PI: Ivan Jelcic, PhD, University of Zurich
An important characteristic of multiple sclerosis is the development of an inflammatory autoimmune attack on
the proteins of the myelin sheath (1). The myelin sheath is a structure that wraps around nerve fibers projecting
from neurons, and its main function is to protect and provide nutrients to the fibers while allowing efficient
transmission of impulses (1). Therefore, damage to the myelin sheath can lead to a range of consequences.
Some of the symptoms associated with myelin sheath damage and multiple sclerosis include numbness,
spasticity, dizziness, fatigue, vision problems and pain. Jelcic et al. (2) attempt to better understand the cells
that are present in people with multiple sclerosis so as to better understand what role immune cells have in the
progression of the disease. It has also been found that a major factor that increases risk of multiple sclerosis is
the presence of the HLA protein, which enables cells to display antigen on their surfaces (3). Therefore, HLA
proteins are very important in triggering the T cell activation that is so important to the adaptive immune
response, but its role also means that HLA could help mount an autoimmune attack if it is able to bind self-antigen
tightly enough.
the proteins of the myelin sheath (1). The myelin sheath is a structure that wraps around nerve fibers projecting
from neurons, and its main function is to protect and provide nutrients to the fibers while allowing efficient
transmission of impulses (1). Therefore, damage to the myelin sheath can lead to a range of consequences.
Some of the symptoms associated with myelin sheath damage and multiple sclerosis include numbness,
spasticity, dizziness, fatigue, vision problems and pain. Jelcic et al. (2) attempt to better understand the cells
that are present in people with multiple sclerosis so as to better understand what role immune cells have in the
progression of the disease. It has also been found that a major factor that increases risk of multiple sclerosis is
the presence of the HLA protein, which enables cells to display antigen on their surfaces (3). Therefore, HLA
proteins are very important in triggering the T cell activation that is so important to the adaptive immune
response, but its role also means that HLA could help mount an autoimmune attack if it is able to bind self-antigen
tightly enough.
One thing often seen in patients with multiple sclerosis is that their T cells are more likely to divide in vitro than
T cells from people without the condition (3). That is similar to the division we would expect to see as a result
of normal activation of immune cells by foreign antigen, but in multiple sclerosis this division seems to come
without the expected antigen stimulus (2). What that means is either that multiple sclerosis bypasses the requirement for antigen recognition or that the T cells recognize and bind self antigen in order to become activated. Jelcic et al. demonstrated that both T cells and B cells were able to proliferate when grown in vitro (2). They called this spontaneous division without antigen recognition auto-proliferation (2).
T cells from people without the condition (3). That is similar to the division we would expect to see as a result
of normal activation of immune cells by foreign antigen, but in multiple sclerosis this division seems to come
without the expected antigen stimulus (2). What that means is either that multiple sclerosis bypasses the requirement for antigen recognition or that the T cells recognize and bind self antigen in order to become activated. Jelcic et al. demonstrated that both T cells and B cells were able to proliferate when grown in vitro (2). They called this spontaneous division without antigen recognition auto-proliferation (2).
They found that TCR signaling initiates proliferation of T cells and that said proliferation was associated with the cytokine IFN-γ (2), as can be seen in Fig 1 below. IFN-γ is also associated with multiple sclerosis (4). It serves as an activatory cytokine that induce macrophage activity, and it is well documented that macrophages cause damage to the myelin sheath in multiple sclerosis (5, 6).
Figure 1. Jelcic et al., (2018). Immune-cell action associated with multiple sclerosis.
In order to further explore the role of B cell- T cell communication in multiple sclerosis, the authors analyzed blood samples from people with the disease being treated with anti-inflammatory drugs and a control group without the disease or treatment. In vitro examination of samples from those being treated with an antibody that increases the number of T cells and immature B cells in blood demonstrated auto-proliferation of T cells and B cells compared to the controls (2). Those receiving an antibody that depletes B cells from their blood exhibited greatly reduced proliferation of T cells compared with controls (2). These results show pretty clearly that B and T cell interactions are important to multiple sclerosis. In the past it has been thought that B cells had no role in multiple sclerosis (2), so this is exciting new evidence that may assist in the development of effective treatments for the disease.
The authors then wanted to find out whether the auto-proliferation of T cells contributes to the development of multiple sclerosis. To answer that question, they looked at cells that came from individual proliferation T cells from the blood of people with multiple sclerosis (2). They examined the variable regions of the TCRs to find their unique pattern that can identify the T cell and its genetically identical clones produced during proliferation (2). They looked at T cells found in brain tissue in multiple sclerosis patients and compared them to those found in their blood stream. Jelcic et al. found that the T cells from blood samples that showed T cell auto-proliferation matched the identity of the T cells found in the brain tissue from the same person (2). What this tells us is that at least some of the auto-proliferating cells in the blood are able to enter the brain and cause damage there and contribute to multiple sclerosis.
It is interesting to think about how these immune cells have developed mechanisms successful enough to bypass the benefits of immune privilege usually associated with the central nervous system. Immune responses in the brain are generally skewed towards a polarized Th2 response that leans more heavily on antibody production (7), and thus causes less harm to the tissue. But the auto-proliferative capabilities of T cells in multiple sclerosis patients obviously challenges that evolutionary advantage. More research is required to understand the mechanisms underlying the T cell antigen recognition that induces auto-proliferation and potentially identify specific antigens associated with the disease that can be targeted for multiple sclerosis treatment.
References
1. Wekerle, H. (2017). Nature, nurture, and microbes: The development of multiple sclerosis. Acta Neurologica
Scandinavica, 136, 22-25.
2. Jelcic, I., Al Nimer, F., Wang, J., Lentsch, V., Planas, R., Jelcic, I., Pinilla, C. (2018). Memory B cells activate
brain-homing, autoreactive CD4+ T cells in multiple sclerosis. Cell, 175(1): 85-100.
Scandinavica, 136, 22-25.
2. Jelcic, I., Al Nimer, F., Wang, J., Lentsch, V., Planas, R., Jelcic, I., Pinilla, C. (2018). Memory B cells activate
brain-homing, autoreactive CD4+ T cells in multiple sclerosis. Cell, 175(1): 85-100.
3. Oksenberg, J. R., Baranzini, S. E., Sawcer, S., Hauser, S. L. (2008). The genetics of multiple sclerosis: SNPs to pathways to pathogenesis. Nature Reviews Genetics, 9(7), 516.
4. Panitch, H., Haley, A., Hirsch, R., Johnson, K. (1987). Exacerbations of multiple sclerosis in patients treated with gamma interferon. The Lancet, 329(8538), 893-895.
5. Panitch, H., Haley, A., Hirsch, R., Johnson, K. (1987). Exacerbations of multiple sclerosis in patients treated with gamma interferon. The Lancet, 329(8538), 893-895.
6. Minagar, A., Shapshak, P., Fujimura, R., Ownby, R., Heyes, M., Eisdorfer, C. (2002). The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis. Journal of the neurological sciences, 202(1-2), 13-23.
7. Carson, M. J., Doose, J. M., Melchior, B., Schmid, C. D., Ploix, C. C. (2006). CNS immune privilege: hiding in plain sight. Immunological reviews, 213(1), 48-65.
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