Section G – Regulation of the immune response
cell response to most antigens is the major histocompatibility complex (MHC).
This complex, which is composed of six major loci (Topics F2, M2) is polymor- phic with allelic forms which encode different amino acids within the peptide- binding region of the MHC class I and class II molecules. This polymorphism is believed to provide the human population as a whole with the chance of bind- ing any new peptides which might arise through mutations of microbes. Those individuals who have MHC molecules able to bind peptides from a new peptide would be selected to survive in a Darwinian way.
T helper cells Th cells are an absolute requirement for immune responses to protein antigens in general, and for helping B cells to make the different classes of antibodies.
The type of response is, in some instances, determined by the nature of the antigen and its mode of entry as well as the effect of regulatory CD4+ T helper subsets, Th1 and Th2, and their cytokine products (Topic F5). The pro-inflam- matory cytokines, IL-2, TNFα and IFNγ, produced by Th1 cells are important for killing of intracellular microbes and the generation of T cytotoxic cells, whereas the anti-inflammatory Th2 cytokines, IL-4, IL-10 and IL-13, are impor- tant for B cell proliferation and differentiation and immunoglobulin class switch to IgA and IgE as well as the IgG2 response to the polysaccharide antigens associated with encapsulated bacteria such as Pneumococcus. Th2 cytokines are also important in helping to eradicate parasitic infections as they lead to the production of IgE and the recruitment of eosinophils which have powerful anti- parasitic functions (Topic H2). Th1 and Th2 cytokines are self regulating and also inhibit each other’s functions (Fig. 1and Topic B2). For example, IL-4 and IL-10 downregulate Th1 responses whereas IFNγ has an antagonistic effect on Th2 cells. Downregulatory mechanisms are necessary to prevent collateral damage as well as being energy conserving. Patients with atopy, i.e. with a genetic predisposition to having high levels of IgE, are believed to poorly regu- late their Th2 cells (Topic K2). In addition, in AIDS there is some suggestion that the response is biased in favor of a Th2 rather than Th1 response (Topic J3).
Most cytokines promote growth of particular cell lineages, attract specific immune cells (chemokines) or contribute to cell activation. Other cytokines can be suppressive. TGFβ inhibits activation of macrophages and the proliferation of B and T cells. IFNαalso has cell growth inhibitory properties. The action of these suppressive cytokines is a primary way that T cells and macrophages Stimulatory and
inhibitory cytokines
156 Section G – Regulation of the immune response
Th1 Th2
IFN-g
IL-4
Suppresses
Suppresses Helps
Helps
Fig. 1. Reciprocal regulation of Th1 and Th2 cells. Th1 cells release IFNgwhich suppresses proliferation of Th2 cells and their IL-4 production. Th2 cells release IL-4 (and IL-10) which suppresses IFN-gproduction by Th1 cells and their proliferation.
regulate immune responses. In addition, the stimulatory and inhibitory action of cytokines produced by Th1 and Th2 cells on each other also plays a major role in determining the type and extent of an immune response (Topic B2).
The activity of the immune system is influenced by other systems and perhaps most importantly by the neuroendocrine axis. Thus, lymphocytes are not only susceptible to regulation by cytokines of the immune system but also by hormones and neurotransmitters. The hypothalamus/pituitary/adrenal (HPA) axis exercises powerful control over the immune response through the release of mediators such as corticotrophin-releasing hormone (CRH), opioids, catechol- amines and glucocorticoids (Fig. 2). While the effector mechanisms for some of these mediators are not fully understood, it is known that they act on both the sensory (mast cells) and cognitive (lymphocytes) cells of the immune system.
Glucocorticoids have wide-ranging regulatory effects on the immune system, including: reducing the number of circulating lymphocytes, monocytes and eosinophils; suppressing cell-mediated immunity by inhibiting the release of the pro-inflammatory cytokines IL-1, IL-2, IL-6, IFNγand TNFα; decreasing antigen presentation; and inhibiting mast cell function. Growth hormone and prolactin, which are produced by the pituitary, are apparently also able to modulate the activity of the immune system. It has been shown that rats which undergo hypophysectomy (destruction of the pituitary) have prolonged allograft survival that is reduced on the reintroduction of prolactin or growth hormone.
Neurotransmitters including adrenaline (epinephrine), noradrenaline (norepi- nephrine), substance P, vasoactive intestinal peptide (VIP) and 5′-hydroxytrypt- Neuroendocrine
system – the HPA axis
G5 – Genes, T helper cells, cytokines and the neuroendocrine system 157
Stress
Neurotransmitters
CRH Glucocorticoids
Nervous system
Inflammatory mediators/
cytokines
Infection
Anterior
pituitary Adrenal Hypothalamus
Immune system
ACTH
Inhibit Stimulates
(e.g. inhibit cytokine production)
Fig. 2. The interconnectivity between the immune and neuroendocrine systems. Infection or stress can affect, either directly or indirectly, both the immune and the nervous systems.
Inflammatory mediators/cytokines released in response to infection not only are involved in the development and regulation of immune responses, but also stimulate the release of immune modulators such as glucocorticoids, which downregulate immune responses.
Stress and inflammatory mediators cause the release of corticotrophin releasing hormone (CRH) by the hypothalamus, which stimulates the pituitary to release ACTH. ACTH causes the adrenal gland to release glucocorticoids, which in turn downregulate the immune system.
amine (5HT) can also have both wide-ranging and specific effects on immune function.
Interestingly, the HPA axis is also directly influenced by the immune system as evidenced by the fact that the cytokines IL-1, TNFα and IL-6, which are released during the inflammatory response, directly affect the hypothalamus, anterior pituitary and adrenal cortex. Thus, immune effector mechanisms are tightly integrated into a network that includes the nervous and endocrine systems.
158 Section G – Regulation of the immune response
Section H – Immunity to infection