Anti‐LGI1 encephalitis is strongly associated with HLA‐DR7 and HLA‐DRB4

Abstract

Leucine-rich glioma-inactivated1 (LGI1) encephalitis is an antibody-associated inflammation of the limbic area. An autoimmune etiology is suspected but not yet proven. We performed human leukocyte antigen (HLA) analysis in 25 nontumor anti-LGI1 patients and discovered a remarkably strong HLA association. HLA-DR7 was present in 88% compared to 19.6% in healthy controls (p = 4.1 × 10 ). HLA-DRB4 was present in all patients and in 46.5% controls (p = 1.19 × 10 ). These findings support the autoimmune hypothesis. An exploratory analysis was performed in a small group of 4 tumor-LGI1 patients. The strong HLA association seems not applicable in these patients. Therefore, the absence of HLA-DR7 or HLA-DRB4 could raise tumor suspicion in anti-LGI1 patients. Ann Neurol 2017;81:193-198.

Distinct HLA associations of LGI1 and CASPR2-antibody diseases

“…Perhaps this implicates further divergence in molecular mechanisms responsible for the generation of both autoantibody specificities within an individual. However, the HLA associations do not appear to distinguish between sub-phenotypes, outcomes or, in contrast to a previous observation, the presence of associated tumours (van Sonderen et al , 2017). Also, the 9–27% frequencies of these HLA variants in healthy Caucasians are far higher than disease prevalence, implicating additional loci, environmental or stochastic influences in disease manifestation.…”

“…1 and Table 2. Consistent with previous smaller reports (Kim et al , 2017; van Sonderen et al , 2017), almost all LGI1-antibody-positive patients carried HLA-DRB1*07:01 (91%, compared to 26% in healthy controls) [OR 27.6 (95% confidence interval, CI 12.9–72.2), P = 4.1 × 10 −26 ]. Further, 13% (9/68) were homozygous for DRB1*07:01, compared to 2% (115/5553) healthy controls [OR 7.3 (95% CI 3.3–14.4), P = 3 × 10 −4 ].…”

“…To extend a previous report (van Sonderen et al , 2017), the HLA-DRB1 paralogue HLA-DRB4 was sequenced and observed to be absent or a null allele in 61% (19/31) of the CASPR2-antibody cohort and 44% (4/9) of the intracellular VGKC-antibody cohort, consistent with the healthy control frequencies. However, only 16% (11/68) of the LGI1-antibody cohort showed an absent or null HLA-DRB4 allele, and these 11 patients all carried HLA-DRB1*07:01 (Supplementary Table 3).…”

“…Second, the presence of dominant HLA class II associations implicates extracellular antigen processing and CD4 T cells in disease initiation (Trowsdale and Knight, 2013), but the LGI1 antibody class I associations found here, and HLA-B*44:03 and HLA-C*07:06 reported in seven patients previously (Kim et al , 2017), are compatible with a role for intracellular antigen processing, including viruses and drugs. These class I differences between studies may be explained by ethnicity, sample size and relatively weak associations (Kim et al , 2017; van Sonderen et al , 2017). Indeed, this extended haplotype and the related complex linkage disequilibrium in this region of the genome warrant further analysis.…”

“…As HLA variants have been implicated in several adverse drug reactions, including those associated with AEDs and immunosuppressants (McCormack et al , 2011; Yip et al , 2015), and have essential antigen-presenting functions (Trowsdale and Knight, 2013), we hypothesized that HLA associations existed in patients with LGI1 antibodies. Indeed, recently, HLA-DRB1*07:01, HLA-DQB1*02:02 and HLA-DRB4 were found to be present in varying proportions of patients with LGI1 antibodies in two cohorts totalling 40 patients, from Korea and the Netherlands (Kim et al , 2017; van Sonderen et al , 2017). …”