Abstract
Paraneoplastic cerebellar degeneration (PCD) is a rare immune-mediated disease that develops mostly in the setting of neoplasia and offers a unique prospect to explore the interplay between tumor immunity and autoimmunity. In PCD, the deleterious adaptive immune response targets self-antigens aberrantly expressed by tumor cells, mostly gynecological cancers, and physiologically expressed by the Purkinje neurons of the cerebellum. Highly specific anti-neuronal antibodies in the serum and cerebrospinal fluid represent key diagnostic biomarkers of PCD. Some anti-neuronal antibodies such as anti-Yo autoantibodies (recognizing the CDR2/CDR2L proteins) are only associated with PCD. Other anti-neuronal antibodies, such as anti-Hu, anti-Ri, and anti-Ma2, are detected in patients with PCD or other types of paraneoplastic neurological manifestations. Importantly, these autoantibodies cannot transfer disease and evidence for a pathogenic role of autoreactive T cells is accumulating. However, the precise mechanisms responsible for disruption of self-tolerance to neuronal self-antigens in the cancer setting and the pathways involved in pathogenesis within the cerebellum remain to be fully deciphered. Although the occurrence of PCD is rare, the risk for such severe complication may increase with wider use of cancer immunotherapy, notably immune checkpoint blockade. Here, we review recent literature pertaining to the pathophysiology of PCD and propose an immune scheme underlying this disabling disease. Additionally, based on observations from patients' samples and on the pre-clinical model we recently developed, we discuss potential therapeutic strategies that could blunt this cerebellum-specific autoimmune disease.
Highlights
The central nervous system (CNS) can be the target of deleterious cellular and humoral immune responses in context of infectious, degenerative, or autoimmune diseases [1,2,3,4]
Paraneoplastic cerebellar degeneration (PCD), one of the most common paraneoplastic neurological syndromes [11], represents a heterogeneous group that differs in clinical features, prognosis, associated tumor and associated antibody [7] (Table 1)
About 50% of PCD cases are related with anti-Yo antibodies, known as CDR2/CDR2L, making anti-Yo antibodies the predominant autoantibody associated with PCD among the 37 other anti-neural antibodies described (Table 1), such as antiHu, anti-Tr, anti-Ri, anti-Ma2, anti-P/Q-type calcium channel, or anti-CV2/CRMP5 [89,90,91]
Summary
The central nervous system (CNS) can be the target of deleterious cellular and humoral immune responses in context of infectious, degenerative, or autoimmune diseases [1,2,3,4]. The anti-CDR2/CDR2L antibody-associated PCD will be the main focus of the current article This type of PCD develops mostly in female patients with gynecologic (ovarian and breast) carcinomas that express the Purkinje neuron-specific CDR2 protein [9] and its paralog CDR2L [14], and in patients with other types of cancers including endometrial, digestive and lung [37, 92,93,94,95]. Through “ectopic” expression of a number of tissue-associated self-antigens, the autoimmune regulator (AIRE) acts as a master regulator of central T-cell tolerance by preventing the development of pathogenic autoreactive T cells [111, 112] Transcription of both Cdr and Cdr2l has been reported in thymic medullary epithelial cells [113].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
