MULTIPLE SCLEROSIS: The Sympathetic Nervous System Mitigates CNS Autoimmunity via b2-Adrenergic Receptor Signaling in Immune Cells

Multiple Sclerosis (MS) is a neurodegenerative disease characterized by destruction of the myelin sheath surrounding nerve cells, caused by the improper functioning of the body’s innate immune cells through targeted destruction of myelin producing cells. In this paper, the researchers used a mouse model for MS known as experimental autoimmune encephalomyelitis (EAE), wherein the mouse is immunized using a myelin associated protein. This immunization causes the mouse’s immune cells to attack their own myelin covered nerves and results in the progression of disease phenotypes. This paper explores the contribution of secreted factors from the Sympathetic Nervous System (SNS) such as noradrenaline (NE) and how they contribute to the modulation of the immune response against the Central Nervous System (CNS). The authors show that increased release of NE, brought about through genetic manipulation, leads to decreased symptom progression in the mouse model, as well as showing a cellular reduction in the invasion of activated immune cells into the brain and a reduction in the release of proinflammatory cytokines, which are known to worsen symptoms. The authors also identify downstream targets of NE signalling through the Adrb2 receptor and show that inhibition of this target leads to worse symptoms of EAE (MS), in the mouse model. The paper identifies an important contribution of the SNS to EAE progression and identify specific targets for possible therapeutics in the future.

By: Nate Dempsey

Araujo, L., Maricato, J., Guereschi, M., Takenaka, M., Nascimento, V., De Melo, F., . . . Basso, A. (2019). The Sympathetic Nervous System Mitigates CNS Autoimmunity via β2-Adrenergic Receptor Signaling in Immune Cells. Cell Reports, 28(12), 3120-3130.e5.

https://doi.org/10.1016/j.celrep.2019.08.042

NEW IMMUNE THERAPEUTIC TARGET: The Mevalonate Pathway Is a Druggable Target for Vaccine Adjuvant Discovery

Modern vaccine design requires both the presence of a antigen, a portion of the pathogen being immunized against, in combination with an adjuvant, a molecule that is capable of triggering the immune response by signalling danger to the immune system. For almost a century the primary adjuvant used in vaccines has been Alum, aluminum salts, however previous data has shown adjuvant activity arising from the usage of statins, a class of drug used to inhibit enzymes in the cholesterol synthesis pathway. Initial testing of polar and nonpolar statin drugs revealed efficacy of non-polar statin drugs in increasing immune response to vaccines. By inhibiting the production of molecular precursors to cholesterol, statins inhibit the modification of key molecular switches belonging to the class of proteins known as GTPases, in particular Rab5.

Exploration of these molecules mechanisms showed that they don’t function via the traditional pathway of sensing pathogen associated molecular patterns (PAMPS) and inducing the pyrogenic response. Researchers demonstrated that the inhibition of endosomal processing proteins via statins increased the retention time of antigens in dendritic cells and therefore increased the magnitude of immune responses through the ability of dendritic cells to cross present to CD8+ and CD4+ T-Cells. The major significance of the ability of statins to induce adjuvancy is their ability to induce TH1-Cell type responses, which are crucial for cancer checkpoint therapies, and which is not induced by the traditional treatment using Alum. Testing in mice models showed increased survival and cancer surveillance ability when statin drugs were combined with anti-PD1 antibodies, the standard for cancer immune checkpoint therapy. Therefore statin drugs display a promising effect in cancer immunotherapy when combined with existing checkpoint therapy.

Xia, Yun, Xie, Yonghua, Yu, Zhengsen, Xiao, Hongying, Jiang, Guimei, Zhou, Xiaoying, . . . Zhang, Yonghui. (2018). The Mevalonate Pathway Is a Druggable Target for Vaccine Adjuvant Discovery. Cell, 175(4), 1059-1073.e21.

LINK: https://doi-org.ezp-prod1.hul.harvard.edu/10.1016/j.cell.2018.08.070

Written By: Nate Dempsey

IMMUNE CELL EPIGENETICS IN AGING: Single-Cell Chromatin Modification Profiling Reveals Increased Epigenetic Variations with Aging (Cell, 2018) – Cheung et al.

In this article, the authors investigated epigenetic modifications (or chromatin marks) — changes in the 3D packaging of genomic data that affect how genes are expressed — in human immune cells. First, they sought to determine whether different cell types in the immune system tend to display distinct sets of chromatin marks. Next, they addressed the connections between immune chromatin marks and age, examining how chromatin marks change with age and whether this variation has more heritable or environmental influences. They developed a mass cytometry technique called EpiTOF to conduct these complex experiments. The authors’ findings underscore the power of epigenetic analysis to both expand our biological understanding and to address human illnesses.  

When exploring epigenetic differences between immune cell types, the authors found that each subtype is characterized by its own set of chromatin marks; furthermore, these changes arise early in cell differentiation, the period when immune cell progenitors diverge to becoming different mature immune cell types. Their findings about which chromatin marks pervade in which cell types provide immunologic insight: for example, mature Memory T cells’ chromatin is more accessible for transcription than naïve T cells, and CD56bright NK cells differentiate along a different hematopoietic lineage than CD56dim NK cells.

In the next section, the authors found that older age is associated with increased epigenetic variability between individuals, as well as between cells within the same individual. Young people have relatively homogenous chromatin modification profiles, but as they age these tend to diversify from others’. In addition, within each individual’s immune system, their cells develop increasingly variable chromatin marks as they age; this single-cell variability is termed epigenetic noise. The authors found that population-level heterogeneity and cell-level noise are related to other age-related signals of genetic and epigenetic deterioration. Then, by comparing groups of identical and fraternal twins the authors discovered that most chromatin mark variance is non-heritable, instead having mostly environmental causes.

The authors conclude that EpiTOF can be used to address epigenetic causes of immune diseases and cancer, and that epigenetic variability between individuals and cells impact transcriptional noise, a well-documented impact of ageing. The authors both expand our knowledge of chromatin marks and purpose potential therapeutic significance while acknowledging that more research is needed before conclusions can be drawn regarding ageing symptoms.

Cheung, P., Vallania, F., Warsinske, H.C., Donato, M., Schaffert, S., Chang, S.E., Dvorak, M., Dekker, C.L., Davis, M.M., Utz, P.J., et al. (2018). Single-Cell Chromatin Modification Profiling Reveals Increased Epigenetic Variations with Aging. Cell 173, 1385-1397.e14.

LINK: https://www.ncbi.nlm.nih.gov/pubmed/29706550

Written By: Zach Altshuler