title: A systemic lupus erythematosus-associated R77H substitution in the CD11b chain of the Mac-1 integrin compromises leukocyte adhesion and phagocytosis.
abstract: The Mac-1 integrin is expressed mainly on myeloid cells and binds several ligands, including members of the ICAM family and the complement factor iC3b. It is involved in essential immunological processes, such as leukocyte extravasation and phagocytosis. In addition, Mac-1 has been described to negatively regulate immune cell signaling. Recently, a single nucleotide polymorphism conferring an amino acid change in the Mac-1 integrin extracellular domain, R77H, was shown to be associated with systemic lupus erythematosus. Here, we demonstrate that the R77H-substituted Mac-1 can be expressed on the cell surface in transfected cells and can undergo conformational changes in response to integrin activation. The affinity of the integrin for ICAMs is only partially reduced, but cell adhesion to ICAM-1 and ICAM-2 is severely compromised, and Jβ2.7 cells expressing R77H substituted integrins are deficient in adhesion to ICAM-1 under shear flow conditions. Importantly, cell adhesion to the complement factor iC3b is also diminished, and COS cells expressing R77H-substituted integrins display reduced iC3b-dependent phagocytosis. In addition, U937 cells expressing R77H-CD11b display increased IL-6 production as compared with WT-CD11b-expressing cells. These results suggest that the R77H substitution results in the deficiency of the mutated integrin to mediate cell adhesion to ligands such as ICAMs and iC3b. These deficiencies may ultimately lead to detrimental effects on the immune system and contribute to the development of systemic lupus erythematosus.
authors: Division of Medical Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom. m.r.macpherson@dundee.ac.uk
authors: Matthew
authors: M
authors: MacPherson
authors: Hwee San
authors: HS
authors: Lek
authors: Alan
authors: A
authors: Prescott
authors: Susanna C
authors: SC
authors: Fagerholm
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000235:genetics* / Q000378:metabolism*; D019556:COS Cells; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003179:Complement C3b / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology*; D008024:Ligands; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000235:genetics* / Q000378:metabolism*; D010587:Phagocytosis; D017434:Protein Structure, Tertiary
chemical_list: D039481:CD11b Antigen; D015850:Interleukin-6; D008024:Ligands; D016177:Macrophage-1 Antigen; D018799:Intercellular Adhesion Molecule-1; D003179:Complement C3b