We constructed a humanized (THX) mouse by grafting non-γ-irradiated, genetically myeloablated immunodeficient mouse neonates with human cord blood CD34+ cells, followed by 17β-estradiol hormonal conditioning. THX mice develop a human lymphoid and myeloid immune system, mount mature antibacterial and antiviral neutralizing antibody responses, and are amenable to develop lupus autoimmunity.