The immunodeficiency is defined by deleterious mutations in TNFRSF13C encoding for B cell-activating factor receptor (Baff-R).
So far only two patients with deleterious mutations in TNFRSF13C have been published encoding for Baff-R (Warnatz et al. 2009). However, several patients have been identified carrying point mutations which may contribute to the manifestation of antibody deficiency, but the evidence is less strict, since these variants are also found in healthy people and the immunological presentation doesn’t reflect the expected phenotype of an absent BAFF-R function.
Deleterious mutations. The index patient had upper airway infections since childhood, the first pneumonia at age 37 and was diagnosed at age 57 after his third pneumonia. His older sister never presented with a remarkable susceptibility to infections until old age. Neither BAFF-R deficient person developed autoimmunity, abnormal lymphoproliferation, nor other signs of immune dysregulation (Warnatz et al. 2009). Additional patients with P21R+/−H159Y genetic variants have a highly variable presentation from asymptomatic to infection – only or complex presentation of CVID, selective IgA deficiency, or IgM deficiency (Lougaris et al. 2016; Pieper et al. 2014; Losi et al. 2005).
BAFF-R belongs to the TNF-receptor family. It is a transmembrane molecule which is expressed on B cell subpopulations. Its single known ligand is BAFF (synonym, Blys). During B cell differentiation, BAFF-R is first expressed on transitional B cells. Its expression is partly depending on B cell receptor signals. After engagement with its ligands, it forms trimers which can bind BAFF triggering PI3K and especially alternative NF-kB signals.
Its signal is essential for sufficient B cells survival especially at the transitional stage which will subsequently allow for further maturation into the naïve B cell stage. Thus, complete BAFF-R deficiency in mice and men is characterized by severely reduced B cell counts, and the analysis of the subpopulations reveals a relative expansion of transitional B cells (Warnatz et al. 2009; Yan et al. 2001). Serum IgG and IgM were reduced in both siblings, while IgA was normal or even elevated reflecting the preserved IgA production in the gastrointestinal mucosa.
The reduction in BAFF binding by the described point mutations is not sufficient to cause the typical phenotype, but it has been shown that the P21R mutation interferes with the multimerization of the complex (Pieper et al. 2014) and might contribute to the immunodeficiency.
Diagnosis is made by genetic analysis of TNFRSF13C. The diagnosis of complete BAFF-R deficiency is suggested by a hypogammaglobulinemia sparing IgA, a severe reduction of B cells with a block at the transitional B cell stage and the lack of BAFF-R surface expression.
No specific therapy is available. Patients who suffer from infection should be placed on immunoglobulin replacement therapy. There is no experience with stem cell transplantation. While this disease should be in general transplantable, the mild phenotype did not require this therapy in the reported patients.