**4.2 Protein tyrosine phosphatase-22 (PTPN22)**

Protein tyrosine phosphatase, non-receptor type 22 (lymphoid) is also known as PTPN22. This in humans is encoded by the *PTPN22 gene* [36]*.* This gene has various variants. The mutations of this gene are associated with increase or decrease in the risk of autoimmune diseases. In many autoimmune diseases, this gene has been found strongly associated after HLA [37]. *rs2476601 (C1858T) is* the best known association of *PTPN22* variants to autoimmune condition including GD. This SNP (R620W) located in the P1 proline - rich motif of *PTPN22* binds with strong affinity to the SH3 domain of tyrosine kinase, Csk. This mutation disrupts the interaction between *PTPN22* and *Csk* [38] and also increases phosphatase activity which inturn suppresses the TCR signaling more efficiently than the wild type [39]. A role of *PTPN22* in T-cell regulation has been found by the results of knocking out the murine homolog of *PTPN22,* which lowered thresholds for T-cell-receptor signaling and inhibited production of IL-2 in these animals [40]. This *PTPN22 620 W* substitution, a gain of function mutation resulting in the reduction of phosphorylation of key signaling molecules and associated downregulation of TCR signaling which inturn leads to the inhibition of expansion of T cells, weakening of the positive selection in the thymus, and decreasing the antibodies' titer by reducing the activity of helper T lymphocytes [41]. Association between the GD and *PTPN22 620 W* polymorphism has been demonstrated in several studies among Caucasians

**Figure 4.** *Classical HLA class I and II pathways.*

with odds ratio as OR 1.5-1.9 [42], which makes *PTPN22 620 W* polymorph one of the strongest known genetic factors influencing to autoimmune diseases. In polish population a gene dose-dependent effect of *PTPN22* 'T' allele on the age of onset of GD has been found [42] but that was not replicated in a cohort study done in UK [43]. The other available results have shown that the *PTPN22* locus contains other functionally important variants, particularly those conferring protection.
