Locally produced cytokine and chemokines influence tissue-specific immune responses

Knowledge of the distinctive immunological characteristics of each tissue is only just emerging. Nevertheless a number of principles can be discerned:

Endothelium controls which leukocytes enter a tissue

Migration of leukocytes into different tissues of the body is dependent on the vascular endothelium in each tissue. For many years, it was thought that the endothelium in different tissues was essentially similar, with the possible exception of tissues such as the brain and retina, which have barrier properties (see below). Despite this common belief, it was well known that inflammation in different tissues had different characteristics, even when the inducing agents were similar.

It is now clear that a major element controlling inflammation and the immune response is the vascular endothelium in each tissue, which has its own characteristics; different endothelia produce distinctive blends of chemokines (Fig. 12.2). In addition the endothelium can transport chemokines produced by cells in the tissue from the basal to the lumenal surface by transcytosis, or by surface diffusion in tissues that lack barrier properties (Fig. 12.3).

Fig. 12.2 Production of chemokines by endothelium derived from different human tissues

Brain endothelium produces high levels of CXCL8 and CXCL10 associated with a TH1-type immune response. Dermal endothelium produces high levels of CCL5 associated with T cell migration, whereas lung endothelium produces high levels of CCL2, a chemokine that causes macrophage migration.

Fig. 12.3 Transport of chemokines

In most tissues, chemokines produced by cells in the tissue can move to the lumenal surface of the endothelium by transcytosis or by movement through the paracellular junctions, to be held on the endothelial glycocalyx. In tissues such as the brain, which have a barrier endothelium, there is limited transcytosis, and almost no paracellular movement of proteins such as chemokines. In these tissues, chemokine production by the endothelium is particularly important in controlling leukocyte migration.

The surface (glycocalyx) of vascular endothelium also varies considerably between tissues, and this affects which chemokines are retained on the lumenal surface, to signal to circulating leukocytes.

Hence the different sets of leukocytes present in each tissue can be partly related to the chemokines synthesized by the cells present, particularly the endothelium. For example, in normal lung there is a high level of macrophage migration, which relates to the high expression of CCL2 (macrophage chemotactic protein-1) by lung endothelium. In allergic asthma, the proportion of eosinophils increases, due to the production of IL-5 and CCL3 (eotaxin), which are characteristic of the TH2 response that tends to predominate in mucosal tissues (Fig. 12.4). By contrast, in the CNS lymphocytes and mononuclear phagocytes predominate in most immune reactions.

Fig. 12.4 Histological section of an airway from a case of fatal asthma

The lumen of an alveolus of the lung is heavily infiltrated with inflammatory exudates, fibrin, and cellular debris. Immunohistochemical staining with monoclonal antibody against EG2 indicates that the majority of cells are eosinophils.

(Courtesy of Arshad SH. Allergy: An Illustrated Colour Text. Philadelphia: Churchill Livingstone, 2002. With permission from Elsevier.)

Some tissues are immunologically privileged

There are certain sites in the body where fully allogeneic tissue can be transplanted without risk of rejection. These include the anterior chamber of the eye, the brain, and testes. Several factors may contribute to the immunological privilege of these sites, some of which affect the initiation of the immune response and some affect the effector phase.

The ‘privileged sites’ were long thought to be locations where adaptive immune responses are so dangerous that the immune system is either not allowed entry, is destroyed upon arrival, or is prevented from functioning. Recent evidence suggests that the concept of privileged sites may have been a misconception based on the limitations of the experimental assay systems. Once the experiments were expanded to include a wider variety of assays it became apparent that privileged sites are not immunologically impaired. They are simply sites that are able to promote certain kinds of beneficial classes of immune responses while suppressing classes that can do irreparable local damage. The mechanisms controlling immune reactions in the CNS are explored below.

The blood–brain barrier excludes most antibodies from the CNS

The blood–brain barrier is a composite structure formed by the specialized brain endothelium and the foot processes of astrocytes. Astrocytes are required to induce the special properties of brain endothelial cells, which have continuous belts of tight junctions connecting them to other endothelial cells (Fig. 12.5). An estimate of the tightness of the barrier is given by its trans-endothelial resistance, which is up to 2000 Ω/cm² in the CNS by comparison with values <10 Ω/cm² in most other tissues. In addition the brain endothelial cells have an array of transporters that allow nutrients into the CNS and a set of multi-drug resistance pumps that prevent many toxic molecules and therapeutic drugs from entering the brain. However, it is the very low permeability of the endothelium to serum proteins which is of particular interest for immunologists (see Fig. 12.5). For example, the level of IgG found in the CNS is normally approximately 0.2% of the level found in serum. The level may rise during an immune reaction as the endothelial barrier becomes more permeable in response to inflammatory cytokines. In some conditions, such as multiple sclerosis, there is often local synthesis of antibody within the CNS, which is reflected in abnormally high antibody levels in cerebrospinal fluid, even accounting for the increased leakage into the CNS. This finding demonstrates that some B cells have migrated into the CNS, and plasma cells have been identified in the spaces surrounding the larger blood vessels. Macrophages also contribute to immune reactions in CNS and they can synthesize some complement components locally (e.g. C3). However the overall level of serum proteins including antibodies and complement rarely exceeds 2% of the levels in serum even in the most severe inflammatory reactions.

Fig. 12.5 The blood–brain barrier

(1) Brain endothelial cells have a continuous ring of tight junctions, identified in this micrograph by the junctional marker ZO-1. The resulting permeability barrier excludes serum proteins from the brain tissue. (2) The graph shows the serum/cerebrospinal fluid (CSF) ratio for different proteins. There is an inverse relationship between molecular size and the level in CSF. Molecules such as transferrin, which are transported into the brain, are present at higher levels than would be expected from their size. Immunoglobulins are not transported.

Neurons suppress immune reactivity in neighboring glial cells