Multiple Lupus‐Associated ITGAM Variants Alter Mac‐1 Functions on Neutrophils. Issue 11 (28th October 2013)

• Record Type: Journal Article
• Authors: Zhou, Yebin; Wu, Jianming; Kucik, Dennis F.; White, Nathan B.; Redden, David T.; Szalai, Alexander J.; Bullard, Daniel C.; Edberg, Jeffrey C.
• Is Part Of: Arthritis and rheumatism. Volume 65:Issue 11(2013:Nov.)
• Page Start: 2907
• Page End: 2916
• Publication Date: 2013-10-28
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; Arthritis -- Periodicals; Rheumatic Diseases -- Periodicals; Rhumatisme -- Périodiques; Arthrite -- Périodiques; 616.72
• DOI: 10.1002/art.38117
• Languages: English
• ISSNs: 0004-3591

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="art38117-sec-0001" sec-type="section"> <title>Objective</title> <p>Multiple studies have demonstrated that single‐nucleotide polymorphisms (SNPs) in the <italic>ITGAM</italic> locus (including the nonsynonymous SNPs rs1143679, rs1143678, and rs1143683) are associated with systemic lupus erythematosus (SLE). <italic>ITGAM</italic> encodes the protein CD11b, a subunit of the β2 integrin Mac‐1. The purpose of this study was to determine the effects of <italic>ITGAM</italic> genetic variation on the biologic functions of neutrophil Mac‐1.</p> </sec> <sec id="art38117-sec-0002" sec-type="section"> <title>Methods</title> <p>Neutrophils from <italic>ITGAM</italic>‐genotyped and ‐sequenced healthy donors were isolated for functional studies. The phagocytic capacity of neutrophil <italic>ITGAM</italic> variants was probed with complement‐coated erythrocytes, serum‐treated zymosan, heat‐treated zymosan, and IgG‐coated erythrocytes. The adhesion capacity of <italic>ITGAM</italic> variants, in adhering to either purified intercellular adhesion molecule 1 or tumor necrosis factor α–stimulated endothelial cells, was assessed in a flow chamber. Expression levels of total CD11b and activation of CD11b were assessed by flow cytometry.</p> </sec> <sec id="art38117-sec-0003" sec-type="section"> <title>Results</title> <p>Mac‐1–mediated neutrophil phagocytosis, determined in cultures with 2 different complement‐coated particles, was significantly reduced in individuals with nonsynonymous variant alleles of <italic>ITGAM</italic>. This reduction in phagocytosis was related to variation at either rs1143679 (in the β‐propeller region) or rs1143678/rs1143683 (highly linked SNPs in the cytoplasmic/calf‐1 regions). Phagocytosis mediated by Fcγ receptors was also significantly reduced in donors with variant <italic>ITGAM</italic> alleles. Similarly, firm adhesion of neutrophils was significantly reduced in individuals with variant <italic>ITGAM</italic> alleles. These functional alterations were not attributable to differences in total receptor expression or activation.</p> </sec> <sec id="art38117-sec-0004" sec-type="section"> <title>Conclusion</title> <p>The nonsynonymous <italic>ITGAM</italic> variants rs1143679 and rs1143678/rs113683 contribute to altered Mac‐1 function on neutrophils. These results underscore the need to consider multiple nonsynonymous SNPs when assessing the functional consequences of <italic>ITGAM</italic> variation on immune cell processes and the risk of SLE.</p> </sec> </abstract>