Background/Purpose: Immune dysregulation refers to alterations in immune signaling leading to development of autoimmunity, infection and atopic disease. Common variable immunodeficiency (CVID), a prototypic disorder of immune dysregulation, is characterized by hypogammaglobulinemia, recurrent infections, poor vaccine responses and diverse complications, including autoimmunity. Although small subsets of CVID have been linked with various genes, the larger genetic landscape of CVID is unknown. Two closely-related familial disorders of immune dysregulation — phospholipase C gamma 2 (PLCγ2) associated antibody deficiency and immune dysregulation (PLAID) and autoinflammatory PLAID (APLAID) — are caused by dominant mutations in PLCG2. These disorders are marked by antibody deficiency and immune dysregulation and are strikingly similar to that observed in CVID. We therefore hypothesized that genetic variants of PLCG2 influence CVID susceptibility.

Methods: Using a combination of Sanger sequencing and targeted deep resequencing, we examined the coding region of PLCG2 in 185 CVID patients and 96 local controls. Variant positions were evaluated for evolutionary conservation (GERP++, SiPhy) and the functional effects of missense changes were predicted (PolyPhen2, SIFT, MutationTaster). Distributions of rare, evolutionarily conserved PLCG2 variants were compared between CVID cases and 37,370 non-Finnish European (NFE) subjects from the Exome Aggregation Consortium using the Sequence Kernel Association Test (SKAT). Effects of PLCG2 mutations on cell activation were examined by overexpressing mutant constructs in a PLCG2 deficient DT40 B cell line.

Results: Among 185 CVID cases, we found 12 missense variants of PLCG2, including 7 rare and 2 novel variants. All rare variants occurred at evolutionarily conserved sites and were predicted to detrimentally affect protein function. Rare variants were observed in 23 CVID patients (12.4%) and SKAT revealed significant enrichment of rare, evolutionarily conserved PLCG2 variants in CVID patients compared to the NFE population (p=5.3E-5). Overexpression studies revealed alterations in downstream signaling in 7 CVID variants: relative to wild type PLCG2, 6 variants lead to basal increases in ERK phosphorylation, while 2 produced enhanced activation following IgM stimulation.

Conclusion: Rare, evolutionarily conserved missense variants of PLCG2 are significantly associated with CVID. Furthermore, most of the rare PLCG2 variants found in CVID patients cause abnormal downstream signaling, in vitro. Based on these results, we conclude that PLCG2 influences susceptibility to CVID. Investigations are ongoing to determine whether PLCG2 mutations predict specific phenotypes or disease courses in CVID.

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/plcg2-variants-influence-cvid-susceptibility-expanding-the-spectrum-of-plcg2-associated-immune-dysregulation/