Lymphoproliferation in Inborn Errors of Immunity: Mechanisms, Manifestations and Clinical Management, with a Focus on...

Lymphoproliferation represents a common and clinically relevant feature across many Inborn Errors of Immunity (IEIs), reflecting the underlying immune dysregulation that characterizes these disorders. In affected individuals, lymphoproliferation may manifest along a broad clinical spectrum, ranging from benign forms such as lymphadenopathy, splenomegaly, and hepatomegaly to malignant transformation, including lymphoma and leukemia. Multiple and heterogeneous pathogenetic mechanisms contribute to lymphoproliferation in IEIs; however, they can be conceptually grouped into two major categories: excessive lymphocyte activation and proliferation, and defective control of proliferation. The association of lymphoproliferation with autoimmune cytopenia classically defined the Autoimmune Lymphoproliferative Syndrome (ALPS), caused by an impairment in FAS-mediated apoptosis. However, a growing number of IEIs present with overlapping autoimmune lymphoproliferative phenotypes driven by diverse monogenic defects or, in many cases, without an identifiable genetic cause. This expanding spectrum has led to the concept of autoimmune lymphoproliferative immunodeficiencies (ALPID), encompassing a continuum of disorders characterized by lymphoproliferation, autoimmunity and diverse genetic backgrounds, requiring disease-specific therapeutic approaches. This narrative review provides an overview of the main IEIs associated with lymphoproliferation focusing on pathogenic pathways, diagnostic evaluation and classification, and current and emerging targeted therapeutic approaches.