Heterozygous Alterations ofTNFRSF13B/TACIin Tonsillar Hypertrophy and Sarcoidosis

Matthaios Speletas,Konstantinos I Gourgoulianis,Zoe Florou,Fotini Bardaka,Zoe Daniil,Anastasios E Germenis,Charalampos Skoulakis,Ulrich Salzer,Efthimia Petinaki

doi:10.1155/2013/532437

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.

Highlights

Recent studies have demonstrated that TNFRSF13B/TACI mutations may contribute to the pathogenesis and/or phenotype of CVID [1,2,3,4]
We investigated if TNFRSF13B/TACI alterations, considered either potent susceptibility factors or modifiers of CVID, may contribute to the development of benign lymphoproliferation
Our results are in favor of our hypothesis, since the mutations identified in the patients affected by tonsillar hypertrophy (TH) without evidence of infectious cause are both deleterious for TACI function and extremely rare in the general population (0.1-0.2%); in addition, the frequency of TNFRSF13B/TACI mutations in TH patients (10.5%) was higher than that expected for the general population (1.2– 3.6% in several healthy control groups) [4, 12, 14]

Summary

Introduction

Recent studies have demonstrated that TNFRSF13B/TACI mutations may contribute to the pathogenesis and/or phenotype of CVID [1,2,3,4]. Salzer et al identified that the presence of specific TNFRSF13B/TACI mutations, as C104R and A181E, has been associated with both a high risk of CVID development and specific aspects of disease phenotype, that is, the presence of benign lymphoproliferation, such as splenomegaly, lymphadenopathy, and autoimmune complications [3]. CVID patients exhibit an increased incidence of autoimmunity and lymphoproliferation [7, 8], while approximately 10% of them display granulomatous inflammatory reactions, which can be accompanied by interstitial lymphoid hyperplasia in lungs (GLILD), a pathologic condition clinically indistinguishable from sarcoidosis [9].

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