Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Heterotrimers of BCL10, MALT1, and CARD adaptors are crucial for NF-κB activation in immunity.
• Defects in MALT1, CARD9, and CARD11 are linked to immune disorders.
• BCL10's role in human immunity, particularly in nonhematopoietic cells, is not fully understood.

Purpose of the Study:

• To characterize the immunological and clinical phenotype of a patient with complete BCL10 deficiency.
• To investigate the cell-type and pathway-specific effects of BCL10 loss-of-function.
• To establish the significance of inherited BCL10 deficiency in combined immunodeficiency.

Main Methods:

• Case study of a child with autosomal-recessive BCL10 deficiency.
• Genetic analysis to identify a homozygous loss-of-function BCL10 mutation.
• Functional assays assessing immune responses in patient's myeloid cells and fibroblasts to pathogen-associated molecular pattern molecules (PAMPs).

Main Results:

• The patient presented with broad immunodeficiency affecting both hematopoietic and nonhematopoietic cells.
• A homozygous BCL10 mutation led to loss of expression and function.
• While myeloid cell responses to PAMPs were normal, NF-κB-mediated fibroblast functions were severely impaired.
• Adaptive immune responses were deficient, similar to murine models, but with distinct human-specific cellular features.

Conclusions:

• Inherited BCL10 deficiency causes a severe combined immunodeficiency with distinct B cell, T cell, and fibroblast defects.
• The impact of BCL10 deficiency is pathway- and cell-type dependent.
• Consideration of BCL10 deficiency is crucial for diagnosing combined immunodeficiency with multi-lineage defects.