Abstract
Autoantigen-directed tolerance can be induced by certain nucleosomal histone peptide epitope/s in nanomolar dosage leading to sustained remission of disease in mice with spontaneous SLE. By contrast, lupus is accelerated by administration of intact (whole) histones, or whole nucleosomes in microparticles from apoptotic cells, or by post-translationally acetylated histone-peptides. Low-dose therapy with the histone-peptide epitopes simultaneously induces TGFβ and inhibits IL-6 production by DC in vivo, especially pDC, which then induce CD4+CD25+ Treg and CD8+ Treg cells that suppress pathogenic autoimmune response. Both types of induced Treg cells are FoxP3+ and act by producing TGFβ at close cell-to-cell range. No anaphylactic adverse reactions, or generalized immunosuppression have been detected in mice injected with the peptides, because the epitopes are derived from evolutionarily conserved histones in the chromatin; and the peptides are expressed in the thymus during ontogeny, and their native sequences have not been altered. The peptide-induced Treg cells can block severe lupus on adoptive transfer reducing inflammatory cell reaction and infiltration in the kidney. In Humans, similar potent Treg cells are generated by the histone peptide epitopes in vitro in lupus patients’ PBMC, inhibiting anti-dsDNA autoantibody and interferon production. Furthermore, the same types of Treg cells are generated in lupus patients who are in very long-term remission (2-8 years) after undergoing autologous hematopoietic stem cell transplantation. These Treg cells are not found in lupus patients treated conventionally into clinical remission (SLEDAI of 0); and consequently they still harbor pathogenic autoimmune cells, causing subclinical damage. Although antigen-specific therapy with pinpoint accuracy is suitable for straight-forward organ-specific autoimmune diseases, Systemic Lupus is much more complex. The histone peptide epitopes have unique tolerogenic properties for inhibiting Innate immune cells (DC), T cells and B cell populations that are both antigen-specifically and cross-reactively involved in the pathogenic autoimmune response in lupus. The histone peptide tolerance is a natural and non-toxic therapy suitable for treating early lupus, and also maintaining lupus patients after toxic drug therapy. The experimental steps, challenges and possible solutions for successful therapy with these peptide epitopes are discussed in this highly focused review on Systemic Lupus.
Highlights
This chronicle with historical perspective focuses first on the early steps of pathogenic autoantibody production in lupus, especially on the role of T helper (Th) cells, and how they can be regulated
A possibility in the case of these peptide epitopes is that in low doses, they could transiently activate autoreactive T cells, which could provide small amounts of IL-2 for generating the regulatory T cells. This proposed mechanism [171], has been demonstrated by a similar situation occurring in the thymus where IL-2 is produced by a small population of self-reactive CD4 single positive (CD4SP) thymocytes, which stimulates Treg precursor cells to differentiate [172]
Emerging studies on epigenetic or metabolic mechanisms for Treg cell stability [192,193,194], and correcting other abnormalities in lupus T cells, such as, metabolic [12, 13], could be potentiated by utilizing the benefits of peptide epitope therapy, in the near future
Summary
This chronicle with historical perspective focuses first on the early steps of pathogenic autoantibody production in lupus, especially on the role of Th cells, and how they can be regulated. For the first time a true autoantigen for spontaneous SLE; namely endogenous nucleosomes from host’s apoptotic cells, and not some speculative component in microbes [63, 64], was found to be the real text book-like hapten- carrier link between the pathogenic Th and B cell in lupus for cognate interaction [57, 60],—and from that critical experimental step further studies led to identification of the histone peptide epitopes in nucleosomes recognized by those Th cells, and showed how to harness those particular epitopes for regulatory T cell induction for lupus therapy, as described below All this was possible in 1980s and early 1990s by cloning the select population of pathogenic antidsDNA autoantibody-producing B cells, and the special autoimmune T helper cells that drive such B cells in lupus. The studies with the pathogenic autoantibody-inducing T helper clones in early 1990s led to the initial identification of one of the major immunogens that drives the pathogenic T helper cells of lupus [57, 60]
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