Decreased inflammatory cytokine production of antigen-specific CD4+ T cells in NMDA receptor encephalitis

Abstract

Anti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis is the most common autoimmune encephalitis with psychosis, amnesia, seizures and dyskinesias. The disease is mediated by pathogenic autoantibodies against the NR1 subunit that disrupt NMDAR function. Antibody infusion into mouse brains can recapitulate encephalitis symptoms, while active immunization resulted also in strong T cell infiltration into the hippocampus. However, whether T cells react against NMDAR and their specific contribution to disease development are poorly understood. Here we characterized the ex vivo frequency and phenotype of circulating CD4+ T helper (TH) cells reactive to NR1 protein using antigen-reactive T cell enrichment (ARTE) in 24 patients with NMDAR encephalitis, 13 patients with LGI1 encephalitis and 51 matched controls. Unexpectedly, patients with NMDAR encephalitis had lower frequencies of CD154-expressing NR1-reactive TH cells than healthy controls and produced significantly less inflammatory cytokines. No difference was seen in T cells reactive to the synaptic target LGI1 (Leucine-rich glioma-inactivated 1), ubiquitous Candida antigens or neoantigens, suggesting that the findings are disease-specific and not related to therapeutic immunosuppression. Also, patients with LGI1 encephalitis showed unaltered numbers of LGI1 antigen-reactive T cells. The data reveal disease-specific functional alterations of circulating NMDAR-reactive TH cells in patients with NMDAR encephalitis and challenge the idea that increased pro-inflammatory NMDAR-reactive T cells contribute to disease pathogenesis.

Autoimmune Epilepsy - Novel Multidisciplinary Analysis, Discoveries and Insights

“…Interestingly, partial support of our hypothesis, that T cells may be damaged in Autoimmune Epilepsy, comes from a recent relevant discovery that patients with NMDAR encephalitis, having NMDA-NR1 antibodies, have significantly lower frequencies of CD154-expressing NR1-reactive helper T cells than healthy controls, and produce significantly less inflammatory cytokines ( 52 ). Are normal T cells, which are beneficial and necessary for the proper functioning of both the immune system and the nervous system ( 97 , 98 , 101 , 96 , 99 ), indeed damaged in patients with several neurological diseases (specified in Table 3 ), as a result of the destruction of the T cells by the patient’s own autoimmune antibodies, which target the Neurotransmitter receptors which T cells express ( Table 3 ), alike neural cells do?…”

“…Type 7 : Autoimmune antibodies to Leucine-rich glioma-inactivated 1 (LGI1), called LGI1 antibodies ( 18 , 34 , 35 , 38 , 39 , 42 , 47 , 48 , 52 , 55 , 57 , 59 , 70 , 71 , 76 , 146 , 169 );…”

Ultrahigh frequencies of peripherally matured LGI1- and CASPR2-reactive B cells characterize the cerebrospinal fluid in autoimmune encephalitis

“…Our observations from UCAs suggest that these peripheral GC reactions are typically initiated by naive B cells with undetectable reactivities against LGI1 or CASPR2. However, as the subsequent somatic hypermutations, affinity maturation, and class switching are very likely GC- and T cell–dependent processes ( 25 ), it remains difficult to resolve the reported absence of LGI1-reactive T cells in the blood of these patients ( 36 ). This represents an area for future consideration.…”

Immunopsychiatry – Innovative Technology to Characterize Disease Activity in Autoantibody-Associated Psychiatric Diseases

“…Furthermore, the autoantibody class seems to play a major role in the underlying pathophysiological mechanism. As membrane-surface autoantibodies like NMDAR autoantibodies are probably pathogenic themselves ( 15 ), T-cell dependent proinflammatory states are probably irrelevant in relation to a membrane-surface autoantibody-associated neuropsychiatric disease such as NMDAR encephalitis ( 16 ), but T-cells are relevant immune cells involved in autoantibodies against intracellular targets associated with neuropsychiatric disease ( 17 ). Other novel autoantibodies have been identified playing a potential tole in specific psychiatric diseases, ie, anti-hypothalamus autoantibodies in anorexia nervosa ( 18 ).…”