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Abnormal IL‐7 signaling may lead to the loss of bone mineral density in common variable immunodeficiency

Editor, The report on osteoporosis in patients with common variable immunodeficiency disorder (CVID) by Safa Baris and colleagues is an interesting finding (1), with decreased bone mineral density (BMD) being associated with lower IgG levels and B-cell counts, older age but more importantly, reduced lung function and bronchiectasis. There is a previous report from another center in Turkey where 6 of 23 patients with CVID (26%) had abnormal BMD and three patients had osteoporosis (2). While the common findings in most patients with low BMD would be severe underlying disease and chronic inflammation or confounding factors such as inhaled or oral corticosteroid use that leads to abnormal BMD, the role of interleukin-7 (IL-7) as a powerful osteoclastogenic cytokine in CVID should not be ignored. IL-7 is known to induce bone loss in vivo (3), supposedly via B220+ cells (early B-cell precursors) that have the capacity to differentiate into osteoclasts. IL-7 increases B-cell production that induces bone loss in mice with intact ovarian function (4), as well as in estrogen-deficient state (5), but more importantly IL-7 upregulates RANKL and TNF-a from splenic T cells that leads to osteoclastic bone loss that was not seen in nude mice (i.e., mice lacking T cells), despite increase in B220+ cells (6). Holm et al. (7) described abnormal IL-7 function in CVID, and those patients who had higher plasma IL-7 levels (>10 pg/ml) had a higher incidence of splenomegaly, bronchiectasis, and autoimmunity (55– 73%), similar features that were associated with low BMD as described by Baris et al. (1). The study by Holm et al. also showed that in CVID high IL-7 producers had increased CD8+ T cells with decreased apoptosis and increased CCR7-negative effector memory T cells (terminally differentiated memory cells). The impaired negative feedback on IL-7 production could therefore account for features of combined immunodeficiency (abnormal Tand B-cell function) in these patients. Several studies have also shown reduced frequency of CD4+CD25+FOXP3+ (regulatory T cells, Tregs) in CVID (8), and newer CD28 superagonistic antibody trials have shown to not only increase Tregs population but also prevent TNF-a-induced bone loss in arthritis models (9). Newer treatment strategies for CVID are needed that have the potential of preventing several complications seen in this heterogeneous disorder.