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State-of-the-art immunosuppressive therapies, though efficient in the treatment of rheumatic inflammatory disorders, in most cases do not provide a cure. Complete immunablation and the associated deletion of the reactive immunological memory followed by reconstitution of the "healthy" immune system from stem cells results in a therapy-free remission in many patients suffering from rheumatic diseases. Chronically activated T helper (Th) lymphocytes seem to play a critical role in this reactive pathogenic memory. We have shown that the transcription factor twist1 is specifically expressed in chronically activated, inflammatory Th cells. Twist1 as a biomarker for such Th cells enables the identification and elucidation of the role of Th cells in chronic inflammation and opens new therapeutic options for the targeted manipulation of the pathogenic, reactive memory, such as the targeted deletion of twist1 expressing pathogenic Th cells.

Current therapeutic options that are based on immunosuppression do not provide a cure for the treatment of chronic inflammation. Though more efficient immunosuppression and the introduction of biologicals such as antibodies targeting cytokines have improved clinical outcomes, immunosuppressive therapy has to be continued to be efficient, thus enhancing the risk of adverse events and undesired side effects. Why can immunosuppression ameliorate, even stop, but not cure chronic inflammation? Is chronic inflammation perpetuated beyond suppression by mechanisms independent of the immune system, or is it perpetuated by components of the immune system which are resistant to a block of ongoing immune reactions? One such component of the immune system is immunological memory. This article will review the role of immunological memory in chronic inflammation, as far as we understand it today, and discuss implications for the development of novel therapeutic strategies aiming at a cure for diseases involving chronic inflammation.

Th lymphocytes are considered to be key players in chronic inflammation. Upon repeated re-stimulation and differential instruction, they can develop a stable memory for the expression of distinct genes coding for cytokines, chemokines, adhesion molecules, and so on. This functional memory contributes considerably to the chronicity of inflammation and its eventual refraction to therapy. Here, we describe the global gene expression profiles of in vitro repeatedly reactivated murine Th1 and Th2 cells, and compare them with those of naive and once activated Th1 and Th2 cells, both before and after re-stimulation (Fig. ​(Fig.11). Figure 1 Hierarchical clustering of differentially expressed genes among doublets of the nine investigated cell populations (w, weeks in culture; res, 3 hours re-stimulated) using Affymetrix Mouse Genome 430A 2.0 Arrays and DNA-Chip Analyzer (dChip). Among differentially expressed genes is a novel transcription factor, which down-modulates NF-κB signalling and is exclusively expressed in repeatedly re-activated Th1 cells. High expression of this gene can be detected in Th cells isolated from the site of inflammation of patients suffering from distinct forms of rheumatic diseases or ulcerative colitis, but not in Th cells isolated from healthy tissue or from blood. Expression of this gene in Th cells at the site of inflammation highlights the role of chronic T-cell activation in chronic inflammation and may represent an endogenous mechanism to limit inflammation. Apart from its diagnostic value, this molecular pathway also points to a new therapeutic target.