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Higher IgG level correlated with vitamin D receptor in the hippocampus of a pristane-induced lupus model

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Abstract

Introduction/objectives

Patients with systemic lupus erythematosus (SLE) may have neurological complications, characterizing neuropsychiatric lupus (NPSLE). Studies have investigated alternative therapies such as vitamin D, which has an effect on the immune system and brain, to control manifestations of SLE. Experimental lupus models may be a good alternative to best study the immunological mechanisms underlying the development of NPSLE, and the animal model of pristane-induced lupus (PIL) may mimic SLE symptoms in humans. Our objective was to evaluate central nervous system involvement and vitamin D supplementation in a PIL model.

Method

Female BALB/c mice were divided into controls (CO; n = 7), PIL (n = 9), and PIL supplemented with vitamin D (VD; n = 7). The hippocampus area was measured and immunoassays were performed for detecting vitamin D receptor (VDR) and IgG.

Results

The PIL group had a higher hippocampal IgG infiltrate when compared to the CO group. Vitamin D showed potential for reducing IgG infiltration. The hippocampus area was similar in all groups. No differences in VDR expression were observed between groups. A positive correlation was observed between the expression of VDR and IgG in the hippocampus.

Conclusion

Our data suggest that increased IgG infiltration into the hippocampus indicated an inflammatory process that may have stimulated VDR expression.

Key Points

• IgG infiltrate is higher in PIL animals than controls

• VDR increases along with IgG infiltrate

• Hippocampal VDR expression does not increase with vitamin D supplementation

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References

  1. D’Cruz DP, Khamashta MA, Hughes GRV (2007) Systemic lupus erythematosus. Lancet 369:587–96. https://doi.org/10.1016/S0140-6736(07)60279-7

    Article  PubMed  Google Scholar 

  2. Uva L, Miguel D, Pinheiro C, Freitas JP, Marques Gomes M, Filipe P (2012) Cutaneous manifestations of systemic lupus erythematosus. Autoimmune Dis. 2012:834291. https://doi.org/10.1155/2012/834291

  3. Tsokos GC, Lo MS, Reis PC, Sullivan KE (2016) New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol 12:716–730. https://doi.org/10.1038/nrrheum.2016.186

    Article  CAS  PubMed  Google Scholar 

  4. Reumatologia SB de (2011) Lúpus. https://www.reumatologia.org.br/orientacoes-ao-paciente/lupus-eritematoso-sistemico-les-cartilha-da-sbr/. Accessed 5 Aug 2020

  5. Ginzler E, Tayar J (2013) Systemic lupus erythematosus. Am Coll Rheumatol 1–6. https://doi.org/10.1007/SpringerReference_61618

  6. De Boer AG, Gaillard PJ (2006) Blood-brain barrier dysfunction and recovery. J Neural Transm 113:455–462. https://doi.org/10.1007/s00702-005-0375-4

    Article  PubMed  Google Scholar 

  7. Liang MH, Corzillius M, Bae SC et al (1999) The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 42:599–608. https://doi.org/10.1002/1529-0131(199904)42:4%3c599::AID-ANR2%3e3.0.CO;2-F

    Article  Google Scholar 

  8. Adorini L (2002) Immunomodulatory effects of vitamin D receptor ligands in autoimmune diseases. Int Immunopharmacol 2:1017–1028

    Article  CAS  Google Scholar 

  9. Chen S, Sims GP, Chen XX et al (2007) Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol 179:1634–1647

    Article  CAS  Google Scholar 

  10. Casseb GAS, Kaster MP, Rodrigues ALS (2019) Potential role of vitamin D for the management of depression and anxiety. CNS Drugs 33:619–637. https://doi.org/10.1007/s40263-019-00640-4

    Article  CAS  PubMed  Google Scholar 

  11. Deluca GC, Kimball SM, Kolasinski J et al (2013) Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol 39:458–484

    Article  CAS  Google Scholar 

  12. Trinko JR, Land BB, Solecki WB et al (2016) Vitamin D3: a role in dopamine circuit regulation, diet-induced obesity, and drug consumption. eNeuro 3:226–231. https://doi.org/10.1523/ENEURO.0122-15.2016

    Article  Google Scholar 

  13. Aranow C (2011) Vitamin D and the immune system. J Investig Med 59:881–886. https://doi.org/10.1533/9780857095749.2.244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yap KS, Morand EF (2015) Vitamin D and systemic lupus erythematosus: continued evolution. Int J Rheum Dis 18:242–249. https://doi.org/10.1111/1756-185X.12489

    Article  CAS  PubMed  Google Scholar 

  15. Eyles DW, Smith S, Kinobe R et al (2005) Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat 29:21–30. https://doi.org/10.1016/j.jchemneu.2004.08.006

    Article  CAS  PubMed  Google Scholar 

  16. Häusler D, Weber MS (2019) Vitamin D supplementation in central nervous system demyelinating disease-enough is enough. Int J Mol Sci 20(1):218. https://doi.org/10.3390/ijms20010218

  17. Jagannath VA, Filippini G, Di Pietrantonj C, Asokan GV, Robak EW, Whamond L, Robinson SA (2018) Vitamin D for the management of multiple sclerosis. Cochrane Database Syst Rev 9(9):CD008422. https://doi.org/10.1002/14651858.CD008422.pub3

  18. VanAmerongen BM, Dijkstra CD, Lips P, Polman CH (2004) Multiple sclerosis and vitamin D: an update. Eur J Clin Nutr 58:1095–1109

    Article  CAS  Google Scholar 

  19. Pierrot-Deseilligny C, Souberbielle JC (2011) Widespread vitamin D insufficiency: a new challenge for primary prevention, with particular reference to multiple sclerosis. Presse Med 40:349–356

    Article  Google Scholar 

  20. Pierrot-Deseilligny C, Souberbielle JC (2017) Vitamin D and multiple sclerosis: an update. Mult Scler Relat Disord 14:35–45

    Article  Google Scholar 

  21. Freitas EC, de Oliveira MS, Monticielo OA (2017) Pristane-induced lupus: considerations on this experimental model. Clin Rheumatol 36:2403–2414. https://doi.org/10.1007/s10067-017-3811-6

    Article  PubMed  Google Scholar 

  22. Luciano-Jaramillo J, Sandoval-García F, Vázquez-Del Mercado M et al (2019) Downregulation of hippocampal NR2A/2B subunits related to cognitive impairment in a pristane-induced lupus BALB/c mice. PLoS ONE 14:e0217190. https://doi.org/10.1371/journal.pone.0217190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kokic V, Martinovic Kaliterna D, Radic M et al (2018) Association between vitamin D, oestradiol and interferon-gamma in female patients with inactive systemic lupus erythematosus: a cross-sectional study. J Int Med Res 46:1162–1171. https://doi.org/10.1177/0300060517734686

    Article  CAS  PubMed  Google Scholar 

  24. Satoh M (1994) Induction of lupus-associated autoantibodies in BALB/c mice by intraperitoneal injection of pristane. J Exp Med 180:2341–2346. https://doi.org/10.1084/jem.180.6.2341

    Article  CAS  PubMed  Google Scholar 

  25. Matheu V, Bäck O, Mondoc E, Issazadeh-Navikas S (2003) Dual effects of vitamin D-induced alteration of TH1/TH2 cytokine expression: enhancing IgE production and decreasing airway eosinophilia in murine allergic airway disease. J Allergy Clin Immunol 112:585–592

    Article  CAS  Google Scholar 

  26. Correa Freitas E, Evelyn Karnopp T, de Souza Silva JM et al (2019) Vitamin D supplementation ameliorates arthritis but does not alleviates renal injury in pristane-induced lupus model. Autoimmunity 52:69–77. https://doi.org/10.1080/08916934.2019.1613383

    Article  CAS  PubMed  Google Scholar 

  27. La Paglia GMC, Leone MC, Lepri G et al (2017) One year in review 2017: systemic lupus erythematosus. Cilinical Exp Rheumatol 35:551–561

    Google Scholar 

  28. Yan L, Wu P, Gao D-M et al (2019) The impact of vitamin D on cognitive dysfunction in mice with systemic lupus erythematosus. Med Sci Monit 25:4716–4722. https://doi.org/10.12659/MSM.915355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ballok DA, Millward JM, Sakic B (2003) Neurodegeneration in autoimmune MRL-lpr mice as revealed by Fluoro Jade B staining. Brain Res. https://doi.org/10.1016/S0006-8993(02)03980-X

    Article  PubMed  Google Scholar 

  30. Zameer A, Hoffman SA (2004) B and T cells in the brains of autoimmune mice. J Neuroimmunol 146:133–139. https://doi.org/10.1016/j.jneuroim.2003.10.052

    Article  CAS  PubMed  Google Scholar 

  31. Sled JG, Spring S, Van Eede M et al (2009) Time course and nature of brain atrophy in the MRL mouse model of central nervous system lupus. Arthritis Rheum 60:1764–1774. https://doi.org/10.1002/art.24523

    Article  PubMed  Google Scholar 

  32. Abbott NJ, Mendonça LL, Dolman DE (2003) The blood-brain barrier in systemic lupus erythematosus. Lupus 12(12):908–15. https://doi.org/10.1191/0961203303lu501oa

  33. Stojanovich L, Smiljanich-Miljkovich D, Omdal R, Sakic B (2009) Neuropsychiatric lupus and association with cerebrospinal fluid immunoglobulins: a pilot study. Isr Med Assoc J 11:359–362

    PubMed  PubMed Central  Google Scholar 

  34. Wen J, Xia Y, Stock A et al (2013) Neuropsychiatric disease in murine lupus is dependent on the TWEAK/Fn14 pathway. J Autoimmun 43:44–54. https://doi.org/10.1016/j.jaut.2013.03.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lam V, Takechi R, Pallabage-Gamarallage M, et al (2015) The vitamin D, ionised calcium and parathyroid hormone axis of cerebral capillary function: therapeutic considerations for vascular-based neurodegenerative disorders. PLoS One 10: https://doi.org/10.1371/journal.pone.0125504

  36. Bivona G, Gambino CM, Iacolino G, Ciaccio M (2019) Vitamin D and the nervous system. Neurol Res 41:827–835

    Article  CAS  Google Scholar 

  37. Molinari C, Morsanuto V, Ghirlanda S, et al (2019) Role of combined lipoic acid and vitamin D3 on astrocytes as a way to prevent brain ageing by induced oxidative stress and iron accumulation. Oxid Med Cell Longev 2019: https://doi.org/10.1155/2019/2843121

  38. Mak A (2018) The impact of vitamin D on the immunopathophysiology, disease activity, and extra-musculoskeletal manifestations of systemic lupus erythematosus. Int J Mol Sci 19(8):2355. https://doi.org/10.3390/ijms19082355

  39. Almerighi C, Sinistro A, Cavazza A et al (2009) 1α,25-Dihydroxyvitamin D3 inhibits CD40L-induced pro-inflammatory and immunomodulatory activity in human monocytes. Cytokine 45:190–197. https://doi.org/10.1016/j.cyto.2008.12.009

    Article  CAS  PubMed  Google Scholar 

  40. Schoenmakers I, Jones KS (2017) Pharmacology and pharmacokinetics. In: Hewison M, Bouillon R, Giovannucci E, Goltzman D (ed) Vitamin D: biochemistry, physiology and diagnostics, 4th edn. Amsterdam, pp 636–663

  41. Rolf L, Muris AH, Hupperts R, Damoiseaux J (2014) Vitamin D effects on B cell function in autoimmunity. Ann N Y Acad Sci 1317:84–91. https://doi.org/10.1111/nyas.12440

    Article  CAS  PubMed  Google Scholar 

  42. Chen S, Sims GP, Chen XX et al (2007) Modulatory effects of 1,25-dihydroxyvitamin D 3 on human B cell differentiation. J Immunol 179:1634–1647. https://doi.org/10.4049/jimmunol.179.3.1634

    Article  CAS  PubMed  Google Scholar 

  43. Zhuang H, Szeto C, Han S, et al (2015) Animal models of interferon signature positive lupus. Front Immunol 6:. https://doi.org/10.3389/fimmu.2015.00291

  44. Karnopp TE, Chapacais GF, Freitas EC, Monticielo OA (2021) Lupus animal models and neuropsychiatric implications. Clin Rheumatol 40:2535–2545. https://doi.org/10.1007/s10067-020-05493-7

    Article  PubMed  Google Scholar 

  45. Jeltsch-David H, Muller S (2014) Neuropsychiatric systemic lupus erythematosus: pathogenesis and biomarkers. Nat Rev Neurol 10:579–596. https://doi.org/10.1038/nrneurol.2014.148

    Article  CAS  PubMed  Google Scholar 

  46. Richard ML, Gilkeson G (2018) Mouse models of lupus: what they tell us and what they don’t. Lupus Sci Med 5:e000199. https://doi.org/10.1136/lupus-2016-000199

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to acknowledge the pathologist Francine Hehn de Oliveira, Chief of Surgical Pathology—Hospital de Clínicas de Porto Alegre, for all the assistance; the Experimental Pathology Unit and Animal Experimentation Unit at Hospital de Clínicas de Porto Alegre; and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil, for a scholarship offered to Thaís Evelyn Karnopp.

Funding

This study was supported by the Research Incentive Fund (FIPE/HCPA) under Grant (No. 18–0246); Conselho Nacional de Desenvolvimento Científico e Tecnológico Universal MCTI/CNPQ under Grant (No. 28/2018); and Research Support Fund of Sociedade de Reumatologia do Rio Grande do Sul.

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Authors and Affiliations

  1. Laboratory of Autoimmune Diseases, Division of Rheumatology, Hospital de Clínicas de Porto Alegre, Centro de Pesquisas Experimentais, Universidade Federal Do Rio Grande Do Sul, Rua Ramiro Barcelos, 2350, sala 12109, Porto Alegre, 90035-003, Brazil

    Thaís Evelyn Karnopp, Eduarda Correa Freitas, Gustavo Flores Chapacais & Odirlei André Monticielo

  2. Graduate Program in Medical Sciences, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil

    Thaís Evelyn Karnopp

  3. Division of Rheumatology, Department of Internal Medicine, Hospital de Clínicas de Porto Alegre, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil

    Thaís Evelyn Karnopp, Eduarda Correa Freitas, Gustavo Flores Chapacais & Odirlei André Monticielo

  4. Graduate Program in Health Promotion, Universidade de Santa Cruz Do Sul - UNISC, Santa Cruz Do Sul, RS, Brazil

    Alexandre Rieger

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  1. Thaís Evelyn Karnopp
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Correspondence to Thaís Evelyn Karnopp.

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Karnopp, T.E., Freitas, E.C., Rieger, A. et al. Higher IgG level correlated with vitamin D receptor in the hippocampus of a pristane-induced lupus model. Clin Rheumatol 41, 1859–1866 (2022). https://doi.org/10.1007/s10067-022-06094-2

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