Section G – Regulation of the immune response
In the case of the cells and molecules of the innate immune system that have evolved to be aggressive towards microbes there are two ways in which self reactivity is prevented: lack of recognition (ignorance) of self cells unless they change their surface structure; and the presence of inhibitory structures/
receptors on the nonimmune cells.
Phagocytes
Phagocytic cells of the innate system, including macrophages and neutrophils, do not normally ‘recognize’ or phagocytose living self cells. However, aging (ery- throcytes), dying or dead cells express new surface molecules that are recognized by phagocytes, which results in the removal of these altered self cells. Phagocytes recognize microbes through pattern recognition receptors, including sugars, e.g.
mannose (Topic B3). Target molecules on the surface of mammalian cells that might be recognized by these receptors are either absent or concealed by other structures, e.g. sialic acids. When an erythrocyte ages, it loses sialic acid exposing N-acetyl glucosamine which the phagocyte now recognizes as non self and phagocytoses (Fig. 1). When nucleated cells die, a large number of surface molecules are exposed which are recognized by phagocytes. One of these molecules, phosphatidyl serine (PS) – a membrane phospholipid, is normally restricted to the inner surface of the cell membrane. When the cell begins to die through apoptosis PS ‘flips’ onto the surface and is recognized by the phagocytes.
Self, non-self discrimination by the innate immune system
142 Section G – Regulation of the immune response
Normal body cell Self cells
Apoptosing cell
Recognition by phagocyte
Erythrocyte
Aged erythrocyte
Fig. 1. Recognition of aged/damaged self cells by phagocytes.
Natural killer cells
These cells play an important role in killing virus-infected cells. They are prevented from killing the non-infected nucleated cells of the body through a balance in signaling involving killer activation receptors (KAR) and killer inhibitory receptors (KIR) that recognize molecules on self cells. The inhibitory receptors recognize MHC molecules on normal cells and prevent their killing by NK cells (Topics B1, F2 and N3). However, when certain viruses infect cells they downregulate expression of molecules (MHC class I) recognized by KIR giving rise to an overriding activation through KAR leading to death of the infected cells (Fig. 2).
The complement system
C3 is activated through the alternative pathway by stabilization of appropriate enzymes on the surface of some microorganisms (Topic B2). This cannot occur
on the body’s cells since they all have inhibitory molecules (Topic D8) on their surface membranes (Fig. 3).
Tolerance to self of lymphocytes and antibodies of the adaptive system is initi- ated at the level of development of T and B cells (Topics A5, C1, F3 and G2) in the primary lymphoid organs (central tolerance). Those lymphocytes escaping elimination at this stage are prevented from responding to self through lack of co-stimulatory signals (e.g. those provided by CD80 or CD86 on APC that are necessary for T cell activation) resulting in anergy or activation-induced cell death by T cells (peripheral tolerance).
The nature of the antigen is also important, since its size, state of aggregation, composition (e.g. protein vs carbohydrate), etc., significantly influence the type of response and its strength (Topic A4). Removal of the antigen and therefore the stimulus results in the response subsiding. Helper T cells are involved in regulating this response and in modulating the functions of other cells, includ- ing dendritic cells, NK cells, macrophages, and cytotoxic T cells. Although this modulation is often mediated through cytokines, it may also involve direct cell–cell interactions. The influence of Th cells can significantly affect the type of response depending at least partly on the kinds of cytokines produced and the particular cell participating in the response. Antibody itself can, in some Regulation by
the adaptive immune system
G1 – Overview 143
NK cell Somatic cell
() ()
No killing of self cell by NK cell KIR
KAR
KAR
Loss of KIR ligand (e.g. MHC class I) following virus infection
NK () cell
NK cell kills since there is no inhibitory stimulus
Virus
Fig. 2. Inhibition of NK cell activity. NK cells recognize self-antigens and travel around the body in search of aberrant self-cells. When they come into contact with a healthy cell they receive two signals – a positive signal to kill via their KAR (killer activation receptors) and a negative signal via their KIR (killer inhibitory receptors). These two signals cancel each other out and the NK cell goes on its way. Some viruses inhibit expression of the self-molecules recognized by the KIR (e.g. MHC class I, HLA-A, B, C in man) which means that the negative signal is absent and the NK cell carries out its lethal duty.
instances, either enhance (IgM) and complement or inhibit (IgG: negative feed- back; Topics E2 and G4) further antibody production.
It is also important to note that the immune system does not function in isola- tion, but rather is influenced by other body systems. In particular, the neuro- endocrine system plays an important role in modulating immune responses.
144 Section G – Regulation of the immune response
C9 C9 C9 C9
C3
C3b
C5
C9 C9
Membrane attack complex
(MAC) C3bBb
C3a C5a
C5b C6 C8 C7
CD59 CD46
CD55 1
2
Fig. 3. Inhibition of complement activation on self-cell surfaces by regulatory proteins.□1 Inhibition of C3 convertase by membrane cofactor proteins (CD46) and decay accelerating factor (CD55).□2 Blocking by CD59 of attachment of C8 and C9 of MAC to membrane, inhibits active lysis.
Section G – Regulation of the immune response