An important step in the BIRC4 forest

In this issue of Blood, Dissanayake and colleagues present their discovery of a novel mutation in the X-linked inhibitor of apoptosis protein (XIAP) gene, also known as BIRC4 (baculovirus inhibitor of apoptosis repeat-containing protein 4) in a 6-year-old boy with recurrent hemophagocytic lymphohistiocytosis (HLH) symptoms due to the rare disorder X-linked lymphoproliferative syndrome type 2 (XLP-2). The patient had a complete response to prolonged interleukin 1β (IL-1β) inhibition.¹ The authors also demonstrate that XIAP deficiency causes IL-1β overproduction in autophagy-stimulating conditions, such as nutrient starvation.

The study is an excellent example of bedside to bench to bedside science. When the child presented with recurrent hyperinflammation, the authors searched for mutation in HLH-predisposing genes. The evaluation unexpectedly revealed an intragenic tandem duplication in the BIRC4 (XIAP) gene, which was not detected in the standard sequencing procedure. Diagnosing such changes requires deletion/duplication analysis or whole genome sequencing. This mutation, although difficult to detect, causes an absence of functional XIAP protein. Based on the clinical course, the natural direction of exploration was to search for dysregulated IL-1β production. Surprisingly, IL-1β production by the patient’s monocytes was not increased upon stimulation with lipopolysaccharide alone or with adenosine triphosphate costimulation, when compared with his healthy father. This phenomenon was also observed in a specially created monocyte/macrophage cell line with CRISPR-introduced XIAP deletion. The expected increase was observed under serum-starvation conditions and was limited to IL-1β, but it did not affect other pro-inflammatory cytokines like tumor necrosis factor-α. The authors confirmed that the increased production of IL-1β was mediated by NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome. Finally, XIAP’s role in promoting autophagy was shown, but without a clear survival advantage of the XIAP-deficient cells.

Many people find it useful to have a mnemonic to learn and remember concepts. The alternative name for the gene involved in this disorder, BIRC4, is similar to the name of the birch tree (Betula L). There are features of the birch tree that make it an apt mnemonic.

Birch bark is a fire starter. Even when wet, the peeling bark easily catches sparks and helps to ignite fire. BIRC4 (XIAP)-deficient patients may easily “catch fire,” causing hyperinflammation, with HLH being its most severe manifestation. Like fire, inflammation is useful when controlled (eg, fighting infection). Unfortunately, in BIRC4 (XIAP) deficiency, although pathologically high inflammation occurs, it does not help fight the infections as both the adaptive immune response and the innate immune response are compromised.² Persistent infection can be one of the mechanisms by which BIRC4 (XIAP) deficiency may cause HLH. Hyperinflammation in BIRC4 (XIAP) deficiency can sometimes be moderate but is usually recurrent,² as seen in the reported case, prompting prolonged IL-1β blockade. This treatment does have the risk of blocking activation of the immune system when it should be engaged in defending against pathogens. The only fully curative treatment method is allogeneic stem cell transplantation. Unfortunately, due to the high risk of life-threatening graft-versus-host disease, its results are far from ideal.³ It remains an open question how long we can prolong the IL-1β blockade. Another emerging potential future treatment option is gene therapy.⁴ Based on the findings presented, an interesting direction for future exploration is the use of autophagy-modulating small molecules, first in the laboratory and, if successful, in the clinic.⁵ 

In summary, Dissanayake et al have described a novel mutation caused by an intragenic tandem duplication in the XIAP (BIRC4) gene in a young boy with the rare disorder XLP-2, which caused repeated episodes of hyperinflammation. Their study is a superb example of how investigating the etiology of a patient’s illness can lead to a better understanding of the mechanisms involved and potential approaches for treatment.

Conflict-of-interest disclosure: R.M. declares no competing financial interests.