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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 R17: KIR HAPLOTYPE R18: KIR ligand genotype (HLA-C group) R19: Locus c (Class I) (b*) Interpretative text of the study |
(b*) KIR GENOTYPE + HLA-C
Class I, WHOLE BLOOD
TECHNIQUE:
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.
INTERACTIONS BETWEEN
HLA-C - KIR AND ITS ROLE IN THE EVOLUTION OF A PREGNANCY
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.
(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);
197:4292-300.
(9) Midleton D. et al. The extensive polymorphism of KIR genes. J Immu nol (2009); 129:8-19.
MOLECULAR STUDY HLA-C GENOTYPE (LOW RESOLUTION), WHOLE BLOOD
DETERMINATION
Molecular typing of human leukocyte antigen (HLA -C class I) alleles at the allele group level (low resolution).
TEST PRINCIPLE
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.
ALLELE GROUPS:
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
APPLICATION IN HUMAN
REPRODUCTION
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).
REFERENCES
(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 -
(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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