Immunopathological characterization of ovarian teratomas associated with anti-N-methyl-D-aspartate receptor encephalitis

Abstract

Encephalitis with anti-NMDAR antibodies (NMDAR-E) is a severe autoimmune neurological disorder, defined by a clinical presentation of encephalitis and the presence of IgG targeting the GluN1 subunit of NMDA receptors in the CSF. An underlying ovarian teratoma is commonly associated with this autoimmune disease suggesting a role of the tumor in immunopathogenesis. In this study, we characterized the salient histopathological features of 27 ovarian teratomas associated with NMDAR-E (3 immature and 24 mature teratomas) and 40 controls without associated encephalitis. All but one NMDAR-E-associated teratomas contained a nervous tissue component, while less than 40% of control teratomas did (p < 0.001). GluN1 expression by teratomatous nervous tissue seemed to be more often glial in NMDAR-E teratomas than in control teratomas (73% vs. 29%, p < 0.05). Strikingly, 3 out of 24 NMDAR-E-associated mature teratomas contained neuroglial tissue exhibiting histopathological features of central nervous system neuroglial tumor, while such glioma-like features are exceptionally described in the literature on ovarian teratomas. Moreover, NMDAR-E associated teratomas differed from sporadic ovarian teratomas by consistent and prominent infiltration of the nervous tissue component by immune cells, comprised of T- and B-cells and mature dendritic cells organized in tertiary lymphoid structures, with IgG and IgA deposits and plasma cells in close contact to the neuroglial tissue.These data demonstrate an association between massive infiltration of NMDAR-E-associated teratomas by immune cells and particular glial features of its neuroglial component, suggesting that this glial tissue might be involved in triggering or sustaining the anti-tumor response associated with the auto-immune neurological disease.Electronic supplementary materialThe online version of this article (10.1186/s40478-019-0693-7) contains supplementary material, which is available to authorized users.

Co-expression of NMDA-receptor subunits NR1, NR2A, and NR2B in dysplastic neurons of teratomas in patients with paraneoplastic NMDA-receptor-encephalitis: a retrospective clinico-pathology study of 159 patients

“…Specifically, the dysmorphic neurons in these teratomas had strong immunoreactivity for NMDAR subunits NR1, NR2A, and NR2B, and subsequent immunofluorescence showed consistent co-localisation of NMDAR subunits with IgG. In contrast, the neurons in most control cases showed negative or weakly positive for NMDAR subunits and no IgG-NMDAR co-localization, supporting the notion that aberrant IgG-NMDAR subunit expression in teratomas play an important role in the pathogenesis of anti-NMDARE [ 2 , 3 , 15 , 18 ].…”

Infiltration of plasma cells in colorectal adenocarcinoma associated with autoimmune encephalitis

“…It is hypothesized that abnormal expression of neuronal antigens in neoplasm initiates autoimmune responses in PAE 8 . This hypothesis is supported by findings in teratoma‐associated anti‐NMDAR encephalitis, where ovarian teratoma is featured by ectopic expression of NMDAR and infiltration of immune cells 9,10 . However, it has not been investigated whether colorectal adenocarcinoma is featured by abnormal expression of neuronal antigens and infiltration of immune cells.…”

“…Although the etiology of PAE remains unclear, it is proposed that expression of neuronal antigens within neoplasms could initiate an autoimmune response which leads to the production of autoantibodies against neuronal antigens 1,8 . This hypothesis is supported by findings in anti‐NMDAR encephalitis where immune cells and neuronal antigens are found in the disease‐associated ovarian teratoma 9,10 . In the current case report, we demonstrate the presence of immune cells and neuronal antigens in the colon cancer of a patient, which further supports this hypothesis.…”

Chemical peritonitis resulting from spontaneous rupture of a mature ovarian cystic teratoma: a case report

“…An extremely rare manifestation of mature cystic teratoma is anti-NMDA-receptor encephalitis. Neurological symptoms develop because of the antibodies generated in response to the neural elements within the teratoma (25).…”