Infection-triggered autoimmunity

Abstract

The recent paradigm that autoimmune encephalitis is associated with autoantibodies that bind to conformational epitopes of cell surface antigens involved in neurotransmission has transformed the field of autoimmune neurology and created new biomarkers for the clinician to define treatable acquired neurologic conditions. In parallel, a growing armamentarium of immune therapeutic agents is becoming available. But fundamental questions remain, particularly “why does this happen?” There is cohort-derived evidence suggesting age and ethnic vulnerability and emerging evidence of HLA associations.1,2 Anti–NMDA receptor (NMDAR) encephalitis, which is defined by a characteristic clinical syndrome and the presence of CSF autoantibodies to the NR1 subunit of the NMDAR, is the most common autoimmune encephalitis. In anti-NMDAR encephalitis, many female adults have an ovarian teratoma that contains NMDAR-expressing neural tissue, providing a hypothetical example of “cross-reactive” autoimmunity between the NMDARs in the tumor and in the brain. However, large cohorts have shown that ovarian teratomas are very uncommon in pediatric patients,3 so what is the “trigger” of the loss of immune tolerance in young children? Some of these children have preceding herpes simplex type 1 (HSV1) encephalitis, a destructive highly inflammatory encephalitis that predominantly affects temporal lobes and surrounding structures. After recovery, approximately 20% of children with HSV1 encephalitis deteriorate with a “second phase” of encephalitis, this time with clinical features typical of anti-NMDAR encephalitis, including florid movement disorders and encephalopathy, associated with the emergence of anti-NMDAR antibodies.4–6 This clear example of HSV1 encephalitis inducing secondary anti-NMDAR encephalitis yielded the hypothesis that the inflammatory destruction of neural tissue with release of neural antigens into the surrounding brain, circulation and then lymphatic system, resulted in a reactivation of autoreactive lymphocytes against NMDAR antigens and production of pathogenic anti-NMDAR antibodies.