Friday, December 22, 2023


Test code, Description and Result Format Modification

Test code Previous: 7772
Test code New: 9954

Effective update from 27/12/2023




     Results Format:

     R1: See attached report



  Results Format:

  R1:   2DL1 GENOTYPE        RV: Absence
  R2:   2DL2 GENOTYPE        RV: Absence
  R3:   2DL3 GENOTYPE        RV: Absence
  R4:   2DL4 GENOTYPE        RV: Absence
  R5:   2DL5 GENOTYPE        RV: Absence
  R6:   2DP1 GENOTYPE        RV: Absence
  R7:   2DS1 GENOTYPE        RV: Absence
  R8:   2DS2 GENOTYPE        RV: Absence
  R9:   2DS3 GENOTYPE        RV: Absence
  R10:  2DS4 GENOTYPE        RV: Absence
  R11:  2DS5 GENOTYPE        RV: Absence
  R12:  3DL1 GENOTYPE        RV: Absence
  R13:  3DL2 GENOTYPE        RV: Absence
  R14:  3DL3 GENOTYPE        RV: Absence
  R15:  3DP1 GENOTYPE        RV: Absence
  R16:  3DS1 GENOTYPE        RV: Absence

  R18: KIR ligand genotype (HLA-C group)
  R19: Locus c (Class I)

  (b*) Interpretative text of the study




KIR Genotyping (killer immunoglobulin -like receptor) from genomic DNA by PCR technology (Polymerase Chai n Reaction), using sequence -specific primers (SSPs) designed for the detection of the 16 human KIR gene:

2DL1, 2DL2, 2DL3, 2DL4, 2DL5, 2DP1, 2DS1,2DS2,2DS3,2DS4, 2DS5, 3DL1, 3DL2, 3DL3, 3DP1, 3DS1.



During the first trimester of pregnancy, infiltration into the decidua of maternal uterus occurs by trophoblastic cells of the blast ocyst. The trophoblast will give place to the placenta, organ which will provide the fetal blood supply. A defect in this process of placentation, produces multiple disorders such as premature births, pre-eclampsia, low fetal growth or spontaneous miscarriage (1).

Studies have shown that part of the regulation of placentation, is produced under the influence of local immunological recognition (2).

The trophoblast cells express high levels of HLA -C which are recognized by the KIR (Killer immunoglobulin-like receptors) of the uNK (Natural Killer cells uterine) (3).

KIRs are expressed from a highly polymorphic family of genes, and the HLA-C of the trophoblast is encoded in an equally polymorphic gene set, derived 50% from the father and 50% from the mother (4, 9). This fact gives rise to a different embryonic HLA-C genotype in each pregnancy, even in the case of same parents (5).

The maternal KIR haplotype can be AA, AB or BB (6). Haplotype A co ntains mainly genes for inhibitory KIRs and haplotypes B have addi tional genes that encode activating KIRs (3). The presence of activating KIRs (haplotype B) confers protection against disorders in pregnancy (7) and their absence (haplotype A), increases the risk of complications ( 5). The balance between activation - inhibition, results in the release of cytokines that favor placental trophoblastic infiltration (8).

The HLA-C ligands for the KIR belong to two allelic groups, C1 and C2. It has been observed that the risk of recurrent miscarriages, pree clampsia, or low fetal growth is increased when mothers own KIR AA haplotype

and the fetus expresses more HLA-C2 genes than maternal cells; moreover when these additional HLA-C2 are inherited from the father (7). This situation takes another outlook in assisted pregnancies, wher e patients often are receptors of more than one embryo and adition ally, those could be the result of a fertilization with an sperm or oocyte donors or both. In these cases, HLA -C molecules expressed by the trophoblast would behave as if they were of paternal origin (3).

With this information we can reach the following conclusion (appli ed to the field of reproductive medicine):

Consideration to take into account in cases where it is necessary sperm or oocytes donors, or both:

- If the receiving woman has a KIR AA haplotype, the better choice for a more efficient and safe implantation of the embryo, seems to be the selection of a semen and egg donors with HLA-C1/C1 haplotype.


 (1) Brosens et al. The `Great Obstetrical Syndromes´ are associated wi th disorders of deep placentation. Am. J. Obstet. Gynecol.(2011);204:193-201.
(2) A. Moffett et al. Variation of maternal KIR and fetal HLA -C genes in reproductive failure: too early for clinical interventi on. Reproductive BioMedicine Online (2016); 33:763-769.
(3) D. Alecsandru et al. Why natural killer cells are not enough: a fu rther understanding of killer immunoglobulin -like receptor and human
leukocyte antigen. Fertility and Sterility (2017) Vol.107 no. 6, 0015-0282.
(4) D. Torres -García et al. Receptores de células NK (KIR): Estructura, función y relevancia en la susceptibilidad de enfermedades. Revista
Instituto Nacional de Enfermedades Respiratorios Ismael Cosío Vill egas (2008), vol.21 No.1
(5) Moffett A. et al. Uterine NK cells: active regulators at the mater nal-fetal interface. J Clinic Invest (2014);124:1872-9.
(6) Uhrberg M. et al. Human diversity in killer cell inhibitory receptor genes. Immunity (1997); 7:753-63.
(7) Hiby SE. et al. Maternal activating KIRs protect against human rep roductive failure mediated by fetal HLA-C2. J Clin Invest (2010); 120:4102-10.
(8) Kennedy PR. et al. Activating KIR2DS4 is expressed by uterine NK c ells and contributes to successful pregnancy. J Immunol (2016);
(9) Midleton D. et al. The extensive polymorphism of KIR genes. J Immu nol (2009); 129:8-19.




Molecular typing of human leukocyte antigen (HLA -C class I) alleles at the allele group level (low resolution).


The technique is based on the reverse hybridization principle. A P CR-SSO is carried out after DNA isolation.

At the PCR, amplification of exons 2 and 3 of the HLA-C locus occurs and PCR products are biotinylated. Then, amplification products are subsequently hybridized using a typing strip. This test is designed to give the best possible resolution at the allele group level (this means the first two digits after the asterisk in an allele name following standard HLA nomenclature, ex. Cw*07Cw*08), although resolution to the allelic level may be possible for the most allele combinations.

Interpretation of the results is based on the allele population frequency.


C1: C*01, C*03 (except C*03:07), C*07 (except C*07:07, C*07:09), C *08, C*12 (except C*12:04, C*12:05), C*14,C*15:07, C*16 (except C*16:02),C2: C*02, C*03:07, C*04, C*05, C*06, C*07:07, C*07:09, C*12:04, C *12:05, C*15 (except C*15:07), C*16:02, C*17, C*18


At a pregnancy, maternal uterine natural killer cells (UNKs) are the dominant immune cells in the uterine mucosa and there are multiple studies that support their important role in establishing normal early placentation (1, 2, 3, 4, 5, 6). There are also evidences of a dir ect ligand-receptor interaction between trophoblastic cells (which show HLA -C class I molecules) and UNKs KIR receptors. This interaction seems to

condition the process of placentation. HLA genotypes are organized into two groups (HLA -C1 and HLA-C2), and although both HLA-C1 and HLA-C2 bind to KIR receptors, the strength of the downstream UNKs response is str ongly influenced by C1 and C2 zygosity of

the new pregnancy. The extreme variability in both the maternal KI R and fetal HLA -C ligands means that each pregnancy will feature a range of different combinations. Therefor e, the balance of KIR genotypes in a given patient and the HLA-C exposure in a given pregnancy may influence the initiation of normal placentation (7).


1). Trundley A., Moffett A. Human Uterine Leukocytes and pregnancy. Tissue Antigens 2004; 63: 1-12.
(2). Caligiuri MA. Human natural killer cells. Blood 2008; 112: 461-9.
(3). Moffett A., Shreeve N. First do no harm: uterine natural kill er (NK) cells in assisted reproduction. Human
Reproduction 2015; 30: 1519-25.
(4). Pace D., Morrison L., Bulmer JN. Proliferative activity in en dometrial stromal granulocytes throughout
menstrual cycle and early pregnancy. J Clin Pathol 1989; 42: 35-9.
(5). Xiong S., Sharkey AM. Kennedy PR, Gardner L, Farrell LE, Cha zara O, et al. Maternal uterine NK cell -
activating receptor KIR2DS1 enhances placentation. J Clin Invest 2013; 123: 4264-72.
(6). Robson A. Harris LK, Innes BA, Lash GE, Aljunaidy MM, Aplin JD, et al. Uterine natural killer cells
initiate spiral artery remodeling in human pregnancy. FASEB J 2012; 26: 4876-85.
(7). Scott J. Morin, Nathan R. Treff, Xin Tao, et al. Combination of uterine natural killer cell immunoglobulin
receptor haplotype and trophoblastic HLA -C ligand influences the risk of pregnancy loss: a retrospective co hort
analysis of direct embryo genotyping data from euploid transfers.

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