The HPA Axis

HPA Axis

The HPA axis has been receiving a lot of attention in recent studies. The studies are looking at potential pre-natal and post-natal roles it plays in schizophrenia. When the body becomes under stress, the hypothalamic-pituitary-adrenal axis (HPA) is used by the hypothalamus to mediate cortisol output (Walker, 2002). For pre- and post-natal development, the HPA axis is an important stress defense (Zhang et al., 2014). The HPA axis releases corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH) and glucocorticoids (GC) (Misiak et al., 2014). Glucocorticoids, like cortisol, are stress hormones and function multiple ways which include the inhibition of inflammatory response and also has an influence on cognitive functioning

(Misiak et al., 2014) as well as other functions that are not listed. Bourdeau et al. (2005) found that repeated exposure to glucocorticoids have been shown to lead to brain structure abnormalities that are found in patients of schizophrenia; these abnormalities include ventricular enlargements, hippocampal atrophy and cortical atrophy. Walker (2002) looked at baseline levels of glucocorticoids in people with schizophrenia and found they have a heightened baseline level and that the severity and expression of symptoms are positively correlated with cortisol levels. Studies are starting to look at the impact of stress on the HPA axis, and prenatal immune activation during maternity.

Maternal HPA Axis
The developing fetus is protected from maternal factors, such as cortisol, other cytokines and maternal factors by the placenta (Gluckman, Hanson and Spencer, 2005).The enzyme 11ß-hydroxy steroid dehydrogenase Type II (11ß-HSD2) is a placenta barrier enzyme that has be shown to protect the developing fetus from maternal cortisol by converting it into an inactive cortisone (Benediktsson, Calder, Edwards and Seckl, 1997). O’Donnell, O’Connor and Glover (2009) found evidence supporting the down regulation of 11ß-HSD2 due to prenatal stress that allowed elevated cortisol levels to cross; excess cortisol levels can decrease ACTH levels and alter adrenal growth and fetal maturation.
They also noted that there is a possibility the placenta barrier enzyme, 11ß-HSD2, may affect other functions and structures of the placenta that can then in turn affect development of the fetus.

Fetal exposure to prenatal stress is capable of reprograming the HPA axis to have an increased responsiveness to glucocorticoids later in life as well as inhibit the secretion of glucocorticoids due to stress (Koenig, Kirkpatrick and Lee, 2002).

The Immune system and Inflammatory Response

The immune system is composed of two parts, the innate and acquired, which respond to antigens present in the body. The innate side is the first line of defense against antigens and matures in the thymus. An antigen that produces an immune response are called immunogens (Delves and Roitt, 2000). A mechanism used in defense by the innate side is inflammation, cytokines in this process that are pro-inflammatory include IL-1ß, IL-6 and tumor necrosis factor (TNF)-alpha (Meyer, 2013). The acquired side is slower in response and matures in the bone marrow. Both cells start in the bone marrow, but T-cells migrate to the thymus, as thymocytes, at an early stage to finish maturation; if the thymocytes do no complete their journey to the thymus they die by performing apoptosis (Parkin and Cohen,

2001).

Innate Immunity
Innate immunity has cellular and humoral components, the cellular components include phagocytes, which consist of neutrophils, monocytes and macrophages and natural killer cells (NK); the humoral components include the complement cascade system and acute phase proteins (Misiak et al., 2014; Alam, 1998). The innate immunity does not solely use an antigen- specific recognition system, whereas the acquired side does (Alam, 1998) although, parts of the innate immunity do benefit from having antibodies present.
Macrophages are a part of innate immunity that have the capability of using antibodies. Macrophages are able to discriminate between self and foreign molecules, in addition, they contain receptors for antibodies. When a molecule is coated with antibodies it enhances phagocytosis (Delves and Roitt, 2000).

Acquired Immunity
Acquired immunity uses antigen-specific receptors for identification and has immunologic memory, unlike innate immunity (Parkin and Cohen, 2001). The immunologic memory allows for faster immune response time to a specific antigen that is has previously encountered (Misiak et al., 2014). This side also has cellular and humoral components. The cellular components include lymphocytes T and B-cells; B-cells use antibodies in the humoral component of the acquired immunity (Misiak et al., 2014; Alam, 1998).

T-Cells
There are subtypes types of T-cells with separate functions in the cellular mediated immune response. These types include: T helper cells, CD4+, and killer T cells which are cytotoxic, CD8+ (Alam, 1998). T helper cells (Th) are furthermore divided in T helper cells 1 (Th1) and T helper cells 2 (Th2). Cytokines are used for communication in the immune system and for other parts of the body including the brain (Parkin and Cohen, 2001). Th1 and Th2 cells secrete different cytokines; Th1 cells produce IL-2, IFN~y or TNF-alpha whereas, Th2 cells produce IL-4, IL-6 and IL-10 (Misiak et al., 2014). Depending on what types of cytokines are present induces different forms of the inflammatory response. If Th1 cytokines are present it will induce cell mediated response and Th2 cytokines will induce antibody mediated response (Parkin and Cohen, 2001).

Killer T-cells are cytotoxic and are responsible for killing pathogens in the body. Parkin and Cohen (2001) stated that killer T-cells have also shown further division and has two subtypes, T cytotoxic 1 (Tc1) and T cytotoxic 2 (Tc2), and each subtype has different cytokines, although it is not clear. Also that some CD8+ cells may have a role in down regulating the lymphocyte response as a suppressor function.

B-cells
B-cells most important function is the production of anti-bodies (Alam, 1998; Parkin and Cohen, 2001). The anti-bodies enhance some components of the innate system, one method is neutralizing antigens by binding to the exterior and attracting macrophages (Parkin and Cohen, 2001). Once an antigen is presented the B-cell will reproduce into a plasma cell, which produces anti-bodies, or a memory cell, to more quickly recognize re-exposure to a previously encountered antigen (Delves and Roitt, 2000).

Prenatal Immune Activation
Evidence has been found supporting that prenatal immune activation (PIA) influences schizophrenia (Easson and Woodbury-Smith, 2014). In the developing central nervous system cytokines are used by cells for signaling, many of the cytokines that are used are also used as immune modulators (Deverman and Patterson, 2009). Disruption of the normal cytokine mediated developmental processes can occur by immune dysregulation which results from maternal infection and prenatal immune activation (Deverman and Patterson, 2009; Meyer, 2013). Following prenatal immune activation, the cytokines and chemokines that are used in the inflammatory response to an infection plays a significant role in the development of neuropsychiatric disorders (Burd, Balakrishnan, & Kannan, 2012). Cytokines also have known essential neurodevelopmental effects including neuronal induction, proliferation, migration and survival; while these roles are essential, abnormal levels of cytokines during critical growth periods can have a negative effect on the neurodevelopment of the fetus (Meyer, 2013; Meyer, Yee and Feldon, 2007). Easson and Woodbury-Smith (2014), as well as Meyer, Yee and Feldon (2007), found support that PIA is associated with structural and functional abnormalities of neurodevelopment- the varying level of its affect depends on the timing, the dosage and the type of cytokine. A study conducted by Ellman et al (2010) looked at increased fetal exposure to maternal IL-8. They found significant associations with increases in ventricular CSF volume and decreases in the left entorhinal volume.

Cytokine Dysregulation
Multiple animal studies (Deverman and Patterson, 2009; Meyer, Yee and Feldon, 2007; Easson and Woodbury-Smith 2014) support the hypothesis that cytokine dysregulation induced by prenatal immune activation can alter neurodevelopmental and behavior in the offspring. A study by Meyer et al. (2005) injected animals with lipopolysaccharide (LPS), mimics bacterial infections, dsRNA poly(I:C), mimics viral infection and the influenza virus and found that the offspring exhibited the same neuropathologies and behavioral abnormalities that are in neurodevelopmental disorders. The study also found that LPS or maternal poly(I:C) also increased IL-1ß, IL-6, IL-10, TNF-alpha and mRNA levels in the developing brain. Meyer (2013) and Patterson (2009) also found similar effects of poly(I:C) in mice. Studies have also found that a variability in IL-1 gene complex is linked with the neuroanatomical abnormalities, including ventricular enlargement, temporal and frontal lobe volume reductions, in people with schizophrenia and that chronic schizophrenic patients have a greater structural change when look at first episode schizophrenic patients (Misiak et al., 2014).

Conclusion
There is a lack of research on immune dysfunction during pregnancy and the effects of neurodevelopment on the fetus in humans, even less on identifying the effects of different cytokines.

The research that is out there does implicate immune system dysfunction in prenatal immune activation as a role in the development of schizophrenia. More research needs to be conducted on looking at the effects of cytokines on the neurodevelopmental processes in humans. There are multiple animal studies that have found neurodevelopmental effects of cytokines on the offspring due to prenatal immune activation (Meyer et al., 2005; Meyer 2013; Patterson 2009; Deverman and Patterson, 2009). The found effects have implications on cytokines on the neurodevelopmental processes in humans. Stress research has shown the decreased effectiveness of the prenatal enzyme 11ß-HSD2 which protects the developing fetus from maternal factors (O'Donnell, O'Connor and Glover, 2009). Future studies are needed to look at what other possible placenta enzymes are down regulated and if that allows other cytokines to cross. More studies like the one conducted by Ellman et al. (2010) needs to be done looking at individual cytokine effects during maternal presentation. The data discussed in the paper supports that prenatal immune activation is linked with structural and functional abnormalities of the neurodevelopment of the fetus's brain. The key factors suggested are the timing, dosage and type of cytokine.

Furthermore, a better understanding of the functions and processes of which the placenta protects the fetus is needed. With research implicating cytokines causing neurodevelopmental abnormalities, treatments could be developed to strengthen the placenta to better protect the fetus and decrease chances of developing schizophrenia and other neurodevelopmental diseases.
Possible limitations to studying schizophrenia through psychoneuroimmunology is the cost of each study and the complexity. This makes obtaining funding difficult. Other limitations to this methodology of study is that there is still much unknown about how the immune system and the effects of cytokines.