The novel XIAP Lys396Ter variant alters mitochondrial membrane potential and endoplasmic reticulum intensity in monocytes of two XIAP-deficient patients.

To the editor:
X-linking inhibitor of apoptosis protein (XIAP), also known as baculoviral IAP
repeat-containing protein 4 (BIRC4) is an endogenous regulator of cell death that primarily
inhibits caspases.1 Beyond its well-established role in apoptosis through caspase-3,
-7 and -9 inhibition, XIAP is also involved in NOD1/2-induced nuclear factor-kB
activation, TNF-receptor signaling and NOD-like receptor (NLRP3) inflammasome
activity.2
XIAP deficiency, first described in 2006,3 is a rare X-linked inborn error of immunity
(IEI) affecting approximately 1–2 in a million males.4 Also known as X-linked
lymphoproliferative disease type 2 (XLP2), it presents with severe immune dysregulation,
including hemophagocytic lymphohistiocytosis (HLH), inflammatory bowel disease
(IBD), autoinflammatory phenomena but also hypogammaglobulinemia, susceptibility
to infections, splenomegaly, and cytopenia.5
While standard immunological tests often reveal no major abnormalities beyond
hypogammaglobulinemia, persistently elevated pro-inflammatory cytokines, particularly
IL-18, are detectable even in remission. During HLH episodes, levels of IL-6, IL-2,
IFNγ, TNFα are markedly increased.6
Currently, hematopoietic stem cell transplantation (HSCT) is the only curative
treatment for patients with HLH or severe IBD. However, conservative management
with immunosuppressants and immunoregulatory therapies remains challenging and
often refractory.2,6 Emerging therapeutic strategies, including targeted cytokine inhibition
(eg anti-IL-18 drugs like MAS825) and autologous HSC gene therapy, are under
investigation.7,8