Multiparous women often exhibit atibodies against foetal HLA antigens inherited from the father. These anti-HLA antibodies belong to the IgG class and should cross the placenta freely, yet, as far as I know, they do seem to cause any harm to the fetus. Any explanation for that?
I might have an answer to my own question. Perhaps there is low expression of cell surface HLA molecules in the fetus which prevents maternal anti-HLA antibodies from causing any harm.
This seems to be true in embryos. See publication below.
At birth, trauma increases the expression of HLA molecules in fetus' cells, e.g. in blood white cells, and mothers can get exposed and sensitized to them.
http://www.ncbi.nlm.nih.gov/pubmed/3286768
Antibodies raised against the HLA are commonly observed in patients having undergone several transfusions, but also in pathological samples from pregnant women at risk.
In pregnant women, the occurrence of such antibodies is frequently associated with more important factors such as Rh or HPA, and in fact the presence of such antibodies is little or no considered.
You're right. HLA were discovered independently of mouse MHCs thanks to the observation that multi-transfused people and multiparous women had antibodies capable of agglutinating donor leukocytes. Below is the original ref. This is why I wonder why those anti-HLA antibodies from multiparous women do not cause harm to fetus as it happens with anti-D antibodies.
http://www.ncbi.nlm.nih.gov/pubmed/13566127
Pedro, This may help- the placenta (not the fetus) is what is in contact with the mothers blood (and hence in contact with circulating antibodies). The placenta is surrounded by a layer of placental trophoblast cells fused into a syncytium and it is this unusual fetally derived placental tissue that is in direct contact with mothers blood. The syncytium is comepletely devoid of HLA class 1 and class 2 expression. However the underlying mesenchyme in the placenta (which is not in direct contact with mothers blood), does express HLA and some of this will of course be paternal. Unless there is a break in the overlying syncytium it never comes into contact with maternal blood.
However this still doesnt explain why maternal anti-HLA antibodies dont cause problems after 36 weeks of prengancy when IgG is transported across the placenta into the fetal circulation to provide passive immunity. If you find an answer to this, do let me know.
For a general review of immunology of prengancy you couldnt do better than reading one of the reviews by Adrian Erlebacher, who is excellent on this
Immunology of the maternal-fetal interface.Erlebacher A.
Annu Rev Immunol. 2013;31:387-411. doi: 10.1146/annurev-immunol-032712-100003. Epub 2013 Jan 3. Review.
Andrew, I´ve searching I could not find anything but I´ve to say I focus on things related with HLA expression. It´s a simple explanation that poor expression of HLA antigens in the fetus may prevent problems with anti-HLA antibodies. After all you need good expression of antigens to cross-link antibodies and elicit effector functions such complement activation.
Pedro, I hope the answer above about the placenta helped a bit, but as regards the fetus-itself, and why maternal anti-HLA antibodies transported across the placenta from mother to baby dont have a detrimental effect, I can assure you there is abundant HLA expression in fetal tissues as we and otehrs have documented this, so this is not the explantation for a lack of effect of the maternal anti HLA antibodies that do get acrodd intyo the fetus. Ad of corse we know that maternal antibodies do get across because this is what causes rhesus disease in newborns.
"Anti-HLA antibodies pose no threat to the fetus, principally owing to their absorption by the placenta and, very likely, the harmless binding of any that do reach the fetal circulation."
"The fetal trophoblast is able to act as a protective barrier by virtue of unique properties, including a lack of conventional class I and class II HLA molecules, that render it insusceptible to immune attack."
Please sea the articles at below:
1: Billington WD. The normal fetomaternal immune relationship. Baillieres Clin Obstet Gynaecol 1992; 6(3): 417-38.
2: Lee J, Romero R, Xu Y, Miranda J, Yoo W, Chaemsaithong P, Kusanovic JP, Chaiworapongsa T, Tarca AL, Korzeniewski SJ, Hassan SS, Than NG, Yoon BH, Kim CJ. Detection of anti-HLA antibodies in maternal blood in the second trimester to identify patients at risk of antibody-mediated maternal anti-fetal rejection and spontaneous preterm delivery. Am J Reprod Immunol 2013; 70(2): 162-75.
If anti-HLA antibodies did not pass the placenta we will have a simple answer but that does not seem to be case. In fact, anti-HLA antibodies may protect RH+ fetuses from hemolytic disease caused by antibodies raised by RH- mothers. It seems that these antibodies can inhibit hemolytic ADCC mediated by monocytes.
http://www.ncbi.nlm.nih.gov/pubmed/1349101
http://www.ncbi.nlm.nih.gov/pubmed/10480291
Is it known what is the subclass of these IgG antibodies? Could these be IgG4?
It's a very good point. IgG4 are good at neutralizing but poor activating the complement and do not exhibit much FcR-mediated functions. I did a quick search and I did not find the isotype subclass of maternal anti-HLA IgG antibodies. However, I found literature relating maternal anti-HLA antibodies with preterm deliveries. So perhaps these antibodies are not always that harmless.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154511/
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