Summary: A new study reveals how autophagy in certain immune cells can lead to the immune system attacking the central nervous system. The findings have implications for the treatment of autoimmune diseases, like multiple sclerosis.
Source: University of Zurich.
Autophagy refers to a fundamental recycling process of cells that occurs in yeast, fungi, plants, as well as animals and humans. This process allows cells to degrade their own components and thus activate energy resources to be able to adapt to nutritional needs. In addition, autophagy plays a central role in steering an organism’s immune response. Autoimmune diseases arise from an abnormal immune response to a normal body part such as the central nervous system in patients with multiple sclerosis.
No autoimmune reaction without autophagy proteins
Led by Jan Lünemann from the Institute of Experimental Immunology at the University of Zurich, a team of neuroimmunologists has now found evidence for another aspect of this cellular “self-digestion”: Autophagy proteins are responsible for triggering autoimmune processes in a mouse model of multiple sclerosis. Upon genetically switching off the autophagy protein ATG5 in certain immune cells, the researchers observed significantly lower levels of pathological T cells in the central nervous system of the mice. As a consequence, the animals failed to develop inflammation in the brain and spinal cord comparable with inflammation that develops in multiple sclerosis.
Immune cells target nerve cells
The researchers have now demonstrated that the autophagy protein ATG5 has an essential function when myelin antigens are presented to immune cells during inflammation processes in the central nervous system. “This reactivation process is thought to play a decisive role in the development of autoimmune neuroinflammation,” says Christian Keller, lead author of the study. In multiple sclerosis – one of the most common autoimmune diseases – T cells attack the myelin sheaths of the body’s own nerve fibers. The immune cells are activated as soon as they come into contact with antigen-presenting cells. Dendritic cells are responsible for antigen presentation. When the myelin sheath becomes defective, the dendritic cells digest the isolation membrane through autophagy and present parts of it to pathological T cells entering the site of the inflammation. “This means they promote the progression of the disease,” explains Keller.
The team plans to use the latest findings as a basis for investigating tissue samples of patients suffering from multiple sclerosis to find out whether autophagy is particularly active in certain immune cells. “In the long run, we want to see whether these new immunopathology findings can be used to develop new treatments for multiple sclerosis,” says Jan Lünemann.
Source: Jan D. Lünemann – University of Zurich
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is adapted from the University of Zurich news release.
Original Research: Abstract for “ATG-dependent phagocytosis in dendritic cells drives myelin-specific CD4+ T cell pathogenicity during CNS inflammation” by Christian W. Keller, Christina Sina, Monika B. Kotur, Giulia Ramelli, Sarah Mundt, Isaak Quast, Laure-Anne Ligeon, Patrick Weber, Burkhard Becher, Christian Münz, and Jan D. Lünemann in PNAS. Published online December 12 2017 doi:10.1073/pnas.1713664114
ATG-dependent phagocytosis in dendritic cells drives myelin-specific CD4+ T cell pathogenicity during CNS inflammation
Although reactivation and accumulation of autoreactive CD4+ T cells within the CNS are considered to play a key role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), the mechanisms of how these cells recognize their target organ and induce sustained inflammation are incompletely understood. Here, we report that mice with conditional deletion of the essential autophagy protein ATG5 in classical dendritic cells (DCs), which are present at low frequencies in the nondiseased CNS, are completely resistant to EAE development following adoptive transfer of myelin-specific T cells and show substantially reduced in situ CD4+ T cell accumulation during the effector phase of the disease. Endogenous myelin peptide presentation to CD4+ T cells following phagocytosis of injured, phosphatidylserine-exposing oligodendroglial cells is abrogated in the absence of ATG5. Pharmacological inhibition of ATG-dependent phagocytosis by the cardiac glycoside neriifolin, an inhibitor of the Na+, K+-ATPase, delays the onset and reduces the clinical severity of EAE induced by myelin-specific CD4+ T cells. These findings link phagocytosis of injured oligodendrocytes, a pathological hallmark of MS lesions and during EAE, with myelin antigen processing and T cell pathogenicity, and identify ATG-dependent phagocytosis in DCs as a key regulator in driving autoimmune CD4+ T cell-mediated CNS damage.
“ATG-dependent phagocytosis in dendritic cells drives myelin-specific CD4+ T cell pathogenicity during CNS inflammation” by Christian W. Keller, Christina Sina, Monika B. Kotur, Giulia Ramelli, Sarah Mundt, Isaak Quast, Laure-Anne Ligeon, Patrick Weber, Burkhard Becher, Christian Münz, and Jan D. Lünemann in PNAS. Published online December 12 2017 doi:10.1073/pnas.1713664114