SLP76 Mutation Associated with Combined Immunodeficiency and EBV-Related Lymphoma

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Primary immunodeficiency (PID) increases susceptibility to severe Epstein-Barr virus (EBV) infections, particularly in early childhood.
• EBV infection and proliferation in a young child, alongside recurrent infections and failure to thrive, suggested an underlying immune defect.

Purpose of the Study:

• To investigate the immunologic and genetic basis of severe EBV infection in a child with suspected T cell immunodeficiency.
• To identify and characterize a novel mutation in the SLP76 gene and its effect on T cell receptor (TCR) signaling.

Main Methods:

• Clinical presentation and immunological evaluation of a 3-year-old patient with severe EBV infection and T cell immunodeficiency.
• Whole-exome sequencing to identify genetic mutations, focusing on the SLP76 gene.
• Functional assays using a SLP76-deficient T cell line, transduced with wild-type or mutant SLP76, to assess TCR signaling pathways (ERK1/2 phosphorylation, CD69 expression, Ca2+ mobilization).

Main Results:

• A novel homozygous mutation (c.991del.C; p. Q331Sfs*6) in the SLP76 gene was identified in the patient.
• The identified SLP76 mutation impaired downstream TCR signaling events, including reduced ERK1/2 phosphorylation, CD69 expression, and Ca2+ mobilization in a T cell line.
• The patient succumbed to EBV-related diffuse large B cell lymphoma, underscoring the severity of the immunodeficiency.

Conclusions:

• The novel SLP76 mutation is linked to a significant human immunodeficiency, characterized by severe EBV susceptibility and T cell dysfunction.
• SLP76 deficiency should be recognized as a monogenetic cause of primary immunodeficiency predisposing to severe EBV infections and complications.
• This study expands the clinical phenotype associated with SLP76 gene mutations and highlights its critical role in T cell signaling and immune defense.