IgA and IgG Hypogammaglobulinemia Are Associated with Mutations in the APRIL/BLYS Receptor TACI in Waldenstrom’s Macroglobulinemia (WM).

IgA and IgG hypogammaglobulinemia are a common finding in patients with WM which may contribute to recurrent infections seen in up to half of WM patients. The etiology for this finding remains unclear. As part of these studies, we investigated the prevalence and genetic basis for IgA and IgG hypogammaglobulinemia among 89 previously untreated patients with the clinicopathological diagnosis of WM. Their median IgM was 2,980 (180–12,400) mg/dl, median BM involvement was 35% (5%–95%) and median B₂M was 2.7 (1.4–13.7 mg/dL). Fifty-six (63%) and 66 (74%) of these patients demonstrated IgG (<700 mg/dL) and IgA (<70 mg/dL) hypogammaglobulinemia, respectively. Importantly, no correlation was seen between serum IgG and IgA levels and BM disease involvement, suggesting no direct impact of disease involvement on the production of uninvolved immunoglobulins. Given these findings, we undertook extensive germline and somatic sequence studies to determine if mutations existed within the APRIL/BLYS receptor TACI, which commonly is mutated in patients with Common Variable Immunodeficiency Disorder (CVID). Six of 29 (21%) sequenced patients displayed variants within TACI, which were present in both tumor cells (n=6) and germline (n=5). Importantly, patients displaying variants in TACI demonstrated significantly lower serum IgG (280 vs. 676 mg/dL; p=0.0009) and IgA (20 vs. 41 mg/dL; p=0.0006) levels versus patients without TACI variants. Lastly, sequence analysis of APRIL, BLYS as well as the TACI downstream TRAF proteins have led to detection of numerous variants which may further account for hypogammaglobulinemia among patients with normal TACI expression. These data suggest that aberrations in TACI signaling may account for IgG and IgA hypogammaglobulinemia in WM, akin to patients with CVID. Moreover, mutations within TACI signaling may have pathological implications for WM since a 300 fold increased incidence of lymphoma has been observed among CVID patients. The impact of TACI mutations on pathogenesis of WM is currently under investigation in our laboratory.