Figure 3: Complement involved in clearing apoptotic cells and
inducing immune tolerance under static state. In the static state,
antigen presenting cells (APC) can orderly phagocytose apoptotic cells
free from inflammation and adaptive immune activation. Complement
activation products C3b/iC3b/C3d and pattern recognition molecules C1q,
MBL can bind to DAMP on the surface of apoptotic cells, these molecules
bind to specific receptors C1qR, CR1, CR3, CR4 on the surface of APC to
mediate phagocytosis and degradation of apoptotic cells. Studies have
found that this process can induce APC to form a tolerance phenotype,
secrete inflammation inhibitors, down-regulate the expression of
costimulatory molecules (MHC, CD86, and CD40), and up-regulate the
expression of inhibitory molecules (PDL-1 and PDL-2). Thereby reducing
the efficiency of antigen presentation, inhibiting the activation of
downstream T cells activation, proliferation and differentiation.
Eventually, the complement system eliminates apoptotic cells in time and
induces immune balance and tolerance.
C1q gene defect is a strong risk factor for SLE48. It
may be related to C1q mediated “waste disposal” disorder as well as
subsequent disrupted immune tolerance. Increased apoptotic cells, free
floating DNA fragments and sub-cellular debris were detected in tissues
in SLE patients, which act as self-antigen to provoke immune activation.
Interestingly, preeclampsiahave many similar pathological features to
SLE, and the risk of SLE patients suffering from PE increased by 2-4
times 49. PE women have an increased accumulation of
apoptotic cells and its debris in placenta and maternal circulation50. Large amount of plasma free-floating DNA in the
maternal circulation were detected in pregnant women before the onset of
PE 51. Indeed, evidence shew that failure in
complement-facilitated phagocytosis of debris may contribute to SLE as
well as pathologic pregnancy 52,53. C1q gene defect is
a strong risk factor for SLE 54,55, and C1q deficiency
can also lead to pathological pregnancy like PE, and anti-C1q antibodies
is associated with recurrent pregnancy loss (RPL)56-58. The level of C1q in the placenta of PE patients
are significantly higher than those of normal pregnant women. Excessive
complement activation leads to increased local recruitment of C1q in the
placenta, especially in areas of fibrinoid necrosis in maternal decidua27. And excessive placental C1q level may be an
indicator of adverse pregnancy outcomes. While too low C1q levels may
impair the elimination of apoptotic cells and also subsequent immune
homeostasis in placenta which threaten pregnancy. C1q deficiency can
lead to pathological pregnancy like PE, and anti-C1q antibodies is
associated with recurrent pregnancy loss (RPL) 56-58.
These evidences indicate that C1q play an important part in the
maintenance of pregnancy.
MBL, the initiator of the LP, is able to bind to specific glucosamine on
the pathogen surface. In humans, MBL deficiency can lead to bacterial,
fungal and viral infections 59. The level of MBL in
the peripheral blood increased in early pregnancy 60.
Endovascular trophoblasts, decidua stroma cells, endothelial cells, and
Hofbauer cells in placenta can express MBL 61. MBL
weakens
the combination ability of LPS to DC cells and inhibits the
differentiation of immature DC cells into the mature one and reduces
their production of IL-12, TNF-α, thus preventing allogeneic T cell
proliferation 62. Moreover, MBL can also suppress TLR3
activation then the following pro-inflammatory cytokine production63, suggesting a possible anti-inflammatory property
of MBL in special conditions. Women with low MBL have excessive TNF-a
production 64, which can induce inflammation and lead
to further trophoblast cell dysfunction 65. Genetic
variations of the MBL-2 gene are associate with susceptibility to SLE
and PE 66,67. MBL2 gene polymorphisms leading to MBL
deficiency are at higher risk of miscarriage in women with rheumatoid
arthritis (RA)68. It has reported that61,69,70 low levels of MBL during pregnancy is closely
related to placenta male-function, such as placental lesions,
inflammation which leading to low gestational age and low birth weight71, recurrent abortions 69,70,72,73,
IUGR, PE, premature delivery and chorioamnionitis74,75.
2.2 C3b/iC3b and its receptors
C3 are mainly synthesized by the liver. But interestingly, placental
locally synthesize complement proteins in high level. The central
components C3, C5 and cascade-components responsible for C3 activation,
like complement factor B (FB), factor D (FD), C1s, C2[Figure 1] are
also found in pre-implantation embryo as well as chorionic tissue76,77. The mRNA analysis unexpectedly revealed the
presence of C4, C3, C6, C7, C8 and C9 in both freshly extracted
trophoblasts and HTR8/SVneo trophoblast cell line, and C4, C3, C6
protein were also detected in its cell supernatant. Cytotrophoblasts
analysis even found complement components at tissue level exceeding in
macrophages known for synthesizing complement components78.
Although complement over-activation is related to many pathological
pregnancy events, now, large amount of immunological and histological
evidences show that complement split products are also significantly
increased in serum and placental physisological pregnancy, indicating an
vigorous systematic and local activation of complement during pregnancy.
Lokki et al. (2014) and Buurma et al. (2012) 79,80demonstrated that C1q along with C3b/iC3b/C3d are stained in normal
placenta and even in pre-implantaion embryo cell surface and zona
pellucida (ZP)81.
C3 is the center complement protein. C3 is cleaved by C3 convertase into
C3a and C3b. C3b is further processed into a potent opsonin iC3b
[Figure1]. iC3b condense on the surface of the apoptotic cells to
enhance its phagocytosis through diverse receptors like CR1, CR3 and
CR4. CR1 (CD35) expressed on most nucleated cells as well as
erythrocytes, it not only regulates C3 breakdown but also involved in
enhancing DAMPs and immune complex phagocytosis
procedure82. CR3 (CD11b/CD18) and CR4 (CD11c/CD18) are
expressed on phagocyte like monocytes and macrophages. They stimulate
iC3b-mediated phagocytosis83,83. Specific antibody
blocking the chains of CR3 can inhibit of up to 40% of apoptotic cell
clearance by splenic DCs 85. iC3b/CR3 is required for
long-term tissue homeostasis86,87, increased apoptotic
cells accumulation, pro-inflammatory cytokines secretion and accelerated
cell degeneration were detected in the brain of CR3 deficient mice88. In addition, these complement receptors also
involved in inducing an immune tolerance state to facilitate removal of
apoptotic cells without elicit adaptive immune activation and further
inflammation.
CR1 was defined as a CIP for its multiple actions in regulating
complement activation which highly expressed on erythrocytes and some
myeloid cells. CR1 can bind to C3b/ C4b trapped immune complexes89 thus transfer them to the phagocytes (like Kupffer
cells, macrophage) in the liver or spleen 90 for their
engulfment 91 (Figure 4). Aligning with the growing
evidences, CR1 was found play context dependent roles in inducing immune
tolerance 92,93. Low level of CR1 was detected on B
cells in rheumatoid arthritis (RA) patients. CR1 is involved in blocking
BCR induced B cell proliferation and differentiation into plasmablasts,
and then antibody production 94. iC3b dose dependently
reduces the TLR9 stimulated activation markers of B cells through CR1.
TLR9 induced cytokine production, antibody production, and B cells
proliferation were all impaired through iC3b/CR1 interaction95. As mentioned above, CR1 can mediate the
elimination of circulating immune complexes and participate in inducing
B cell anergy to self-antigens depending on the micro-environment.
Because of the immune complex clearance and complement regulating
ability, CR1 deficiency are involved in some inflammatory or
self-tolerance disorder-related disease like SLE. SLE is characterized
by the accumulation of IC and auto-antibodies 96, and
it can induce systematic chronic inflammation thus leading to tissue
destruction. Increased apoptotic cell, sub-cellular debris and ICs
derived from the placentation procedure pose a greater challenge to
mother, thus, generally, SLE become worse during pregnancy97. Reduced cell level of CR1 was detected in patients
with SLE, an independent risk factor leading to pathological pregnancy98. At present, it is not clear whether CR1 is
directly involved in adaptive immune tolerance in the local placenta.
However, it is currently known that CR1 gene defects are related to
pregnancy diseases such as PE and premature birth, and it is more common
in the severe HELLP syndrome 99, where inflammation is
an important feature of all these diseases 99,100.