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PREECLAMPSIA- ECLAMPSIA
INTRODUCCIÓN
1
PROPÓSITO
Fig. 2 Fig. 3.
Jena Dauset Baruj Benacerraf
2
Fue su descubrimiento fundamental para que años más tarde el inglés Medawar
(Fig. 4), seguidor de las teorías del australiano Frank Mcfarlane Burnet (Fig. 5), se
aplicaran esos conocimientos al injerto de trasplante de tejidos y órganos.
Fig. 4 Fig. 5
Peter B. Medewar Frank Mcfarlane
LA PLACENTA
COMPARTIMENTOS PLACENTARIOS
Y TIPO DE CELULAS
Líquido amniótico
Células dendríticas
Membrana amniótica
Decidua parietal
Trofoblasto corionico
Vasos fetales
Espacio intervelloso
Sinciotrofoblasto
Vellosidad terciaria
Citotrofoblasto
Diagrama de Beer.
Desde muy temprano, a los 4 días de la formación del zigoto las capas externas
del blastocisto al implantarse en el endometrio en proceso de decidualización dan
origen a las vellosidades que de acuerdo con su grado de maduración serán de 1,
2, 3, orden. Están rodeadas por el citotrofoblasto que tiempo después, perdiendo
sus límites intercelulares por efecto de fosfolípidos que actúan como moléculas de
adhesión, evolucionan a sincintio expuesto directamente a la sangre materna que
lo baña en el espacio intervelloso, es la placentación hemocorial. De acuerdo con
su ubicación el trofoblasto inicialmente es vellositario, luego se prolonga hacia la
decidua (trofoblasto de anclaje), la penetra como también al miometrio (trofoblasto
intersticial) y más adelante, a través de las arterias espirales invade la circulación
materna (trofoblasto vascular) hasta colonizar en los capilares pulmonares
(trofoblasto tisular) donde permanecerá desde las primeras semanas de la
gestación hasta su finalización. Sus células serán detectables en la sangre venosa
periférica materna.
TOLERANCIA
7
CD25. Este incremento se produce inmediatamente después de la concepción y
se mantiene hasta después del parto.
Los antígenos paternos, que son presentados al sistema inmune materno por el
trofoblasto, inducen la activación de los linfocitos B y la síntesis de anticuerpos.
Sin embargo, estos anticuerpos no activan el complemento, con la consiguiente
destrucción de las células del embrión, debido a la presencia de los factores
inmunosupresores secretados por la placenta y la decidua; así moléculas
maternas MCP y DAF transforman localmente el anticuerpo citotóxico por un
anticuerpo bloqueante de la respuesta; el mecanismo de dicho bloqueo es doble:
se une al anticuerpo “secuestrándolo” e induce su degradación. Además, algunos
antígenos del trofoblasto expresados por el sincitio son “camuflados”
recubriendose por sialumucinas o por anticuerpos antiidiotipo reduciendo su
antigenicidad de modo que el sistema inmune materno no actúe frente a ellos.
DECIDUA
De acuerdo con Iglesias y cols., los leucocitos son componentes importantes del
endometrio humano. Durante la fase proliferativa del ciclo menstrual llegan a
formar el 10% de las células estromales, en momentos previos a la implantación
9
constituyen el 20% y en las etapas tempranas del embarazo, cuando el
endometrio se convierte en decidua, los leucocitos llegan a constituir el 30% de
sus células. En particular los linfocitos T y las células NK constituyen poblaciones
heterogéneas, con subpoblaciones acordes con el patrón de citoquinas que
secretan. Las células NK tienen morfología de granulares grandes y comienzan a
desaparecer al término de la gestación. Tienen gránulos en su citoplasma que a
su vez contienen perforinas y grancinas lo cual indica que tienen importante
actividad citolítica. Por estar en contacto con el trofoblasto intersticial y ser
abundantes en el momento de la implantación las células NK se consideran
importantes en dicho proceso y en el desarrollo y crecimiento de la placenta.
Tienen las células NK receptores (KIR 2-KIR 3) que interactúan con los antígenos
HLA – G, E y C del trofoblasto extravelloso modulando la implantación y la
invasión de este último como también la trasformación vascular de las arterias
espirales.
12
microcosmos celular con participación de granulocitos, macrófagos, monocitos,
linfocitos B y T, NK y dendríticas.
A partir de los trabajos morfológicos de Brosens y cols son conocidos los cambios
que ocurren en la circulación útero-placentaria y más específicamente en las
arterias espirales y por ende en su endotelio, en las basales y en las radiadas en
el curso del embarazo normal.
La capa media de las arteriolas es reemplazada por material fibrinoide dentro del
cual está embebido el trofoblasto invasor. Hay baja resistencia al flujo sanguíneo
con la consiguiente suplencia nutricia al feto en desarrollo. Sustituida
temporalmente la capa muscular de los vasos estos se tornan flexuosos,
verdaderos sacos pseudoaneurismáticos facilitándose así la perfusión
uteroplacentaria que se reflejará en el espacio intervelloso convertido en un
sistema de alta capacitancia, baja resistencia y baja presión. La no presencia de la
segunda migración ha sido interpretada como manifestación de rechazo
inmunológico al trasplante, y la ausencia de trofoblasto intravascular en las
arterias basales irradiadas combinada con el desequilibrio entre autacoides
vasodilatadores endoteliales, prostaciclina (PG12) y óxido nítrico (NO), y
vasoconstrictores, Tromboxano (TXA2) prostaglandina (PGH2) entre otros, con
predomino de estos últimos, como los causantes de la disminución de la perfusión
uteroplacentaria y por consiguiente de la isquemia de la decidua, del espacio
intervelloso y de la placenta en general. Habrá producción de radicales libres de
O2 y peroxidación de lípidos que inactivarán el NO e inhibirán su liberación
endotelial. Ver diagrama.
1. Citoquinas.
Debe anotarse que la placenta también puede producir citoquinas de Th1. Las
células placentarias expresan eritropoyetina, la molécula prototipo para la
regulación transcripcional por hipoxia en mamíferos. El TNF alfa y la IL-1 tienen
secuencias de DNA próximas homólogas al elemento realzador de la respuesta a
la hipoxia del gen de la eritropoyetina favoreciendo una relación molecular
potencial no probada entre la hipoxia placentaria y la estimulación de la
producción de citoquinas. Las células endoteliales disfuncionales son sometidas a
activación y producen moléculas de adhesión leucocito-endotelio que median la
adherencia de las células inflamatorias. Este proceso inductivo es mediado por
citoquinas producidas por células inflamatorias y células endoteliales activadas. La
preeclampsia se asocia con niveles incrementados de estas moléculas de
adhesión, incremento que puede ser un evento temprano. Aumentos en los niveles
15
de antagonistas de los receptores de IL-6 e IL-1 en la preeclampsia se
correlacionan con concentraciones elevadas de estas moléculas de adhesión.
Los neutrófilos activados liberan enzimas como la elastasa la cual puede destruir
la actividad del endotelio. Los niveles plasmáticos de elastasa están aumentados
en la preeclampsia y se correlacionan con los marcadores de disfunción endotelial.
En el embarazo normal tanto los niveles séricos de TNF y de IL-6 y los niveles de
sus receptores solubles se incrementan con la edad gestacional. Lo mismo es
cierto para los complejos inmunes circulantes y la activación del complemento. Los
neutrófilos a su vez pueden ser activados por factores del complemento. Los
marcadores de activación de este último están incrementados en la preeclampsia
y se correlacionan con los niveles de elastasa y de neopterina y con los niveles
elevados de IL-6. El embarazo normal se caracteriza por neutrófilos activados
como se comprueba por el incremento del calcio intracelular ionizado y los niveles
circulantes de neopterina, lactoferrina y defensina. La activación de los neutrófilos
está aumentada aún más en la preeclampsia. El incremento en la expresión basal
de CD 11b neutrofílica en la preeclampsia es fuerte indicación de activación de
neutrófilos in vivo y se correlaciona con los niveles plasmáticos de ácido úrico.
Sacks y cols. encontraron que en el embarazo normal tanto los granulocitos como
los monocitos tienen aumentos significativos de los niveles de CD 11b, CD64 y
CD14 comparados con los de la mujer no embarazada mientras que en la
preeclampsia hay una activación leucocitaria mayor caracterizada por un fenotipo
alterado y una producción incrementada de especies reactivas de oxigeno
intracelular. El embarazo normal puede representar un estado inflamatorio ”leve”
16
mientras que la preeclampsia esta caracterizada por un grado exagerado de
inflamación.
MORFOFISIOLOGÍA
17
Desde la concepción del nuevo ser, la embriogénesis y desarrollo, hasta la muerte
tiene el órgano endotelial participación ineludible; de ahí su enorme trascendencia.
Está conformado por los siguientes elementos: la célula endotelial, el pericito
subendotelial o dendrocito, la célula muscular lisa vascular, las membranas
basales de cada uno de estos elementos y la matriz extracelular. Su conjunto
constituye una unidad histofuncional.
ENDOTELIO E INMUNOLOGÍA
En cuanto al embarazo como trasplante, para que éste sea exitoso se requiere
una respuesta inicial proliferativa en el momento de la implantación para producir
citoquinas necesarias como factores de crecimiento para el trofoblasto y
angiogénesis para la decidua –inmunotropismo- seguido por un proceso
antiinflamatorio para proseguir con el desarrollo y crecimiento. Si esta etapa no se
da el blanco de respuesta inflamatoria es la célula endotelial y su superficie de
tromboresistente se torna trombogénica, la suplencia de sangre materna al
embrión se demerita y muere. Este fenómeno, presente en la preeclampsia, es
similar al que ocurre en el rechazo al trasplante de órganos.
Mientras que los cambios consistentes con lesión celular endotelial puedan ser
demostrados en las mujeres preeclampticas, ¿existe evidencia para soportar ésta
como la causa más que el resultado de otros trastornos fisiológicos en esta
enfermedad? Puesto que los estudios longitudinales que confirman la lesión
celular endotelial in vivo en mujeres preeclampticas no están disponibles aún, ésta
pregunta no puede ser contestada definitivamente. Si la lesión celular endotelial es
la causa de la hipertensión y la proteinuria, se podría afirmar que la evidencia de
esta lesión puede anteceder al trastorno clínico en su máxima expresión. Como se
anotó, éste es el caso. La relación incrementada de la actividad del antígeno del
factor VIII, el recuento plaquetario reducido y los niveles plasmáticos
incrementados de beta-tromboglobulina y fibronectina, todos anteceden al
21
trastorno clínico por días a semanas. El hallazgo clásico de Gant y cols indica que
la sensibilidad vasopresora aumentada a la angiotensina II puede ser demostrada
tan temprano como en la semana 18 a 22 de la gestación.
Una característica de la lesión celular endotelial que hace que esta aparezca como
un evento primario en la preeclampsia es su tendencia a autoacelerarse. La
pérdida del efecto citoprotector del endotelio puede llevar a un incremento del
vasoespasmo y a la coagulación intravascular, lo cual puede reducir la perfusión
distal al sitio de la lesión. Este fenómeno puede incrementar la extensión de la
lesión celular endotelial creando un círculo vicioso. Tal modelo es compatible con
el curso clínico de la preeclampsia la cual solamente desaparece después de la
expulsión de la placenta.
En la actualidad la identidad del factor (es) que causa la lesión celular endotelial
en la preeclampsia es especulativo. Los datos que han sido presentados sugieren
la presencia de anticuerpos anti-células endoteliales en las mujeres
preeclampticas. La desaparición de la preeclampsia después del parto y trabajos
22
preliminares que demostraron la desaparición rápida del efecto citotóxico del suero
después del parto, indican que éste factor tiene una vida media relativamente
corta y es poco probable que sea una inmunoglobulina. Factores peptídicos como
el Factor de Crecimiento Derivado de las Plaquetas también han sido propuestos
como candidatos potenciales. Hubel y colaboradores han sugerido que la
peroxidación lipídica, la cual está incrementada en las mujeres preeclampticas
lesiona las membranas celulares y puede jugar un importante papel en la
enfermedad. Sería uno más de los círculos viciosos patogénicos del síndrome.
24
tejido nervioso, médula adrenal, músculo liso vascular, plaquetas, neutrófilos y
probablemente otras células del organismo humano.
26
mecanismos controla el tono vascular y el flujo sanguíneo, tanto en el ámbito
sistémico, como los cambios necesarios en el ámbito local, según se requiera.
27
Las concentraciones séricas elevadas de colesterol, trialciglicéridos (TAG), VLDL,
LDL y los bajos niveles de HDL son factores que intervienen en el daño endotelial
y por tal razón se han asociado con el desarrollo de PE. En las mujeres con
preeclampsia la actividad lipolítica está aumentada, lo que determina una mayor
captación por las células endoteliales de ácidos grasos libres que luego son
reesterificados a TAG. En la preeclampsia puede encontrarse acumulación de
lípidos en células endoteliales, glomerulares y miocárdicas (la hiperlipidemia
crónica puede alterar la estructura y función de las membranas endoteliales con la
consiguiente lesión y disfunción endotelial; las lipoproteínas se acumulan dentro
de la íntima en sitios de lesión, lo cual proporciona la oportunidad para su
oxidación). Las LDL oxidadas son citotóxicas para las células endoteliales y
ávidamente captadas por macrófagos, formándose células espumosas. Todos
estos cambios son considerados como precursores en la formación de placas
ateromatosas.
EPÍLOGO
28
Las páginas precedentes proporcionan información actualizada acerca de los
logros científicos alcanzados recientemente. Gracias a los investigadores
empeñados en dilucidar aspectos ignorados aún hoy relacionados con la
inmunobilogía de la reproducción y más concretamente de sus desórdenes. Con el
reconocimiento del embarazo como un alotrasplante susceptible en condiciones
normales de ser tolerado y en algunas patológicas como la preeclampsia
eclampsia, manifestación de rechazo, se ha abierto un amplio campo de
perspectivas que permiten avizorar el desentrañamiento del origen de tan grave
complicación.
LECTURAS RECOMENDADAS:
Brosens IA, Robertson WB, Dixon HG, The role of the spiral arterias in the
pathogenesis of preeclampsia. Obstet Gynecol Annu 1972;1:177-191.
Chaonat G. The riddle of the fetal allograft Ann Intitute Pasteur Immunol. 1984;135:
301.
Morris NH, Eaton BM, Dekker GA. Nitric oxide, the endothelium, pregnancy, and
preeclampsia. Br. J. Obstet Gynaecol 1996;103:4-15.
Starkey PM. The deciduas and factors controlling placentation. In: Redman CWG,
Sargents LL, Starkey PM (eds). The human Placenta. Oxford, Blackwell Scientific
Publication; 1993. p. 362-413.
Shorter SC, Starkey PM, Ferry BL, et al. Antigenic heterogeneity of human
cytotrophoblast and evidence for the transient expression of MHC class I antigens
distinc from HLA-G. Placenta. 1993;14:571-582.
Clark DA. Cytokines, deciduas, and early pregnancy. Oxf Rev Reprod Biol.
1993;15:83-110.
Conrad KP. Benyo DF. Placental cytokines and the pathogenesis of preeclampsia.
Am J Reprod Biol. 1997;37:240-249.
31
Need JA, Bell B, Meffin E, et al. Preeclampsia in pregnancies from donor
inseminations. J Reprod Immunol. 1983;5:329-338.
Redman CWG, Bodmer JC, Bodmer WF, Beilin LJ, Bonnar J. HLA antigens in
severe preeclampsia. Lancet. 1978;2:397.
32
GESTATIONAL IMMUNOENDOTHELIOSIS
Preeclampsia-Eclampsia
INTRODUCTION
According to the WHO 500,000 women die each year in the world as a result of
pregnancy-related complications, with PE appearing as the first cause. For the
epidemiologists Myers and Baker one patient dies every three minutes for this
cause. The perinatal mortality rate is not fully known.
Over the centuries the names and classifications of disease have proliferated as a
consequence of the ignorance of its etiology and in good part of its
pathophysiology. With regard to names, divisions and subdivisions, as of 1969
Rippmann, quoted by Lindheimer, had collected more than 60 names in English
and more than 40 in German applicable to the “hypertensive disorders of
pregnancy”, all of them controversial and in good part a product of what someone
called “delusional fabrication”. Two hundred and sixty years later, the name
Eclampsia proposed by Bossier de Sauvages in 1739 is still present. This term,
derived from the Greek word that means lightning, explosion or flash, was applied
to the sudden onset, as was said, of seizures in tranquil surroundings, a
conception that is contrary to the evidence in the sense that it is actually the
aggravation of a premonitory status with progressively alarming signs and
symptoms: Hypertension, proteinuria, and edema, among the first, and headache,
visual phenomena, and epigastric pain, predominating as secondary, and that
together make up the clinical picture of pre-eclampsia. According to Dexter,
33
mentioned by Dieckmann, the term had been used by Varandeaus in its text of
Gynecology published in 1619.
PURPOSE
To them will the author of these pages refer on a par with the description owing to
the true PE, under whose heading not a few fallacies have been swathed. At the
end of an updated review of the syndrome, the author intends to introduce a
terminology whose semantics has a meaning that translates the mechanism of
what someone has called the disease of hypotheses, and more recently the
disease of cascades.
The discovery of the human leukocyte antigen (HLA), the loci of genes encoding
the Major Histocompatibility Complex (CMH) located on the short arm of
chromosome 6 in humans by Jean Dausset (Fig 2), and of its functions by Baruj
Benacerraf (Fig 3) cleared the path of reproductive immunology so that, with the
exception of the erythrocyte, all nucleated cells in the human body, the sperm
included, are capable of expressing antigens, and therefore to induce humoral and
cellular responses.
Fig. 2 Fig. 3.
Jean Dausset Baruj Benacerraf
34
This was a fundamental discovery that led years later the English biologist Peter
Medawar (Fig 4), a follower of the theories of Australian Frank Mcfarlane Burnet
(Fig 5), to apply this knowledge to tissue grafting and organ transplantation.
Fig. 4 Fig. 5
Peter B. Medawar Frank Mcfarlane
They opened the way for pregnancy being considered as a transplant—in this case
a gestational one, as was confirmed after years by the research of Rupert
Billingham (Fig 6) and Alan Beer (Fig 7) in England and the US, and of Gérard
Chaouat (Fig. 8) in France, and for the potential explanation for its non-repudiation
under normal conditions, knowing that the gestational couple is formed by two
genetically foreign organisms, one coming from the father and expressed by the
fetus and the trophoblast, placed in contact with one of maternal origin. These
investigators adventured some possibilities: It was said in the beginning that the
uterus, as well as the anterior chamber of the eye, was an immunologically
35
privileged place, that the fetus had no antigenic properties, that the mother was
immunologically depressed, and, finally, that the placenta would act as a barrier to
prevent graft rejection. Currently, there are several mechanisms that explain the
tolerance to the isotransplant, which are intertwined taking as a fundamental
substrate the immune system and its biological modulation, as we will see below.
THE PLACENTA
COMPARTIMENTOS PLACENTARIOS
Y TIPO DE CELULAS
Líquido amniótico
Células dendríticas
Membrana amniótica
Decidua parietal
Trofoblasto corionico
Vasos fetales
Espacio intervelloso
Sinciotrofoblasto
Vellosidad terciaria
Citotrofoblasto
Beer Diagram
Gaps (lacunae) begin to appear in the syncytiotrophoblast that are filled with a
mixture of maternal blood from broken endometrial capillaries, and secretions from
the eroded uterine glands. The fluid in the lacunar spaces passes to the embryonic
disk by diffusion. As maternal blood flows into the lacunae, the embryo has access
to oxygen and nutrients. A communication is established between the arterial and
venous branches of the maternal vessels and the lacunae, and, therefore, a
mother-embryo circulatory system emerges. The oxygenated blood goes into the
lacunae from the spiral arteries in the decidua, and the deoxygenated blood is
removed through the veins of the decidua.
The 10-day embryo and its associated membranes are fully embedded in the
decidua. The gap in the decidual epithelium is filled in by an “occluding plug”, a
fibrinous blood clot. The end of the second week is characterised by the
appearance of the primary chorionic villi. The proliferation of the cells of the
cytotrophoblast produces cellular protrusions that grow into the
syncytiotrophoblast. It is believed that the growth of the cytotrophoblastic
protrusions is induced by the underlying extraembryonic somatic mesoderm.
These protrusions are the primary chorionic villi, the first stage in the development
of the human placental villi. The syncytiotrophoblast begins to produce a hormone,
human chorionic gonadotropin (hCG), which enters the maternal circulation
through the lacunae in the syncytiotrophoblast.
Very early, i.e., within 4 days after the formation of the zygote, the outer layers of
the blastocyst implanting into the endometrium, in the decidualizacion process,
give origin to the villi, which according to their degree of maturation will be of the
1st, 2nd, or 3rd order. They are surrounded by the cytotrophoblast, which later, after
losing its intercellular limits by the effect of phospholipids that act as adhesion
molecules, evolves into a syncytium directly exposed to the maternal blood that
bathes it in the intervillous space, in what is known as hemochorial placentation. In
accordance with its location, the trophoblast is initially villous, then it reaches the
decidua (anchoring trophoblast), penetrates it as well as the myometrium
(interstitial trophoblast), and later, through the spiral arteries, invades the maternal
circulation (vascular trophoblast) until it colonizes the pulmonary capillaries (tissue
trophoblast), where it will remain from the first few weeks of pregnancy, until its
completion. Its cells will be detectable in the maternal peripheral venous blood.
The trophoblastic cells are the source of several classes of antigens and receptors:
The first, HLA-G, C and E, recently described by Kovatz, expressed by the extra-
villous cytotrophoblast, are of great importance due to their involvement in the
antigen/antibody mechanisms involved in the gestational transplant, as will be seen
later. Also important are the TLX antigens or cross-reacting trophoblast/lymphocyte
antigens. These have been involved in the auto-anti-idiotypic network of the
immune response during pregnancy. The maternal recognition response is directed
against them.
The Membrane Cofactor Protein and the Decay-accelerating Factor are other
proteins expressed by the trophoblast. They function to control the excessive
activation of the complement, and there are some who believe that they also
control their lysis by the complement-activating antibodies. The trophoblastic cells
are also a source of retroviral antigens and receptors, placental alkaline
phosphatase, 2-macroglobulin, Fcg III receptors, and transferrin, all of them
involved in transplacental transport mechanisms.
TOLERANCE
Whereas the rejection of a transplant would occur due to the signals from the
tissue damage caused by the surgery itself, which would be interpreted as alarms
by the immune system to start the effector response, the non-occurrence of an
immune rejection or the maternal tolerance to the fetus is due to the fact that
healthy fetuses do not send damage signals.
There are different mechanisms involved in the tolerance of the mother to the
fetus. First, there is a selective expression of Class I HLA molecules by the extra-
villous trophoblast: Type G and C HLA molecules, as are now known the
molecules that have replaced the classical HLA-A and B. The expression of HLA-G
by trophoblast cells, in turn, is induced by maternal IL-10. The emergence of its
soluble forms, turns it into the pregnancy-maintaining molecule, allowing the
embryo to live in a genuine symbiosis with the mother, without being attacked by
natural killer cells (NK) or cytotoxic CD8 T lymphocytes in the blood from the
decidua, when both types of destructive cells are activated by the presence of
antigens from the father.
The soluble HLA-G molecule stimulates antigen-presenting cells, which lose their
ability to respond to stimulation by antigen, differentiating themselves into cells for
which this molecule has a suppressive function. HLA-C is a potent inhibitor of NK
cells. Moreover, for Beer, HLA-G of paternal origin is responsible for stimulating the
production of blocking antibodies in their camouflage role.
The paternal antigens, which are presented to the maternal immune system by the
trophoblast, induce the activation of B lymphocytes and the synthesis of antibodies.
However, these antibodies do not activate the complement, with the consequent
destruction of the cells of the embryo, due to the presence of immunosuppressive
factors secreted by the placenta and decidua; thus, maternal molecules MCP and
DAF locally transform the cytotoxic antibody by a response-blocking antibody; the
mechanism of that blockage is twofold: It binds to the antibody “kidnapping” it, and
induces its breakdown. Moreover, some trophoblast antigens expressed by the
syncytium are “camouflaged” by being covered by sialomucins or idiotype
antibodies, thus reducing their antigenicity so that the maternal immune system
fails to act against them.
Nitric oxide exerts key functions in the symbiosis between the mother and the
embryo. At the beginning of implantation, NO is produced by trophoblastic NOS in
the blastocyst and released to the surrounding milieu. Thus, it promotes the
relaxation of the endometrium that favors implantation, and also activates
guanylate cyclase, with the subsequent elevation of the intracellular levels of
GMPc. This second messenger is involved in several functions necessary for
development. However, high levels of NO, caused by the iNOS activity in maternal
macrophages induced by INF-γ as part of the inflammatory response, can induce
apoptosis in blastocyst cells through a mechanism involving the caspase cascade.
DECIDUA
Shortly after fertilization, the endometrium begins its transformation into decidua,
the maternal structure of the placenta, composed of polygonal cells with a large
nucleus. Apart from hosting trophoblastic cells, it also contains granulocytes,
macrophages, T and B lymphocytes, dendritic cells and Natural Killer cells (NK).
An entire cellular microcosm where the transplanted organ is recognized by its
host, and where there is large cybernetic activity—information and control, the
former exercised by antigens, and the latter by humoral and cellular responses,
with profuse involvement of cytokines, growth factors, and hormones.
Regulatory T cells accumulate in the uterus and suppress the response to the
paternal antigens. They increase in numbers in the first and third quarters. They
control the response through cellular interactions and the production of TGF β
L10. Cytokines are low molecular weight moieties with varied local effects.
According to the pattern of production of cytokines produced by T lymphocytes,
four patterns can be identified. The most important ones for local tolerance are the
T helper I (THI) and T helper 2 (Th2) patterns. Thl cells secrete interleukin 2 (IL-2)
and interferon gamma (IFN-γ), which generate inflammatory and cytotoxic immune
responses. In contrast, Th2 cells secrete IL-4 and IL-10 that promote humoral and
anti-inflammatory responses.
Type Th2 T-cells would be involved during normal pregnancy through the local
production of IL-4, IL-6, IL-10, granulocyte macrophage colony-stimulating factor
(GM-CSF), type 1 colony-stimulating factor (CSF-1), which would allow placental
growth and survival. In contrast, and according to this same thesis, a response of
the Th1 type would cause fetal resorption during pregnancy mediated by NK cells
(activated by INF-γ) or LAK cells (NK cells activated by IL-2).
The decidua shows a predominant Th2-type cytokine pattern, whose effect is not
limited to infiltrating leukocytes, with the trophoblast being the main source of IL-4
and IL-10. Although a balance between cytokines Th1/Th2 has been used to
explain a successful pregnancy, this paradigm may be oversimplifying.
Among the multifunctional activities of the placenta, its participation in the
dynamics of gestational graft tolerance or rejection stands out. Paternal HLA
antigens, among others, expressed by trophoblast and dendritic cells contained in
the villous stroma, also rich in antigens, induce both humoral and cellular maternal
responses.
The placenta is essentially an allograft. In the words of Dekker and Sibai, its
implantation involves a system of allogeneic recognition by NK cells rather than by
42
T cells. Nearly 75% of all decidual cells express CD45, thus reflecting their bone
marrow origin.
The syncytiotrophoblast is devoid of the classic HLA antigens of types I and II.
Although this prevents their recognition by maternal T-lymphocytes, the loss of
class I molecules results in these cells becoming susceptible to attack by NK cells,
but the union of a maternal IgG antibody to an 80 kDa protein present in the
syncytiotrophoblast may be important to prevent the attack of the NK cells. The
invading cytotrophoblast, where the cells are in direct contact with the maternal
tissue, expresses the relatively non-polymorphic HLA-G molecule described
by Kovats et al in 1990, which protects it from being recognized by NK cells. The
invading cytotrophoblast also expresses HLA-C. Considering important positions in
the binding peptide, HLA-C is also less polymorphic as compared with both HLA-A
and HLA-B. NK cells express killer-inhibiting and -activating receptors that are able
to recognize the HLA Class I molecules. The repertoire of receptors expressed by
the large natural lymphocytes differs from woman to woman. HLA-C seems to be
the most relevant in influencing the function of NK cells. The two killer-inhibiting
receptors that are specific for all of the HLA-C alleles, also recognize the HLA-G,
suggesting that the HLA-G is the universal inhibitor of histolysis caused by NK
cells.
43
REGNANCY IS A TRANSPLANT, AND AS SUCH CAN BE ACCEPTED OR
REJECTED
From the morphologic works of Brosens et al., changes are known to occur in the
uterus-placental circulation and more specifically in the spiral arteries, and
therefore in their endothelium, both in the basal and the radiated arteries in the
course of a normal pregnancy.
44
The middle layer of the arterioles is replaced by fibrinoid material which embeds
the invading trophoblast. There is low resistance to blood flow with the consequent
supply of nutrients to the developing fetus. The muscular layer of the vessels being
temporarily replaced, these become flexuous, true sack-like pseudoaneurysms,
thereby facilitating the uterus-placental perfusion that will be reflected in the inter-
villous space now turned into a high-capacitance, low-resistance, and low-pressure
system. The non-occurrence of the second migration has been interpreted as a
manifestation of immune graft rejection, and the absence of intravascular
trophoblast in the radiated basal arteries, combined with the imbalance between
the endothelial vasodilator autacoids, prostacyclin (PG12) and nitric oxide (NO),
and vasoconstrictors, thromboxane (TXA2) prostaglandin (PGH2) among others,
with a predominance of the latter, as the cause of the decrease in uterus-placenta
perfusion and therefore of the ischemia of the decidua, the inter-villous space, and
the placenta in general. There will be a production of O2-free radicals and lipid
peroxidation, which will inactivate NO and inhibit its release from the endothelium.
See the diagram.
Studies and publications by Dekker and B.M. Sibai have focused, among other
things, on the relationship between abnormal immune factors and preeclampsia.
The repeated exposure of a woman to the antigens contained in the sperm may
prevent preeclampsia. In contrast, the use of barrier methods doubles the risk of
developing the disease. Robillard et al interviewed 1011 women about maternity
and the duration of cohabitation prior to conception.
For both groups (primiparous and multiparous women), the duration of cohabitation
before conception was inversely related to the incidence of preeclampsia. Both
short exposure to sperm and artificial insemination with donor sperm led to a
significant increase in the risk of preeclampsia. Orally transmitted sperm antigens
stimulate the intestinal lymphoid tissue causing a type Th2 cellular response.
Based on this report, Dekker surveyed 41 primiparous and 44 multiparous women.
In the group with preeclampsia fewer women (44%) had a shorter time of
cohabitation with their partner before pregnancy as compared with the control
group (82%). However, the protective effect of exposure to semen is not fully
understood. This can occur because the T cells in the lower tract having special
receptors can recognize antigens and launch a sensitization response.
45
Additionally, TGF-beta 1 in the seminal plasma can initiate an endometrial
infiltration by leukocytes with an up-regulation of the expression of the granulocyte-
macrophage colony-stimulating factor, and a decreased expression of IL-2. This
causes a transient state of hyporesponse of T lymphocytes to paternal class 1
HLA.
Low levels of HLA-G of the invading cytotrophoblast can escape the maternal
immune surveillance. Colbert et al., were the first to observe a low level of mRNA
for HLA-G in the trophoblast of preeclamptic patients as compared with those with
a normal pregnancy. This may be the result of a low number of trophoblastic cells.
Will et al., found that the cells of the invading cytotrophoblast stained for
cytokeratin expressed HLA-G, whereas in eclampsia, cytotrophoblast clusters were
devoid of HLA-G. Similar findings were reported by Lim et al. The attenuated
release of HLA-G in the invading cytotrophoblast can be relevant in the
pathogenesis of preeclampsia, but whether this phenomenon is caused by a
trophoblastic alteration or the result of a structural genetic mutation is not yet
clarified.
PE has an immune origin. If preeclampsia is caused by immune maladaptation,
what mediators cause endothelial activation? When the leukocytes of the decidua
are activated, a series of mediators can be released that can act with endothelial
cells:
1. Cytokines
Cytokines are the first candidates to be the molecules responsible for endothelial
activation in preeclampsia. Most studies have reported increased levels of TNF-α
and IL-1 and increased levels of soluble TNF-α receptors and IL-1 receptor
antagonists. The serum levels of IL-2 (an important cytokine in the pathway of T
cells) are also increased in preeclampsia. Increased plasma levels of ceruplasmin,
complement activity, Alpha 1 antitrypsin, and haptoglobin, and decreased levels of
albumin and transferrin in preeclampsia, are characteristics of an acute-phase
46
reaction that could be related to increased levels of IL- 6. The source of these Th1
cytokines can be the leukocytes of the decidua. Decidual production of IL-2 is
increased in preeclampsia, which can lead to a proliferative and cytotoxic activity
also increased in the large uterine granular lymphocytes and also to the conversion
into lymphokine-activated killer cells.
It should be noted that the placenta can also produce Th1 cytokines. Placental
cells express erythropoietin, the prototype molecule for transcriptional regulation by
hypoxia in mammals. TNF-alpha and IL-1 have DNA sequences homologous to the
hypoxia response-enhancing element in the erythropoietin gene, thus promoting a
not yet proven potential molecular relationship between placental hypoxia and the
stimulation of the production of cytokines. Dysfunctional endothelial cells are
subjected to activation and produce leukocyte-endothelium adhesion molecules
that mediate the adhesion of the inflammatory cells. This inductive process is
mediated by cytokines produced by inflammatory cells and activated endothelial
cells. Preeclampsia is associated with increased levels of these adhesion
molecules, an increase that can be an early event. Increases in the levels of IL-6
and IL-1 receptor antagonists in preeclampsia are correlated with high
concentrations of these adhesion molecules.
Activated neutrophils release enzymes such as elastase, which can destroy the
activity of the endothelium. Elastase plasma levels are increased in preeclampsia,
and correlate with markers of endothelial dysfunction. In normal pregnancy both
the serum levels of TNF-α and IL-6 and their soluble receptors increase with
gestational age. The same is true for circulating immune complexes and
complement activation. Neutrophils in turn can be activated by factors of the
complement. Complement activation markers are increased in preeclampsia, and
47
correlate with the levels of elastase and neopterin, and with increased levels of IL-
6. Normal pregnancy is characterized by activated neutrophils, as evidenced by the
increase in intracellular ionized calcium and the circulating levels of neopterin,
lactoferrina, and defensin. Neutrophil activation is even more increased in
preeclampsia. The increase in the basal expression of neutrophilic CD 11b in
preeclampsia is a strong indication of neutrophil activation in vivo, and is correlated
with the plasma levels of uric acid. Sacks et al., found that in normal pregnancy
both granulocytes and monocytes exhibit significant increases in the levels of
CD11b, CD64 and CD14 as compared to those of the non-pregnant women,
whereas in preeclampsia there is a greater leukocyte activation characterized by
an altered phenotype and an increased intracellular production of reactive oxygen
species. Normal pregnancy may represent a “mild” inflammatory state, whereas
preeclampsia is characterized by an inordinate degree of inflammation.
Lipid peroxides and oxygen free radicals are highly reactive and very harmful
compounds. In normal pregnancy, the former increase, but antioxidants also do so
to counteract their toxic actions. In women with preeclampsia, however, the
circulating levels of lipid peroxides are increased, but antioxidant activity is
diminished. Activated leukocytes are an important source of free oxygen radicals in
preeclampsia. Furthermore, activated leukocytes can irreversibly convert
endothelial xanthine dehydrogenase into oxidized xanthine thus causing the
endothelial release of oxygen free radicals. The placenta is another special source
of free radicals in preeclampsia. With regard to the antioxidants, the problem in
preeclampsia is complex, but the disease in general cannot be characterized by an
antioxidant deficiency. Water-soluble antioxidant nutrients such as ascorbic acid,
alpha-tocopherol and beta-carotene are initially consumed, followed by lipid-
soluble antioxidants. The oxidative imbalance in preeclampsia is closely related to
the activity of TNF. Because antioxidants control the redox state of mitochondrial
glutathione, which is an important endogenous modulator of the production of TNF-
α, they selectively inhibit the release of this factor.
MORPHOPHYSIOLOGY
Since the conception, embryogenesis and development of the new being, until its
death, the endothelial organ has an inescapable involvement; hence its enormous
significance. It is composed of the following elements: Endothelial cells, pericytes
or subendothelial dendrocytes, vascular smooth muscle cells, the basal
membranes of each one of these elements, and the extracellular matrix. Together,
these elements form a histofunctional unit.
49
Controls the vascular tone and is a rheological vasomodulator, releases
vasodilating and vasoconstricting autacoids.
Perceives mechanical forces such as shearing, and therefore is sensitive to
tension and pressure.
Has both pro and anticoagulant properties; regulates platelet aggregation and anti-
aggregation.
Possesses an antigenic system of its own, captures immunological and chemical
signals.
Has anti-inflammatory properties.
Factory free radicals.
It is a para-neuron, belonging to the neuroendocrine system.
50
ENDOTHELIAL CELL INJURY IN PREECLAMPSIA-ECLAMPSIA
One feature of the endothelial cell injury that causes it to appear as a primary event
in preeclampsia is its tendency to self-accelerate. The loss of the cytoprotective
effect of the endothelium can lead to an increase of vasospasm and intravascular
coagulation, which can reduce the perfusion distal to the injury site. This
phenomenon can increase the extent of the endothelial cell injury creating a vicious
circle. Such a model is compatible with the clinical course of preeclampsia, which
only disappears after the expulsion of the placenta.
The obstetric conditions that increase the risk of preeclampsia include hydatidiform
mole, multiple pregnancy, and immune and non-immune hydrops fetalis. All these
conditions are associated with an increased trophoblastic mass and a relative
decrease in placental perfusion.
Reduced perfusion causes the release of circulating factors harmful to the vascular
endothelium. As a result, the perfusion of many organs is also reduced and
therefore the progression of preeclampsia, a vicious circle, leads to a greater
reduction in the perfusion of the placenta.
At present, the identity of the factor(s) that cause(s) the endothelial cell injury in
preeclampsia is only speculative. The data that have been presented suggest the
presence of anti-endothelial cell antibodies in women with preeclampsia. The
disappearance of the preeclampsia after childbirth and preliminary work that
showed the rapid disappearance of the cytotoxic effect of the serum after in the
postpartum period, indicate that this factor has a relatively short half-life and is
53
unlikely to be an immunoglobulin. Peptide factors such as platelet-derived growth
factor have also been proposed as potential candidates. Hubel et al., have
suggested that lipid peroxidation, which is increased in women with preeclampsia,
injures cell membranes and can play an important role in the disease. It would be
one more of the pathogenic vicious circles occurring in the syndrome.
The injured endothelial cells activate the coagulation cascade and lose their
integrity as a barrier against the extravasation of fluid into the extravascular space,
and as a buffer against the vasoconstrictor effect of normally circulating
vasopressors. The ensuing intravascular coagulation, loss of fluid from the
intravascular space and increased sensitivity to vasopressors result in the clinical
syndrome of preeclampsia. The process starts rapidly from the insufficient
trophoblastic invasion of the arteries of the placental bed, and manifests itself
clinically in late pregnancy as the endothelial lesion self-accelerates. Once the
situation starts, it will continue until the endothelial damage stops after delivery.
New perspectives on the endothelial cell function and the reinterpretation of the
information previously available indicate that preeclampsia is more than just
pregnancy-induced hypertension. The unification of the hypotheses that take into
account the multiplicity of abnormalities associated with the preeclampsia
syndrome will likely lead to the clarification and a better treatment of this complex
pathological process. This much is suggested by the papers published by
renowned immunologists and gynecologists, Roberts and Taylor among others.
The endothelium is involved to various conditions, such as the abnormal
implantation of the embryo and several types of abortion, abnormal placentation,
dysfunctional uterine bleeding, endometriosis and adenomyosis, gestational
trophoblastic disease and, of course, cancer, with the angiogenesis process in
charge of the endothelial cells playing a significant role in all of them; its
involvement in the evolution of the septic shock of gynecological and, more
frequently, of obstetric cause, is also known. But it is in in the pathogenesis,
development and consequences of Preeclampsia-Eclampsia, one of the most
characterized enigmas of medical science, where the endothelium plays a leading
role. The efficient cause of the disease has remained in the twilight through
history, and at the dawn of the twenty-first century it continues to pose a universal
challenge because, in spite of the efforts of researchers and clinicians, the
maternal and perinatal morbidity rates have not been reduced to a significant
extent, as well as its incidence rate. Therefore, for the World Health Organization
(WHO) Preeclampsia-Eclampsia “is a priority public health problem in the whole
world”. The ignorance of its etiology has not been able to prevent its occurrence,
which until the present remains an inexorable phenomenon. Notwithstanding the
above the contributions of the morphophysiology, immunology, endotheliology and
molecular biology have made it easier to understand during the past 20 years in
good part of the reason of its clinical manifestations, signs and symptoms.
54
The above refers to the local phenomena that occur both in normal situations and
in the cases of Preeclampsia-Eclampsia. It is obvious that in the general circulatory
system the effects of the disease on the endothelium of blood vessels are equally
important; liver, kidney and brain circulation is severely impaired in the mother, but
the rest of her organs and systems do not go unscathed.
The damaged vascular endothelium also expresses antigens, which, at their turn,
may turn their cells important immune targets; anti-endothelium antibodies are
often reported that, together with immune complexes and endothelial cells, alter
the function of their autacoids in addition to promoting the release of mitogens and
growth factors detectable in the laboratory before the onset of the signs and
symptoms of the disease.
Due to its strategic location, between the circulating blood and the vascular wall,
the endothelium interacts with both cells and neurohormonal mediators, thus
controlling the state of vascular contractility. The most important stimulus for the
release of nitric oxide (NO) is shearing stress and the narrowing of the pulsatile
vascular wall, as well as the systemic and local release of vasoactive substances.
56
role in maintaining the fibrinolytic balance and exhibits an antiplatelet effect through
the release of NO and prostacyclin.
Endothelin promotes the proliferation of smooth muscle cells and the secretion of
extracellular matrix, thus contributing to the formation of atherosclerotic plaques. It
is a regulatory peptide distributed through many organic systems, with powerful
physiological and pathological effects, preeclampsia among others.
The similarity of endothelin with neurotoxins suggests that its activity is based on
the modulation of ionic channels. Its effect is known to depend on the presence of
calcium, and that is not modified by cholinergic or serotoninergic blockade. It is
now known that ET-1 promotes the entry of calcium into the cells by two
mechanisms, 1) direct non-dihydropyridine-dependent calcium mobilization; 2)
calcium channel-dependent movement. The role of ET-1 in vascular tone
regulation is indisputable; for this effect to occur an intact endothelium is required,
where the actions of prostacyclin and NO can concur (both stimulated by ET-1) to
antagonize its vasoconstrictor effect. The following biomolecular effects of
endothelin are known: 1) A positive inotropic effect; (2) A positive chronotropic
effect; 3) Mobilizes intracellular calcium; 4) A mitogenic and myocyte hypertrophing
action; 5) Vascular remodeling; 6) Inhibits renin release; 7) Stimulates vasopressin,
adrenaline, atrial natriuretic factor, nitric oxide, and prostacyclin activity; 8)
Atherogenic action; 9) Constricts both efferent and afferent glomerular arterioles.
The sum of all these mechanisms controls both vascular tone and blood flow at the
systemic level, and with the necessary changes at the local level, as required.
57
deportation; 5) Cytokines; 6) Free radicals (oxidative stress); 7) Leukocyte
membrane antigens, intercellular adhesion molecules) and 8) endothelins.
Free radicals are the products of a complex process involving enzyme systems
that act in PMN cells, macrophages, and endothelial cells. The superoxide radical
is generated by a specialized enzyme system (NADPH oxidase) situated in the
plasma membrane and in the phagocytosis vacuoles. NADPH provides electrons
and requires a flavoprotein, a ubiquinone and cytochrome b (b245 or B558) as
coenzymes. The spontaneous or catalytic (by the superoxide dismutase)
interaction of superoxide molecules generates hydrogen peroxide that is not a free
radical, but is able to exert toxic effects through two main mechanisms: The
myeloperoxidase / halide / hydrogen peroxide system (Klebanoff system) and the
formation of the hydroxyl radical.
High serum levels of cholesterol, triacylglycerides (TAG), VLDL, LDL and low
levels of HDL are involved in endothelial damage, and for this reason they have
been associated with the development of PE. Lipolytic activity is increased in
women with preeclampsia, determining a greater uptake of free fatty acids by
endothelial cells that are then resterified to TAG. In preeclampsia, lipids can
accumulate in endothelial, glomerular, and myocardial cells (chronic hyperlipidemia
can alter the structure and function of endothelial membranes, with the consequent
endothelial injury and dysfunction; lipoproteins accumulate in the tunica intima in
sites of injury, thus providing an opportunity for oxidation). Oxidized LDL are
cytotoxic for endothelial cells and avidly captured by macrophages, forming foam
cells. All these changes are considered as precursors of the formation of
atheromatous plaques.
An increase in oxidative stress and lipid peroxidation has been found in placentas
of women with preeclampsia (along with their products in the serum of these
patients), which supports the hypothesis of the release of placental substances that
cause an extensive endothelial damage; an imbalance results in the factors
produced by the endothelium: Decreased production of and response to nitric
oxide (NO), a vasodilator, which inhibits the migration of smooth muscle cells in
58
blood vessels, platelet aggregation and leukocyte adhesion to the endothelium,
and, as mentioned before, increases the production of and response to endothelial
substances that promote vasoconstriction and platelet aggregation.
For Roberts and Taylor (op cit.), the current understanding of preeclampsia has
been biased by an excessive attention to the high blood pressure that
accompanies the disease. Multiple studies indicate that pathological and
pathophysiological changes in women with preeclampsia are not the result of an
increase in blood pressure, and that the perinatal outcome does not correlate well
with the degree of elevation. Necropsy findings in women who died with eclampsia
are best explained by hypoperfusion of end organs rather than by high blood
pressure. In addition, the morphological changes found in in the kidneys of women
with preeclampsia are not seen in any other form of hypertension. Other
pathophysiological changes, such as the activation of the coagulation cascade,
increased sensitivity to vasopressors, reduced plasma volume, and alterations in
the function of the renal proximal tubule, precede the increase in blood pressure.
These authors have suggested that preeclampsia can be explained by the
endothelial dysfunction at the expense of factors produced as a result of a
decreased placental perfusion.
EPILOGUE
From the paragraphs contained in this review of concepts one can deduce that
preeclampsia-eclampsia has an immunogenetic basis, an opinion supported by
statistical, epidemiological, and clinical analyses, by laboratory and
histopathological assays; and by the experimental recognition of antigens,
antibodies, cytokines, hormones, autacoids and other elements that are actively
involved in the decidua, the organ where the transplant is recognized since its
implantation. Preeclampsia-eclampsia is a continuum that starts at fertilization,
follows during placentation, and ends with the endothelial involvement. It is an
abnormal biological process of paternal origin through his antigens or of maternal
origin through her antibodies and an irregular cytotoxic response; both processes
could be synergistic.
The host has complex and subtle immunomodulatory mechanisms that can fail for
various causes, resulting in the disease. Great importance has been given to
59
trophoblastic antigens, especially the recently discovered HLA-G factor, and their
relationship with T cells and the TH2 phenomenon. Free fatty acids, lipid
peroxidation, free radicals, tumor necrosis factor, fibronectin degradation products,
fragments deported from the trophoblast as a result of placental ischemia,
exaggerated inflammatory response, activation of neutrophils by leukotrienes with
release of elastases and other proteases that injure the endothelium, increased
concentration of interleukins 1 and 6, are all factors involved in endothelial
dysfunction. Endothelial dysfunction at its turn involves disorders affecting
angiogenesis, coagulation, and rheology, with the activation of autacoids and its
consequences: Vasoconstriction, thrombosis and atherosis, all of which intervene
in the alteration of the homeostasis and contribute to immune maladaptation or are
its consequences.
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