Converging evidence from human genetics, patient-derived immune cells, and animal models indicates that diminished SHP-1 activity promotes persistent autoreactive lymphocyte responses, exaggerated inflammatory signaling, and tissue-specific injury across systemic lupus erythematosus, rheumatoid arthritis, neutrophilic dermatoses, multiple sclerosis, psoriasis, and type 1 diabetes. This evidence concerns the gene PTPN6 and systemic lupus erythematosus.