The Association with HLA-DRB1*11:01 in Anti-CASPR2 Syndromes Is Exclusive to Limbic Encephalitis
Sergio Muniz-Castrillo1, Vicente Peris Sempere1, Louis Comperat2, Anne-Laurie Pinto2, Selina Yogeshwar1, Bastien Joubert2, Jerome Honnorat2, Emmanuel Mignot1
1Stanford University, 2French Reference Center for Paraneoplastic neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Lyon, France
Objective:
To further characterize the association between human leukocyte antigen (HLA) and autoimmune neurological diseases with antibodies against contactin-associated protein-like 2 (CASPR2), including phenotype correlation.
Background:
Anti-CASPR2 neurological diseases comprise three main phenotypes: limbic encephalitis (LE), acquired neuromyotonia and Morvan syndrome. Despite some degree of clinical overlap, detailed clinical descriptions have shown that manifestations are distinctly disease-specific. Furthermore, additional immunological and oncological associations (malignant thymoma in Morvan syndrome) are different across the three groups and reflect distinct underlying pathogeneses. Interestingly, anti-CASPR2 neurological diseases have been associated with the HLA allele DRB1*11:01, but we have previously shown in a small cohort that the association might be present only in LE patients.
Design/Methods:
Four-digit resolution HLA genotypes were imputed from available Genome Wide Association data, and carrier frequencies compared between anti-CASPR2 patients (n=61) and controls (n=338), stratified by phenotype (LE=45, Morvan=9, neuromyotonia=7). Fisher exact tests and logistic regressions controlled by principal component analysis were used.
Results:
No HLA association was observed in neuromyotonia and Morvan syndrome. In contrast, LE was strongly associated with DQA1*05:05 (OR=5.4, 95% CI 2.5-11.5, p=1.5e-04), DQB1*03:01 (OR=4.3, 95% CI 2.0-9.4, p= 2.1e-03), DRB1*11:01 (OR= 8.5, 95% CI 3.9-18.7, corrected p=1.7e-06), and DRB3*02:02 (OR= 4.9, 95% CI 2.2-11.4, corrected p=3.4e-04) in the context of the common DR11~DQ3 haplotype. Importantly however, DQA1*05:05, DQB1*03:01 and DRB3*02:02 were no longer significant after controlling for DRB1*11:01, whereas DRB1*11:01 was still significant after controlling for DQB1*03:0 and DRB3*02:02, but not DQA1*05:05, indicating a primary DRB1*11:01 association. No secondary associations were found in non-DRB1*11:01 carriers or across DRB1*11:01 heterozygotes. DRB1*11:01 homozygosity was associated with a 10.9-fold increased risk versus heterozygotes (p=1.3e-03).
Conclusions:
HLA association is specific to DRB1*11:01 and to patients with LE, with a strong effect of homozygocity. The specific association to LE suggests a different pathogenesis versus other anti-CASPR2 phenotypes.