Department of Clinical Immunology, Laboratory of Immunogenetics and Tissue Immunology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland.
Department of Reproductive Medicine, Gameta Hospital, Rzgów, Poland.
Front Immunol. 2022 Jan 17;12:791399. doi: 10.3389/fimmu.2021.791399. eCollection 2021.
Successful reproduction depends on many factors. Male factors contribute to infertility in approximately 50% of couples who fail to conceive. Seminal plasma consists of secretions from different accessory glands containing a mixture of various cytokines, chemokines, and growth factors, which together can induce a local immune response that might impact on a male's as well as a female's fertility. Human leukocyte antigen (HLA)-G expression has been suggested as an immunomodulatory molecule that influences pregnancy outcome. The gene encodes either membrane-bound or/and soluble proteins. The aim of this study was the evaluation of HLA-G polymorphisms and their impact on soluble HLA-G (sHLA-G) production. We tested the polymorphism in three positions: rs1632947: c.-964G>A; rs1233334: c.-725G>C/T in the promoter region; rs371194629: c.∗65_∗66insATTTGTTCATGCCT in the 3' untranslated region. We tested two cohorts of men: 663 who participated in fertilization (test material was blood or sperm), and 320 fertile controls who possessed children born after natural conception (test material was blood). Since 50% of men visiting assisted reproductive clinics have abnormal semen parameters, we wondered if men with normal sperm parameters differ from those with abnormal parameters in terms of polymorphism and secretion of sHLA-G into semen. We found that certain rs1632947-rs1233334-rs371194629 haplotypes and diplotypes were associated with male infertility, while others were protective. Normozoospermic men with the A-C-del haplotype and A-C-del/A-C-del diplotype secreted the most sHLA-G into semen (574.1 IU/mL and 1047.0 IU/mL, respectively), while those with the G-C-ins haplotype and G-C-ins/G-C-ins diplotype - the least (80.8 IU/mL and 75.7 IU/mL, respectively). Men with the remaining haplotypes/diplotypes secreted sHLA-G at an intermediate level. However, only in one haplotype, namely G-C-ins, did we observe strong significant differences in the concentration of sHLA-G in the semen of men with teratozoospermia compared to men with normal sperm parameters (p = 0.009). In conclusion, fertile men differ in the profile of polymorphism from men participating in IVF. Among all haplotypes, the most unfavorable for male fertility is the G-C-ins haplotype, which determines the secretion of the lowest concentration of the soluble HLA-G molecule. This haplotype may reduce sperm parameters.
成功的繁殖取决于许多因素。在未能怀孕的夫妇中，约有 50%的夫妇的男性因素导致不孕。精液由来自不同附属腺体的分泌物组成，其中包含各种细胞因子、趋化因子和生长因子的混合物，这些物质共同诱导局部免疫反应，可能会影响男性和女性的生育能力。人类白细胞抗原（HLA）-G 的表达被认为是一种免疫调节分子，影响妊娠结局。该基因编码膜结合或/和可溶性蛋白。本研究的目的是评估 HLA-G 多态性及其对可溶性 HLA-G（sHLA-G）产生的影响。我们在三个位置检测了 多态性：rs1632947：c.-964G>A；rs1233334：c.-725G>C/T 在启动子区域；rs371194629：c.∗65_∗66insATTTGTTCATGCCT 在 3'非翻译区。我们测试了两组男性：663 名参与受精的男性（测试材料为血液或精子）和 320 名生育能力正常的对照组男性（测试材料为血液），这些对照组男性的孩子是通过自然受孕出生的。由于 50%的男性不育症患者的精液参数异常，我们想知道具有正常精子参数的男性是否与具有异常参数的男性在 多态性和 sHLA-G 分泌方面存在差异。我们发现，某些 rs1632947-rs1233334-rs371194629 单倍型和二倍型与男性不育有关，而其他单倍型和二倍型则具有保护作用。具有 A-C-del 单倍型和 A-C-del/A-C-del 二倍型的正常精子男性将最多的 sHLA-G 分泌到精液中（分别为 574.1 IU/mL 和 1047.0 IU/mL），而具有 G-C-ins 单倍型和 G-C-ins/G-C-ins 二倍型的男性则分泌最少（分别为 80.8 IU/mL 和 75.7 IU/mL）。具有其他单倍型/二倍型的男性则以中等水平分泌 sHLA-G。然而，只有在一个单倍型（G-C-ins）中，我们观察到畸形精子症男性与具有正常精子参数的男性相比，sHLA-G 在精液中的浓度存在显著差异（p=0.009）。总之，与接受 IVF 的男性相比，生育能力正常的男性在 多态性特征上存在差异。在所有单倍型中，对男性生育能力最不利的是 G-C-ins 单倍型，它决定了可溶性 HLA-G 分子的最低浓度的分泌。这种单倍型可能会降低精子参数。
