Rheumatoid arthritis (RA) represents a major global public health challenge, with approximately 1% of the world’s population suffering from this disease. In the absence of a cure, patients require ongoing and very often lifelong treatment. While environmental, genetic, and epigenetic factors have all been linked to the development of RA, a key, universally accepted initiating factor in disease development is the loss of immunological tolerance to self-antigens. Currently, most treatment approaches utilise agents that suppress the immune system or inflammatory response. However, there is no currently available treatment to re-establish self-tolerance, the key driving factor in the initiation of the disease. In this review, we will explore how peripheral tolerance mechanisms fail in RA, leading to disease initiation and progression. We will explore how dendritic cells (DCs), a central and nonredundant cell type in maintaining immune tolerance, contribute to RA and discuss molecular strategies to switch these immunogenic and self-reactive cells to tolerogenic cells. Finally, in addition to understanding the fundamental mechanisms of how peripheral tolerance mechanisms are lost, it is also important to know where this dysregulation occurs. Therefore, in this review, we will also discuss emerging research on sites of disease initiation in the context of tolerance.

Rheumatoid arthritis (RA) represents a major global public health challenge, with approximately 1% of the world’s population suffering from this disease. In the absence of a cure, patients require ongoing and very often lifelong treatment. While environmental, genetic, and epigenetic factors have all been linked to the development of RA, a key, universally accepted initiating factor in disease development is the loss of immunological tolerance to self-antigens. Currently, most treatment approaches utilise agents that suppress the immune system or inflammatory response. However, there is no currently available treatment to re-establish self-tolerance, the key driving factor in the initiation of the disease. In this review, we will explore how peripheral tolerance mechanisms fail in RA, leading to disease initiation and progression. We will explore how dendritic cells (DCs), a central and nonredundant cell type in maintaining immune tolerance, contribute to RA and discuss molecular strategies to switch these immunogenic and self-reactive cells to tolerogenic cells. Finally, in addition to understanding the fundamental mechanisms of how peripheral tolerance mechanisms are lost, it is also important to know where this dysregulation occurs. Therefore, in this review, we will also discuss emerging research on sites of disease initiation in the context of tolerance.