Deleted in colorectal cancer (netrin-1 receptor) antibodies and limbic encephalitis in a cat with hippocampal necrosis

Hasegawa, Daisuke; Ohnishi, Yumi; Koyama, Eiji; Matsunaga, Satoru; Ohtani, Shouhei; Nakanishi, Akio; Shiga, Takanori; Chambers, James K.; Uchida, Kazuyuki; Yokoi, Norihiko; Fukata, Yuko; Fukata, Masaki

The cat was negative for LGI1 but we found DCC antibodies that might be the cause of autoimmune LE and FHN. To our knowledge, diseases associated with DCC or its antibodies have not been reported in cats (nor in dogs) to date. Although DCC was first suggested as a candidate tumor suppressor gene for colorectal cancer, subsequent studies proved DCC is 1 of the receptors of netrin-1 that is an axon guidance molecule (secretory protein). 15, 16 Netrin-1 and DCC mediate axon guidance or neuronal migrations. Netrin-1 and DCC knockout mice have commissural dysplasia in the central nervous system. 10, 15 Also, DCC has been identified as a causative gene of congenital mirror movement in human. 17 DCC regulates synaptic function including NMDA receptordependent synaptic plasticity in maturated brains. 18, 19 Anti-DCC autoantibodies are associated more with thymoma and myasthenia gravis and less with LE. 8, 20 In 1 human study, however, 4 of 12 patients with DCC antibodies were diagnosed as LE although F I G U R E 4 The case cat serum antibodies do not bind to leucinerich glioma inactivated 1 (LGI1). COS7 cells were transfected with cell-surface expressed LGI1 tagged with the FLAG epitope and GPI anchor signal. Transfected cells were fixed and doubly stained with serum immunoglobulin G (IgGs) (right column, red) together with the antibodies to the FLAG tag (left column, green). Human LE patient serum was used as a positive control (tops). Nuclear DNA was stained by Hoechst 33342 (blue) to distinguish untransfected cells. Scale bar, 20 μm. See also the Supporting Information the association was not statistically significant. 8 These LE patients with DCC antibodies had also LGI1 antibodies that were significantly associated with LE. Thus, LE of these patients might have originated from LGI1 antibodies rather than DCC antibodies. However, we excluded the association of LGI antibodies in the present cat; therefore, this might be the first LE case associated only with DCC antibodies through human and feline autoimmune LE. Recent studies suggested DCC and netrin-1 contribution to synaptic excitation. 18, 19 Therefore, the possibility of direct contribution of DCC antibodies to the pathogenesis of LE should be considered in the future.