The SAP-SLAM receptor system plays a critical role in immune regulation, with SAP deficiency leading to apoptosis resistance in T cells and disrupting immune homeostasis, as seen in XLP-1. This disorder, characterized by uncontrolled lymphoproliferation, often presents with a variable clinical spectrum. We report a case of XLP-1 with dysgammaglobulinemia in a patient initially diagnosed with pediatric-onset CVID. Through quantitative and functional analysis of the SH2D1A c.164G > A (p.Arg55Gln) variant, we confirmed its pathogenicity. Our findings demonstrate that this variant significantly impairs B cell differentiation and proliferation independently of T cell interactions. These results support the pathogenic nature of SH2D1A R55Q and advocate for its reclassification as a pathogenic mutation.

Chronic lymphocytic leukemia (CLL) patients are immunocompromised and highly vulnerable to serious recurrent infections. Conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs) are principal sensors of pathogen challenge and are essential in orchestrating innate and adaptive immune responses to resolve infection. This study identified significant deficiencies in six functionally distinct DC subsets in blood of untreated CLL (UT-CLL) patients and selective normalization of pDCs in response to acalabrutinib (a Bruton tyrosine kinase inhibitor) therapy. DCs are continuously replenished from hematopoiesis in bone marrow (BM). Four BM developmental intermediates that give rise to cDCs and pDCs were examined and significant reductions identified in UT-CLL patients supporting a precursor/progeny relationship. The deficiencies in blood DCs and BM DC progenitors were significantly associated with alterations in the Flt3/FL signaling pathway critical to DC development and function. The CLL International Prognostic Index (CLL-IPI), a highly accurate model to predict progression-free survival and time-to-first treatment (TTFT), revealed that cDC1 and pDC were reduced in High/Very High CLL-IPI compared to Low CLL-IPI patients. Notably, UT-CLL patients with shared DC subset deficiencies had shorter TTFT, uncovering a profound alteration in innate immunity with the potential to instruct therapeutic decision-making.

X lymphoproliferative syndrome type 1 (XLP1) is a rare inborn error of immunity due to mutations of SH2D1A, encoding for slam-associated protein (SAP). The clinical phenotype includes severe mononucleosis, hemophagocytic lymphohistiocytosis (HLH), and B-cell lymphomas. We report the case of a child affected with XLP1 who presented with an incomplete HLH, triggered by Epstein-Barr virus (EBV) and treated with rituximab, involving orbits and paranasal sinuses. The lesion was indistinguishable from lymphoma, complicating diagnosis and treatment. In addition, considering the high incidence of lymphoma in patients with XLP1, histology helped define its nature, driving therapeutic choices. We described an unusual presentation of incomplete HLH in a patient affected with XLP1: an EBV-driven infiltration of the orbits and paranasal sinuses. This led us to a challenging differential diagnosis of lymphoma-associated hemophagocytic syndrome, which can be frequently observed in patients with XLP1. Considering the extremely poor prognosis of this clinical finding, we sought for a prompt diagnosis and managed to obtain it and to immediately establish the right treatment on the basis of the pathological finding.

X-linked lymphoproliferative disease (XLP) is either caused by loss of the SLAM-associated protein (SAP; XLP-1) or the X-linked inhibitor of apoptosis (XIAP; XLP-2). In both instances, infection with the oncogenic human Epstein Barr virus (EBV) leads to pathology, but EBV-associated lymphomas only emerge in XLP-1 patients. Therefore, we investigated the role of XIAP during B cell transformation by EBV. Using humanized mice, IAP inhibition in EBV-infected mice led to a loss of B cells and a tendency to lower viral titers and lymphomagenesis. Loss of memory B cells was also observed in four newly described patients with XIAP deficiency. EBV was able to transform their B cells into lymphoblastoid cell lines (LCLs) with similar growth characteristics to patient mothers' LCLs in vitro and in vivo. Gene expression analysis revealed modest elevated lytic EBV gene transcription as well as the expression of the tumor suppressor cell adhesion molecule 1 (CADM1). CADM1 expression on EBV-infected B cells might therefore inhibit EBV-associated lymphomagenesis in patients and result in the absence of EBV-associated malignancies in XLP-2 patients.