doi: 10.1177/1352458520963896. Epub 2021 Jun 7.
CNS demyelination associated with immune dysregulation and a novelCTLA-4 variant
Affiliations
- PMID:34097529
- PMCID: PMC8358566
- DOI: 10.1177/1352458520963896
Item in Clipboard
CNS demyelination associated with immune dysregulation and a novelCTLA-4 variant
Stefania Kaninia et al. Mult Scler.2021 Aug.
Display options
Format
Display options
Format
Abstract
Background: The cytotoxic T-lymphocyte antigen-4 (CTLA-4) pathway acts as a negative immune regulator of T-cell activation and promotes self-tolerance.
Case: We report the first case of biopsy-proven central nervous system inflammatory demyelination in the context of primary immunodeficiency and a novelCTLA-4 variant.
Conclusion: This case has significant implications for the development of novel treatments for autoimmune conditions including multiple sclerosis and further emphasises the need for caution with clinical use of CTLA-4 immune checkpoint inhibitors in those with a history of inflammatory demyelination.
Keywords: CTLA-4; demyelination.
Conflict of interest statement
Figures
Neuroimaging: (a–c, e) T2 axial MRI brain, (d) gadolinium-enhanced T1 axial MRI brain and (f) fluid-attenuated inversion recovery (FLAIR) coronal MRI brain. (g–l) Histology of cerebellar white matter biopsy. Neuroimaging at presentation (a) demonstrated an intrinsic lesion in the right cerebellar peduncle with surrounding oedema which improved with corticosteroids (b) but relapsed on steroid wean (c). The intrinsic cerebellar lesion demonstrated nodular enhancement (d). Follow-up neuroimaging at 3 years shows a small focus of gliosis at the site of cerebellar biopsy with resolution of inflammatory changes (e and f). Histological examination of cerebellar white matter biopsy: (g) H&E 20× demonstrating moderate parenchymal mixed inflammatory infiltrate of lymphocytes, plasma cells, and microglia with perivascular cuffing by lymphocytes without underlying vasculitis. Inset highlighting perivascular infiltrate of atypical lymphocytes. (h) CD3 20× highlighting both a parenchymal and perivascular T-cell infiltrate. (j) Luxol fast blue 20× highlighting evidence of diffuse white matter demyelination without perivascular accentuation of myelin loss. (i) CD8 20× and (k) CD4 20× – demonstrating a 2:1 ratio of CD4:CD8 T cells. (l) PD-1 20×: 30%–40% of the CD4-positive cells co-express PD-1 in keeping with Helper T cells. Bar = 100 μm.
Similar articles
- The Role of Cytotoxic T-Lymphocyte Antigen 4 in the Pathogenesis of Multiple Sclerosis.Basile MS, Bramanti P, Mazzon E.Basile MS, et al.Genes (Basel). 2022 Jul 24;13(8):1319. doi: 10.3390/genes13081319.Genes (Basel). 2022.PMID:35893056Free PMC article.Review.
- Neurological manifestation of immune system dysregulation resulting from CTLA-4 receptor mutation: a case report.Kolcava J, Litzman J, Bednarik J, Stulik J, Stourac P.Kolcava J, et al.Mult Scler Relat Disord. 2020 Oct;45:102313. doi: 10.1016/j.msard.2020.102313. Epub 2020 Jun 21.Mult Scler Relat Disord. 2020.PMID:32623363
- What did we learn from CTLA-4 insufficiency on the human immune system?Mitsuiki N, Schwab C, Grimbacher B.Mitsuiki N, et al.Immunol Rev. 2019 Jan;287(1):33-49. doi: 10.1111/imr.12721.Immunol Rev. 2019.PMID:30565239Review.
- CTLA-4 and autoimmunity: new insights into the dual regulator of tolerance.Romo-Tena J, Gómez-Martín D, Alcocer-Varela J.Romo-Tena J, et al.Autoimmun Rev. 2013 Oct;12(12):1171-6. doi: 10.1016/j.autrev.2013.07.002. Epub 2013 Jul 11.Autoimmun Rev. 2013.PMID:23851140Review.
- CTLA-4: From mechanism to autoimmune therapy.Hosseini A, Gharibi T, Marofi F, Babaloo Z, Baradaran B.Hosseini A, et al.Int Immunopharmacol. 2020 Mar;80:106221. doi: 10.1016/j.intimp.2020.106221. Epub 2020 Jan 30.Int Immunopharmacol. 2020.PMID:32007707Review.
Cited by
- The Role of Cytotoxic T-Lymphocyte Antigen 4 in the Pathogenesis of Multiple Sclerosis.Basile MS, Bramanti P, Mazzon E.Basile MS, et al.Genes (Basel). 2022 Jul 24;13(8):1319. doi: 10.3390/genes13081319.Genes (Basel). 2022.PMID:35893056Free PMC article.Review.
- Advances in immune checkpoint-based immunotherapies for multiple sclerosis: rationale and practice.Daei Sorkhabi A, Komijani E, Sarkesh A, Ghaderi Shadbad P, Aghebati-Maleki A, Aghebati-Maleki L.Daei Sorkhabi A, et al.Cell Commun Signal. 2023 Nov 9;21(1):321. doi: 10.1186/s12964-023-01289-9.Cell Commun Signal. 2023.PMID:37946301Free PMC article.Review.
- A Family with a Novel CTLA4 Haploinsufficiency Mutation and Neurological Symptoms.Grammatikos A, Johnston S, Rice CM, Gompels M.Grammatikos A, et al.J Clin Immunol. 2021 Aug;41(6):1411-1416. doi: 10.1007/s10875-021-01027-1. Epub 2021 May 6.J Clin Immunol. 2021.PMID:33956248Free PMC article.No abstract available.
References
- Cooper N, Te Water Naude J, Connor PP.Neuromyelitis optica complicating autoimmune lymphoproliferative syndrome in a 4-year-old girl. Br J Haematol 2011; 152(3): 247. - PubMed
- Engelhardt JJ, Sullivan TJ, Allison JP.CTLA-4 overexpression inhibits T cell responses through a CD28-B7-dependent mechanism. J Immunol 2006; 177: 1052–1061. - PubMed
Publication types
MeSH terms
Substances
Related information
LinkOut - more resources
Full Text Sources
Medical