Neuroimmune functional interactions

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15 Neuroimmune functional interactions


The connection between the nervous system and the immune system has been postulated seriously for the past century, and in the past two decades in particular we have experienced an explosion in the amount of interest and research into the neuroimmune communication and integration systems. Experimental evidence from the fields of psychology, immunology, and neurology has demonstrated that the immune system is not an autonomously regulated system but is influenced and modulated by bidirectional communication with the central nervous system. In fact, it is getting very difficult to separate what constitutes psychology, neurology, and immunology when we talk about the functions of the big three supersystems. The key role of the immune system is the defence against antigens and pathogens that attempt to enter our bodies. Allergic hypersensitivity and autoimmunity are two situations where the immune system for some reason reacts inappropriately against a certain antigen or starts attacking the components of our own bodies, respectively. Understanding how and why this happens may lead us to a way of manipulating the activity of the immune system in order to relieve suffering in our fellow man. We are learning more and more everyday and the exciting discovery of cortical asymmetry, and its influence on immune function has given us another virtually uncharted avenue of exploration. Brain asymmetry is associated with different patterns of immune reactivity. Left brain deficits have been associated with a decline in NK and T-cell activity and IL-2 production, suggesting a dominance of the left side of the brain in immunomodulation.

Overview of the immune system

The immune system is a complex system of interacting components including physical barriers, bone marrow, lymphoid tissues, leukocytes, and soluble mediators. These elements function together to recognise, engulf, and destroy invading microbes, tumour cells, and any substance recognised as non-self. For the immune system to mount an effective response to invading antigens an intricate series of cellular events must occur. The antigen must be recognised and, if deemed necessary, bound and processed by antigen-presenting cells, which must then communicate with activated T and B cells. The T-helper cells must then assist in the activation and formation of B cells and cytotoxic T cells. Activated cells must then undergo a series of proliferative steps that involve activation of second and third messengers and selective genetic proliferation that result in an adequate response to the antigen presenting. Once an antigen has presented, a memory cell must be produced to enable a more efficient and deadly defence should the antigen present again in the future (Roitt 1994). To further complicate matters, all of these complex activities must be accomplished in a controlled and selective manner so as not to destroy cells or tissues not contaminated or of use to the host.

Cells of the immune system

Although all of the components of the immune system must function in a multifactorial interactive process in order to function effectively, the most crucial cell types involved are the leukocytes or white blood cells (WBCs), which form the mobile foot soldiers of the immune system (Fig. 15.1). Leukocytes normally account for about 1% of total blood volume. In normal circumstances the WBC number between 4000 and 11 000 per cubic millimetre of blood, with an average of 7000 (Marieb 1995; Guyton & Hall 1996).

Leukocytes are grouped into two major categories, granulocytes and agranulocytes, based on their structural and chemical properties. Granulocytes contain highly specialised cytoplasmic granules. Agranulocytes lack any obvious intercellular granules. Granulocytes include neutrophils, basophils, and eosinophils. Agranulocytes include the T and B lymphocytes and non-T and non-B lymphocytes.

Neutrophils, or polymorphonuclear leukocytes, are derived from pleuripotent haematopoietic stem cells and eventually differentiate from myeloid cells in the bone marrow. Neutrophils are short-lived cells with a lifespan of hours to days, but are present in large numbers in the bone marrow, peripheral blood, and marginal pool, which is a reserve of cells adherent to the walls of postcapillary venules. These cells are crucial to the host defence against bacteria and some fungi. Neutrophils and monocytes can move from the bloodstream into the tissues by a process called diapedesis. In this process the leukocytes squeeze through tiny pores in the vessel walls by assuming the size and shape of the pores. Once in the tissues the cells move around by amoeboid-like motion (Guyton & Hall 1996).

Neutrophils become phagocytic upon encountering bacteria and bacterial killing is promoted by a process called respiratory burst, in which oxygen is metabolised to produce hydrogen peroxide, an oxidising, bleach-like substance which kills bacteria. Neutrophils can become actively phagocytic immediately upon confrontation with an antigen and do not have to experience a period of maturation as do other cells like monocytes which need to undergo activation processes to eventually mature into macrophages.

Eosinophils are filled with large, course granules that contain a variety of unique digestive enzymes. These cells exhibit chemotaxis to the sites of basophil and mast cell activation but are weak phagocytes for pathogens. These cells are mainly involved in attacking parasitic organisms too large to be phagocytised and are also probably involved in the deactivation of inflammatory substances released by mast cells and basophils to prevent widespread activity of these agents to other tissues not involved.

Basophils are the rarest white blood cells. They are morphologically very similar to the large mast cells that inhabit tissues exposed to the outside environment such as nasal passages and the lungs. Their cytoplasm contains large cytoplasmic granules containing histamine, heparin, bradykinin, slow-reacting substance of anaphylaxis, and serotonin. Histamine is an inflammatory chemical that acts as a vasodilator, which makes blood vessels ‘leaky’ and also attracts other WBC to the site of injury or inflammation. Heparin is a substance that reduces the ability of blood to clot.

The agranulocytes, as stated above, include lymphocytes and monocytes. Monocytes are only agranulocytic before they mature to macrophages and become granulocytic in nature.

Monocytes are derived from myeloid precursor cells in the bone marrow, which migrate through the circulation to the tissues where they mature as macrophages. Monocytes have very little contribution to immunity until they have matured into macrophages. Often, in people who are actively fighting a serious infection, the numbers of monocytes in the blood will increase but have little involvement in the immunological processes until they are activated and mature into macrophages. Macrophages are highly mobile and are actively phagocytic. These cells have lifespans ranging from months to years depending on how often and to what severity they are called upon to fight antigens (Guyton & Hall 1996). These cells have three important immunological roles:

The macrophages are particularly concentrated in the lung and the liver where they are referred to as Kupffer cells, and the lining of the spleen sinusoids and lymph node medullary sinuses. They also occur in large concentrations in the glomerulus of the kidney where they are referred to as mesangial cells, in the brain where they are known as the microglial cells, and in bone where they form the class of cells called osteoclasts which engulf components of bone in the remodelling process.

When neutrophils and macrophages attack pathogens a number of them are also killed in the battle. The resulting necrotic tissue, dead macrophages, dead neutrophils, and tissue-fluid accumulation due to the process of inflammation, results in an interesting mixture referred to as pus. Generally, after a few days the pus is reabsorbed by the surrounding tissues and most of the evidence that it ever existed disappears. Occasionally, this process does not occur, and a pus-filled cavity called an abscess may form that needs to be mechanically drained before healing can occur.

Lymphocytes are the primary cells of the cellular immune response. These cells originally derive from pluripotent stem cells in the bone marrow and eventually differentiate into T cells, B cells, non-T cells, and non-B cells in the various lymphoid tissues of the body. Lymphocytes develop in the thymus and populate the germinal centres in the lymph nodes and spleen. Although there are large numbers of lymphocytes in the body very few are present normally in the peripheral blood. Usually the only lymphocytes present in the blood are those travelling to a specific lymphoid tissue or those travelling to the site of an infection. About 80% of the lymphocytes present in peripheral blood are T cells, which have many important functions including (Simon 1991):

There are three major populations of T cells that are antigen-bearing: helper T cells, cytotoxic T cells, and suppressor T cells. Both the helper and suppressor T cells are involved in the regulation aspect of the immune response, mainly the initiation and termination, respectively. Recent understanding of the structural differences in the membrane glycoproteins of these cells has led to a new classification system. CD4 or T4 cells express a specific glycoprotein structural receptor on their membranes specific for primary helper T cells. Two classes of helper T cells have also been distinguished and are referred to as Th1 and Th2 classes. These cells show different levels of activation and cytokine production that regulates the shift between cellular and humeral immunity processes (see below). The CD4 receptor moiety is the suspected attachment site for the HIV virus, which exclusively targets helper T cells. CD8 or T8 cells express a specific glycoprotein structural receptor on their membranes specific for both cytotoxic and suppresser T cells populations (Marieb 1995).

B lymphocytes develop in the bone marrow and undergo a secondary differentiation when exposed to an antigen to become non-dividing plasma cells which secrete immunoglobulins or antibodies. Plasma cells develop an elaborate intercellular rough endoplasmic reticulum which is capable of secreting huge amounts of antibody. Non-T, non-B cells do not carry the surface marker glycoproteins of either T or B cells. The major cell type of this class is the natural killer cells, which are capable of killing a large variety of non-specific targets without the presence of antibody or without the prior sensitisation of antibodies present (Simon 1991). These cells are augmented by interferons, which are a family of broad-spectrum antiviral agents synthesised by cells when they become infected with a viral agent (Heaney & Golde 1998).

Innate and specific immunity

The characteristics of innate immunity or non-specific immunity include its limited capacity to distinguishing one microbe from another, and it is a system that functions in much the same way against most infectious agents. The principle components of innate immunity are:

The complement system is a collection of a variety of proteins (approximately 20) present in the plasma and paracapillary tissue spaces. Many of these proteins exist in the form of precursors that can activate a cascade of reactions that terminate in the death or destruction of a target pathogen (Fig. 15.2). In normal circumstances the precursors remain inactive in the plasma unless they are activated in one of two ways:

Innate immunity provides the early line of defence against microbes. In contrast to innate immunity, specific immunity involves more highly evolved defence mechanisms stimulated by exposure to infectious agents and has the ability to increase the magnitude of response with each successive exposure to a particular antigen.

The characteristics of adaptive or specific immunity are specificity for distinct molecules, specialisation, and ‘memory’ capability that allows a more vigorous response to repeated exposure to the same microbe. The components of specific immunity are the lymphocytes and their products. Foreign substances that induce specific responses such as the production of antibodies are called antigens. These two systems do not function in isolation but act in an integrated fashion. Innate immunity not only provides early defence against microbes, but also plays an important role in the induction of specific immune responses. One mechanism that illustrates this cooperative effort occurs when a macrophage is exposed to an inflammatory stimulus; it secretes protein hormones called cytokines that promote activation of the lymphocytes specific for the microbial antigens. Another mechanism of interaction occurs when macrophages that have ingested microbes secrete a particular cytokine which stimulates development of T lymphocytes particularly effective at activating macrophage activity. Thus, the interactions between innate and specific immunity are bidirectional (Roitt 1994).

Specific immune responses are able to combat microbes that have evolved to successfully resist innate immunity. The specific responses may also function by enhancing the activities of the innate system such as in the binding of antibodies (produced by the specific system) to bacteria, which markedly enhances complement activation (innate system). Specific immune responses are classified into two types based on the components of the system that mediate these responses: humoral and cell-mediated immunity. Both types of immunity are initiated by exposure to an antigen.

Humoral response

The primary humoral responses occur when an antigen binds to the surface receptors of a B-lymphocytic cell, causing activation of a variety of second and third messengers that eventually result in the activation and replication of cellular DNA to initiate synthesis of antibodies or immunoglobulins (Igs). The activation of surface receptors causes the B lymphocyte to multiply into a series of clones that mature into plasma cells capable of secreting antibodies (Igs) against the antigen (Fig. 15.5). Some of these B lymphocytes become memory cells, which are capable of storing the memory of the assaulting antigen in case re-exposure occurs in the future. This results in the secondary humoral response, which involves the IgM antibodies and is much more vigorous and rapid than the primary response. The antibodies produced combine with the specific antigen that stimulated their production and form an antigen–antibody complex that allows other cells such as macrophages, natural killer cells, and neutrophils to recognise and destroy the antigen-bearing complex.


The antibody molecule or immunoglobulin (Ig) is composed of two identical heavy and two identical light chain peptides held together by interchain disulfide bonds (Figs 15.6 and 15.7). Five classes of antibody have been identified, each with a variety of subgroups also identified. These classes of antibody are IgG, IgA, IgM, IgE, and IgD.

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