Dual JAK3/TEC inhibition may induce hair regrowth in alopecia areata
12 Nov 2024
Dual JAK3/TEC inhibition may induce hair regrowth in alopecia areata (AA), an autoimmune disorder characterized by nonscarring hair loss.
AA is a relatively common disease with a global prevalence of 2.11 percent. In Asian AA patients, 85.5 percent had disease onset before the age of 40 years. [J Am Acad Dermatol 2020;82:675-682; Clin Dev Immunol 2013:2013:348546]
As a T cell–mediated autoimmune disorder, AA is characterized by chronic inflammation of hair follicles, resulting in nonscarring hair loss that usually occurs in patches on the scalp and/or around the body. [Am J Clin Dermatol 2023;24:895-912; J Autoimmun 2019:98:74-85] The pathophysiology involves immune cell accumulation and infiltration in and around the lesional hair bulbs, resulting in a “swarm of bees” appearance. The autoimmune activities of these perifollicular infiltrations, consisting of T cells (60–80 percent CD4+ and 20–40 percent CD8+), natural killer (NK) cells, NKG2D+ T cells, dendritic cells and mast cells, during the anagen (growth) phase cause collapse of the hair follicle immune privilege and hair loss. [Clin Dev Immunol 2013:2013:348546; J Autoimmun 2019:98:74-85; Exp Dermatol 2020;29:703-725]
Literature suggests that CD8+NKG2D+ T cells are key cytolytic effectors responsible for the autoimmune attack of the hair follicle. While inciting factors of AA, such as trauma, infection and stress, promote secretion of inflammatory markers, including interferon (IFN)-γ, triggering immune cell activity at the hair follicle, activated CD8+NKG2D+ T cells produce IFN-γ that binds to JAK1/2 receptors on follicular epithelial cell. This induces secretion of interleukin (IL)-15 that binds to JAK1/3 receptors on the CD8+NKG2D+ T cells, thus producing more IFN-γ and creating a proinflammatory positive feedback loop. Activated CD8+ T cells in turn attack follicular epithelial cells, leading to hair loss. [Nat Med 2014;20:1043-1049; Am J Clin Dermatol 2023;24:895-912; Nat Med 2014;20:989-990; Curr Res Immunol 2021:2:7-11]
In addition, AA lesions are characterized by overexpression of major histocompatibility complex (MHC) class I molecules, to which autoantigen-reactive CD8+ T cells bind, compromising the hair follicle immune privilege. In vitro studies have shown that IFN-γ upregulates MHC class I expression in the hair follicles of AA lesions. [Am J Clin Dermatol 2023;24:895-912; Clin Dev Immunol 2013:2013:348546]
Tyrosine kinase expressed in hepatocellular carcinoma (TEC) signalling is also involved in multiple T-cell–mediated inflammatory diseases, including AA. Studies have shown that the TEC family of kinase – a group of nonreceptor tyrosine kinases – are activated downstream of the T cell receptor (TCR), which is necessary for T cell activation in AA patients. [ACS Chem Biol 2019;14:1235-1242; Sci Signal 2016;9:rs7]
Despite the autoimmune perturbations, the inflamed hair follicles are preserved. Thus, reversing AA is possible. [J Autoimmun 2019:98:74-85]
The above findings suggest JAK and TEC signalling pathways as potential therapeutic targets for hair loss caused by AA. Recent studies have demonstrated that dual JAK3/TEC inhibition induces hair regrowth by multiple mechanisms, including inhibiting IL-15 signalling and downstream signalling of TCR involving TEC kinases, downregulating MHC class I expression and cytolytic functions of CD8+ T cells, and reducing production of IFN-γ and infiltration of CD8+ T cells as well as proinflammatory signalling. [ACS Chem Biol 2019;14:1235-1242; JCI Insight 2021;6:e142205; J Allergy Clin Immunol 2022;149:1318-1328]
AA is a relatively common disease with a global prevalence of 2.11 percent. In Asian AA patients, 85.5 percent had disease onset before the age of 40 years. [J Am Acad Dermatol 2020;82:675-682; Clin Dev Immunol 2013:2013:348546]
As a T cell–mediated autoimmune disorder, AA is characterized by chronic inflammation of hair follicles, resulting in nonscarring hair loss that usually occurs in patches on the scalp and/or around the body. [Am J Clin Dermatol 2023;24:895-912; J Autoimmun 2019:98:74-85] The pathophysiology involves immune cell accumulation and infiltration in and around the lesional hair bulbs, resulting in a “swarm of bees” appearance. The autoimmune activities of these perifollicular infiltrations, consisting of T cells (60–80 percent CD4+ and 20–40 percent CD8+), natural killer (NK) cells, NKG2D+ T cells, dendritic cells and mast cells, during the anagen (growth) phase cause collapse of the hair follicle immune privilege and hair loss. [Clin Dev Immunol 2013:2013:348546; J Autoimmun 2019:98:74-85; Exp Dermatol 2020;29:703-725]
Literature suggests that CD8+NKG2D+ T cells are key cytolytic effectors responsible for the autoimmune attack of the hair follicle. While inciting factors of AA, such as trauma, infection and stress, promote secretion of inflammatory markers, including interferon (IFN)-γ, triggering immune cell activity at the hair follicle, activated CD8+NKG2D+ T cells produce IFN-γ that binds to JAK1/2 receptors on follicular epithelial cell. This induces secretion of interleukin (IL)-15 that binds to JAK1/3 receptors on the CD8+NKG2D+ T cells, thus producing more IFN-γ and creating a proinflammatory positive feedback loop. Activated CD8+ T cells in turn attack follicular epithelial cells, leading to hair loss. [Nat Med 2014;20:1043-1049; Am J Clin Dermatol 2023;24:895-912; Nat Med 2014;20:989-990; Curr Res Immunol 2021:2:7-11]
In addition, AA lesions are characterized by overexpression of major histocompatibility complex (MHC) class I molecules, to which autoantigen-reactive CD8+ T cells bind, compromising the hair follicle immune privilege. In vitro studies have shown that IFN-γ upregulates MHC class I expression in the hair follicles of AA lesions. [Am J Clin Dermatol 2023;24:895-912; Clin Dev Immunol 2013:2013:348546]
Tyrosine kinase expressed in hepatocellular carcinoma (TEC) signalling is also involved in multiple T-cell–mediated inflammatory diseases, including AA. Studies have shown that the TEC family of kinase – a group of nonreceptor tyrosine kinases – are activated downstream of the T cell receptor (TCR), which is necessary for T cell activation in AA patients. [ACS Chem Biol 2019;14:1235-1242; Sci Signal 2016;9:rs7]
Despite the autoimmune perturbations, the inflamed hair follicles are preserved. Thus, reversing AA is possible. [J Autoimmun 2019:98:74-85]
The above findings suggest JAK and TEC signalling pathways as potential therapeutic targets for hair loss caused by AA. Recent studies have demonstrated that dual JAK3/TEC inhibition induces hair regrowth by multiple mechanisms, including inhibiting IL-15 signalling and downstream signalling of TCR involving TEC kinases, downregulating MHC class I expression and cytolytic functions of CD8+ T cells, and reducing production of IFN-γ and infiltration of CD8+ T cells as well as proinflammatory signalling. [ACS Chem Biol 2019;14:1235-1242; JCI Insight 2021;6:e142205; J Allergy Clin Immunol 2022;149:1318-1328]