Why do we still have no cure for chronic inflammatory diseases? One reason could be that current therapies are based on the assumption that chronic inflammation is driven by persistent ‘acute’ immune reactions. Here we discuss a paradigm shift by suggesting that beyond these reactions, chronic inflammation is driven by imprinted, pathogenic ‘memory’ cells of the immune system. This rationale is based on the observation that in patients with chronic inflammatory rheumatic diseases refractory to conventional immunosuppressive therapies, therapy-free remission can be achieved by resetting the immune system; that is, by ablating immune cells and regenerating the immune system from stem cells. The success of this approach identifies antigen-experienced and imprinted immune cells as essential and sufficient drivers of inflammation. The ‘dark side’ of immunological memory primarily involves memory plasma cells secreting pathogenic antibodies and memory T lymphocytes secreting pathogenic cytokines and chemokines, but can also involve cells of innate immunity. New therapeutic strategies should address the persistence of these memory cells. Selective targeting of pathogenic immune memory cells could be based on their specificity, which is challenging, or on their lifestyle, which differs from that of protective immune memory cells, in particular for pathogenic T lymphocytes. The adaptations of such pathogenic memory cells to chronic inflammation offers entirely new therapeutic options for their selective ablation and the regeneration of immunological tolerance.
Chronic inflammatory rheumatic diseases are driven by long-lived, adapted memory cells: memory plasma cells, memory B and T lymphocytes and imprinted innate cells.
Memory cells have passed all physiological tolerance checkpoints; they are refractory to conventional therapeutic efforts that aim to restore tolerance.
Elimination of pathogenic memory cells is a prerequisite for the restoration of immunological tolerance and achievement of therapy-free remission.
Analysis of transcriptomes and physiology of pathogenic memory cells has revealed novel therapeutic candidate targets for their selective elimination and suggests that combination therapies could be relevant.
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This work was supported by the European Research Council Advanced Grant IMMEMO (ERC-2010-AdG.20100317 Grant 268987), the Deutsche Forschungsgemeinschaft (TRR130 P16 and P15, and TRR241 B03), Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 777357 and no. 831434, the state of Berlin and the European Regional Development Fund (ERDF 2014–2020, EFRE 1.8/11, Deutsches Rheuma-Forschungszentrum Berlin) and the Leibniz ScienceCampus Chronic Inflammation. H.D.C. is supported by the Dr. Rolf M. Schwiete Foundation.
The authors declare no competing interests.
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- Specific antigen receptors
Cells of the immune system express millions of different antigen receptors, each of them specifically recognizing particular structures. Each B lymphocyte expresses a particular antibody and each T lymphocyte a particular T cell receptor, enabling them to recognize and react to a defined chemical structure, the antigen.
- Immunological tolerance
Ablation or inactivation of B and T lymphocytes with antigen receptors specific for the body’s own and harmless antigens.
- Immunological memory
Imprinting and maintenance of the immune cells of an immune reaction when the reaction is over. Memory plasma cells provide protection by secretion of antibodies, and memory B and T lymphocytes provide rapid and enhanced secondary immune reactions.
- Homeostatic proliferation
Proliferation of memory lymphocytes induced by cytokines, in the absence of antigen.
- Plasma cell niche
A local environment organized by mesenchymal stromal cells, which provides survival signals for memory plasma cells.
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Maschmeyer, P., Chang, HD., Cheng, Q. et al. Immunological memory in rheumatic inflammation — a roadblock to tolerance induction. Nat Rev Rheumatol (2021). https://doi.org/10.1038/s41584-021-00601-6