25/01/2018
The Fetal Allograft Survival is a mysterious phenomenon, so is the Pathogenesis of Preeclampsia. An interesting hypothesis is presented for peer review.
Dynamic Graft Hypothesis explains both these phenomena. This hypothesis is not based on conjecture. It has a sound logical basis.
What is the Dynamic Graft hypothesis?
The Dynamic graft hypothesis explains the mysterious tolerance to certain allografts and the rejection of others. According to this hypothesis, a graft that never changes the set of antigens it presents to the host is a static graft. A renal transplant, for example, presents the same set of antigens from the day 1 till it is rejected by the host. A dynamic graft, on the other hand, is capable of subtle changes in the set of antigens it presents to the host.
The hypothesis postulates that:
1) In normal pregnancy, the fetal allograft survives because trophoblast is a Dynamic Graft.
2) A Growing tumor evades immune surveillance as cancer is a Dynamic Graft.
3) HIV infection perpetuates because HIV induces a situation simulating a Dynamic Graft.
4) A surgical solid organ allograft is usually rejected (sooner or later), as it is a Static Graft.
5) In miscarriage, the allograft is rejected, as the trophoblast no more qualifies as a Dynamic Graft.
6) In preeclampsia, the Unfortunate fetal allograft is neither totally rejected (as in miscarriage), nor is it totally tolerized (as in normal pregnancy).
The Dynamic graft hypothesis approaches the problem of preeclampsia by discussing:
A) The physiology of pregnancy in the section 'Fetal Allograft Survival: Concept of Dynamic Graft'.
B) The derangement in the normal mechanism, in the section on 'Pathogenesis of Preeclampsia'.
Fetal Allograft Survival: Concept of Dynamic Graft (Abstract):
T lymphocytes play a central role in graft rejection. The process involves antigen recognition, clonal expansion and targeted immune response. Two important things need consideration:
1. These processes are extremely specific for the given antigen.
2. There is a time lag of a few days between the recognition of specific graft antigens and the effector response against them.
A dynamic graft, e.g. the trophoblast, uses this window period very effectively. Owing to its inherent pluripotency, it starts producing a slightly different set of proteins in its cytoplasm, thus presenting on its cell surface a newer set of MHC class I:neo-peptides. By the time, the clonally expanded host effector T cells converge to unleash a lethal attack on the graft cells presenting that particular set of antigens, the older set is simply missing . The CD8+ cytotoxic T cells undergo apoptosis (apoptosis of neglect), while some of the CD4+ T-helper cells turn into regulatory T cells (Tregs) leading to specific acquired tolerance to that particular set of trophoblastic antigens. This is not a one-off phenomenon, the cycle repeats over and over, enabling the dynamic graft to survive in an otherwise competent host immune environment. On the other hand, a static graft, e.g. a renal transplant, presents only one and the same set of graft antigens and is usually rejected, sooner or later, in spite of using immunosuppressive drugs.
Pathogenesis of Preeclampsia (Abstract):
During normal pregnancy the trophoblast evades the maternal immune attack by inducing acquired immune tolerance to its progressively newer stage-specific phenotypes. Out of such numerous (physiologically adaptive) phenotype changes, one involves the expression of pro-angiogenic molecules - vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) by the invasive cytotrophoblasts. Preeclampsia is a disease of trophoblast, in which the allograft fails to change its phenotypes in time. It fails to change its phenotype from epithelial to vascular type resulting in inadequate invasion and remodeling of the spiral arterioles of the placental bed. The uterine spiral arteries remain narrow, high-resistance vessels resulting in placental hypoxia. Varying degrees of host-versus-graft reaction ensues against the unfortunate allograft, the extreme situations resulting in separation of the graft Abruptio Placentae.
Thus, in the preeclampsia syndrome, the unfortunate fetal allograft is neither totally tolerated (as in a normal pregnancy) nor is it totally rejected (as in a miscarriage). Defective angiogenesis and the ongoing alloimmune rejection reaction results in the preeclampsia syndrome. Tardier the trophoblast, higher is the degree of illness. Milder forms present as Gestational hypertension (BP > 140/90 mmHg), while the more severe forms result into preeclampsia (+ proteinuria > 300 mg/24h), eclampsia (+ seizures) and HELLP (hemolysis, elevated liver enzymes, low platelet) syndrome. Milder forms of the disease can be treated conservatively, however, the only definitive curative treatment is the delivery of the baby along with every single bit of the hapless trophoblast.
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