There are humoral and cellular effector molecules in both the innate and the adaptive immune systems (Table 1). Several of the same mechanisms are used in both types of immune responses, especially in killing of target cells, suggesting that the evolution of immune responses has been conservative in terms of genes, though with much redundancy to ensure the life- preserving nature of the immune systems in the face of rapid evolution of pathogenic microbes.
Antibodies
Antibodies are the best- described effector mechanisms in adaptive immunity. They are the effector arm of B cells and are secreted as soluble molecules by plasma cells in large quantities, to be carried in the blood and lymph to distant sites. As shown in Table 1, there are five major isotypes of antibodies, each with different functions.
Table1. Immunoglobulin classes and their functions
IgM is a large molecule whose major physiological role is intravascular neutralization of organisms (especially viruses). IgM has five complement- binding sites, resulting in excellent complement activation and subsequent removal of the antigen–antibody–complement complexes by complement receptors on phagocytic cells or complement- mediated lysis of the organism.
IgG is a smaller immunoglobulin that penetrates tissues easily. Placental transfer is an active process involving specific placental receptors for the Fc portion of the IgG molecule, termed FcRn (Fc receptor of the neonate). The FcRn receptor is also present on epithelial and endothelial cells and is an important regulator of IgG metabolism. Of the four subclasses, IgG1 and IgG3 activate complement most efficiently and are responsible for clearing most protein antigens, including the removal of microorganisms by phagocytic cells. IgG2 and IgG4 react predominantly with carbohydrate antigens (in adults) and are relatively poor opsonins (promoters of phagocytosis).
IgA is the major mucosal immunoglobulin. Attachment of the ‘secretory piece’ prevents digestion of this immunoglobulin in the intestinal and bronchial secretions. IgA2 is the predominant subclass in secretions and neutralizes antigens that enter via these mucosal routes. IgA, the monomeric IgA in serum, is capable of neutralizing antigens that enter the circulation, but IgA1 is sensitive to bacterial proteases and therefore less useful for host defence at mucosal surfaces. IgA has additional functions via its receptor (FcaR or CD89), present on mononuclear cells and neutrophils, for activation of phagocytosis, inflammatory mediator release and antibody- dependent cell- mediated cytotoxicity (ADCC).
There is little free IgD or IgE in serum or normal body fluids, since these act as surface receptors on mature B cells or mast cells, respectively.
As mentioned previously, mechanisms of recombination in immunoglobulin production, whether for BCR or antibody production, are the same initially (Fig. 1). Once V, D and J region rearrangement has taken place, further variation is introduced when antibodies are made, by the introduction of point mutations in the V region genes. This process, known as somatic hypermutation, occurs in the lymphoid germinal centres and is critically dependent on activation- induced cytidine deaminase (AID), an enzyme responsible for deamination of DNA. Somatic hypermutation helps to increase the possible number of combinations and accounts for the enormous diversity of antibody specificities (1014), which by far exceeds the number of different B cells in the body (1010).
Fig1. 2 Immunoglobulin genes (see text for explanation).
Cytokines and chemokines
Cytokines are soluble mediators secreted by macrophages or monocytes (monokines) or lymphocytes (lymphokines). These mediators act as stimulatory or inhibitory signals between cells; those between cells of the immune system were known as interleukins (a phrase that has fallen out of general usage since the range of soluble molecules has widened so tremendously, though the individual names persist to avoid confusion). As a group, cytokines share several common features. Among the array of cytokines produced by macrophages and T cells, IL- 1 and IL- 2 are of particular interest due to their pivotal role in amplifying immune responses. IL- 1 acts on a wide range of targets (Table 2), including T and B cells. In contrast, the effects of IL- 2 are largely restricted to lymphocytes. Although IL- 2 was originally identified on account of its ability to pro mote the growth of T cells, it has similar trophic effects on IL- 2 receptor- bearing B and NK cells. The considerable overlap between actions of individual cytokines and interleukins is summarized in Table 3.
Table2. Actions of interleukin- 1
Table3. Clinically important cytokines grouped by effect on immune or inflammatory responses, to show source and site of action
Table3. (Continued)
Cytokines that induce chemotaxis of leucocytes are referred to as chemokines, a name derived from chemo + kine, i.e. something chemical to help movement. Some cytokines and interleukins have been redefined as chemokines as their function becomes clearer, e.g. IL- 8 = CXCL8. Chemokines are structurally similar proteins of small molecule size (8–10 kDa), which are able to diffuse from the site of production to form a local concentration gradient along which granulocytes and lymphocytes can migrate towards the stimulus. There are two types of movement: migration of leucocytes to sites of inflammation and that of differentiating cells moving to a specific activation site; chemokines are involved in both. There are therefore two main types: the inflammatory chemokines (CXC), coded for by genes on chromosome 17 and attractants for granulocytes, and the homeostatic chemokines, acting as attractants for lymphocytes (CC) and coded by genes on chromosome 4. The corresponding receptors on inflammatory cells are designated CXCR on neutrophils and CCR on lymphocytes; there are exceptions!
Molecules for lysis and killing
The other major sets of effector molecules are the cytolytic molecules, though less is known about their diversity or mechanisms of action. They include perforin, a C9- like molecule present in secretory lysosomes in CD8 T cells and in NK cells that polymerizes to form pores to enable large proteins to enter the cell. These cell types also secrete gran zymes, enzymes that induce apoptosis in target cells (Table 1). Macrophages and polymorphonuclear leucocytes also contain many substances for the destruction of ingested microbes, some of which have multiple actions, such as TNF. The duplication of the functions of this essential phylogenetically ancient protein during evolution underlines the continued development of mammalian immunity to keep up with microbial invaders.
