The present invention is directed to isolated recombinant human ADA2 proteins, ADA2 biologically active fragments, and ADA2 fusion proteins. The proteins of the invention can be surprisingly used to restore ADA2 activity in subjects having loss-of-function mutations in ADA2 and increase differentiation of monocytes into macrophages, e.g., M2 macrophages, e.g., M2c macrophages, stimulate CD4+ T cell proliferation, and increase endothelial cell development. More specifically, the ADA2 proteins, ADA2 biologically active fragments, and ADA2 fusion proteins of the invention can be used to treat subjects having ADA2-associated diseases or disorders, including but not limited to, polyarteritis nodosa, Sneddon Syndrome, vasculitis, ischemic stroke, hemorrhagic stroke, lacunar stroke, aneurysm in the celiac artery, skin rash, skin necrosis, livedo racemosa, hepatosplenomegaly, organ failure, retinal artery occlusion, optic nerve atrophy, diplopia, cranial nerve palsy, strabismus, and low serum IgM.