Outside-In vs Inside-Out Paradigms in Patients with Multiple Sclerosis

Antibodies attacking neurons. Conceptual computer illustration of autoimmune neurologic diseases.
Study researchers examined the different paradigms on the pathophysiology of MS, the outside-in and the inside-out theories.

According to the outside-in paradigm, microbes trigger the autoimmune pathogenic process leading to multiple sclerosis (MS), while the inside-out paradigm suggests the autoimmune pathogenic process is triggered by an internal event. Both concepts support the theory that MS develops following 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 development of autoimmune diseases. However, some self-antigens may escape negative selection in a process that remains incompletely understood.

While the cause of MS is unknown, studies have suggested the immune system has a significant role in the pathogenesis of the chronic neuroinflammatory disease. While many previous studies were undertaken to identify the events leading to the autoimmune reaction, data are limited.

According to the primary lesion theory posited in 1989 by Terence Wilkin, autoimmunity is a physiologic “response to sustained excess antigen turnover in diseased tissues (the primary lesion).”

The outside-in concept is a paradigm based on an autoimmune process secondary to an exogenous trigger, such as an infection. It is believed that autoreactive T and B cells present in the immune repertoire of genetically susceptible hosts are activated by an 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 by the lifelong exposure to environmental and internal microbes.

Myelin blisters, swelling formed by focal detachments of myelin sheaths from seemingly normal axons, may be an early feature of myelin degeneration from which fragments carrying citrullinated antigens are released. The following disintegration of axon-myelin units possibly causes the excess systemic release of post-translationally modified myelin. T cells may hyper-react to these antigens and induce clinical and pathological aspects of MS.

The data support the Wikin’s primary lesion theory for autoimmunity in MS, as citrullinated myelin fragments released from the primary lesion lead to a secondary attack on the central nervous system by hyper-reactive T cells.

“It could be argued that autoimmunity in MS may result from a combination of outside–in and inside–out pathogenic events. However, the data discussed in this publication tilt the balance toward the notion that the core pathogenic process in MS essentially comprises an inside–out sequence of events,” concluded the researchers.


‘t Hart BA, Luchicchi A, Schenk GJ, Stys PK, Geurts JJG. Mechanistic underpinning of an inside-out concept for autoimmunity in multiple sclerosis. Ann Clin Transl Neurol. Published online June 22, 2021. doi:10.1002/acn3.51401