Analysis of TACI mutations in CVID & RESPI patients who have inherited HLA B*44 or HLA*B8

Abstract

Background: Recent reports have suggested that Common Variable Immunodeficieny (CVID) can present as an autosomal dominant trait dependent on the inheritance of a set of uncommon mutations/alleles of TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) involving exons 3 or 4. Penetrance, however, appears to be incomplete. Among our clinic population, the greatest genetic linkage for CVID is to the major histocompatibility complex (MHC) on chromosome 6. The majority of our patients have inherited HLA *DQ2, *DR7, *DR3(17), *B8, and/or *B44. Of these, HLA*B44 was present in almost half of the patients and was thus the most common susceptibility allele. HLA *B44 was also found to be over-represented among patients who presented to our clinic with adult-onset recurrent sinopulmonary infections (RESPI) and normal serum immunoglobulin levels, a cohort that included first and second degree relatives of patients with CVID. One of the two original reports of the association between TACI and CVID also reported Human Leukocyte Antigen (HLA) haplotypes. Of 13 affected subjects, nine had inherited HLA *B8 and six had inherited HLA B44. This raised the possibility that TACI mutations might synergize with MHC class I alleles to enhance susceptibility to humoral immune deficiency.

Histocompatibility Complex Status and Mendelian Randomization Analysis in Unsolved Antibody Deficiency

“…In a study designed by Waldrep et al (12) to test for the possibility of synergy (epistasis) between a mutant transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI) and genes located near the MHC class I locus, they stratified patients based on the variants identified in the TNFRSF13B gene. Although the strength of the…”

“…Physiologically, 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). Given the high prevalence of autoimmune disorders in CVID patients, several studies have investigated the frequency of different MHC alleles in subgroups of CVID patients (11,12). Furthermore, few reports from different ethnic CVID cohorts have also emphasized a possible contribution of the MHC, mainly class II molecules in patients with gastrointestinal autoimmunity, on the predisposition to CVID (13).…”

Common Variable Immunodeficiency with Genetic Defects Identified by Whole Exome Sequencing

“…TNFRSF13B belongs to the tumor necrosis factor receptor (TNFR) superfamily, which encodes transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) and plays a vital role in the maturation and survival of peripheral B cells [ 31 ]. Heterozygous variations in TNFRSF13B are disease-modifying mutations rather than disease-causing mutations, which may increase the risk for developing CVID and are also found in healthy individuals [ 4 , 18 , 32 ].…”

“…The TNFRSF13B mutations can participate in the pathogenesis of CVID through the epistatic interactions with mutations of other genes [ 33 ]. In addition, the TNFRSF13B mutations were reported to have an incomplete penetrance, which may explain the different phenotypes between family members harboring the same variants [ 4 , 31 , 34 , 35 ].…”

Human B cell defects in perspective

“…The strong influence of the MHC region has been noted in several other cohorts; in one, the majority of patients inherited HLA *DQ2, *DR7, *DR3 [17], *B8 and/or *B44. B44 was present in almost half and was the most common susceptibility allele [54]. …”