-Vukanić, Z., Dimitrijevic, M., & Leposavić, G. (2014) · Genetika · doi:10.2298/gensr1401287b · Cited by 6 · see citing works
“This is consistent with earlier reports indicating that in rodents, aging influences susceptibility to EAE development in a strain-specific manner (KALLEN and NILSSON, 1989; LUDOWYK et al., 1993; DITAMO et al., 2005; TARJANYI et al., 2009).”
ResultKis‐Tóth, K., Radács, M., Olasz, K., van Eden, W., Mikecz, K., & Glant, T. T. (2012) · International Immunology · doi:10.1093/intimm/dxs057 · Cited by 6 · see citing works
Self-citationOlasz, K., Gál, S., Khanfar, E., Balogh, P., Németh, P., Berki, T., & Boldizsár, F. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252111683 · Cited by 4 · see citing works
“Moreover, earlier, we described complex changes in the T cell, macrophage and dendritic cell populations as well as the immune response in aging BALB/c mice, which could contribute to arthritis susceptibility in older mice [57].”
BackgroundKhanfar, E., Olasz, K., Gál, S., Gajdócsi, E., Kajtár, B., Kiss, T., Balogh, P., Berki, T., & Boldizsár, F. (2024) · Clinical & Experimental Immunology · doi:10.1093/cei/uxae013 · Cited by 4 · see citing works
“S1A) which was in line with the cytokine composition observed in numerous previous studies [8, 24, 30, 31].”
Gál, S., Gajdócsi, E., Khanfar, E., Olasz, K., Simon, D., Balogh, P., Berki, T., Németh, P., & Boldizsár, F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24129809 · Cited by 4 · see citing works
“Similarly decreased B1 cell percentage in the spleen was also found in BALB/c mice during aging [33].”
BackgroundAndreas, N., Müller, S., Templin, N., Jordan, P. M., Schuhwerk, H., Müller, M., Gerstmeier, J., Miek, L., Andreas, S., Werz, O., et al. (2021) · Arthritis Research & Therapy · doi:10.1186/s13075-021-02596-7 · Cited by 3 · see citing works
“Similar to the increasing incidence of RA in human beyond the age of 30, arthritis in mouse models can only be properly induced if the mouse has reached a certain age before immunization [26].”
BackgroundRecombinant Human Proteoglycan Aggrecan‐G1 Domain‐induced Arthritis (GIA) Mouse Model
Olasz, K., & Boldizsár, F. (2024) · Current Protocols · doi:10.1002/cpz1.1053 · Cited by 2 · see citing works
“The age of mice is also critical for PGIA, with the best results being obtained when using 5-to 6-month-old mice (Tarjanyi et al., 2009).”
BackgroundTreating Rheumatoid Arthritis Through the Life Course
Serhal, L., Lwin, M. N., & Edwards, C. J. (2020) · Springer eBooks · doi:10.1007/978-3-030-44234-7_14 · Cited by 1 · see citing works
Bidirectional regulation between B cells and T cells
Margry, B. (2014) · Utrecht University Repository (Utrecht University)
Andreas, N., Müller, S., Templin, N., Jordan, P. M., Schuhwerk, H., Müller, M., Gerstmeier, J., Miek, L., Andreas, S., Werz, O., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16435839
Andreas, N., Müller, S., Templin, N., Jordan, P. M., Schuhwerk, H., Müller, M., Gerstmeier, J., Miek, L., Andreas, S., Werz, O., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16435830
Andreas, N., Müller, S., Templin, N., Jordan, P. M., Schuhwerk, H., Müller, M., Gerstmeier, J., Miek, L., Andreas, S., Werz, O., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16435833
Andreas, N., Müller, S., Templin, N., Jordan, P. M., Schuhwerk, H., Müller, M., Gerstmeier, J., Miek, L., Andreas, S., Werz, O., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16435836
Andreas, N., Müller, S., Templin, N., Jordan, P. M., Schuhwerk, H., Müller, M., Gerstmeier, J., Miek, L., Andreas, S., Werz, O., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16435827
- Authors
- Tarjanyi, O., Boldizsar, F., Nemeth, P., Mikecz, K., & Glant, T. T.
- Affiliations
- Rush University Medical Center (US)
- Corresponding author
- Glant, Tibor T
- ORCID
- Mikecz, Katalin
- Venue
- Immunity & Ageing
- Published
- 2009-06-11
- Volume
- 6
- Issue
- 1
- Pages
- 8-8
- ISSN
- 1742-4933 (ISSN-L)
- PMC
- PMC2704168
- OpenAlex
- W2142550028
- Cited by
- 32
- References
- 53
- Citations by year
- 2024: 4 · 2023: 2 · 2022: 1 · 2021: 5 · 2020: 3 · 2019: 1 · 2018: 2 · 2014: 4 · 2013: 1 · 2012: 3
- FWCI
- 2.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Immunity & Ageing (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Grainger Foundation
- Rush University
- National Institutes of Health
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P01AR045652)
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
- Keywords
- rheumatoid arthritis, immunosenescence, aging, arthritis susceptibility, proteoglycan-induced arthritis, BALB/c mice, T cell response, Th1 cytokines, memory T cells, CD28, antigen-presenting cells, regulatory T cells
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