Transcript
Role of complement in axonal integrity
Jan Lünemann, MD, MBA
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- Axonal damage can occur early and can contribute significantly to disease accumulation, to disability accumulation in CIDP. So, inhibition of axonal damage and maintenance of axonal integrity is a valid therapeutic strategy in CIDP. So, which mechanisms are in place that maintain axonal integrity during the steady state? First and foremost, there are, it is a communication network between Neuronal cells and Schwann cells, which is very important during development of the nervous system and also in maintaining function of the peripheral nervous system, not only along efficient action potential transmission, but also mediating homeostasis and repair after peripheral nerve injury. Peripheral nerves and neuronal cells in particular are very high in energy demand. They're very active cells, so. And so, they require a lot of energy, which is usually provided by mitochondria. So, these mitochondria function is very important for axonal integrity. And also the turnover of mitochondria is very, very important. There's also evidence that the complement system is important in maintaining axonal integrity in addition to its cytotoxic or inflammation-related functions. Now, the term "complement" has first been coined by Paul Ehrlich and described as a serological factor that is necessary but not sufficient to induce lysis of target cells. And not sufficient because he and his colleagues hypothesised that it requires an additional factor which recognise the target cell, and then bridges to the complement.
They called that additional intermediate factor immune body. Today known as antibody. And this is why the antibody-induced complement pathway, it's traditionally referred to as the classical pathway. But it's the evolutionary copy basically of the more older lectin-induced pathway. The only difference mainly basically are the triggers of both pathway. The classical pathway is induced by recognition of multimeric Fc antibody molecules or IgM molecules, while the lectin-pathway is induced by recognition of carbohydrate structures. For example, on microbial cells, or by damaged mammalian cells. Now, activation of C1q then leads to activation of early complement components C4, C2, which then form the C3 convertase complex. And C3 is the most abundant plasma complement protein. And the cleavage of C3 basically initiates the terminal complement pathway, which ultimately can lead to the formation of the terminal complement complex or the MAC Attack Complex and induce cell lysis, but complement does so much more than that. So, even more proximal to C5, generation of C3 cleavage products, for example, C3b is very important. Opsonizing microbial cells, for example, or damaged cells from macrophages for elimination. C3a is a very pro-inflammatory molecule as is C5a. And there are special receptors on immune cells, particularly innate immune cells that recognise these inflammatory complement component. So, this is a very efficient pathway.
This is why it needs to be regulated very tightly. And this is done by both humoral and cell-associated inhibitory factors, which basically target the so-called amplification loop, these three C3 conversion. And also the formation of the membrane attack complex. And a very important molecule is CD59. This is a cell-associated molecule, which is anchored into the cell membrane. And if the anchors are not functional, SN PNH for example, Paroxysmal Nocturnal Hemoglobinuria or PNH, then complement activation cannot be controlled anymore as excessive, and this leads to lysis of red blood cells. And can also lead to attack of, for example, Schwann cells, which can translate into a clinical syndrome similar to what is seen in CIDP, for example.. It's a very rare condition. Most diseases associated with complement overactivation are induced by antibody mediated complement activation. So, but they are also physiological actions of complement. And one very important mechanism is synaptic pruning. So, synaptic pruning is a mechanism that helps in hard wiring neuronal circuits during development and helps in eliminating synapses that are not needed. So, and this happens through attacking of unwanted synapses. Like C1q during brain development. And then, C3 is released as activated and C3bx as in opsonin. So, for a local microglia, which then recognise and eliminate these synapses. These microglia can also, in addition, be activated by C3a because they have specific receptors for C3a. So, such a mechanism is very important during brain development. But there's also evidence that such mechanisms can lead to neuropathology in, for example, neurodegenerative diseases such as Alzheimer's diseases.
So, synaptic pruning can be both physiological and pathologic, dependent on the circumstances. There's also evidence that the complement system helps in or promotes axonal growth depending on the complement factors you look at. So here, C1q seems to be different from the more downstream complement factors. So, C1q is a molecule that probably serves more functions than just complement activation. There's evidence that C1q helps outgrowths of axons during development, but also during axonal damage now. And also down-regulates inflammatory responses while further downstream molecules such as C1/ C3, for example, as evidence that this inhibits axonal outgrowth. And there's of course, the formation of the membrane attack complex, which can help eliminating damaged cells. Also, neuronal cells. On the other hand, there is complement inhibitory function of CD59, for example, in other molecules that restrain complement activation and protect cells, including neuronal cells from damage.
Plus, there's the additional mechanisms independent of membrane attack complexes is that C3a and C5b can act directly on immune cells and activate these immune cells within the immune system, but also locally within the nervous system, such as activating microgliosis. So, these are just a few prominent complement-mediated mechanisms that take place in the nervous system and that help maintaining axonal integrity, but they can also be detrimental in certain circumstances. And so, just to highlight that, a complement does much more than just forming a poor, or just forming the membrane attack complexes, it has much more functions on different levels. Physiological and pathological functions and complement functions appear to be specifically important for nervous system function and homeostasis. And diseases that are associated with dysfunctional complement are of course, rare genetically fixed diseases such as CD59. Dysfunction seen in some patients with demyelinating neuropathy, but many diseases, particular neuromuscular diseases, there's evidence that complement plays a prominent role in mediating a disease pathology. This includes Myasthenia Gravis, CIDP, MMN. We also have data from clinical trials, also have approved therapies for complement inhibitors showing clinical efficacy in these disease conditions.
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