Toll-like receptor 3 deficiency in autoimmune encephalitis post–herpes simplex encephalitis

Armangué, Thaís; Baucells, Benjamin J.; Vlagea, Alexandru; Petit‐Pedrol, Mar; Esteve‐Solé, Ana; Deyà‐Martínez, Àngela; Ruiz‐García, Raquel; Juan, Manel; Diego, Rebeca Pérez de; Dalmau, Josep; Alsina, Laia

doi:10.1212/nxi.0000000000000611

Cited by 25 publications

(12 citation statements)

References 7 publications

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“…However, patients with mutations in IL-1 receptor-associated kinase-4 (IRAK-4), which is implicated in the signaling pathways of all TLRs except TLR3, were not more susceptible to viral infections, suggesting that sensing through TLRs 7, 8, and 9 may be redundant for protection against these infections (139). The implication of TLR3 in the susceptibility to HSE was definitely highlighted by the identification of several autosomal dominant or autosomal recessive mutations in the TLR3 gene in children (140)(141)(142)(143) and adults (142,144,145). Several reports describing a series of deficiencies in the TLR3-dependent signaling pathway further confirmed the importance of this axis in protective immunity against HSE.…”

Section: Genetic Predisposition To Develop Hsementioning

confidence: 99%

Immunomodulatory Strategies in Herpes Simplex Virus Encephalitis

Piret

Boivin

2020

Clin Microbiol Rev

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SUMMARY Herpes simplex virus 1 (HSV-1) can be responsible for life-threatening HSV encephalitis (HSE). The mortality rate of patients with HSE who do not receive antiviral treatment is 70%, with most survivors suffering from permanent neurological sequelae. The use of intravenous acyclovir together with improved diagnostic technologies such as PCR and magnetic resonance imaging has resulted in a reduction in the mortality rate to close to 20%. However, 70% of surviving patients still do not recover complete neurological functions. Thus, there is an urgent need to develop more effective treatments for a better clinical outcome. It is well recognized that cerebral damage resulting from HSE is caused by viral replication together with an overzealous inflammatory response. Both of these processes constitute potential targets for the development of innovative therapies against HSE. In this review, we discuss recent progress in therapy that may be used to ameliorate the outcome of patients with HSE, with a particular emphasis on immunomodulatory agents. Ideally, the administration of adjunctive immunomodulatory drugs should be initiated during the rise of the inflammatory response, and its duration should be limited in time to reduce undesired effects. This critical time frame should be optimized by the identification of reliable biomarkers of inflammation.

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Section: Genetic Predisposition To Develop Hsementioning

confidence: 99%

Immunomodulatory Strategies in Herpes Simplex Virus Encephalitis

Piret

Boivin

2020

Clin Microbiol Rev

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“…These findings, together with the previous observation of HSE in patients with either XR NEMO deficiency (impairing IFN-α/β and -λ production upon viral infection)(78) and AR complete STAT1 deficiency (61) (impairing IFN-α/β and -λ responses), suggested that TLR3-dependent IFN-α/β and/or -λ immunity is crucial for host defense against HSV1 in the CNS. It has been suggested that other mutations of these and other TLR3 or IFN pathway genes probably underlie HSE in adults or children (79)(80)(81). It has been further shown in a series of experiments that TLR3 pathway-deficient fibroblasts (68)(69)(70)(71)(72)(73)(74) and induced pluripotent stem cell (iPSC)-derived cortical neurons and oligodendrocytes (75) are much more susceptible to HSV1 infection than control cells, probably due to impaired TLR3-dependent IFN-β and IFN-λ production.…”

Section: Hsv1/hsv2 Immunitymentioning

confidence: 99%

Human inborn errors of immunity to herpes viruses

Jouanguy

Béziat

Mogensen

et al. 2020

Current Opinion in Immunology

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Infections with any of the nine human herpes viruses (HHV) can be asymptomatic or lifethreatening. The study of patients with severe diseases caused by HHVs, in the absence of overt acquired immunodeficiency, has led to the discovery or diagnosis of various inborn errors of immunity. The related inborn errors of adaptive immunity disrupt α/β T-cell rather than B-cell immunity. Affected patients typically develop HHV infections in the context of other infectious diseases. However, this is not always the case, as illustrated by inborn errors of SAP-dependent Tcell immunity to EBV-infected B cells. The related inborn errors of innate immunity disrupt leukocytes other than T and B cells, non-hematopoietic cells, or both. Patients typically develop only a single type of infection due to HHV, although, again, this is not always the case, as illustrated by inborn errors of TLR3 immunity resulting in HSV-1 encephalitis in some patients and influenza pneumonitis in others. Most severe HHV infections in otherwise healthy patients remains unexplained. The forward human genetic dissection of isolated and syndromic HHV-

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“…Furthermore, HSV1 encephalitis may also trigger AE mostly with anti-NMDAR antibodies [ 22 ]. However, post-herpetic AE seems to be a different etiopathogenic entity with a likely distinct genetic predisposition that could involve Toll-like receptor 3 [ 100 ].…”

Section: Molecular Biomarkers In Anti-nmdar Encephalitismentioning

confidence: 99%

Current Status of Biomarkers in Anti-N-Methyl-D-Aspartate Receptor Encephalitis

Ciano-Petersen

Cabezudo‐García

Muñiz‐Castrillo

et al. 2021

IJMS

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The discovery of biomarkers in rare diseases is of paramount importance to allow a better diagnosis, improve predictions of outcomes, and prompt the development of new treatments. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a rare autoimmune disorder associated with the presence of antibodies targeting the GluN1 subunit of the NMDAR. Since it was discovered in 2007, large efforts have been made towards the identification of clinical, paraclinical, and molecular biomarkers to better understand the immune mechanisms that govern the course of the disease as well as to define predictors of treatment response and long-term outcomes. However, most of these biomarkers are still in an exploratory phase, with only a few candidates reaching the final phases of the always-complex process of biomarker development, mainly due to the low incidence of the disease and its recent description. Clinical and paraclinical markers are probably the most widely explored in anti-NMDAR encephalitis, five of them combined in a clinical score to predict 1 year outcome. On the contrary, soluble molecules, such as persistent antibody positivity, antibody titers, cytokines, and other inflammatory mediators, have been proposed as biomarkers of clinical activity, inflammation, prognosis, and treatment response, but further studies are required for their clinical validation including larger and more homogenous cohorts of patients. Similarly, genetic susceptibility biomarkers are still in the exploratory phase and, therefore, weak conclusions can for now only be achieved. Thus, further studies are warranted to define biomarkers and unravel the underlying mechanisms driving rare diseases such as anti-NMDAR encephalitis. Future international collaborative studies with prospective designs that enable the enrollment of large cohorts will allow for the identification and validation of novel biomarkers for clinical decision-making.

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Toll-like receptor 3 deficiency in autoimmune encephalitis post–herpes simplex encephalitis

Cited by 25 publications

References 7 publications

Immunomodulatory Strategies in Herpes Simplex Virus Encephalitis

Immunomodulatory Strategies in Herpes Simplex Virus Encephalitis

Human inborn errors of immunity to herpes viruses

Current Status of Biomarkers in Anti-N-Methyl-D-Aspartate Receptor Encephalitis

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