Multiple lupus-associated ITGAM variants alter Mac-1 functions on neutrophils

Area of Science:

• Immunology
• Genetics
• Cell Biology

Background:

• Single-nucleotide polymorphisms (SNPs) in the ITGAM locus are linked to systemic lupus erythematosus (SLE).
• ITGAM encodes CD11b, a key component of the β2 integrin Mac-1, crucial for neutrophil function.
• Understanding the functional impact of ITGAM genetic variation is vital for SLE research.

Purpose of the Study:

• To investigate how ITGAM genetic variations affect the biological functions of neutrophil Mac-1.
• To determine the specific effects of nonsynonymous SNPs (rs1143679, rs1143678, rs1143683) on Mac-1-mediated neutrophil activities.

Main Methods:

• Isolated neutrophils from healthy donors with known ITGAM genotypes.
• Assessed neutrophil phagocytic capacity using complement-coated erythrocytes and zymosan particles.
• Evaluated neutrophil adhesion to intercellular adhesion molecule 1 and activated endothelial cells via flow chamber experiments.
• Measured CD11b expression and activation using flow cytometry.

Main Results:

• Nonsynonymous ITGAM variants significantly reduced Mac-1-mediated neutrophil phagocytosis of complement-coated particles.
• Phagocytosis via Fcγ receptors was also diminished in neutrophils with variant ITGAM alleles.
• Neutrophil firm adhesion was significantly reduced in individuals carrying variant ITGAM alleles.
• These functional deficits were independent of total CD11b expression or activation levels.

Conclusions:

• Nonsynonymous ITGAM variants (rs1143679, rs1143678/rs113683) alter Mac-1 function in neutrophils.
• These findings highlight the importance of considering multiple SNPs when evaluating ITGAM's role in immune cell function and SLE pathogenesis.
• Altered Mac-1 function due to ITGAM variation may contribute to the increased risk of systemic lupus erythematosus.