Toll-like Receptor 3 Defect in a Patient with Autoimmune Encephalitis Following HHV-6 Encephalitis

Introduction Toll-like receptors play an important role in innate immunity. The toll-like receptor 3 (TLR3) genes encodes a transmembrane protein that recognizes dsRNA and helps eradicate viral infections through the activation of NF-kappaB and production of type I interferons. Case Description The patient is a 13-year-old girl with Rubinstein-Taybi syndrome (RSTS) who presented at 8 years old for first-time generalized tonic-clonic (GTC) seizure. Workup was notable for cerebral spinal fluid (CSF) positive for HHV-6, which was of unknown clinical significance; she was discharged on an anti-epileptic. At 10 years old, she experienced another GTC seizure with CSF that was again positive for HHV-6. It was felt that this detection of HHV-6 was a latent infection and that influenza A was possibly driving her encephalitis given positive nasopharyngeal PCR testing. Given prolonged symptoms, an autoimmune encephalitis panel was obtained, which was positive for glial fibrillary acidic protein (GFAP) antibodies. She improved with intravenous immunoglobulin and steroids. Since her GFAP autoimmune encephalitis, she has experienced recurrent sinopulmonary infections. Initial immunologic workup showed a mildly decreased IgA and a decreased percentage of isotype-switched (IgM-/IgD-) memory B cells, which is not unexpected in patients with RSTS due to B cell maturation defects. Her pneumococcal titers were non-protective, but family deferred revaccination. Genetic testing showed a heterozygous variant in TLR3 (c.1234C>G (p.Leu412Val)). Discussion Genetic testing showed a heterozygous variant in TLR3 (c.1234C>G (p.Leu412Val)) not previously reported in the literature to be associated with TLR3-related conditions. The genotype-phenotype relationship identified between the patient’s TLR3 variant is immunodeficiency 83 (IMD83), which is associated with an increased susceptibility to severe viral infections, including herpes simplex virus (HSV), varicella zoster virus, and influenza A virus. IMD83 has been associated with HSV encephalitis due to impaired TLR3-dependent interferon production in central nervous system cells. While there appears to be no clear association between IMD83 and autoimmune encephalitis, TLR3 defects have been associated with autoimmune predisposition, given that appropriate endosomal expression of TLR3 may prevent activation by host nucleic acids and the development of autoimmunity. This case highlights the importance of monitoring patients with TLR3 defects for both viral and autoimmune encephalitis.