Failing immunological tolerance for critical self-antigens

Failing immunological tolerance for critical self-antigens is the problem underlying most chronic inflammatory diseases of humans. Despite the success of novel immunosuppressive biological drugs, the so-called biologics, in the treatment of diseases such rheumatoid arthritis (RA) and type 1 diabetes, none of these approaches does lead to a permanent state of medicine free disease remission. Therefore, there is a need for therapies that restore physiological mechanisms of self-tolerance. Heat shock proteins (HSPs) have shown disease suppressive activities in many models of experimental autoimmune diseases through the induction of regulatory T cells (Tregs). Also in first clinical trials with HSP-based peptides in RA and diabetes, the induction of Tregs was noted. Due to their exceptionally high degree of evolutionary conservation, HSP protein sequences (peptides) are shared between the microbiota-associated bacterial species and the self-HSP in the tissues. Therefore, Treg mechanisms, such as those induced and maintained by gut mucosal tolerance for the microbiota, can play a role by targeting the more conserved HSP peptide sequences in the inflamed tissues. In addition, the stress upregulated presence of HSP in these tissues may well assist the targeting of the HSP induced Treg specifically to the sites of inflammation.

Genome-wide association studies have underscored the genetic association of the major histocompatibility complex (MHC) region with autoimmune diseases, in which case various predisposing alleles have been found. The main function of MHC molecules is to present processed peptides for the recognition of antigen-specific T cells. And such T cells have the capacity to damage healthy tissues when they are not tightly controlled. The exact mechanisms triggering autoimmune diseases are unknown, but the presence of pro-inflammatory T cells in target organs as well as the strong link with MHC loci highlights the important role for adaptive immune responses in their development. The most accepted hypothesis proposes that for the initiation of an autoimmune disease, an immune response with pro-inflammatory characteristics needs to be directed against specific tissue antigens in genetically susceptible individuals. Regulatory mechanisms exist in the periphery to control such effector responses to avoid excessive tissue damage. Mechanisms include the following: regulatory T cells (Tregs), direct inactivation of effector T (Teff) cells by induction of anergy or apoptosis and activities mediated by tolerogenic antigen-presenting cells (APCs). However, there is an increasing understanding that pro-inflammatory responses directed to self-antigens become chronic in autoimmune diseases because regulatory mechanisms fail to control them.

Immunogenetics: Open access journal focuses on the genetic research areas of autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, Crohn’s disease, diabetes mellitus type 1, systemic lupus erythematous, etc.

Immunogenetics is the branch of medical genetics that explores the relationship between the immune system and genetics.

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Contact Details
Robert Solomon
Managing Editor
Immunogenetics: open access