Chapter 9 The immune response
Chapter 8 described the development of B and T cell repertoires. At birth, the immature immune system consists of B cells selected for low-affinity antibody production, while the T cell repertoire consists of T cell antigen receptors (TCRs) potentially able to recognize foreign but usually not self peptides presented by major histocompatibility complex (MHC) molecules on antigen-presenting cells (APCs). The latter must also provide co-stimulatory signals for full T cell activation.
During the vulnerable few months following birth, while immune system maturation is continuing, the infant receives protection against pathogens from the mother’s ‘experienced’ immune system. Maternal immunoglobulin G (IgG) antibodies cross the placenta and provide passive immunity. The IgA antibodies in mother’s milk protect the infant’s digestive system. By the age of 9 months, all maternal IgG antibodies will have been catabolized and suckling may have been terminated. The infant must now be able to mobilize its own adaptive immune response mechanisms to fight off potential pathogens.
Antibodies, or immunoglobulins (Igs), are the secreted products of B lymphocytes, which have become activated following binding of antigen to their B cell receptors (BCRs). The specificity for antigen of the secreted antibody is the same as that of the BCR, so they will bind to the same antigen that induced their production. The formation of the antigen–antibody complex may result in:
The basic Y-shaped, four-chain structure of the antibody molecule is shown in Figure 9.1. Antigen-binding specificity is provided by the combined variable (V) regions of heavy (H) and light (L) chains. Since the basic Ig unit has two such pairings, the molecule can bind two identical epitopes; i.e. it is bivalent. The Ig heavy-chain constant region, particularly domains 2 and 3, which make up the Fc region, largely determines the biological activity of the molecule.
There are five distinct classes of Ig (IgG, IgA, IgM, IgD, IgE), four subclasses of IgG (IgG1, IgG2, IgG3, IgG4) and two subclasses of IgA (IgA1, IgA2). These are derived from usage of different heavy-chain genes, as described in Chapter 8. The different structures and properties of Ig molecules are summarized in Figure 9.2.
Cytokines are low-molecular-weight hormone-like glycoproteins secreted by leukocytes and various other cells in response to a number of stimuli, which are involved in communication between cells, particularly those of the immune system. Lymphocyte-derived cytokines are known as lymphokines, those produced by monocyte/macrophages as monokines. Many of the cytokines are referred to as interleukins (ILs), a name indicating that they are secreted by some leukocytes and act upon other leukocytes. They are required for the initiation and regulation of all stages of the immune response, from stem cell differentiation to effector cell activation. Their action is mediated by binding to specific receptors on target cells; often the receptor may be released from the target cell in soluble form so that it may intercept the cytokine and act as an inhibitor. There are also other forms of cytokine inhibitors responsible for keeping these molecules under tight regulation. Each cytokine has several different activities (pleiotropy), and the same activity may be produced by several different cytokines (redundancy). The response of a cell to an individual cytokine depends on the context in which it receives the signal, e.g. its state of differentiation and activation and the presence of other cytokines in the microenvironment.
Chemokines are a family of low-molecular-weight, structurally related cytokines that promote adhesion of cells to endothelium, chemotaxis and activation of leukocytes. They are involved in leukocyte trafficking, providing specific signals for lymphocyte entry into lymphoid and other tissue.
Table 9.1 outlines the main sources and activities of cytokines. It is not exhaustive, and new cytokines and activities are undoubtedly awaiting discovery. The exciting field of cytokine research has led to the isolation of genes for cytokines and their receptors and inhibitors and the ability to manufacture these molecules by recombinant DNA technology. There is optimism that therapeutic use of these reagents will, in the near future, benefit patients with infections, autoimmunity, allergy and other immunologically mediated diseases.
|Cytokine||Main producers||Major actions|
|IL-1||Macrophages||Mediator of inflammation; augments immune response|
|IL-2||T cells||T cell activation and proliferation|
|IL-3||T cells||Haematopoiesis (early progenitors)|
|IL-4||T cells||T cell, B cell, mast cell proliferation; IgE production|
|IL-5||T cells||B cell proliferation; IgA production; eosinophil, basophil differentiation|
|IL-6||Macrophages, T cells||Mediator of inflammation; B cell differentiation|
|IL-7||Bone marrow cells, thymic stroma||Haematopoiesis (lymphocytes)|
|IL-9||T cells||T cell proliferation|
|IL-10||Macrophages, T cells||Inhibitor of cytokine production|
|IL-11||Bone marrow stromal cells||Haematopoiesis (early progenitors)|
|IL-12||Macrophages||T cell differentiation|
|IL-13||T cells||Similar to IL-4|
|IL-14||T cells||Proliferation of activated B cells|
|IL-15||Stromal cells||Similar to IL-2|
|IL-16||T cells||T cell chemotaxis|
|IL-17||T cells||Mediator of inflammation and haematopoiesis|
|IL-18||Macrophages||Similar to IL-12|
|IFN-α||Leukocytes||Activation of macrophages, NK cells; upregulation of MHC expression; protection of cells against virus infection|
|IFN-γ||T cells, NK cells|
|LT||T cells||Mediator of inflammation; killing of tumour cells; inhibition of tumour growth|
|OSM||Macrophages, T cells|
|TGF-β||Macrophages, lymphocytes, endothelial cells, platelets||Wound healing; IgA production; suppression of cytokine production|
|TNF-α||Macrophages, T cells||Mediator of inflammation; killing of tumour cells|
|gmCSF||T cells||Haematopoiesis (granulocytes, monocyte/macrophages)|
IL, interleukin; IFN, interferon; LT, lymphotoxin; OSM, oncostatin M; TGF, transforming growth factor; TNF, tumour necrosis factor; CSF, colony-stimulating factor; g, granulocyte; m, monocyte/macrophage; NK, natural killer; Ig, immunoglobulin; MHC, major histocompatibility complex.
B cells are highly efficient APCs. They receive signal 1 for activation by binding antigen, often concentrated on the surface of follicular dendritic cells within lymph node germinal centres, to the BCR, and then proceed to internalize antigen and process peptides on to MHC II molecules for presentation to T-helper cells (Fig. 9.3). They are then induced to express co-stimulatory B7 and can therefore provide signal 2 for T-helper cell activation through CD28. Activated T-helper cells are induced to express CD40L for binding to B cell CD40. Interaction between these two molecules induces B cell activation, Ig production and isotype switching.
IL-12 is not usually the dominant cytokine at the site of B–TH interaction, so T-helper cells induced by B-APC will generally be of the TH2 type, secreting IL-4, IL-5 and IL-10. These lymphokines further promote B cell proliferation, activation and isotype switching.
The T lymphocytes use their TCRs to recognize short antigenic peptides bound to MHC class I or class II molecules. This requires that protein antigens be processed and directed to the site of MHC assembly within an MHC-expressing cell. While virtually any cell type can process peptides on to MHC I molecules, ‘/>