Current Immunology Reviews (Discontinued) - Volume 5, Issue 3, 2009

The maternal immune-system must be modified in order to tolerate the semi-allogeneic conceptus. Because maternal alloreactive lymphocytes are not depleted, local mechanisms have to play a key role in altering the immune response. Both humoral and cellular immunity are affected. Th1/Th2 cytokine balance is not essential to have normal pregnancies. Alloreactive Th1 cells must be regulated, for instance, by regulatory T cells. Animal and human experiments showed that Treg number and/or function are diminished in spontaneous abortions. Miscarriage can be prevented by transfer of Treg from normal pregnant mice. Treg at the maternal-fetal interface avoid fetal allo-rejection by means of the creation of a “tolerant” microenvironment characterized by expression of IL-10, TGF-β, HO-1 and IDO, rather than diminishing the Th1 cytokines. Treg or CTLA-4 expression on Treg enhances IDO expression. T-regFoxp3+ can increase placental HO-1. In turn, HO-1 may lead to up-regulation of TGF-β, IL-10 and CTLA-4. The role of progesterone, β-HCG and hPGH and their relation to uNK cell and Treg activity are discussed. A new linking between trophoblast apoptosis, Treg, aPL and NK cell is also raised. Finally, a relationship between HLA-haplotypes and HLA-G molecule, Babs, NK cells, Th1/Th2/Th3/Tr1/Treg balance, aPL and cytotoxic TCD8+, CD4+ is discussed.

Serine Proteases control a wide variety of physiological and pathological processes in multi-cellular organisms, including blood clotting, cancer, cell death, osmo-regulation, tissue re-modeling and immunity to infection. T lymphocytes are required for adaptive cell mediated immunity and serine proteases are not only important for effector function but also for homeostatic regulation of cell numbers. Serine Proteases Inhibitors (Serpins) are the physiological regulators of serine proteases activity. In this review, I will discuss the role of serpins in controlling the recognition of antigen, effector function and homeostatic control of T lymphocytes through the inhibition of physiological serine protease targets. An emerging view of serpins is that they are important promoters of cellular viability through the inhibition of executioner proteases. This will be discussed in the context of the T lymphocyte survival during effector responses and the development and persistence of long-lived memory T cells. The potent anti-apoptotic properties of serpins can also work against adaptive cellular immunity by protecting viruses and tumors from eradication by cytotoxic T cells (CTL). Given the important role serpins play in T lymphocyte immunity, I will review the progress to date in developing new immunotherapeutic approaches based directly on serpins or knowledge gained from identifying their physiologically relevant protease targets.

Natural killer (NK) cells constitute a major component of the innate immune system and have key roles in early immune responses to pathogens. Although NK cells can be directly activated by pathogens, other sensor cells which recognize pathogen-associated pattern molecules are required for the full activation of NK cells. The NK-activating capacity is observed in myeloid dendritic cells (mDCs), plasmacytoid DCs, macrophages and monocytes. The tropism of the pathogen and the route of invasion influence which sensor cells participate in the NK activation. Influenza virus, measles virus and respiratory syncytial virus can infect human mDCs and induce the ligands of the NK activating receptor NKG2D. Up-regulated NKG2D ligands on mDCs contribute to the mDC-mediated NK activation. By contrast, HCV does not replicate in mDCs and is not an immunostimulatory agent against mDCs. In this case, mDCs are stimulated after detecting dsRNA in the HCV-infected apoptotic hepatocytes via TLR3 and elicit NK activation though a direct cell/cell contact. The TLR3 signal seems to lead the up-regulation of key molecules on the surface membrane of mDCs to enhance NK activity by direct linkage.

T lymphocyte helper (Th) responses start from the activation of naive Th0 cells that get polarized towards Th1, Th2, Treg and Th17. Such polarization is achieved by delivering activation stimuli to naive T cells in the presence of given cytokines and by triggering certain receptors rather than others; indeed, the cytokine conditioning environment where cells get their activation signal is considered pivotal in determining the quality of the T cell response, and viruses seem to exert at least part of their influence on the antiviral response through cytokines. Indeed, the direction of polarization, and immune reactivity in general, have long been known to be influenced by viral infections. Because dendritic cells (DCs) not only start a response by Th0 but are also in charge of polarizing the Th immune response, they are also key determinants of the pathogenetic outcome of viral infection.

The human endometrium is an important site for contact between the host and pathogens ascending the reproductive tract, and thus plays an important role in female reproductive tract immunity. Toll-like receptors (TLRs) are involved in recognition of pathogens and ligation of TLRs results in the production of cytokines and chemokines important for both immune and reproductive functions of the endometrium. The reproductive tract is unique since it hormonally controls expression levels of soluble immune mediators and influx of immune cells to mediate these functions. Since TLRs have the potential to induce alterations in cytokine production through ligand recognition, TLR ligation could significantly affect endometrial health. This review focuses on the importance of TLR expression and function within the endometrium and examines the impact of steroid hormones on TLR function. The importance of TLR3 is also reviewed, as it is expressed at high levels during the window of implantation (WOI), when other TLRs and antiviral molecules are either not expressed or expressed at very low levels. Although TLR3 is not the only TLR demonstrating cycle-dependent expression, its upregulation during the WOI may indicate a unique role for TLR3 in the functioning of the endometrium and in preparation for embryo implantation.

Many leukocytes express on their surface specific receptors for immunoglobulins, termed Fc Receptors. Fc Receptors are a key component of host defense due to their ability to bind antibodies attached to infected cells or invading pathogens, thus leading to their destruction. Activation of various leukocytes through Fc Receptor stimulation results in the initiation of a plethora of cellular responses aimed at the destruction of potential pathogens. Consequently, there has been a lot of interest in elucidating the biochemical signals that Fc Receptors promote to activate these leukocyte functions. This review describes the main types of Fc Receptors, and the signal transduction pathways that are initiated by these receptors in various leukocytes. Recent discoveries on the modulation of Fc Receptor signaling by association with lipid rafts are also discussed. Emphasis is made on the signaling mechanisms governing phagocytosis, which is perhaps the best-characterized Fc Receptor-mediated cellular response. In addition, new findings on the regulatory role of Fc Receptors on immune function are also discussed.

In preeclampsia, poor placentation is an important predisposing factor and endothelial damage underlies disease manifestations. Although the processes leading to endothelial damage are not fully understood, the maternal innate immune system, particularly neutrophils, has been identified as key players. In preeclampsia there is evidence of increased neutrophil activation, marked by up-regulation of neutrophil integrin expression, and increased production of the protease elastase and reactive oxygen species. Direct evidence of neutrophil mediated endothelial cell damage is also reported. The placenta may release various factors that stimulate neutrophil activation in response to reduced perfusion due to poor placentation. They include increased production of pro-inflammatory cytokines, oxidative damage products, and syncytiotrophoblast microvesicles. The relationship between neutrophil activation and endothelial damage argues for a role for neutrophils in the pathogenesis of preeclampsia. In this review, we focus on the phenotypic and metabolic characteristics of neutrophils in normal pregnancy and preeclampsia in order to identify the potential cellular and molecular processes that contribute to the maternal endothelial damage seen in preeclampsia.