By using a broad approach (ex-vivo human cells and immortalized PMN and macrophage lines expressing the hCD11b variants) and by analysing the main human CR3 expressing cells (monocytes, neutrophils, macrophages and DCs) herein we demonstrate that in these cells the lupus susceptibility allele (77H) impairs only the uptake of hiC3b-coated targets without altering other CR3-mediated functions including TLR7/8-induced cytokine secretion and neutrophil extravasation. Here, CRIPTO3 is linked to systemic lupus erythematosus.