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Osteopontin: a new addition to the constellation of cytokines which drive T helper cell type 1 responses in Crohn’s disease
  1. J N Gordon,
  2. T T MacDonald
  1. Division of Infection, Inflammation, and Repair, University of Southampton School of Medicine, Southampton General Hospital, Southampton, UK
  1. Correspondence to:
    Professor T T MacDonald
    Bart’s and the London School of Medicine and Dentistry, Turner St, London E1 2AD, UK; t.t.macdonaldsoton.ac.uk

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Osteopontin, a cytokine which promotes Th1 immune responses, is overexpressed in the gut of patients with Crohn’s disease or ulcerative colitis. The main cellular source of this cytokine appears to be gut plasma cells.

Crohn’s disease appears to be caused by an excessive CD4+ T helper cell type I response directed against undefined antigens of the commensal bacterial flora.1 T cells from affected areas of Crohn’s disease mucosa produce enhanced amounts of interferon γ (IFN-γ) and tumour necrosis factor α. Other markers of Th1 cells, such as expression of the transcription factor T-bet, the high affinity β2 chain of the interleukin 12 (IL-12) receptor, and activated STAT4, all indicate that the mucosal environment in Crohn’s disease favours Th1 polarisation.1

It is important to emphasise that CD4 T cells in normal bowel are also Th1 skewed and express T-bet, so that the differences seen in Crohn’s disease are quantitative rather than qualitative.2 Normal mucosal T cells are however susceptible to apoptosis, whereas this is not the case in Crohn’s disease,3 suggesting that it is the persistence and accumulation of Th1 cells which drives tissue injury.

Factors which commit virgin T cells to the Th1 or Th2 pathway are still under investigation. T-bet appears to be of primary importance.4 It is induced by IFN-γ itself and is capable of promoting IFN-γ production, not only in Th1 cells, but also in Th2 cells. T-bet also increases expression of the IL-12Rβ2 chain. Macrophage and dendritic cell derived IL-12 is crucial in Th1 immune responses.5 The IL-12 receptor is made of two chains, β1 and β2, but only the β2 chain can signal and phosphorylate STAT4 which then migrates to the nucleus and further boosts IFN-γ production. Other factors also augment Th1 polarisation. IL-18 activates the transcription factors AP-1 and nuclear factor κB in T cells, and acts synergistically with IL-12 to boost IFN production. Type 1 interferons can also activate STAT4. IL-7, IL-15, and IL-21 also act in synergy with IL-12 to boost IFN-γ production and all, including IL-18, are overexpressed in Crohn’s disease.6 The IL-12 p40 chain can form a heterodimer with p19 protein to form a recently described cytokine, IL-23, which appears to be important in the activation of memory Th1 cells.5 There are no publications on IL-23 in Crohn’s disease.

In this issue of Gut, Sato and colleagues7 identify osteopontin (also known as early T lymphocyte activation Eta-1) as yet another cytokine involved in the Th1 response of Crohn’s disease (see page 1254). Osteopontin is a 60 kDa phosphoprotein constitutively secreted by epithelial cells and bone.8 It contains the characteristic RGD sequence seen in extracellular matrix proteins and shares receptor binding on cells with extracellular matrix proteins, including αv and β1 integrins. It also binds to CD44. Osteopontin is expressed in many distinct forms depending on differential splicing and the glycosylation/phosphorylation status of the core protein. Proteolytic cleavage by thrombin and matrix metalloproteinases also changes its function. Osteopontin is important in many different tissues. In the bone it regulates calcium deposition and it is also a chemoattractant for cancer cells. However, it is also important in the immune system as it is made by activated T cells, macrophages, and dendritic cells. These cells also have osteopontin receptors.9

Osteopontin increases the adhesion of activated T cells and is a T cell chemoattractant, but importantly it supports Th1 responses and inhibits Th2 responses9; thus its identification in Crohn’s disease adds another member to the increasing number of cytokines which drive Th1 immune responses (fig 1). Osteopontin deficient mice show impaired Th1 immune responses and fail to make granulomas.9 There was therefore a strong rationale for looking at osteopontin in Crohn’s disease. Sato and colleagues7 now show that osteopontin transcripts and protein are elevated in Crohn’s disease and ulcerative colitis. Osteopontin also increases IL-12 production specifically in Crohn’s disease lamina propria mononuclear cells but has little effect on IL-10 production. Arguably, the most important finding of the paper is the source of the osteopontin. There was a predictable increase in immunoreactivity in epithelial cells, macrophages, and around granulomas in Crohn’s disease. However, the most striking feature in inflammatory bowel disease (IBD) was coexpression of osteopontin with mucosal IgM, IgG, and IgA plasma cells. Especially in Crohn’s disease, osteopontin was particularly associated with IgG plasma cells. This result has some similarities with a previous study on osteopontin in Crohn’s disease and normal ileum where production in plasma cells was also noted, although overall no differences were seen between controls and Crohn’s samples.10 However, gene array analysis has shown markedly increased osteopontin transcripts in ulcerative colitis colon compared with normal colon.11

Figure 1

 Diagrammatic indication of the cytokines, transcription factors, and signalling molecules which polarise virgin CD4 cells into T helper cell type I cells. Interferon γ (IFN-γ) induces the transcription factor T-bet which induces the high affinity interleukin (IL)-12 receptor on T cells. IL-12 can then bind to its receptor, and activate STAT4, which goes to the nucleus and activates IFN-γ transcription. A plethora of other cytokines can synergise with IL-12 to boost IFN-γ production. IL-23, an IL-12-like cytokine, seems to be more important in activating memory cells. A crucial component of this pathway is the feedback loop by which IFN-γ continues to drive T cells along a Th1 pathway.

The role of plasma cells in IBD has been somewhat overlooked in recent years, with most emphasis on cellular immunity. However, quantitatively, plasma cells are as abundant as T cells in normal and inflamed gut. By far the largest population of plasma cells in normal and inflamed gut secrete IgA, generally considered to be a beneficial non-phlogistic antibody. In IBD, the largest quantitative increase is in IgA plasma cells, but the biggest proportional increase is in IgG plasma cells as these are uncommon in the normal gut. In Crohn’s disease, IgG plasma cells tend to be found around ulcers whereas in ulcerative colitis they are present along the length of the diseased mucosa.12 It has been suggested that some of this IgG has specificity for gut autoantigens, such as epithelial tropomysin, indicating that at least part of the pathogenesis of ulcerative colitis may involve antibody mediated autoimmunity.12 The results of Sato et al suggest that IgA and IgG plasma cells may be far more important than previously considered, with a role greater than simply being antibody secreting factories.

The work of Sato and colleagues7 also poses some interesting questions. Is osteopontin always made by plasma cells and is its presence in the gut merely a feature of the fact that the gut contains more plasma cells than the rest of the body combined? Do plasma cells secrete bioactive osteopontin? If osteopontin is present in plasma cells in healthy gut, why does it not deliver a survival signal to CD4 cells? Is osteopontin involved in the migration of T cells into normal and inflamed gut? It would also be of interest to examine trinitrobenzene sulphonic acid colitis in osteopontin deficient mice.

The importance of the therapeutic benefit of neutralising Th1 inducing cytokines in Crohn’s disease is well demonstrated by the clinical success of anti-IL-12 antibodies.13 However, the antibody used in this study is against the p40 subunit of IL-12 and theoretically can also neutralise IL-23. However, there may be considerable heterogeneity between patients in the relative importance of other Th1 inducing cytokines, such as IL-18 and osteopontin, which deserve further investigation.

Note in Proof

Osteopontin, a cytokine which promotes Th1 immune responses, is overexpressed in the gut of patients with Crohn’s disease or ulcerative colitis. The main cellular source of this cytokine appears to be gut plasma cells.

REFERENCES

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Footnotes

  • Conflict of interest: None declared.

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