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LPD Associated with Epstein–Barr Virus Infection
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Primary immunodeficiencies are a group of heterogeneous disorders with immune system abnormalities that confer susceptibility to recurrent infections, autoimmunity, lymphoproliferation, granulomatous process, atopy, and malignancy [2]. Out of approximately 250 primary immunodeficiencies recognized so far, a small subgroup is associated with mutations in the genes that encode proteins involved in B cell development and/or function. These primary immunodeficiencies compromise the function of cytotoxic lymphocytes through alterations in TCR signaling (RasGRP1, ZAP70, PI3 K, ITK), actin cytoskeleton arrangements (CORO1A, WASP), co-stimulation (LRBA, MAGT1), leukocyte development (GATA2, MCM4), lymphocyte cell death (XIAP, STK4, CTPS1), and cytotoxic effector (CD16, NKG2D, SLAM receptors like 2B4, CD27), allowing effective EBV control of B cells and subsequent development of a spectrum of clinical manifestations (including the development of lymphomas), that are collectively referred to as EBV-driven LPD or LPD associated with EBV infection (Figure 75.1) [3].
Emerging targets for the treatment of lupus erythematosus: There is no royal road to treating lupus
Published in Modern Rheumatology, 2019
Signaling abnormalities in T cells from patients with SLE are represented by altered T-cell receptor signaling largely due to decreased protein levels of the CD3ζ chain and the resultant hyperactivated calcineurin pathway and downregulated MAPK pathway that result in unbalanced transcription factors and skewed cytokine production (reviewed elsewhere [60,61]) (Figure 3). Transcription, translation, and degradation of the CD3ζ chain are controlled by multiple mechanisms, such as splicing factor SRSF1 [62] and the mammalian target of rapamycin (mTOR) pathway. Global DNA hypomethylation is another well-known feature of lupus T cells and is due in part to reduced levels of DNA methyltransferase 1 (DNMT1). DNMT1 is regulated by the MAPK-Erk signaling pathway, but also by microRNAs. In T cells from patients with SLE, overexpression of miR-21 and miR-148a suppress DNMT1 expression, and the former miR also targets RasGRP1, which is upstream of Ras [63]. We previously found that increased alternative splicing of RasGRP1 results in decreased protein levels in T cells from patients with SLE [64]. Splicing of RasGRP1 is also controlled, at least in part, by SRSF1, which has been confirmed to be decreased in Japanese patients with SLE (unpublished observation).
Primary Immunodeficiency and Thrombocytopenia
Published in International Reviews of Immunology, 2022
Maryam Mohtashami, Azadehsadat Razavi, Hassan Abolhassani, Asghar Aghamohammadi, Reza Yazdani
UNC13D gene is the main gene underlying the FHL type 3 disorder. Lysis and degranulation of NK cells are impaired in patients with FHL3 deficiency [256]. RAS guanyl-releasing protein 1 (RASGRP1) is involved in the cell signaling pathway of T- cells via its guanine nucleotide exchange factor role. Also, some disorders have been observed in immune cells by RASGRP1 deficiency such as defective proliferation, activation and motility of T- cells and B- cells or impaired cytotoxicity with defective granule convergence and actin accumulation in NK cells [257].
Clinical Profile and Outcomes of Primary Immunodeficiency and Malignancy in Childhood at a Tertiary Oncology Center in Developing Country
Published in Pediatric Hematology and Oncology, 2022
Derya Özyörük, Zeliha Güzelküçük, Ayse Metin, Suna Emir, Arzu Yazal Erdem, Dilek Kacar, Ayca Koca Yozgat, Can Baris Aker, Selma Çakmakçı, Sonay Incesoy Özdemir, Neriman Sari, Meriç Kaymak Cihan, Namık Yasar Özbek, İnci Ergürhan İlhan
RASGRP1 deficiency is a primary immunodeficiency that has been recently described and characterized by CD4+ T cell lymphopenia and Epstein-Barr virus (EBV)-associated B cell lymphoma. The recurrent infections, hepatosplenomegaly, lymphadenopathy, autoimmune features, EBV-associated lymphoproliferation and B cell lymphoma are prominent findings of RASGRP1 deficiency.20 In the present study, 2 patients with RASGRP1 deficiency had presented with EBV-associated lymphoproliferation and B cell lymphoma.