Lymphocyte signal transduction defects in cutaneous sarcoidosis and implications for treatment

Sarcoidosis is a multiorgan immunological disease characterized by an exaggerated inflammatory response leading to non-caseating granuloma formation. Cutaneous sarcoidosis lesions serve as an accessible site for biopsy that can assist with earlier identification and treatment of sarcoid disease. This review synthesizes recent advances in the understanding of cutaneous sarcoidosis immunopathogenesis, with a focus on lymphocyte signaling, and describes the therapeutic implications of this immune dysregulation. While it is known that Th1 and Th17 cell subsets contribute to general non-caseating granuloma formation, recent studies identify Th17.1 cells as the predominant producers of IFN-γ, challenging classical paradigms. Th2 polarization and elevated thymus and activation-regulated chemokine (TARC) levels, along with regulatory T cell dysfunction and PD-1 overexpression, contribute to chronic inflammation and fibrosis in the cutaneous sarcoidosis disease state. The JAK/STAT pathway is notably upregulated in cutaneous sarcoid granulomas, and JAK inhibitors have demonstrated promising efficacy as an avenue for treatment. Additional immune mechanisms at play in cutaneous sarcoidosis include mTOR and TLR dysregulation as well as B-cell dysfunction. Infectious triggers and DNA polymorphisms associated with genetic susceptibility further support the multifactorial nature of cutaneous sarcoidosis. Based on current literature and clinical guidelines, we propose treatment options for cutaneous sarcoidosis which target dysregulated aspects of the immune response. While prednisone and corticotropin gel remain the only FDA-approved therapies for cutaneous sarcoidosis, improved understanding of sarcoidosis signaling may lead to promising new therapeutic approaches. With the growing understanding of lymphocyte signaling defects in cutaneous sarcoidosis, physicians will be better equipped to identify and treat the underlying mechanisms of this disease.