According to the outside-in paradigm, microbes trigger the autoimmune pathogenic process that leads to multiple sclerosis (MS), while the inside-out paradigm suggests that the autoimmune pathogenic process is triggered by an internal event. Both concepts support the theory that MS develops after an autoimmune attack on the central nervous system, according to a review published in Annals of Clinical and Translational Neurology.
The immune system learns to tolerate necessary antigens, including self antigens, and tolerance of self antigens prevents the development of autoimmune diseases. However, some self antigens can escape negative selection in a process that is not yet fully understood.
Although the cause of MS is unknown, studies have shown that the immune system plays a significant role in the pathogenesis of chronic neuroinflammatory disease. While many previous studies were done to identify the events that led to the autoimmune reaction, the data are limited.
Continue reading
According to the primary lesion theory proposed by Terence Wilkin in 1989, autoimmunity is a physiological “response to persistent excessive antigen turnover in diseased tissues (the primary lesion).”
The outside-in concept is a paradigm based on an autoimmune process that is secondary to an exogenous trigger such as infection. It is believed that autoreactive T and B cells, which are present in the immune repertoire of genetically susceptible hosts, are activated by infection.
According to the inside-out concept, the trigger for the autoimmune process is endogenous and develops from an antigen-experienced immune system that has been trained through lifelong exposure to environmental and internal microbes.
Myelin bubbles, swelling caused by focal detachment of the myelin sheaths from seemingly normal axons, can be an early feature of myelin degeneration, in which fragments with citrullinated antigens are released. The subsequent disintegration of axon-myelin units may cause the excessive systemic release of post-translationally modified myelin. T cells can hyperreact to these antigens and induce clinical and pathological aspects of MS.
The data support Wikin’s primary lesion theory of autoimmunity in MS, as citrullinated myelin fragments released from the primary lesion lead to secondary attack on the central nervous system by hyperreactive T cells.
“One could argue that autoimmunity in MS can result from a combination of outside-in and inside-out pathogenic events. However, the data discussed in this paper tend to suggest that the core pathogenic process in MS is essentially an inside-out sequence of events, ”the researchers concluded.
reference
‘t Hart BA, Luchicchi A, Schenk GJ, Stys PK, Geurts JJG. Mechanistic underpinning an inside-out concept of autoimmunity in multiple sclerosis. Ann Clin Transl Neurol. Published online June 22, 2021. doi: 10.1002 / acn3.51401
