IMPACT OF MATERNAL HIV INFECTION AND HEART ON PLASMA IMMUNOGLOBIUNS AND CYTOKINE SECRETION BY B AND T LYMPHOCTYTE

1.1Background of the Study

Pregnancy, also known as gestation, is the time during which one or more offspring develops inside a woman (Shriver, 2015). A multiple pregnancy involves more than one offspring, such as with twins (Wylie, 2005). Pregnancy can occur by sexual intercourse or assisted reproductive technology (Shehan, 2016). Childbirth typically occurs around 40 weeks from the last menstrual period (LMP) (Abman, 2011 and Shriver, 2015). Pregnancy is typically divided into three trimesters. The first trimester is from week one through 12 and includes conception, which is when the sperm fertilizes the egg. The second trimester is from week 13 through 28, while the third trimester is from 29 weeks through 40 weeks (Shriver, 2015).

Normal pregnancy is a state characterized by many physiologic haematological changes, which appear to be pathological in the non – pregnant state (Chandra, 2012). The haematologic system must adapt in a number of ways such as provision of vitamins and minerals for foetal haematopoiesis (iron, vitamin B12, folic acid) which can exacerbate maternal anaemia, and preparation for bleeding at delivery, which requires enhanced haemostatic function, while these changes facilitate healthy pregnancy, they also increase the risk of some conditions (e.g. venous thromboembolism) (Mohammed et al., 2016). Pregnancy is influenced by many factors, some of which include culture, environment, socioeconomic status, and access to medical care (Yip, 2000). Haematological profile is measured all over the world to estimate general health, because, it is a reliable indicator and is a simple, fast and cost-effective test (Shen et al., 2010). During pregnancy, changes occur and can be observed in haematological indices such as Red Blood Cell (RBC) count, haemoglobin (Hb) concentration platelet (PLT) count, and white Blood cell (WBC) count. For example, the RBC and PLT counts are decreased, partly as a result of the physiological haemodilution that occurs in pregnancy (Dhariwal et al., 2016), while others are increased, such as the WBC count (Akingbola et al.,2006). Many of the haematological indices are also influenced by many factors such as sex, seasonal variation, lactation, healthy and nutritional status (Smith, 1993). Some studies such as Osonuga et al., (2011) and Shaw et al., (2010), have also identified the haematological indices as being affected by pregnancy.

Pregnancy is a physiologically immunocompromised state during which alterations in T – lymphocyte subsets may occur (Tanjong et al., 2012). It requires physiologc adaptations in all

maternal systems including the immune system. This process is complex and includes modifications at different levels and compartments of the maternal immune system. Although many of these changes are only partially explored and understood, recent investigations have shown that during pregnancy, maternal circulating immune cells undergo modifications in cell counts, phenotypes, functions, and ability to produce soluble factors, such as cytokines. The ultimate goal is to establish and maintain a successful pregnancy, which involves a state of selective immune tolerance, immune suppression and immunomodulation in the presence of a strong antimicrobial immunity. The mammalian immune system has evolved to co-exist with these needs by down-regulating potentially dangerous T-cell-mediated immune responses, while activating certain components of the innate immune system, such as monocytes and neutrophils. This unique dysregulation between different components of the immune system plays a central role in the maternal adaptation to pregnancy (Luppi, 2003).

Cytokines are signaling proteins, usually less than 80 kDa in   size, which regulate a wide range of biological functions including innate and acquired immunity, hematopoiesis, inflammation and repair, and proliferation through mostly extraellular signaling. They are secreted by many cell types at local high concentrations and are involved in cell - cell interactions,have an effect on closely adjacent cells, and therefore function in a predominantly paracrine fashion. They may also act at a distance by secretion of soluble products into the circulation (endocrine or systemic effect) and may have effects on the cell of origin itself (autocrine effect) (Chung, 2009). Despite the unique ability of the immune system to highly specific antigenic recognition, its susceptibility to cytokines allows these molecules to dominate all kinds of immune reactions. These proteins, produced in an autocrine or paracrine fashion, bind to specific receptors initiating thus a cascade of reactions on different targets having beneficial or harmful effects since their redundancy and/or pleiotropic nature may account for all possible reactions (Vassiliadis et al., 1998). With T-helper (Th) lymphocytes being the major producers of cytokines, it is believed that the equilibrated balance of Th1 versus Th2 cytokines defines the welfare of the organism. If Th1 type cytokines are indeed deleterious to pregnancy, T- helper 2(Th2) type cytokines may be conducive to pregnancy and Th2 type immunity has been proposed to be the normal profile in successful pregnancy (Raghupathy et al., 2000).

In Pregnancy, Th1-1mediated responses were shown to induce abortion (Wegman et al., 1993) and therefore Th1 was regarded as „the bad‟ immune reaction. Accordingly, all cytokines countering Th1 responses were regarded as Th2, like IL-4 and IL-10. Although IL-10 was originally launched as a cytokine produced by Th2 cytokine, it is not strictly a Th2 cytokine, but

rather a more general immunomodulating cytokine. Indeed IL-10 inhibits Th1, but in fact it also inhibits Th2 immunity, as it does inhibit several other inflammatory mediators (Commins et al., 2010). IL-10 is better classified as an anti-inflammatory cytokine. In the simplified Th1/Th2 model, pro-inflammatory cytokines are often regarded as belonging to the Th1 subset in fields where Th1 is the disease-promoting response, for example, in organ-specific autoimmunity and in pregnancy. Of note, inflammation is a hallmark of other T helper subsets like the Th2. Consequently, pro-inflammatory cytokines like tumor recrosis factor (TNF) are also present in Th2-mediated pathology such as allergic inflammation, and the pro-inflammatory cytokine IL-6 is, for example, involved in the development of Th17. Therefore, it is important to view cytokines from different perspectives and distinguish the T helper (Th1/Th2/Th17) perspective from the pro-versus anti-inflammatory perspective. However, the most relevant approach is to denote the referred cytokine by name rather than to its belonging to a certain group. Here, IL-2 deserves some extra attention because, it is often referred to as a Th1 cytokine, although it is a growth factor necessary for the activation of all the T helper subsets (Commins et al., 2010).

The immune system, in order to ensure protection from microbial infections, auto-immune reactions, graft rejection, allergies etc, shifts the balance towards one of the other family of cytokines (Th2). Pregnancy is a natural example of an immune reaction occurring for a determined time period in the organism which opposes the rules of graft rejection. The semi – or allogenic fetal components growing in the privileged site of uterus, not only escape maternal immune attack but are supported by the maternal immune system (Vassiliadis et al., 1998).

Normal pregnancy is a hypercoagulable state, a physiological safety valve aimed at preventing excessive maternal blood loss at delivery (Ibeh et al., 2015). Pregnancy and the puerperium are well-established risk factors for venous thromboembolism (VTE), a disease that includes pulmonary embolism (PE) and deep venous thrombosis (DVT).Approximately 30% of apparently isolated episodes of PE are associated with silent DVT, and in patients presenting with symptoms of DVT, the incidence of silent PE raises from 40-50%. VTE is both more common and more complex to diagonose in those patients who are pregnant than in those who are not (Marik and Plante, 2008). ). Women are up to 5times more likely to develop DVT during pregnancy than when not pregnant (Jacobsen et al., 2008).

Estimates of the incidence of Venous Thrombo Embolism(VTE) vary between 1 in 1000 and 1 in 2000 deliveries (Hui and Lili, 2012) and the incidence is higher during the third trimester of pregnancy, and in the puerperium. Pregnancy is normally associated with significant changes in all aspects of the classic triad of Virchow: Venous stasis, endothelial damage and enhanced

coagulation, to the extent that the procoagulant effect becomes dominant (O‟Riordan and Higgins, 2003). In late pregnancy the concentrations of many coagulation factors are increased to twice their levels in non-pregnant women (Bremme, 2003). The modifications of the coagulation system result from hormonal changes and are part of a complex physiological adaptation of the human female organ to pregnancy. Its purpose is to ensure rapid and effective control bleeding from the placental site and prevent fetal haemorrhage during delivery and the puerperium. Placental separation is a severe and acute challenge to haemostasis (Bremme, 2003).

This study was undertaken to determine the CD4+ cell count, and levels of some cytokines and haematological parameters of apparently healthy pregnant women attending Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra state.