Gompels, Mark

Grammatikos, Alexandros

Kaninia, Stefania

Patel, Nik

Renowden, Shelley

Rice, Claire M

Urankar, Kathryn

English

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. Conclusions: 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.<br/

Explore Bristol Research

                          Kaninia, S., Grammatikos, A., Urankar, K., Renowden, S., Patel, N.,Gompels, M., & Rice, C. M. (2021). CNS demyelination associatedwith immune dysregulation and a novel CTLA-4 variant. MultipleSclerosis Journal. https://doi.org/10.1177/1352458520963896Publisher's PDF, also known as Version of recordLicense (if available):CC BYLink to published version (if available):10.1177/1352458520963896Link to publication record in Explore Bristol ResearchPDF-documentThis is the final published version of the article (version of record). It first appeared online via SAGE Publicationsat https://journals.sagepub.com/doi/full/10.1177/1352458520963896 . Please refer to any applicable terms ofuse of the publisher.University of Bristol - Explore Bristol ResearchGeneral rightsThis document is made available in accordance with publisher policies. Please cite only thepublished version using the reference above. Full terms of use are available:http://www.bristol.ac.uk/red/research-policy/pure/user-guides/ebr-terms/https://doi.org/10.1177/1352458520963896https://doi.org/10.1177/1352458520963896MULTIPLESCLEROSIS MSJJOURNALjournals.sagepub.com/home/msj 1Multiple Sclerosis Journal 1 –4DOI: 10.1177/ 1352458520963896© The Author(s), 2021.  Article reuse guidelines:  sagepub.com/journals-permissionsIntroductionCytotoxic T-lymphocyte antigen-4 (CTLA-4) is CD28 homologue which negatively regulates T-cell activation and promotes tolerance; in contrast to CD28, CTLA-4 binding fails to stimulate T cells. Indeed, CTLA-4 variants are recognised to cause immune dysregulation disorders and CTLA-4 block-ade is employed in cancer therapy. However, the use of CTLA-4 checkpoint inhibitors has been compli-cated by the emergence of autoimmunity, including demyelination.1 We report the first case of biopsy-proven central nervous system (CNS) inflammatory demyelination in the context of primary immunodefi-ciency and a novel CTLA-4 variant.Case reportA 51-year-old woman presented with a 3-week history of poor balance, nausea and right-sided facial sensory disturbance. Her medical history was significant for bronchiectasis, necrotising granulomatous lymphadeni-tis, iron deficiency anaemia, eczema, idiopathic throm-bocytopenic purpura, recurrent sinusitis, osteonecrosis of the jaw induced by bisphosphonates, diverticulitis, bowel salt malabsorption and vitamin D deficiency. The patient’s daughter had recurrent episodes of CNS inflammation as a child and in adulthood she developed autoimmune hepatitis, autoimmune haemolytic anaemia and bronchiectasis. The patient’s son was known to have type I diabetes, thyroid disease, pernicious anaemia and autoimmune encephalitis. FAS sequencing for autoim-mune lymphoproliferative syndrome (ALPS) was nor-mal and, at the time of presentation, extended panel screening for primary immunodeficiency was ongoing. There was prior exposure to corticosteroids but no other immunomodulatory treatment.On examination, there was reduced light touch sensa-tion in the mandibular and maxillary distribution of the right trigeminal nerve with dysarthria, mild right upper limb weakness and dysmetria. Microcytosis (MCV 80.5 fL) with low ferritin (12 µg/L), lymphope-nia (0.87 × 109/L) and hypogammaglobulinaemia (IgG 5.2 g/L) were noted. Cerebrospinal fluid (CSF) analysis showed mildly elevated protein concentra-tion (0.75 g/L), with normal white cell count (4/mm3) and the presence of unmatched (type 2) oligoclonal bands indicative of intrathecal IgG synthesis. CSF cytology and flow cytometry were non-diagnostic. Screening for infection including atypical organisms was negative although low-level Epstein–Barr virus (EBV) DNA was detected in her serum (EBV PCR 95 copies/mL; EBV DNA 1.98 log10 copies/mL). Brain magnetic resonance imaging (MRI) demonstrated a CNS demyelination associated with immune dysregulation and a novel CTLA-4 variantStefania Kaninia, Alexandros Grammatikos, Kathryn Urankar, Shelley A Renowden,  Nikunj K Patel, Mark M Gompels and Claire M RiceAbstractBackground: The cytotoxic T-lymphocyte antigen-4 (CTLA-4) pathway acts as a negative immune regu-lator 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 autoim-mune 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, demyelinationDate received: 14 July 2020; revised: 21 August 2020; accepted: 14 September 2020.Correspondence to:  S Kaninia  Clinical Neurosciences, Translational Health Sciences, Bristol Medical School, University of Bristol, Learning & Research Building, Level 1, Southmead Hospital, Bristol BS10 5NB, UK. dd18854@bristol.ac.ukStefania Kaninia  Claire M Rice  Clinical Neurosciences, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK/North Bristol NHS Trust, Bristol, UKAlexandros Grammatikos  Kathryn Urankar  Shelley A Renowden  Nikunj K Patel  Mark M Gompels  North Bristol NHS Trust, Bristol, UK963896MSJ0010.1177/1352458520963896Multiple Sclerosis JournalS Kaninia, A Grammatikoscase-report20202020Case ReportMultiple Sclerosis Journal 00(0)2 journals.sagepub.com/home/msjgadolinium-enhancing lesion in the right cerebellar peduncle with surrounding oedema and effacement of the fourth ventricle (Figure 1(a) and (d)).Given clinical concern regarding CNS lymphoma, cerebellar biopsy was offered but was initially declined by the patient. Empirical treatment with pulsed methylprednisolone was initiated with clini-cal and radiological improvement (Figure 1(b)). However, relapse occurred on attempted corticoster-oid wean; brain imaging demonstrated extension of the cerebellar lesion (Figure 1(c)). Biopsy of the right cerebellar peduncle lesion was subsequently performed. This demonstrated a florid active inflam-matory and demyelinating process. The T-cell infil-trate was composed of CD4 and CD8 cells (approximately 2:1) and an estimated 30%–40% of the CD4 cells co-expressed programmed cell death protein 1 (PD-1), indicating T-cell activation (Figure 1(g)–(l)).Subsequently, a virtual sub-panel of 194 genes asso-ciated with primary immunodeficiencies screened using Agilent ‘Focused Exome’ custom target enrich-ment system (SureSelectXT) and Next Generation Sequencing demonstrated that the patient (and her affected family members) were heterozygous for a novel, likely pathogenic frameshift deletion variant in CLTA-4 exon 1:c.81dup p.(leu28Serfs*32). An additional novel heterozygous missense variant was identified in the autosomal recessive gene LRBA in exon 42: c.642T>C, p.(Phe2142Leu) but was con-sidered of uncertain clinical significance given that only bi-allelic function loss variants have been linked with disease previously.Pulsed corticosteroid therapy and oral taper was ini-tiated with clinical benefit and sirolimus (an mTOR inhibitor which blocks the CD28 signalling path-way) was introduced as a steroid-sparing agent. Subsequently, the patient has been neurologically stable; reduced sensation in the maxillary nerve dis-tribution on the right with a mild postural upper limb tremor but no eye signs or dysmetria. There has been resolution of neuroimaging changes and no recur-rence of inflammatory CNS demyelination (Figure 1(e) and (f)).DiscussionMendelian disorders of adaptive immunity have previously been reported to be associated with demyelination,2 and similarities reported in the aberrant peripheral B-cell responses of those with multiple sclerosis (MS) and immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome are notable.3In the largest case series reporting the clinical phe-notype of CTLA-4 insufficiency, neurological involvement including autoimmune encephalitis or encephalomyelitis was reported in 28% of patients. This included three patients with cerebral perivascu-lar lymphocytic infiltrates but, although demyelina-tion was suspected clinically, this was not identified histologically.4 Here, we report CNS inflammatory demyelination and a novel, likely pathogenic CTLA-4 frameshift deletion variant occurring in the context of primary immunodeficiency.Increased CTLA-4 expression is protective in experi-mental allergic encephalomyelitis.5 Although CTLA-4 polymorphisms are unlikely to have a significant effect on MS susceptibility,6 the CTLA-4 polymorphism rs5742909 has been associated with reduced remyelina-tion in MS7 and people with MS are known to have reduced expression of CTLA-4.8 Furthermore, therapeu-tic use of immune checkpoint inhibitors acting via the CTLA-4 pathway has been associated with clinically relevant demyelination.1 Disappointingly however, abatacept, a humanised CTLA4-IgG fusion protein, failed to demonstrate benefit in relapsing-remitting MS although note is made of the small study size.9Given that lymphoma occurs with increased inci-dence in patients with autoimmunity including CTLA-4 variants,4 there should be a low threshold to pursue a tissue diagnosis where there is evidence of neuroin-flammation. This is particularly important given the delays in diagnosis which may be incurred following empirical corticosteroid treatment.10This report of clinically relevant demyelination associated with an inflammatory T-cell infiltrate occurring in the context of a pathogenic CTLA-4 variant, supports CTLA-4 as a regulator of T-cell activation and immune tolerance and is further evi-dence that perturbation of the CTLA-4 pathway can cause clinically relevant inflammatory demyelina-tion. This has significant implication for the devel-opment of novel treatments for autoimmune conditions including MS but also emphasises the need for caution with clinical use of CTLA-4 immune checkpoint inhibitors, particularly in those with a history of immune-mediated demyelination. Consideration should be given to screening for CTLA-4 variants in individuals with a history com-patible with autoimmunity and CNS inflammatory disease, particularly following exclusion of lymphoma.S Kaninia, A Grammatikos et al.journals.sagepub.com/home/msj 3Figure 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.Multiple Sclerosis Journal 00(0)4 journals.sagepub.com/home/msjDeclaration of Conflicting InterestsThe author(s) declared no potential conflicts of inter-est with respect to the research, authorship and/or publication of this article.FundingThe author(s) disclosed receipt of the following finan-cial support for the research, authorship and/or publi-cation of this article: No targeted funding reported. S.K. is supported by an ECTRIMS (European Committee for Treatment and Research in Multiple Sclerosis) fellowship.Patient consentWritten consent for publication has been obtained from the patient.References 1. Dalakas MC. Neurological complications of immune checkpoint inhibitors: What happens when you ‘take the brakes off’ the immune system. Ther Adv Neurol Disord 2018; 11: 1–9. 2. Cooper N, Te Water Naude J and Connor PP. Neuromyelitis optica complicating autoimmune lymphoproliferative syndrome in a 4-year-old girl. Br J Haematol 2011; 152(3): 247. 3. Kinnunen T, Chamberlain N, Morbach H, et al. Specific peripheral B cell tolerance defects in patients with multiple sclerosis. J Clin Invest 2013; 123(6): 2737–2741. 4. Schwab C, Gabrysch A, Olbrich P, et al. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. J Allergy Clin Immunol 2018; 142(6): 1932–1946. 5. Engelhardt JJ, Sullivan TJ and Allison JP. CTLA-4 overexpression inhibits T cell responses through a CD28-B7-dependent mechanism. J Immunol 2006; 177: 1052–1061. 6. Roxburgh RH, Sawcer S, Maranian M, et al. No evidence of a significant role for CTLA-4 in multiple sclerosis. J Neuroimmunol 2006; 171(1–2): 193–197. 7. Fransen NL, Crusius JBA, Smolders J, et al. Post-mortem multiple sclerosis lesion pathology is influenced by single nucleotide polymorphisms. Brain Pathol 2020; 30(1): 106–119. 8. Mohammadzadeh A, Rad IA and Ahmadi-Salmasi B. CTLA-4, PD-1 and TIM-3 expression predominantly downregulated in MS patients. J Neuroimmunol 2018; 323: 105–108. 9. Khoury SJ, Rochon J, Ding L, et al. ACCLAIM: A randomized trial of abatacept (CTLA4-Ig) for relapsing-remitting multiple sclerosis. Mult Scler 2017; 23(5): 686–695. 10. Rice CM, Renowden SA, Urankar K, et al. Brain biopsy before or after treatment with corticosteroids? Neuroradiology 2020; 62: 545–546.Visit SAGE journals online journals.sagepub.com/home/msj SAGE journals

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

https://research-information.bris.ac.uk/files/279670070/1352458520963896.pdf

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

Abstract

Similar works

Full text

Available Versions

Explore Bristol Research