The putative role of C1858T polymorphism of protein tyrosine phosphatase PTPN22 gene in human autoimmunity

Autoimmune diseases represent a heterogeneous group of conditions whose incidence is increasing worldwide. This has stimulated studies on their etiopathogenesis, derived from a complex interaction between genetic and environmental factors, in order to improve prevention and treatment of these diseases. An increasing amount of epidemiologic investigations has associated the presence of the C1858T polymorphism in the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene to the onset of several autoimmune diseases including insulin-dependent diabetes mellitus (Type 1 diabetes). PTPN22 encodes for the lymphoid tyrosine phosphatase Lyp. This belongs to non-receptor-type protein tyrosine phosphatases involved in lymphocyte activation and differentiation. In humans, Lyp may have a role in the negative regulation of T cell receptor signaling. The single nucleotide polymorphism C1858T encodes for a more active phosphatase Lyp R620W. This has the ability to induce a higher negative regulation of T cell receptor signaling. Thus, C1858T could play an important role at the level of thymocyte polarization and escape of autoreactive T lymphocytes, through the positive selection of otherwise negatively selected autoimmune T cells. In this review we discuss the physiological role exerted by the PTPN22 gene and its encoded Lyp product in lymphocyte processes. We highlight the pathogenic significance of the C1858T PTPN22 polymorphism in human autoimmunity with special reference to Type 1 diabetes. Recently the genetic variation in PTPN22 was shown to induce altered function of T and B-lymphocytes. In particular BCR signaling defects and alterations in the B cell compartment were reported in T1D patients. We finally speculate on the possible development of novel therapeutic treatments in human autoimmunity aiming to selectively target the variant Lyp protein in autoreactive T and B lymphocytes.