{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Members of the GIMAP family (GTPases of immunity‐associated proteins) are preferentially expressed by cells of the hematopoietic system and serve as critical regulators of lymphocyte survival, differentiation, and function. For example, studies on GIMAP1 indicate that it is indispensable for the survival of peripheral B cells and may also contribute to skeletal muscle cell viability affecting appendicular lean mass variation, suggesting broader roles in tissue cell survival (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, work on GIMAP3 demonstrates that it cooperates with other family members – notably GIMAP5 – to support T‐cell homeostasis, as combined deficiencies exacerbate the reduction in T‐cell numbers (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Among the family members, GIMAP5 has been most extensively characterized. It is essential for the full intrathymic maturation and peripheral survival of both CD4⁺ and CD8⁺ T lymphocytes, as well as for natural killer and NKT‐cell development. GIMAP5 functions in a hematopoietic cell–intrinsic manner by facilitating noncanonical antigen–receptor signals and regulating intracellular pathways, including optimal T-cell receptor and interleukin-7 receptor signaling. In several studies, GIMAP5 has been shown to modulate intracellular Ca²⁺ homeostasis by promoting mitochondrial buffering of Ca²⁺, a function that is critical for sustained Ca²⁺ entry and cellular survival (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Altered GIMAP5 expression or function—arising from mutations, frameshifts, or polymorphisms that affect mRNA processing—is associated with impaired lymphocyte survival and dysregulated immune responses. Such alterations correlate with increased susceptibility to autoimmune conditions including type 1 diabetes and systemic lupus erythematosus, likely due to disruptions in regulatory T-cell populations and aberrant cytokine responses (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, GIMAP5 has been implicated in the maintenance of hematopoietic stem cell quiescence and progenitor cell survival through its influence on anti‐apoptotic factors and mitochondrial integrity (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " In addition, its role in modulating key intracellular signaling cascades—such as facilitating the inactivation of GSK3β to promote c-Myc induction and NFAT nuclear import—further underscores its importance in T-cell activation (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, studies have also linked GIMAP5 dysfunction to non–lymphoid abnormalities, including liver pathology characterized by altered hepatic endothelial cell identity and portal hypertension (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, current evidence indicates that GIMAP1, GIMAP3, and particularly GIMAP5 are integral to the survival and function of lymphocytes, with their coordinated activity ensuring proper immune homeostasis. Disruptions in their function contribute to defective immune regulation and autoimmunity, emphasizing their potential as targets for therapeutic intervention.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Louise M C Webb, Preeta Datta, Sarah E Bell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "GIMAP1 Is Essential for the Survival of Naive and Activated B Cells In Vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1501582"}], "href": "https://doi.org/10.4049/jimmunol.1501582"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26621859"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26621859"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Shu Ran, Yong-Jun Liu, Lei Zhang, et al. 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