Common Variable Immunodeficiency at the End of a Prospering Decade: Towards Novel Gene Defects and Beyond

Hermann Eibel; Ulrich Salzer; Klaus Warnatz


Curr Opin Allergy Clin Immunol. 2010;10(6):526-533. 

In This Article

BAFF-receptor Deficiency

BAFF-receptor (BAFF-R), TACI, and BCMA are members of the TNF-R family, which regulate the survival and homeostasis of B cells at different stages of B lymphocyte differentiation.[2] All three receptors bind a TNF-like ligand, termed BAFF or BLyS, although at different affinities. TACI and BCMA also bind the BAFF-related ligand APRIL. Both ligands are produced by nonhematopoietic stroma cells and by hematopoietic immune cells.[2,3] During B-cell maturation, immature IgM+ B cells start to express BAFF-R. Expression increases steadily through transitional B-cell stages and is maintained at high levels by mature, marginal zone, and switched memory B cells up to the stage of plasma cells, which are BAFF-R but BCMA+. TACI is highly expressed by human marginal zone B cells and IgG+/IgA+/IgE+ switched memory B cells, but low to absent on mature naive and transitional B cells. Whereas BCMA supports the survival of long-lived plasma cells, the role of TACI in regulating B-cell survival is yet not fully understood. BAFF-R has a unique role as it forms together with the B-cell antigen receptor (BCR) the essential signaling component for the survival of almost all transitional and mature B lymphocyte subsets. Although the BAFF-R and BCR signaling pathways are to some extent overlapping, the induction of the survival signals differs. For the BCR, experiments with knock-in mouse models allowing the ablation of BCR expression from resting B cells of adult mice provided evidence for so-called tonic signals generated in the absence of antigen by the assembly of a functional BCR composed from the signaling components Ig-α, Ig-β, and the μ heavy chain.[4,5] In contrast, BAFF-R signaling needs constant activation by BAFF[6–9] as demonstrated by the rapid loss of peripheral B cells in mice treated with a monoclonal antibody blocking BAFF-R/BAFF interactions.[10••] Downstream of BAFF-R, TRAF3-dependent activation of NIK[11–14] induces processing of the 100-kDa precursor form of NFkB2 into transcriptionally active p52 inducing the expression of antiapoptotic target genes like BclXL[15] and Mcl1.[16] In parallel, PI3K-dependent activation of AKT inhibits PTEN and FOXO1, increases through mTOR the metabolic fitness, and prepares the cells for antigen-induced proliferation and survival.[16–19] Since components of the AKT signaling pathway play also a central role in BCR-dependent survival it is likely that BCR signals are modulated by BAFF-R signals and vice versa. The latter has recently been demonstrated by Stadanlick et al..[20]

So far, only mutations in the TACI (TNFRSF13B)[21–25] and in the BAFF-R gene (TNFRSF13C)[26,27••] have been found to be associated with CVID. Mutations in BCMA have not been identified yet, most likely since they would only affect the long-term humoral memory but not the generation of short-lived plasma cells and serum levels of the immunoglobulins produced by these cells.[28] In contrast to the high polymorphism and frequency of mutations in TACI, homozygous mutations ablating the function of BAFF-R are rare as they were found so far only in a pair of siblings from a consanguineous family.[27••] In these BAFF-R-deficient individuals, the B-cell phenotype and the functional defects of the residual B-cell compartment are striking and are similar to murine BAFF-R deficiency.[2] Without BAFF-R, human B-cell development is arrested at the stage of transitional B cells. Therefore, BAFF-R-deficient patients are severely B-lymphopenic lacking almost completely follicular, marginal zone and memory B-cell subsets with the exception of IgA+ memory B cells and IgA secreting plasma cells from mucosal tissues.[27••] The undisturbed development of mucosal B-cell subsets results in a unique type of 'CVID' since BAFF-R-deficient patients have normal or even elevated IgA serum concentrations but very low IgG titers. The impaired development of marginal zone B cells precludes the generation of plasma cells producing an efficient humoral immune response against encapsulated bacteria, which is demonstrated by the lack of antibodies directed against pneumococcal polysaccharides after vaccination with the 23-valent T-cell independent vaccine Pneumovax. Clinically this results in an increased susceptibility to respiratory infections. Surprisingly, T-cell-dependent recall antibody responses are less affected since upon re-vaccination with tetanus toxoid of one of the two BAFF-R-deficient individuals the residual fraction of transitional and mature B cells can still develop into plasma cells producing a greater 20-fold increase in serum TT-specific IgG antibodies.

Both BAFF-R-deficient siblings share the same severe cellular and immunological phenotype and both show impaired antibody responses in vitro and in vivo. This contrasts with the late onset of the clinical presentation since severe respiratory infections started first in one sibling at the age of 37 years and the other at the age of 70 years. In this patient, B-cell numbers were higher than in the other sibling suggesting that individual differences in generating precursor B cells in the bone marrow, in the output of transitional B cells or in the selection of B cells may compensate the lack of BAFF-R function. BAFF-independent survival was also demonstrated in studies performed in mice treated with an anti-BAFF-R monoclonal antibody blocking the interactions between BAFF and BAFF-R.[10••] Although most of the follicular and marginal B cells did not survive the treatment, B1 B cells, and a fraction of follicular B cells were spared suggesting that BCR signals of some B cells may render them less dependent on BAFF-R signals. Since survival-regulating factors, like NIK, NF-kB2, PI3K, AKT, MCL1, or FOXO1, located downstream of both receptors, interact in a complex way, individual levels in the expression and activity of these genes may contribute to the variability of the humoral immune responses and the clinical manifestations of BAFF-R-deficient individuals.

In conclusion, BAFF-R and BCR are the most important survival receptors of B cells. Nevertheless, the lack of BAFF-R function can be compensated to some extent by the plasticity of the immune system allowing protective immune responses in spite of human BAFF-R deficiency.


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