Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare immunological disorder caused by defective apoptosis, commonly due to pathogenic variants in the FAS gene. We report a comprehensive clinical, immunophenotypic, molecular, and functional evaluation of nine members of a consanguineous Brazilian family harboring the pathogenic FAS (NM_000043.6:c.748C > T) variant. The index case, an 11-year-old boy, presented with recurrent cytopenias, splenomegaly, and increased double-negative T cells. Genetic analysis identified additional variants in CASP10 (NM_032977.4:c.1202_1208del), and LRBA (NM_001364905.1:c.2450-7C > T), evidencing a complex genotype. Functional assays confirmed different levels of impaired FAS-mediated apoptosis in some affected individuals. Among nine family members studied, four out them met clinical and molecular criteria for ALPS, demonstrating incomplete penetrance and variable phenotype. All affected individuals share the same variants in FAS and CASP10, yet their clinical presentations differ significantly. Clinical manifestations and elevated double-negative T cells were observed exclusively in male individuals. Notably, a female family member harboring both FAS and CASP10 variants remained asymptomatic, supporting previous findings of incomplete penetrance and suggesting that sex-related factors-possibly including hormonal influences-may modulate clinical expression in ALPS. Introduction of sirolimus therapy led to sustained remission in the index case. This study report a successful integration of multimodal diagnostic strategy for accurate identification and management of ALPS, and it highlights the potential role of targeted therapies in improving outcomes.
© 2025 Guido, Camargo, Silva, Dias, de Pontes, Santos Júnior, Toscano, Tavares, Antunes and de Melo.

While CD95 is an apoptosis-inducing receptor and has emerged as a potential anticancer therapy target, mounting evidence shows that CD95 is also emerging as a tumor promoter by activating nonapoptotic signaling pathways. Gammaherpesviral infection is closely associated with lymphoproliferative diseases, including B cell lymphomas. The nonapoptotic function of CD95 in gammaherpesvirus-associated lymphomas is largely unknown. Here, we show that stimulation of CD95 agonist antibody drives the majority of sensitive gammaherpesvirus-transformed B cells to undergo caspase-dependent apoptosis and promotes the survival and proliferation of a subpopulation of apoptosis-resistant B cells. Surprisingly, CD95-mediated nonapoptotic signaling induced beta interferon (IFN-β) expression and correlatively inhibited B cell receptor (BCR)-mediated gammaherpesviral replication in the apoptosis-resistant lymphoma cells without influencing BCR signaling. Further analysis showed that IFN-β alone or synergizing with CD95 blocked the activation of lytic switch proteins and the gene expression of gammaherpesviruses. Our findings indicate that, independent of its apoptotic activity, CD95 signaling activity plays an important role in blocking viral replication in apoptosis-resistant, gammaherpesvirus-associated B lymphoma cells, suggesting a novel mechanism that indicates how host CD95 prototype death receptor controls the life cycle of gammaherpesviruses independent of its apoptotic activity.
Gammaherpesviruses are closely associated with lymphoid malignancies and other cancers. Viral replication and persistence strategies leading to cancer involve the activation of antiapoptotic and proliferation programs, as well as evasion of the host immune response. Here, we provide evidence that the stimulation of CD95 agonist antibody, mimicking one of the major mechanisms of cytotoxic T cell killing, inhibits B cell receptor-mediated gammaherpesviral replication in CD95 apoptosis-resistant lymphoma cells. CD95-induced type I interferon (IFN-β) contributes to the inhibition of gammaherpesviral replication. This finding sheds new light on the CD95 nonapoptotic function and provides a novel mechanism for gammaherpesviruses that helps them to escape host immune surveillance.
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