Scaling the tips of the ALPS

Abstract

This special issue contains four review articles that describe advances in analysis of mutations responsible for the autoimmune lymphoproliferative syndrome (ALPS). This disease is triggered by a family of mutations in genes involved in the extrinsic apoptotic pathway such as FAS, FASL and CASP10 . Advances in sequencing technology have enabled extended genetic testing of patients with various defects in alternative biological have pathways that can cause ALPS-like syndromes. Various gene mutations were identified which affect the CTLA-4 immune checkpoint, the STAT3 pathway and the RAS/MAPK pathway. Tips gleaned from analyses of the different gene mutations involved in ALPS and ALPS-like syndromes are contributing to a better understanding of their functional consequences. Genetic diagnoses of the disease should help us to identify specific therapeutic targets and design personalized treatment for each patient.

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

“…Somatic mutations in KRAS/NRAS genes account for ALPS-like conditions classified in International Union of Immunological Societies as phenocopies of IEIs. 7,8 Our observation highlights the importance to explore somatic gene variants in patients with a specific clinical immunological picture. The assessment of apoptosis may be useful to properly convey the diagnostics.…”

Paediatric‐onset Evans syndrome: Breaking away from refractory immune thrombocytopenia

“…A genetic cause of early‐onset AIC was first described in the context of ALPS with mono‐allelic FAS mutations (ALPS‐FAS) in the middle of the 1990s 20 . One important consideration is that, despite the presence of a monogenic cause, autoimmune diseases are not necessarily expressed as a Mendelian trait, and several family members, carriers of the same causal gene mutation as the patient's, may remain healthy all lifelong.…”

“…A genetic cause of early-onset AIC was first described in the context of ALPS with mono-allelic FAS mutations (ALPS-FAS) in the middle of the 1990s. 20 One important consideration is that, despite the presence of a monogenic cause, autoimmune diseases are not necessarily expressed as a Mendelian trait, and several family members, carriers of the same causal gene mutation as the patient's, may remain healthy all lifelong. In the context of ALPS-FAS, some FAS mutations exhibit a clinical non-penetrance, and an additional somatic event affecting the second FAS allele has been found to be responsible for the disease onset.…”

We refuse to die – T cells causing havoc

“…Rieux-Laucat, Kanellopoulos and Ojcius offer a comprehensive introduction to the four articles about mutations related to the autoimmune lymphoproliferative syndrome (ALPS) and ALPS-like syndromes. All articles underline the impact somatic mutations exert as causing or contributing factors to autoimmunity disorders, finally guiding our understanding for a need of specific and personalized treatment approaches [ 14 ].…”