Membrane-bound programmed cell death-1 (mPD-1) and membrane-bound programmed cell death-ligands (mPD-Ls) have soluble forms, which are soluble programmed cell death-1 (sPD-1) and soluble programmed cell death-ligands (sPD-Ls) [including soluble programmed cell death-ligand 1 (sPD-L1) and soluble programmed cell death-ligand 2 (sPD-L2)]. sPD-1 and sPD-L2 are mainly produced by alternative splicing isoforms of PD-1 mRNA, while sPD-L1 is produced by matrix metalloproteinases (MMPs) cutting membrane-bound programmed cell death-ligand 1 (mPD-L1). sPD-1 and sPD-Ls play an important role in autoimmune regulation via blocking the mPD-1 /mPD-L1 pathway, while connective tissue disease (CTD) is a kind of disease caused by autoimmune reaction, and abnormal function of mPD-1/mPD-L1 can occur in the occurrence and development of many autoimmune diseases. Therefore, sPD-1 and sPD-Ls play an important role in the pathogenesis of CTD caused by autoimmune reaction via blocking the mPD-1 /mPD-L1 pathway. It is of great practical significance to understand clinical value of sPD-1 and sPD-Ls in various CTDs for improving the quality of life of patients and the underlying mechanism.