Cytotoxic T-lymphocyte antigen-4 haploinsufficiency: clinical and neuroimaging findings in a clinical center cohort

Authors

• MK Schindler
• G Uzel
• S Pittaluga
• NT Tagg
• DS Reich
• I Cortese

Abstract

CTLA-4 is an inhibitory receptor constrictively expressed on T-regulatory cells and critical for their function in immune homeostasis. Patients with CTLA-4 haploinsufficiency develop lymphocytic infiltrates of target organs, mainly gut and lungs, autoimmune cytopenias, and recurrent infections due to hypogammaglobulinemia. In the original series of patients reported with this defect, few patients also manifested central nervous system (CNS) involvement also due to inflammatory infiltrates. Identification of additional patients with CNS involvement has prompted us to study the neurological and radiological manifestation in detail and help raise the recognition of this disorder. A cohort of 6 affected patients with CNS involvement initially manifested symptoms associated with mass lesions including headaches, vomiting, and seizures. Although neurologic examination was largely normal with only subtle findings, magnetic resonance imaging showed contrast-enhancing supra- and infratentorial abnormal foci in white-matter predominant areas and leptomeninges. Typically lesions demonstrated little edema, however, some exhibited substantial mass effect. CSF findings were typically positive for a mild lymphocyte predominant pleocytosis. Treatment with corticosteroids and sirolimus led to resolution of symptoms and improvement of the imaging abnormalities. CTLA-4 haploinsufficiency induces a striking dissociation between clinical and radiographic findings. This is consistent with the histopathology showing lymphocytic infiltration without prominent destruction of neurons and white matter, and distinct from inflammatory conditions such as multiple sclerosis in which the immune response specifically targets CNS structures.

Scientific Focus Area: Neuroscience

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