Barbosa Rita R, Silva Susana L, Silva Sara P, Melo Alcinda C, Pereira-Santos M Conceição, Barata João T, Hammarström Lennart, Cascalho Marília, Sousa Ana E
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal.
J Clin Immunol. 2014 Jul;34(5):573-83. doi: 10.1007/s10875-014-0047-y. Epub 2014 May 9.
B-cell survival and differentiation critically depend on the interaction of BAFF-R and TACI with their ligands, BAFF and APRIL. Mature B-cell defects lead to Common Variable Immunodeficiency (CVID), which is associated with elevated serum levels of BAFF and APRIL. Nevertheless, BAFF-R and TACI expression in CVID and their relationship with ligand availability remain poorly understood.
We found that BAFF-R expression was dramatically reduced on B cells of CVID patients, relative to controls. BAFF-R levels inversely correlated with serum BAFF concentration both in CVID and healthy subjects. We also found that recombinant BAFF stimulation reduced BAFF-R expression on B cells without decreasing transcript levels. On the other hand, CVID subjects had increased TACI expression on B cells in direct association with serum BAFF but not APRIL levels. Moreover, splenomegaly was associated with higher TACI expression, suggesting that perturbations of TACI function may underlie lymphoproliferation in CVID.
Our results indicate that availability of BAFF determines BAFF-R and TACI expression on B cells, and that BAFF-R expression is controlled by BAFF binding. Identification of the factors governing BAFF-R and TACI is crucial to understanding CVID pathogenesis, and B-cell biology in general, as well as to explore their potential as therapeutic targets.
B细胞的存活和分化严重依赖于BAFF-R和TACI与其配体BAFF和APRIL的相互作用。成熟B细胞缺陷会导致常见变异型免疫缺陷病（CVID），这与血清中BAFF和APRIL水平升高有关。然而，CVID中BAFF-R和TACI的表达及其与配体可利用性的关系仍知之甚少。
我们发现，与对照组相比，CVID患者B细胞上的BAFF-R表达显著降低。在CVID患者和健康受试者中，BAFF-R水平均与血清BAFF浓度呈负相关。我们还发现，重组BAFF刺激可降低B细胞上的BAFF-R表达，但不降低转录水平。另一方面，CVID患者B细胞上的TACI表达增加，且与血清BAFF直接相关，而与APRIL水平无关。此外，脾肿大与较高的TACI表达相关，这表明TACI功能的紊乱可能是CVID中淋巴细胞增殖的基础。
我们的结果表明，BAFF的可利用性决定了B细胞上BAFF-R和TACI的表达，且BAFF-R表达受BAFF结合的控制。确定调控BAFF-R和TACI的因素对于理解CVID发病机制及一般B细胞生物学，以及探索它们作为治疗靶点的潜力至关重要。
