The identification of anti-NMDA receptor (NMDAR) encephalitis about 12 years ago made it possible to recognise that some patients with rapidly progressive psychiatric symptoms or cognitive impairment, seizures, abnormal movements, or coma of unknown cause, had an autoimmune disease. In this disease, autoantibodies serve as a diagnostic marker and alter NMDAR-related synaptic transmission. At symptom onset, distinguishing the disease from a primary psychiatric disorder is challenging. The severity of symptoms often requires intensive care. Other than clinical assessment, no specific prognostic biomarkers exist. The disease is more prevalent in women (with a female to male ratio of around 8:2) and about 37% of patients are younger than 18 years at presentation of the disease. Tumours, usually ovarian teratoma, and herpes simplex encephalitis are known triggers of NMDAR autoimmunity. About 80% of patients improve with immunotherapy and, if needed, tumour removal, but the recovery is slow. Animal models have started to reveal the complexity of the underlying pathogenic mechanisms and will lead to novel treatments beyond immunotherapy. Future studies should aim at identifying prognostic biomarkers and treatments that accelerate recovery.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(19)30244-3.pdf

An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models.

The realization that autoantibodies can contribute to dysfunction of the brain has brought about a paradigm shift in neurological diseases over the past decade, offering up important novel diagnostic and therapeutic opportunities. Detection of specific autoantibodies to neuronal or glial targets has resulted in a better understanding of central nervous system autoimmunity and in the reclassification of some diseases previously thought to result from infectious, 'idiopathic' or psychogenic causes. The most prominent examples, such as aquaporin 4 autoantibodies in neuromyelitis optica or NMDAR autoantibodies in encephalitis, have stimulated an entire field of clinical and experimental studies on disease mechanisms and immunological abnormalities. Also, these findings inspired the search for additional autoantibodies, which has been very successful to date and has not yet reached its peak. This Review summarizes this rapid development at a point in time where preclinical studies have started delivering fundamental new data for mechanistic understanding, where new technologies are being introduced into this field, and - most importantly - where the first specifically tailored immunotherapeutic approaches are emerging.

/pdf/autoantibodies-in-neurological-disease-45sr9c18zz.pdf

Autoantibodies in neurological disease

The autoimmune encephalitides are a group of autoimmune conditions targeting the central nervous system and causing severe clinical symptoms including drug-resistant seizures, cognitive dysfunction and psychiatric disturbance. Although these disorders appear to be antibody mediated, the role of innate immune responses needs further clarification. Infiltrating monocytes and microglial proliferation at the site of pathology could contribute to the pathogenesis of the disease with resultant blood brain barrier dysfunction, and subsequent activation of adaptive immune response. Both innate and adaptive immune cells can produce pro-inflammatory molecules which can perpetuate ongoing neuroinflammation and drive ongoing seizure activity. Ultimately neurodegenerative changes can ensue with resultant long-term neurological sequelae that can impact on ongoing patient morbidity and quality of life, providing a potential target for future translational research.

/pdf/innate-immunity-in-the-central-nervous-system-a-missing-giblk4orvm.pdf

Innate Immunity in the Central Nervous System: A Missing Piece of the Autoimmune Encephalitis Puzzle?

Recently, several autoimmune neurological diseases have been defined by the presence of autoantibodies against different antigens of the nervous system. These autoantibodies have been demonstrated to be specific and useful biomarkers, and most of them are also pathogenic. These aspects have increased the value of autoantibodies in neurological practice, as they enable to establish more accurate diagnosis and to better understand the underlying mechanisms of the autoimmune neurological diseases when they are compared to those lacking them. Nevertheless, the exact mechanisms leading to the autoimmune response are still obscure. Genetic predisposition is likely to play a role in autoimmunity, HLA being the most reported genetic factor. Herein, we review the current knowledge about associations between HLA and autoimmune neurological diseases with autoantibodies. We report the main alleles and haplotypes, and discuss the clinical and pathogenic implications of these findings.

/pdf/associations-between-hla-and-autoimmune-neurological-28m8zr1i5i.pdf

Associations between HLA and autoimmune neurological diseases with autoantibodies

Paraneoplastic neurological syndromes (PNSs) are rare complications of systemic cancers that can affect all parts of the central and/or peripheral nervous system A body of experimental and clinical data has demonstrated that the pathogenesis of PNSs is immune-mediated Nevertheless, the mechanisms leading to immune tolerance breakdown in these conditions remain to be elucidated Despite their rarity, PNSs offer a unique perspective to understand the complex interplay between cancer immunity, effect of immune checkpoint inhibitors (ICIs), and mechanisms underlying the attack of neurons in antibody-mediated neurological disorders, with potentially relevant therapeutic implications In particular, it is reported that ICI treatment can unleash PNSs and that the immunopathological features of PNS-related tumors are distinctive, showing prominent tumor-infiltrating lymphocytes and germinal center reactions Intriguingly, similar pathological substrates have gained further attention as potential biomarkers of ICI-sensitivity and oncological prognosis Moreover, the genetic analysis of PNS-associated tumors has revealed specific molecular signatures and mutations in genes encoding onconeural proteins, leading to the production of highly immunogenic neoantigens Other than PNSs, autoimmune encephalitides (AEs) comprise a recently described group of disorders characterized by prominent neuropsychiatric symptoms, diverse antibody spectrum, and less tight association with cancer Other triggering factors seem to be involved in AEs Recent data have shed light on the importance of preceding infections (in particular, herpes simplex virus encephalitis) in inducing neurological autoimmune disorders in susceptible individuals (those with a selective deficiency in the innate immune system) In addition, in some AEs (eg LGI1-antibody encephalitis) an association with specific host-related factors [eg, human leukocyte antigen (HLA)] was clearly demonstrated We provide herein a comprehensive review of the most recent findings in the field of PNSs and AEs, with particular focus on their triggering factors and immunopathogenesis

https://journals.sagepub.com/doi/pdf/10.1177/1756286420932797

Pathophysiology of paraneoplastic and autoimmune encephalitis: genes, infections, and checkpoint inhibitors.

Background and objective Aetiology and pathogenesis of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, the most common autoimmune encephalitis, is largely unknown. Since an association of the disease with the human leucocyte antigen (HLA) has not been shown so far, we here investigated whether anti-NMDAR encephalitis is associated with the HLA locus. Methods HLA loci of 61 patients with anti-NMDAR encephalitis and 571 healthy controls from the Chinese Han population were genotyped and analysed for this study. Results Our results show that the DRB1*16:02 allele is associated with anti-NMDAR encephalitis (OR 3.416, 95% CI 1.817 to 6.174, p=8.9×10−5, padj=0.021), with a higher allele frequency in patients (14.75%) than in controls (4.82%). This association was found to be independent of tumour formation. Besides disease susceptibility, DRB1*16:02 is also related to the clinical outcome of patients during treatment, where patients with DRB1*16:02 showed a lower therapeutic response to the treatment than patients with other HLA alleles (p=0.033). Bioinformatic analysis using HLA peptide-binding prediction algorithms and computational docking suggested a close relationship between the NR1 subunit of NMDAR and the DRB1*16:02. Conclusions This study for the first time demonstrates an association between specific HLA class II alleles and anti-NMDAR encephalitis, providing novel insights into the pathomechanism of the disease.

https://jnnp.bmj.com/content/jnnp/90/6/652.full.pdf

Xiaoli Yang

Papers

HLA class II allele DRB1*16:02 is associated with anti-NMDAR encephalitis.