Farewell to a Yin and Yang of BAFF Receptor in Humoral Immunity?
Farewell to a Yin and Yang of BAFF Receptor in Humoral Immunity?
Purpose of Review: The complex system of the tumour necrosis factor ligands BAFF and APRIL and their three receptors BCMA, TACI and BAFF receptor and its role in B-cell development and function is the objective of extensive research. Whereas the importance of BAFF/ BAFF receptor interactions for B-cell survival could be clearly demonstrated, TACI is believed to counteract BAFF activity as a negative regulator in the murine model. The primarily immunodeficient phenotype of human TACI deficiency, however, claims a distinct function of this receptor in human peripheral B-cell development, class switch recombination and terminal differentiation.
Recent Findings: Common variable immunodeficiency comprises a heterogeneous group of antibody deficiency syndromes characterized by impaired terminal B-cell differentiation. By means of molecular genetics common variable immunodeficiency is still ill-defined, but the description of the deficiency of the inducible costimulator in a small subgroup of common variable immunodeficiency patients set the starting point for the molecular dissection of this disease entity. The recent discovery of genetic defects in the tumour necrosis factor receptor superfamily members TACI and BAFF receptor in patients with common variable immunodeficiency denotes further advances in this field.
Summary: In this review we will discuss recent progress made in the understanding of the BAFF/ APRIL-TACI/ BCMA/ BAFF receptor system in relation to the recent discovery that mutations in human TACI cause a primary humoral immunodeficiency. This suggests a refined role for TACI in human B-cell biology.
The diagnosis of common variable immunodeficiency (CVID; OMIM #240500) is based on: (1) an impaired ability to produce specific antibodies after exposure to pathogens; (2) markedly reduced serum levels of IgG, IgA and frequently IgM; and (3) the exclusion of other causes for antibody deficiency. CVID has an estimated prevalence of one in 25 000 in Europeans and is the most prevalent human primary immunodeficiency requiring medical attention. Most cases of CVID are sporadic; however, at least 10% are familial, with a predominance of autosomal dominant over autosomal recessive inheritance. Many families have been identified with CVID and selective IgA deficiency (sIgAD) in closely related individuals. CVID is characterized by recurrent bacterial infections, and is complicated by autoimmune manifestations in up to 20% of patients and lymphoproliferation (splenomegaly) in approximately one third. A comprehensive description of the clinical and immunological phenotype of CVID is given by Goldacker and Warnatz in this issue of the journal (pp. 000-000).
We recently demonstrated that CVID may be a monogenic disorder in some autosomal recessive CVID families caused by homozygous mutations in the inducible co-stimulator of activated T cells (ICOS). However, the screening of large CVID and hyper-IgM patient collectives revealed that mutations in ICOS only account for up to 2% of CVID cases.
Within the past year, however, three new monogenic defects in CVID patients have been described. These are depicted in Table 1 : (1) TACI/ TNFRSF13B; (2) CD19 deficiency and (3) BAFFR/ TNFRSF13C.
In contrast to ICOS deficiency, in which a severe B-cell phenotype is caused by impaired T-cell help, these three new genetic defects causing CVID are genuine B-cell defects. As the original publications on CD19 and BAFFR mutations have not yet been released, we will focus in this review on TACI deficiency.
Purpose of Review: The complex system of the tumour necrosis factor ligands BAFF and APRIL and their three receptors BCMA, TACI and BAFF receptor and its role in B-cell development and function is the objective of extensive research. Whereas the importance of BAFF/ BAFF receptor interactions for B-cell survival could be clearly demonstrated, TACI is believed to counteract BAFF activity as a negative regulator in the murine model. The primarily immunodeficient phenotype of human TACI deficiency, however, claims a distinct function of this receptor in human peripheral B-cell development, class switch recombination and terminal differentiation.
Recent Findings: Common variable immunodeficiency comprises a heterogeneous group of antibody deficiency syndromes characterized by impaired terminal B-cell differentiation. By means of molecular genetics common variable immunodeficiency is still ill-defined, but the description of the deficiency of the inducible costimulator in a small subgroup of common variable immunodeficiency patients set the starting point for the molecular dissection of this disease entity. The recent discovery of genetic defects in the tumour necrosis factor receptor superfamily members TACI and BAFF receptor in patients with common variable immunodeficiency denotes further advances in this field.
Summary: In this review we will discuss recent progress made in the understanding of the BAFF/ APRIL-TACI/ BCMA/ BAFF receptor system in relation to the recent discovery that mutations in human TACI cause a primary humoral immunodeficiency. This suggests a refined role for TACI in human B-cell biology.
The diagnosis of common variable immunodeficiency (CVID; OMIM #240500) is based on: (1) an impaired ability to produce specific antibodies after exposure to pathogens; (2) markedly reduced serum levels of IgG, IgA and frequently IgM; and (3) the exclusion of other causes for antibody deficiency. CVID has an estimated prevalence of one in 25 000 in Europeans and is the most prevalent human primary immunodeficiency requiring medical attention. Most cases of CVID are sporadic; however, at least 10% are familial, with a predominance of autosomal dominant over autosomal recessive inheritance. Many families have been identified with CVID and selective IgA deficiency (sIgAD) in closely related individuals. CVID is characterized by recurrent bacterial infections, and is complicated by autoimmune manifestations in up to 20% of patients and lymphoproliferation (splenomegaly) in approximately one third. A comprehensive description of the clinical and immunological phenotype of CVID is given by Goldacker and Warnatz in this issue of the journal (pp. 000-000).
We recently demonstrated that CVID may be a monogenic disorder in some autosomal recessive CVID families caused by homozygous mutations in the inducible co-stimulator of activated T cells (ICOS). However, the screening of large CVID and hyper-IgM patient collectives revealed that mutations in ICOS only account for up to 2% of CVID cases.
Within the past year, however, three new monogenic defects in CVID patients have been described. These are depicted in Table 1 : (1) TACI/ TNFRSF13B; (2) CD19 deficiency and (3) BAFFR/ TNFRSF13C.
In contrast to ICOS deficiency, in which a severe B-cell phenotype is caused by impaired T-cell help, these three new genetic defects causing CVID are genuine B-cell defects. As the original publications on CD19 and BAFFR mutations have not yet been released, we will focus in this review on TACI deficiency.