KIR  and  HLA-C  genes in male infertility

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Abstract

Purpose

Approximately 50% of men reporting to clinics for assisted reproduction have abnormal sperm parameters; we therefore considered whether they differ from fertile males in terms of the frequency of KIR and HLA-C genes, suggesting the involvement of NK cells and some T cells in the inflammatory reaction that can occur in the testes, vas deferens, or epididymis.

Method

We tested a total of 1064 men: 445 of them were patients who, together with their female partners, participated in in vitro fertilization (IVF), 298 men whose female partners suffered from recurrent spontaneous abortion. Three hundred twenty-one fertile men constituted the control group. KIRs were genotyped using KIR Ready Gene kits and HLA-C by PCR-SSP methods.

Results

We found differences in KIR gene frequencies between men who became fathers via natural conception and men who participated in in vitro fertilization for KIR2DL2 ( p/p _corr. = 0.0015/0.035, OR = 1.61), KIR2DL5 gr.2 ( p/p _corr. = 0.0023/0.05, OR = 1.64), KIR2DS2 ( p/p _corr. = 0.0019/0.044, OR = 1.59), and KIR2DS3 ( p/p _corr. = 0.0016/0.037, OR = 1.67). KIRs in Cen AA region were significantly overrepresented in fertile males than in IVF males ( p/p _corr. = 0.0076/0.03, OR = 0.67), whereas Cen AB + Cen BB frequency was higher in IVF males than in fertile males ( p/p _corr. = 0.0076/0.03, OR = 1.50). We also observed a limited association in KIR-HLA-C combinations.

Conclusion

Fertile men differ in profile of KIR genes and KIR-HLA-C combinations from men participating in IVF.

Electronic supplementary material

The online version of this article (10.1007/s10815-020-01814-6) contains supplementary material, which is available to authorized users.

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Most cited references 39

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Synergistic polymorphism at two positions distal to the ligand-binding site makes KIR2DL2 a stronger receptor for HLA-C than KIR2DL3.

Makoto Yawata, Paul J Norman, Nobuyo Yawata … (2008)

Interactions between HLA-C ligands and inhibitory killer cell Ig-like receptors (KIR) control the development and response of human NK cells. This regulatory mechanism is usually described by mutually exclusive interactions of KIR2DL1 with C2 having lysine 80, and KIR2DL2/3 with C1 having asparagine 80. Consistent with this simple rule, we found from functional analysis and binding assays to 93 HLA-A, HLA-B, and HLA-C isoforms that KIR2DL1*003 bound all C2, and only C2, allotypes. The allotypically related KIR2DL2*001 and KIR2DL3*001 interacted with all C1, but they violated the simple rule through interactions with several C2 allotypes, notably Cw*0501 and Cw*0202, and two HLA-B allotypes (B*4601 and B*7301) that share polymorphisms with HLA-C. Although the specificities of the "cross-reactions" were similar for KIR2DL2*001 and KIR2DL3*001, they were stronger for KIR2DL2*001, as were the reactions with C1. Mutagenesis explored the avidity difference between KIR2DL2*001 and KIR2DL3*001. Recombinant mutants mapped the difference to the Ig-like domains, where site-directed mutagenesis showed that the combination, but not the individual substitutions, of arginine for proline 16 in D1 and cysteine for arginine 148 in D2 made KIR2DL2*001 a stronger receptor than KIR2DL3*001. Neither residue 16 or 148 is part of, or near to, the ligand-binding site. Instead, their juxtaposition near the flexible hinge between D1 and D2 suggests that their polymorphisms affect the ligand-binding site by changing the hinge angle and the relative orientation of the two domains. This study demonstrates how allelic polymorphism at sites distal to the ligand-binding site of KIR2DL2/3 has diversified this receptor's interactions with HLA-C.

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The activation of bystander CD8 + T cells and their roles in viral infection

Tae-Shin Kim, Eui-Cheol Shin (2019)

During viral infections, significant numbers of T cells are activated in a T cell receptor-independent and cytokine-dependent manner, a phenomenon referred to as “bystander activation.” Cytokines, including type I interferons, interleukin-18, and interleukin-15, are the most important factors that induce bystander activation of T cells, each of which plays a somewhat different role. Bystander T cells lack specificity for the pathogen, but can nevertheless impact the course of the immune response to the infection. For example, bystander-activated CD8+ T cells can participate in protective immunity by secreting cytokines, such as interferon-γ. They also mediate host injury by exerting cytotoxicity that is facilitated by natural killer cell-activating receptors, such as NKG2D, and cytolytic molecules, such as granzyme B. Interestingly, it has been recently reported that there is a strong association between the cytolytic function of bystander-activated CD8+ T cells and host tissue injury in patients with acute hepatitis A virus infection. The current review addresses the induction of bystander CD8+ T cells, their effector functions, and their potential roles in immunity to infection, immunopathology, and autoimmunity.

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Male infertility: a public health issue caused by sexually transmitted pathogens.

Fabrícia Gimenes, Raquel P Souza, Jaqueline Bento … (2014)

Sexually transmitted diseases (STDs) are caused by several pathogens, including bacteria, viruses and protozoa, and can induce male infertility through multiple pathophysiological mechanisms. Additionally, horizontal transmission of STD pathogens to sexual partners or vertical transmission to fetuses and neonates is possible. Chlamydia trachomatis, Ureaplasma spp., human papillomavirus, hepatitis B and hepatitis C viruses, HIV-1 and human cytomegalovirus have all been detected in semen from symptomatic and asymptomatic men with testicular, accessory gland and urethral infections. These pathogens are associated with poor sperm quality and decreased sperm concentration and motility. However, the effects of these STD agents on semen quality are unclear, as are the effects of herpes simplex virus type 1 and type 2, Neisseria gonorrhoeae, Mycoplasma spp., Treponema pallidum and Trichomonas vaginalis, because few studies have evaluated the influence of these pathogens on male infertility. Chronic or inadequately treated infections seem to be more relevant to infertility than acute infections are, although in many cases the exact aetiological agents remain unknown.

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Author and article information

Contributors

Karolina Wilczyńska: karolina.wilczynska@hirszfeld.pl

Paweł Radwan: pradwan@gameta.pl

Rafał Krasiński: rkrasinski@gameta.home.pl

Michał Radwan: mradwan@gameta.pl

Jacek R. Wilczyński: jrwil@post.pl

Andrzej Malinowski: amalinowski@kki.pl

Ewa Barcz: ewa.barcz@interia.pl

Izabela Nowak:

ORCID: http://orcid.org/0000-0002-9127-1089

izabela.nowak@hirszfeld.pl

Journal

Journal ID (nlm-ta): J Assist Reprod Genet

Journal ID (iso-abbrev): J. Assist. Reprod. Genet

Title: Journal of Assisted Reproduction and Genetics

Publisher: Springer US (New York )

ISSN (Print): 1058-0468

ISSN (Electronic): 1573-7330

Publication date (Electronic): 20 May 2020

Publication date PMC-release: 20 May 2020

Publication date (Print): August 2020

Volume: 37

Issue: 8

Pages: 2007-2017

Affiliations

[1 ]GRID grid.413454.3, ISNI 0000 0001 1958 0162, Department of Clinical Immunology, Laboratory of Immunogenetics and Tissue Immunology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, , Polish Academy of Sciences, ; Wrocław, Poland

[2 ]Department of Reproductive Medicine, Gameta Hospital, Rzgów, Poland

[3 ]Faculty of Health Sciences, The State University of Applied Sciences in Płock, Płock, Poland

[4 ]GRID grid.8267.b, ISNI 0000 0001 2165 3025, Department of Surgical and Oncological Gynecology, , Medical University of Łódź, ; Łódź, Poland

[5 ]Department of Surgical, Endoscopic and Oncologic Gynecology, Polish Mothers’ Memorial Hospital–Research Institute, Łódź, Poland

[6 ]GRID grid.13339.3b, ISNI 0000000113287408, First Chair and Clinic of Obstetrics and Gynecology, , Medical University of Warsaw, ; Warszawa, Poland

Author information

Izabela Nowak http://orcid.org/0000-0002-9127-1089

Article

Publisher ID: 1814

DOI: 10.1007/s10815-020-01814-6

PMC ID: 7467998

PubMed ID: 32436047

SO-VID: b0806074-5ec5-44c1-9819-9929c02c0e39

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 13 March 2020

Date accepted : 10 May 2020

Funding

Funded by: Polish National Science Centre

Award ID: 2014/13/B/NZ5/00273

Award Recipient : Izabela Nowak

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: kir,hla-c polymorphism,in vitro fertilization embryo transfer,infertility,semen,sperm quality and recurrent spontaneous abortion

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ScienceOpen disciplines: Genetics

Keywords: kir, hla-c polymorphism, in vitro fertilization embryo transfer, infertility, semen, sperm quality and recurrent spontaneous abortion

KIR and HLA-C genes in male infertility

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Genome Integrity

Most cited references 39

Synergistic polymorphism at two positions distal to the ligand-binding site makes KIR2DL2 a stronger receptor for HLA-C than KIR2DL3.

The activation of bystander CD8 + T cells and their roles in viral infection

Male infertility: a public health issue caused by sexually transmitted pathogens.

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