Figure 5.
The schematic illustrates the proposed pathogenesis of S A P deficiency-associated lymphoproliferation. S A P (S L A M-associated protein), encoded by S H 2 D 1 A, is deficient in T and N K cells, impairing S L A M receptor-mediated signaling, cytotoxic function, and effective control of Epstein-Barr virus (E B V)-infected B cells. In the presence or absence of E B V infection, defective T slash N K-cell cytotoxicity and dysregulated immune signaling lead to polyclonal B-cell expansion, accompanied by abnormal T slash N K-cell activation and proliferation and reduced anti-E B V immunity (e.g., impaired I F N-mediated inflammatory responses). This stage corresponds to lymphoproliferative disorder (L P D). With acquisition of additional somatic mutations in B cells, clonal selection occurs, resulting in oligoclonal or monoclonal B-cell expansion. Progressive genetic alterations ultimately drive transformation into B-cell lymphoma. Colored circles represent different lymphocyte populations and clonal states, and directional arrows indicate stepwise progression from S A P deficiency to polyclonal expansion and finally malignant clonal evolution.
Proposed mechanisms of lymphoma development in XLP1. EBV infection, in combination with the intrinsic immunoregulatory defects caused by SAP deficiency, induces polyclonal proliferation of both B and T lymphocytes, resulting in a LPD. The acquisition of somatic variants in this context promotes the emergence and expansion of oligoclonal or monoclonal B cell populations, ultimately leading to the development of lymphoma.