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. 2021 Aug;27(9):1464-1467.
doi: 10.1177/1352458520963896. Epub 2021 Jun 7.

CNS demyelination associated with immune dysregulation and a novel CTLA-4 variant

Stefania Kaninia  1 , Alexandros Grammatikos  2 , Kathryn Urankar  2 , Shelley A Renowden  2 , Nikunj K Patel  2 , Mark M Gompels  2 , Claire M Rice  1
Affiliations

CNS demyelination associated with immune dysregulation and a novel CTLA-4 variant

Stefania Kaninia et al. Mult Scler. 2021 Aug.

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 novel CTLA-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.

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Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Figures

Figure 1.
Figure 1.
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.
See this image and copyright information in PMC

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