Trained immunity as a possible newcomer in autoinflammatory and autoimmune diseases pathophysiology

Abstract

Autoimmune disorders have been well characterized over the years and many pathways—but not all of them–have been found to explain their pathophysiology. Autoinflammatory disorders, on the other hand, are still hiding most of their molecular and cellular mechanisms. During the past few years, a newcomer has challenged the idea that only adaptive immunity could display memory response. Trained immunity is defined by innate immune responses that are faster and stronger to a second stimulus than to the first one, being the same or not. In response to the trained immunity inducer, and through metabolic and epigenetic changes of hematopoietic stem and progenitor cells in the bone marrow that are transmitted to their cellular progeny (peripheral trained immunity), or directly of tissue-resident cells (local innate immunity), innate cells responsiveness and functions upon stimulation are improved in the long-term. Innate immunity can be beneficial, but it could also be detrimental when maladaptive. Here, we discuss how trained immunity could contribute to the physiopathology of autoimmune and autoinflammatory diseases.

When inflammatory stressors dramatically change, disease phenotypes may transform between autoimmune hematopoietic failure and myeloid neoplasms

“…The severity of AIDs commonly parallels the severity of chronic infectious conditions ( 111 , 112 ), which provides persuasive evidence that chronic infections contribute to the perpetuation and acceleration of autoimmune responses. Low-affinity autoimmune lymphocytes can escape the process of clonal selection and clonal deletion ( 113 – 116 ), and the development of AIDs critically requires the engagement of environmental factors to disturb immune homeostasis and generate high-affinity autoimmune lymphocytes by somatic mutations in the antigen-binding region (affinity mutation) ( 117 – 119 ).…”

“…High-affinity antibodies or emCTLs cross-react with epitopes of autoantigens in certain tissues (molecular mimicry) ( 120 – 123 ). After being trained in response to microbial infections, these autoreactive lymphocytes migrate to remote organs, exert an immunological attack, and induce tissue damage when recognizing cognate autoantigens ( 117 – 119 ). 2) When tissue is infected by pathogenic microbes, autoreactive lymphocytes in the inflamed niche can be activated and trained by antigen-presenting cells and autoantigens, which form high-affinity autoimmune B and T cells and exert an immunological attack on corresponding tissues (bystander activation) ( 124 – 126 ).…”

Update on autoinflammatory diseases

“…Initial stimulation of innate cells via pattern recognition receptors (PRRs) leads to metabolic, mitochondrial, and epigenetic alterations, providing the cells with a more rapid and robust immune response upon re-exposure. This “memory” is the defining feature of trained immunity [8 ▪ ,9 ▪▪ ,10 ▪ ].…”

“…It has also been shown that β-glucan, a potential inducer of trained immunity, can block NLRP3 inflammasome [18]. Metabolic and epigenetic changes have also been identified in other monogenic SAIDs, such as FMF, mevalonate kinase deficiency (MKD), tumor necrosis factor receptor associated periodic syndrome (TRAPS), as well as in polygenic diseases such as chronic nonbacterial osteomyelitis and Behcet disease, highlighting an important role that trained immunity can play in the pathophysiology of SAID [9 ▪▪ ,13 ▪ ,19–21].…”