The Cytokine Network
In the previous chapter cytokines were introduced as a collection of distinct molecules and receptors, but with a bewildering spectrum of regulatory effects on immunity and immune responses. Numerous cells can make one or several cytokines, depending on the circumstances. Very few cytokines are confined to a single function (pleiotropy) and very few functions rely on a single cytokine (redundancy). There are obvious advantages in this arrangement, for example the chance loss of a single cytokine or cytokine receptor gene would be unlikely to cause serious trouble – although there are exceptions to this (see Fig. 33). The analogy has even been made with language: one can communicate reasonably well with alphabets progessively lacking individual letters, but there would come a point where all messages would read the same. Many cytokines have related structures, and are thought to have evolved via repeated gene duplication (see Chapters 46 and 47). Presumably the present number of cytokines and functions is what nature, through evolution, has found to be adequate without too much in the way of unwanted effects. Interestingly, some cytokines (e.g. interferons) are highly species-specific, others much less so.
The figure shows the combinations of cytokines responsible for the main pathways of immune cell development, differentiation, interaction and function, together with some of the side effects that can result from over-activity. As knowledge has accumulated, cautious attempts have been made to use cytokines in the clinic, although not many have yet become standard therapeutical agents. In fact, the most dramatic effects have come from blocking excessive cytokine activity, and both natural inhibitors and soluble receptors are being extensively tried out. At present, the amelioration of some cases of rheumatoid arthritis by anti-TNF antibodies is probably the best-known example; some others are mentioned on the opposite page.
Bone marrow (see also Figs 4 and 15). Unlike most other tissues of the body, the number of each type of immune cell varies greatly, depending on the amount of immune activity (hence the white blood cell count is often used as an indicator of disease; see Fig. 44). In addition, the turnover of cells in the immune system is very high (about 1010 neutrophils alone are formed and die each day in a healthy adult). Cytokines have a major role in regulating the proliferation, differentiation and commitment of immune and other blood cells from multipotent stem cells in the bone marrow. Some of these cytokines (stem cell factor, IL-7, IL-11) are made by bone marrow stromal cells, others (IL-3, IL-5, granulocyte macrophage colony-stimulating factor [GM-CSF], macrophage colony-stimulating factor [M-CSF], granulocyte colony-stimulating factor [G-CSF]) by T cells, macrophages or other tissues of the body. GCSF, which stimulates the development of granulocytes, is used to boost the production of neutrophils after bone marrow transplantation.
Immature B lymphocytes differentiate and proliferate in the bone marrow independently of antigen, in response to IL-7 and other cytokines. Once mature B cells have recognized their specific antigen, their differentiation into memory cells and plasma (antibody- producing) cells is controlled by cytokines from T helper (Th) cells such as IL-2, IL-4 and IL-6. Cytokines are particularly involved in Ig class switching, e.g. IL-4 for IgE, IL-5 and TGF-β for IgA.
Thymus Here T cells mature and are selected for MHC and antigen specificity (see also Figs 16 and 17). Thymic stromal cells produce cytokines of which IL-7 is the best known, but cell surface molecules known as Notch also play a part. The older concept of thymus hormones (e.g. thymosin) is still debatable.
T lymphocytes both secrete IL-2 and express receptors for it so that they can stimulate their own proliferation (autocrine); this molecule was formerly known as T-cell growth factor (TCGF). Different T-cell subsets go on to predominantly secrete different cytokines: Th1 cells activate macrophages via IFNγ, Th2 cells regulate B cells as described above, and the newly recognized Th17 subset activates polymorphonuclear leucocytes (PMN) via IL-17. Several TREG subsets have been described, all with the ability to suppress Th cells. Interestingly, the expression of very high levels of one chain of the IL-2 receptor, CD25, is characteristic of regulatory T cells, and IL-2 deficiency leads preferentially to a deficit in regulatory T cells. The cytokines TGF-β and IL-10 mediate some of these activities. The differentiation of these different T subsets is itself regulated by cytokines: IL-12 secreted by dendritic cells, for example, favours TH1 development, IL-4 from mast cells favours TH2, and IL-23 and TGF-β favour TH17 cells.
Macrophages act as key sentinels found within all organs of the body, releasing cytokines on contact with microbes which then initiate immune responses. Macrophages are the main source of the inflammatory cytokines TNF, IL-1 and IL-6. These cytokines are released into the blood stream, and act systemically, controlling the vasculature, the hypothalamus, muscle and liver. The antiviral cytokines IFNα and IFNβ are produced in very high amounts by a rare blood cell, the plasmacytoid dendritic cell.
Natural killer (NK) cells (see also Fig. 15). Their main function is to kill virus-infected and some tumour cells, but they are also important sources of IFNγ. Several cytokines are involved in their development (IL-12, IL-15) and activation (IL-12, IL-18, IFNα,β).
Microbial killing IFNα and β have a major role early in virus infections, both by damage to viral RNA and by enhancing MHC class I expression. Macrophage-derived TNF, IL-1 and IL-6 initiate the acute phase response, fever and, via IFNγ, the killing of intracellular microbes. In helminth infections Th2 cell-derived IL-4 and IL-5 are responsible for IgE production and eosinophilia, respectively.
Inflammation Here changes to vascular endothelium are critical, and TNF has a leading role, stimulating the increased production of adhesion molecules on the inner surface of blood vessels (see Fig. 7), the secretion of chemokines and the autocrine activation of macrophages. In severe infections or injuries, excessive TNF can get into the circulation, leading to shock and multiple organ damage. Type I acute inflammation (hypersensitivity) is interesting in that several relevant genes (IL-3, IL-4, IL-5, IL-9, IL-13) lie together on chromosome 5q (see Fig. 47), which is known to be a susceptibility locus for allergies.
Leucocyte migration Most leucocytes are very motile, not only circulating in blood, but leaving the blood, crossing the endothelium and migrating though lymphoid and non-lymphoid tissues. The chemokines have a key role in chemotaxis, the regulation of leucocyte traffic (e.g. attracting neutrophils, lymphocytes and monocytes to inflammatory sites) and the maintenance of the correct lymphoid architecture. The manipulation of chemokine pathways for therapy has so far been limited, partly because many of the chemokines have multiple and overlapping functions, and can bind to many different receptors.
Cytokines in therapy Early enthusiasm for cytokine treatment of tumours and infections, particularly HIV, has been dampened by severe side effects and, in many cases, ineffectiveness. At present the main cytokines in clinical use are IFNα for viral hepatitis, IFNα and IL-2 for certain tumours, notably renal, and IFNβ for treatment of multiple sclerosis. More dramatically successful is the use of cytokine antagonists (generally in the form of monoclonal antibodies) to control chronic inflammatory diseases, e.g. anti-TNF in rheumatoid arthritis. Anti-TNF is also under study for osteoarthritis, gout and heart failure. Disappointingly, it is only moderately beneficial in septic shock. An alternative approach is to use soluble receptors to block cytokine activity; the IL-1 receptor is the leading example.