Brain-resident memory T cells generated early in life
predispose to autoimmune disease in mice
Steinbach, K., Vincenti, I., Egervari, K. et al
Sci Transl Med. 2019 Jun 26;11(498). pii: eaav5519. doi: 10.1126/scitranslmed.aav5519
The Bottom Line: Results in mice must be interpreted with great caution in terms of how they apply to human disease. However, the observations in the above paper, done in mice, are an important “proof of concept.” They show that a mild viral infection of the brain very early in life results in a persistent population of anti-viral immune cells in the brain along with a population of cells that can stimulate these immune cells. Both populations make the brain more vulnerable to a subsequent MS-like autoimmune disease. If this is the case in humans, that viral infections are involved in triggering MS, and there is evidence suggestive of this in this paper and elsewhere, it would be an important advance, not only in understanding what early environmental events triggers the disease, but also possibly ways of preventing it.
Key Points:
1. There is persuasive evidence that an environmental exposure early in life is involved in “triggering” MS many years later.
2. Infections have been suggested as the source of such exposure, with increasing data implicating that at least one of the “triggering” viruses is the Epstein-Barr virus, the virus that can cause infectious mononucleosis or “mono.” What is not known is how infections early in life increase susceptibility to MS.
3. The above paper describes what happened in the brains of mice infected with a mild, modified mouse virus at two different ages, either very early in life or as young adults.
4. Five weeks later, after the mice recovered from their mild brain infections, brains from both groups showed persistent populations of anti-virus immune cells (T cells), but only in the very young infected mice were there also populations of cells that had been infected with virus and survived. Virus-infected cells had been eliminated from the brains of adult-infected mice.
5. In both groups of mice there also were populations of brain cells called activated microglia. Microglia are brain cells that can interact with T cells. They have the ability to stimulate T cells and increase the severity of an immune reaction. Microglia are especially potent when activated.
6. Five weeks after the initial brain infection the scientists injected both groups of mice (those infected very early in life with virus and those infected as young adults) with immune T cells directed against a protein of myelin called MOG, or myelin oligodendrocyte glycoprotein.
7. The anti-MOG T cells traveled to the brains of both groups of mice and caused a central nervous system disease called experimental autoimmune encephalomyelitis (EAE). EAE is a brain inflammation similar in many ways to that seen in persons with MS.
8. While both groups of mice developed EAE, there were important differences in the brains of the two groups and in the kind of EAE that developed.
9. While both groups of mice developed EAE, the younger infected mice not only had more severe brain inflammation but also inflammation in different parts of the central nervous system leading to a different set of EAE symptoms (“atypical symptoms”). These were not seen in adult-infected mice.
10.Under the microscope, the inflammation in the young-infected, but not adult-infected mice was mainly near pockets of previously viral-infected cells and activated microglia, indicating that tissue in the regions of previous viral infection were especially susceptible to EAE.
11.Genes expressed by immune cells were also different in the two groups of mice. More inflammation-controlling genes were expressed in immune cells from young-infected mice compared to adult-infected mice. The particular chemical made by these genes was called “CCL5.” CCL5 is a powerful attractor of T cells and microglia, increasing the intensity of inflammation in the young-infected brains.
12.Many activated microglia were found in brains of young-infected mice, with very few present in adult-infected mice, another reason for increased susceptibility to immune attack.
13.The scientists studied tissues from MS brains, in particular areas of normal appearing white matter. They found increased numbers of CCL5-expressing immune cells in areas of cells that were similar to the activated microglia seen in young-infected mouse brains. This suggests, but of course does not prove, that, similar to what was seen in mice, there are areas in MS brains that may be more susceptible to the subsequent development of lesions.
It’s still not known whether MS is a single disease or a syndrome resulting from multiple causes all leading to a similar pattern of brain inflammation. What is known is that, while there is a genetic component to disease susceptibility, even genetic identity, as in the case of identical twins, is not sufficient to cause disease. Something else is needed. What that is is not known, but analyzing data from migrations studies to and from geographic areas with a high risk or low risk for developing MS, it appears that an environmental event very early in life, before age 13 years, plays a role in triggering the disease.
The nature of this “triggering event” is not known, but virus infections have been considered among the more likely factors. Virus infections can be very mild, at times not even clinically detectable, and viruses can remain in cells for decades (latent infections) without causing cells death, but possibly subtly altering cell function. The above paper describes two important phenomena in mice. One is that a mild viral brain infection occurring early in life results in long term changes in the brain that increase susceptibility to subsequent immune attack. Second, that the age at which the infection occurs is critical, being more potentially harmful if it occurs every early in life. As noted above, observations in mice do not necessarily mean that similar phenomena occur in humans, but the results of the above experiments will allow researchers to look for evidence of similar events occurring in humans, If successful in identifying previous viral infections as a major trigger of MS in humans, treatment with vaccines or anti-viral drugs in individuals especially susceptible to MS, such as those with certain susceptibility genes, or those with a strong family history of MS, could possibly prevent the development of the disease.
The abstract is available at this site.