Type I interferon activation in RAS-associated autoimmune leukoproliferative disease (RALD)

Natural history of Ras‐associated autoimmune leukoproliferative disorder: A 20‐year follow‐up of a NRAS‐mutated patient excluding a malignant progression

“…9 In RALD, immunological alterations, as well as decreased naïve lymphocytes, the peripheral oligoclonal T-and B-cell expansion 10 and the intrinsic apoptotic defect 9 could contribute to a large spectrum of clinical and immunological manifestations (Figure 1). 1,6,11 JMML is a rare aggressive myelodysplastic/myeloproliferative disorder of early childhood that shares clinical features with RALD. In 90% of JMML, a GoF somatic mutation in NRAS, KRAS or PTPN11 is identified, or diagnosed in the context of RASopathies (germline mutations in RAS/MAPK pathway genes as NF1 and CBL).…”

Isoform‐specific functions of Ras in T‐cell development and differentiation

“…GTPase activating proteins enhance the intrinsic GTPase activity switching active Ras-GTP to inactive Ras-GDP. P-loop (amino acids [10][11][12][13][14][15][16][17], switch-I (amino acids [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40], and switch-II (amino acids 60-74) regions of Ras compose the active site whose orderly conformation upon GTP binding allows interaction with Rasbinding domains on the Ras-effector proteins. The impaired GTP dissociation leads to constitutive Ras activation and causally associates with malignancy [6,7].…”

“…As newer evidence for somatic and germline mutations in Ras genes in different diseases, termed RASopathies, emerge, understanding the complex roles of Ras isoforms in T-cell development and effector function becomes imperative. RASopathies include the autoimmune lymphoproliferative syndrome caused by somatic mutation in N-Ras [26] and Rasassociated autoimmune leukoproliferative disease, causing recurrent infection and generalized lymphadenopathy [27]. As Ras is essential for T-helper subsets differentiation (Table 1) [28,29], Ras hyperactivation results in an abnormal effector T-cell repertoire [22].…”