The hallmark of autoimmune lymphoproliferative syndrome (ALPS) is abnormal lymphocyte homeostasis characterized by non-malignant clonal cell expansion causing severe autoimmunity mostly directed toward blood cells . In a small number of patients with ALPS and related disorders, mutations in either NRAS or KRAS have been reported causing an ALPS like disease, designated as Ras associated lymphoproliferative disease (RALD). Inhibition of apoptosis resulting in clonal cell expansion in such patients is mediated by a somatic mutation causing resistance to interleukin-2 (IL-2) depletion-dependent apoptosis. Herein, we report a RALD patient displaying KRAS mutation and try to characterize cell receptor repertoire clonality at diagnosis and during progression of her disease. Our patient presented with multiple infections as well as autoimmunity and lymphadenopathy. When we assessed her immune system using multiple tools she displayed decreased levels of T cell receptor excision circle (TREC) copies which indicates decrease new T cell production and thymic function. In addition she displayed a decreased ratio of Kappa deleting receptor excision circle (KREC) SJ\CJ which suggests both a falling bone marrow as well as loss of peripheral B cell homeostasis. This loss in homeostasis further manifested as peripheral proliferation and clonal expansion. The clonality became more prominent during the years both regarding B and T cells demonstrated both by T-cell receptor spectratyping using FACS, B cell receptor repertoire using PCR and by next generation sequencing (NGS). As seen in our patient there was a correlation between the clinical and immunological status. By exploring and understanding the immunological repertoire in RALD patients, this will enable better understanding of the homeostasis imbalance.
