Gharagozlou Saber, Wright NicolaA M, Murguia-Favela Luis, Eshleman Juliette, Midgley Julian, Saygili Seha, Mathew Georgie, Lesmana Harry, Makkoukdji Nadia, Gans Melissa, Saba Julie D
Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
Department of Pediatrics, Cummings School of Medicine, University of Calgary, Alberta, Canada.
Adv Biol Regul. 2024 Dec;94:101058. doi: 10.1016/j.jbior.2024.101058. Epub 2024 Oct 22.
Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is a genetic disease associated with renal, endocrine, neurological, skin and immune defects. SPLIS is caused by inactivating mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). SPL catalyzes the irreversible degradation of the bioactive sphingolipid sphingosine-1-phosphate (S1P), a key regulator of lymphocyte egress. The SPL reaction represents the only exit point of sphingolipid metabolism, and SPL insufficiency causes widespread sphingolipid derangements that could additionally contribute to immunodeficiency. Herein, we review SPLIS, the sphingolipid metabolic pathway, and various roles sphingolipids play in immunity. We then explore SPLIS-related immunodeficiency by analyzing data available in the published literature supplemented by medical record reviews in ten SPLIS children. We found 93% of evaluable SPLIS patients had documented evidence of immunodeficiency. Many of the remainder of cases were unevaluable due to lack of available immunological data. Most commonly, SPLIS patients exhibited lymphopenia and T cell-specific lymphopenia, consistent with the established role of the S1P/S1P1/SPL axis in lymphocyte egress. However, low B and NK cell counts, hypogammaglobulinemia, and opportunistic infections with bacterial, viral and fungal pathogens were observed. Diminished responses to childhood vaccinations were less frequently observed. Screening blood tests quantifying recent thymic emigrants identified some lymphopenic SPLIS patients in the newborn period. Lymphopenia has been reported to improve after cofactor supplementation in some SPLIS patients, indicating upregulation of SPL activity. A variety of treatments including immunoglobulin replacement, prophylactic antimicrobials and special preparation of blood products prior to transfusion have been employed in SPLIS. The diverse immune consequences in SPLIS patients suggest that aberrant S1P signaling may not fully explain the extent of immunodeficiency. Further study will be required to fully elucidate the complex mechanisms underlying SPLIS immunodeficiency and determine the most effective prophylaxis against infection.
鞘氨醇磷酸裂解酶不足综合征（SPLIS）是一种与肾脏、内分泌、神经、皮肤和免疫缺陷相关的遗传性疾病。SPLIS由SGPL1基因的失活突变引起，该基因编码鞘氨醇磷酸裂解酶（SPL）。SPL催化生物活性鞘脂鞘氨醇-1-磷酸（S1P）的不可逆降解，S1P是淋巴细胞迁出的关键调节因子。SPL反应是鞘脂代谢的唯一出口点，SPL不足会导致广泛的鞘脂紊乱，这可能会进一步导致免疫缺陷。在此，我们综述了SPLIS、鞘脂代谢途径以及鞘脂在免疫中的各种作用。然后，我们通过分析已发表文献中的可用数据，并辅以对10名SPLIS儿童的病历回顾，探讨了与SPLIS相关的免疫缺陷。我们发现93%的可评估SPLIS患者有免疫缺陷的记录证据。其余许多病例由于缺乏可用的免疫学数据而无法评估。最常见的是，SPLIS患者表现出淋巴细胞减少和T细胞特异性淋巴细胞减少，这与S1P/S1P1/SPL轴在淋巴细胞迁出中的既定作用一致。然而，也观察到B细胞和NK细胞计数低、低丙种球蛋白血症以及细菌、病毒和真菌病原体的机会性感染。对儿童疫苗接种的反应减弱较少见。通过筛选定量近期胸腺迁出细胞的血液检测，在新生儿期发现了一些淋巴细胞减少的SPLIS患者。据报道，一些SPLIS患者在补充辅因子后淋巴细胞减少有所改善，表明SPL活性上调。SPLIS患者采用了多种治疗方法，包括免疫球蛋白替代、预防性抗菌药物以及输血前血液制品的特殊制备。SPLIS患者中多样的免疫后果表明，异常的S1P信号可能无法完全解释免疫缺陷的程度。需要进一步研究以充分阐明SPLIS免疫缺陷的复杂机制，并确定预防感染的最有效方法。
