Parenchymal cells, in turn, regulate inflammation by the release of soluble cytokines and chemokines, as well as via cell-cell interactions. While many changes in the tissue induced by inflammation may promote further inflammation and target cell killing, counter-regulatory pathways that affect the resolution of inflammation and protect against tissue damage are also activated. In this way the tissue provides both positive and negative signals that could regulate the progression of an autoimmune response. Some examples of these pathways are given below.
Inflammatory molecules released by the target tissue
The migration of activated lymphocytes into the target organ is dependent on the expression of chemokines and adhesion molecules within the tissue. Activated cells of the innate immune system are effective producers of chemokines 9, but studies on tissue from patients with autoimmune disease have demonstrated that tissue cells also produce chemokines (Table 1). Parenchymal cells express a range of chemokines after stimulation with pro-inflammatory cytokines in vitro (e.g., in 10, 11), suggesting that this is a typical tissue response to inflammation. That chemokines expressed by the target tissue are important for autoimmune disease progression has been suggested by findings in several animal models. For example, Frigerio et al. 12 showed that islet β cells strongly express the CXCR3 ligands CXCL9 (Mig) and CXCL10 (IP-10), and that CXCR3 deficiency delays the development of insulitis and diabetes in the rat insulin promoter-GP LCMV-induced model. More recently, van Loo et al. 13 demonstrated that inhibition of NF-κB activation selectively in CNS-resident cells prevents the expression of inflammatory molecules, including chemokines (e.g., RANTES and CXCL10), and protects from experimentally induced encephalomyelitis.
Table 1. Examples of immunomodulatory molecules expressed in the target tissue of human autoimmune disease and their proposed contribution to disease pathogenesis
|Immunomodulatory molecule||Diseasea)||Tissue cell type||Proposed mechanism||Reference|
|Chemokines||CXCL10MCP-1||MS||Astrocytes in MS lesions||Recruitment of T cells Recruitment and activation of monocytes and T cells||717273|
| ||CXCL13||SS||Epithelial cells in acini and ducts of inflamed salivary glands||Recruitment of B and T cells||74|
| ||CXCL10Mig||HT||Thyroid follicular cells||Recruitment of T cells||75|
| || || || || || |
|Cytokines||IFN-α||T1D||Pancreatic beta cell||Up-regulation of MHC I expression, increased recognition by cytotoxic T cells||76|
| ||IL-15 ||CeD||Intestinal epithelium||Activation (incl. up-regulation of NKG2D expression) and survival of intraepithelial lymphocytes, induction of MICA expression on enterocytes||19,20|
| || || || || || |
|Costimulatory factors||Fractalkine||RA||Fibroblast-like synoviocytes ||Providing a costimulatory signal to T cells||77|
| ||NKG2D ligands||RA||Proliferating synovial cells (fibroblast-like synoviocytes?)||Proliferation and cytokine production by CD4+CD28– T cells||30|
| ||NKG2D ligands||CeD||Intestinal epithelium||Activation of innate immune response, costimulatory signal to gliadin-specific CD8 T cells||29|
| || || || || || |
|Other molecules||B cell activating factor (BAFF)||RA||Fibroblast-like synoviocytes ||Survival of B cells in the inflamed joint||78|
| || || || || || |
The target tissue also produces cytokines that promote growth and survival of recruited lymphocytes. Production of B cell-activating factor (BAFF) by fibroblast-like synoviocytes has been found in the inflamed joint of patients with rheumatoid arthritis (RA) 14, in salivary glands of patients with Sjögren's syndrome 15, and in lesions in patients with MS 16. BAFF regulates B cell survival and maturation, and may also affect T cell responses (reviewed in 17). IL-15 is a T cell growth factor and its expression in the tissue in many inflammatory diseases may promote chronic inflammation and local tissue damage 18. This cytokine is produced by intestinal epithelial cells from patients with Celiac disease (CeD) 19, 20 and pancreatic islets following in vitro cytokine exposure 10. It is also produced by myocytes during experimental myasthenia gravis 21. Collectively, these observations suggest that by responding to pro-inflammatory cytokines parenchymal cells may directly influence the recruitment, activation, and survival of potentially self-reactive B and T cells. Antagonists for a number of chemokine receptors (e.g., CCR1, CCR2 and CXCR3) are currently in Phase I–II clinical trials aimed at treating RA, MS and psoriasis (reviewed in 9), and their primary site of action is likely to be in the target tissue itself.
Regulation by direct interaction between target and immune cells
Once autoreactive lymphocytes have been recruited to the target tissue, their activity may be further influenced by direct interaction with target cells. One of the most evident changes associated with cytokine exposure in parenchymal tissues is the up-regulation of MHC class I molecules. As discussed above, up-regulation of MHC class I is necessary for conversion to a destructive autoimmunity (e.g., in 4, 8, 22). Elements of the immunoproteosome antigen-processing pathway are also induced by cytokines in autoimmune target cells (e.g., in 23, 24). Changes that the target tissue undergoes during inflammation may, therefore, modify the avidity of the cytotoxic immunological synapse, and facilitate recognition by low-affinity CD8 T cells 25. In this way, target cells may be able to control recognition by autoreactive T cells to limit cytotoxic killing 26, and increased expression of MHC class I and other molecules that increase recognition may play a significant role in promoting autoimmune tissue destruction.
Anomalous expression of NKG2D ligands by the target tissue is also emerging as a common feature of many immune-mediated diseases. NKG2D is an activating receptor on NK cells and a costimulatory receptor on T cells 27. Up-regulated expression of NKG2D ligands occurs in the intestine of patients with active CeD. Locally produced IL-15 (see above) increases NKG2D expression in intraepithelial lymphocytes (IEL). This induces a phenotypic change that enables IEL to mediate epithelial cell damage in an antigen-independent way, by recognition of the NKG2D ligand MIC 28, 29. Synoviocytes in RA patients also express MIC molecules. CD4+CD28– effector cells within inflamed synovia up-regulate NKG2D in response to IL-15 and TNF, and MIC ligands induce proliferation and cytokine production in these cells 30. MHC class II expression has rarely been seen in parenchymal cells, but it is possible that CD4 T cells may also acquire direct cytotoxic capacity through TCR-independent, NKG2D-mediated mechanisms. Ogasawara et al. 31 have shown that NKG2D is highly expressed on pancreatic islet-infiltrating CD8 T cells in the NOD mouse. The murine NKG2D ligand Rae-1 is not generally expressed in normal tissues but is induced during stress, infection and transformation, and is expressed in the islets of NOD mice. NKG2D ligation was shown to be important for diabetes development since blocking NKG2D in NOD mice prevented diabetes. Moreover, the accumulation of proliferating CD8 T cells was reduced specifically in the pancreas, suggesting that activated CD8 T cells in the target tissue are uniquely dependent on NKG2D costimulation. Taken together, these observations suggest that NKG2D-NKG2D ligand interactions contribute to T cell activation and increase cytotoxicity of T cells within the target tissue. The inappropriate expression of NKG2D ligands by the target tissue, in conjunction with the induction of NKG2D by cytokines such as IL-15 and TNF, may therefore be important steps in the development of immune-mediated tissue damage and some autoimmune diseases.
The negative costimulatory molecule PD-L1 (also known as B7-H1) is also up-regulated in murine islets during diabetes progression 32, 33, and its expression in β cells is highly inducible by cytokine treatment in vitro (N.H. and N.S., unpublished data). PD-L1 deficiency greatly accelerates the onset of diabetes in NOD mice, but chimeric mice expressing PD-L1 only in hematopoietic cells remain susceptible to rapid onset diabetes. This indicates that PD-L1 expression in a non-immune cell type is key for diabetes regulation. Islets lacking PD-L1 transplanted into diabetic NOD mice are more rapidly destroyed than wild-type islets, demonstrating that islet PD-L1 expression confers protection against autoimmune destruction 34. It is not yet known how islet PD-L1 inhibits tissue destruction. However, systemic deficiency in PD-L1 and PD-L2 was shown to potentiate the acquisition of effector function during T cell priming, raising the intriguing possibility that this may be linked to the lack of PD-L1 expression in islets 34.
Many other receptor-ligand systems that may play an immunoregulatory role within the tissue during autoimmunity are also coming to light. In a recent publication, Liu et al. 35 suggest that neuron-T cell interactions can convert CD4 effector T cells into Foxp3-expressing regulatory T cells (Treg), promoting neuron survival in vitro and suppressing EAE in vivo. The mechanism of Treg induction is thought to be MHC independent and occur via the interactions of TGF-β and B7 molecules expressed by neurons with their co-receptors expressed on effector CD4 T cells. Moreover, CD40L binding to target cell expressed CD40 molecules may lead to chemokine expression by the target cell 36. A regulatory role for the ligand CD200 (previously denoted OX2) has also been suggested, since CD200 deficiency increases the severity or onset of multiple autoimmune diseases in mouse models, including EAE, collagen-induced arthritis (CIA) 37, autoimmune alopecia 38 and uveitis 39, 40. CD200 interacts with CD200R on myeloid cells, and is thought to modulate the myeloid cell activation threshold 41, 42. Besides being expressed by B and T cells, CD200 is expressed by endothelial cells and neurons 43, and future studies will hopefully demonstrate whether lymphoid or tissue deficiency of the ligand is accountable for the augmented disease severities discussed above.
These examples provide support for the idea that interactions between immune cells and the tissue modulate both innate and adaptive responses. While this field is still developing, both cytokine secretion and cell-contact dependent mechanisms have been shown to occur (Fig. 1), and this communication may affect both the susceptibility of the target to killing, and the potential of self-reactive lymphocytes to destroy.
Figure 1. Immune responses to self are regulated at the target tissue level. During inflammation cytokines like TNF-α and the IFN induce the expression of cell surface molecules, as well as the release of cytokines and chemokines, by parenchymal cells. These molecules have important regulatory functions that may either hinder or facilitate an autoimmune attack.
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