Abstract
The pathogenesis in the majority of patients with common variable immunodeficiency (CVID), the most common symptomatic primary immunodeficiency, remains unknown. We aimed to compare the minor and major histocompatibility complex (MHC) markers as well as polygenic scores of common genetic variants between patients with monogenic CVID and without known genetic mutation detected. Monogenic patients were identified in a CVID cohort using whole exome sequencing. Computational full-resolution MHC typing and confirmatory PCR amplicon-based high-resolution typing were performed. Exome-wide polygenic scores were developed using significantly different variants and multi-variant Mendelian randomization (MR) analyses were used to test the causality of significant genetic variants on antibody levels and susceptibility to infectious diseases. Among 83 CVID patients (44.5% females), monogenic defects were found in 40 individuals. Evaluation of the remaining CVID patients without known genetic mutation detected showed 13 and 27 significantly associated MHC-class I and II alleles, respectively. The most significant partial haplotype linked with the unsolved CVID was W*01:01:01-DMA*01:01:01-DMB*01:03:01:02-TAP1*01:01:01 (P < 0.001), where carriers had a late onset of the disease, only infection clinical phenotype, a non-familial form of CVID, post-germinal center defects and a non-progressive form of their disease. Exclusion of monogenic diseases allowed MR analyses to identify significant genetic variants associated with bacterial infections and improved discrepancies observed in MR analyses of previous GWAS studies with low pleiotropy mainly for a lower respiratory infection, bacterial infection and Streptococcal infection. This is the first study on the full-resolution of minor and major MHC typing and polygenic scores on CVID patients and showed that exclusion of monogenic forms of the disease unraveled an independent role of MHC genes and common genetic variants in the pathogenesis of CVID.
Highlights
Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency (PID), characterized by impairment of antibody production, recurrent infections and immune dysregulation, in particular, autoimmunity [1]
11 patients were from multiplex families and 7 cases progressed to CVID from another form of antibody deficiency during the course of the disease (IgA deficiency and IgG subclass deficiency, 14.2% with an unsolved disease)
We demonstrated the importance of exclusion of monogenic CVID on the evaluation of the effects of major histocompatibility complex (MHC) alleles and polygenic allele scores in Mendelian randomization (MR) analyses in the remaining patients
Summary
Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency (PID), characterized by impairment of antibody production, recurrent infections and immune dysregulation, in particular, autoimmunity [1]. Minor and major histocompatibility complex (MHC) genes are the most polymorphic genomic region and specific MHC loci determine the presentation of antigens via B cells to T cells to elicit a germinal center reaction. Both MHC class I and II molecules are critical in B cells for stimulating antibody class switching and affinity maturation (MHC class II primarily to follicular helper T cells) and supporting presentation of polysaccharides antigens (mainly via positive signals of MHC class I primarily to natural killer T-cells) [8,9,10]. In some multiplex families with co-occurrence of CVID and selective immunoglobulin A (IgA), deficiency, MHC markers have been suggested to play a role both in inheritance and as predictors of progressive disease [14]
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