Heterozygous Alterations ofTNFRSF13B/TACIin Tonsillar Hypertrophy and Sarcoidosis

Abstract

TNFRSF13B/TACI defects have been associated with CVID pathogenesis and/or phenotype, especially the development of benign lymphoproliferation and autoimmunity. Our purpose was to investigate the role of TNFRSF13B/TACI defects in the pathogenesis of two common lymphoproliferative disorders, namely, sarcoidosis and tonsillar hypertrophy (TH). 105 patients (71 with sarcoidosis and 34 with TH, including 19 without infectious causative and 15 due to Haemophilus influenzae) were analyzed for TNFRSF13B/TACI defects. Two out of 19 TH patients without infectious cause (10.5%) and 2 patients with sarcoidosis (2.8%) displayed rare TNFRSF13B/TACI defects (I87N, L69TfsX12, E36L, and R202H, resp.). Both mutations identified in TH patients have been assessed as deleterious for protein function, while the patient with the R202H mutation and sarcoidosis exhibited also sIgG4D. Our study further supports the notion that TNFRSF13B/TACI defects alone do not result in CVID but may be also found frequently in distinct clinical phenotypes, including benign lymphoproliferation and IgG subclass deficiencies.

Genetic polymorphisms of innate and adaptive immunity as predictors of outcome in critically ill patients

“…Interestingly enough, all TACI-C104R carriers displayed an undiagnosed mild to moderate hypogammaglobulinemia, and half of them an immune-mediated disease (COPD). These findings are in accordance with previous related studies (Barroeta Seijas et al 2012;Sáenz-Cuesta et al 2012;Speletas et al 2013), and may uncover the precise role of functional TACI SNPs in the phenotype and/or prognosis of several immune-mediated conditions, including sepsis. Finally, a further validation of this finding with a larger patient sample would allow exploring a potential mediator effect (Baron and Kenny 1986) of TACI-C104R polymorphism upon the association of APACHE II score with ICU mortality.…”

Clinical Associations of Biallelic and MonoallelicTNFRSF13BVariants in Italian Primary Antibody Deficiency Syndromes

“…TACI mutations have been identified in patients affected by a variety of clinical conditions including primary antibody deficiencies, sarcoidosis, and tonsillar hypertrophy [ 35 ]. In PADs, TACI has been analyzed in several cohorts from different geographical areas and mainly in CVID patients among whom the prevalence of mutations is 5–10%.…”

TACI Mutations in Primary Antibody Deficiencies: A Nationwide Study in Greece

“…Interestingly, Zhang et al and Salzer et al were the first to observe a higher prevalence of autoimmune cytopenias and benign lymphoproliferation in CVID patients [ 10 , 17 ], and our study further supports these associations. However, TACI defects have also been reported in patients with sarcoidosis and tonsillar hypertrophy [ 18 ], but not in patients with systemic lupus erythematosus or other autoimmune disorders [ 19 ]. On the other hand, although heterozygous TACI defects have been demonstrated to be pathogenic in “in vitro” studies [ 20 ], such defects have been observed in both relatives of PAD patients without overt disease and healthy individuals [ 7 , 9 , 18 ].…”

“…However, TACI defects have also been reported in patients with sarcoidosis and tonsillar hypertrophy [ 18 ], but not in patients with systemic lupus erythematosus or other autoimmune disorders [ 19 ]. On the other hand, although heterozygous TACI defects have been demonstrated to be pathogenic in “in vitro” studies [ 20 ], such defects have been observed in both relatives of PAD patients without overt disease and healthy individuals [ 7 , 9 , 18 ]. Therefore, considering that accumulating evidence suggests several PAD patients have a complex rather than a monogenic inheritance [ 5 , 21 ], the monoallelic TACI alterations should be primarily considered as susceptibility factors and/or modifiers of PAD.…”