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Autoimmunity or immune deficiency? On the role and function of regulatory T cells in chronic arthritis
Arthritis Research & Therapy volume 7, Article number: S4 (2005)
Human autoimmune diseases are characterized by chronic, non-remitting inflammation. In the early phase of chronic arthritis auto-reactive T cells initiate a cascade of events that leads to chronic inflammation. Following the initial phase of the disease, other cells such as macrophages and monocytes mainly mediate the ongoing non-specific inflammation. At this later stage, auto reactive T cells presumably do not play an important role in sustaining the chronic inflammation. Mechanisms underlying the perpetuation of this cascade of non-specific inflammation are still poorly understood. As a consequence, treatment of the disease until now has been mainly focused on non-specific suppression of inflammation. In patients with chronic arthritis, such juvenile idiopathic arthritis (JIA) and rheumatoid arthritis (RA) blockade of the tumour necrosis factor alpha pathway has proven to be a very potent treatment option. On the other hand, such treatment is costly and fails to induce a long-lasting remission of the disease. As a consequence long-term treatment with immune suppressive agents is necessary, which increases not only the costs of the treatment but also harbours considerable risk for long-term side effects. Thus, the need for additive and/or alternative strategies is growing. Ideally such alternative treatment should be safe, not expensive and specifically modulate cells that are responsible for the inflammation and/or counter-regulation. Lately, a lot of attention has focused on the role of regulatory T cells for the control of autoimmunity. There are currently two well-characterized types of regulatory T cells, Tr1 cells and CD4+CD25+ T regulatory cells. The CD4+CD25+ T regulatory cells are a heterogeneous group of cells identified by the expression of CD25 and the transcription factor foxP3. We recently showed that these so-called naturally occurring T regulatory cells and regulatory T cells with specificity towards heat shock proteins may play a role in determining disease outcome in JIA [1, 2]. Following autologous stem cell transplantation for arthritis T regulatory cell function is restored coinciding with a remission of the arthritis (de Kleer et al., submitted). Moreover, oral treatment with a peptide (dnaJP1), derived from heat shock protein dnaJ, restored T regulatory cells in peripheral blood mononuclear cells from patients with RA .
Thus, due to insufficient numbers of regulatory T cells, feedback mechanisms fail, resulting in an unrestrained proinflammatory immune response and severe tissue damage in RA and JIA. A lack of a counter-regulatory mechanism based by regulatory T cells is at least in part responsible for the perpetuation of inflammation . Heat shock proteins may be instrumental in restoring the immunological balance and thus contribute to a long-lasting disease remission.
de Kleer IM, Wedderburn LR, Taams LS, Patel A, Varsani H, Klein M, de Jager W, Pugayung G, Giannoni F, Rijkers G, et al: CD4+CD25(bright) regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis. J Immunol. 2004, 172: 6435-6443.
de Kleer IM, Kamphuis SM, Rijkers GT, Scholtens L, Gordon G, de Jager W, Hafner R, Van De Zee, Van Eden W, Kuis W, Prakken BJ: The spontaneous remission of juvenile idiopathic arthritis is characterized by CD30+ T cells directed to human heat-shock protein 60 capable of producing the regulatory cytokine interleukin-10. Arthritis Rheum. 2003, 48: 2001-2010. 10.1002/art.11174.
Prakken BJ, Samodal R, Le TD, Giannoni F, Yung GP, Scavulli J, Amox D, Roord S, de Kleer I, Bonnin D, Lanza P, et al: Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheumatoid arthritis. Proc Natl Acad Sci USA. 2004, 101: 4228-4233. 10.1073/pnas.0400061101.
Sakaguchi S: Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004, 22: 531-562. 10.1146/annurev.immunol.21.120601.141122.
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Prakken, B., de Kleer, I. Autoimmunity or immune deficiency? On the role and function of regulatory T cells in chronic arthritis. Arthritis Res Ther 7, S4 (2005). https://doi.org/10.1186/ar1509
- Rheumatoid Arthritis
- Heat Shock Protein
- Juvenile Idiopathic Arthritis
- Regulatory Cell
- Autologous Stem Cell Transplantation