The role of **complement inhibition in progressive multiple sclerosis (MS)** centers on controlling an overactive immune response that contributes to ongoing nerve damage and disease progression. Complement is a part of the immune system that helps clear pathogens and damaged cells, but in MS, especially its progressive forms, excessive complement activation can worsen inflammation and tissue injury in the central nervous system (CNS).
In progressive MS, the immune system attacks the myelin sheath—the protective covering of nerve fibers—leading to chronic neurodegeneration. Complement proteins become activated in this process, amplifying inflammation by marking cells for destruction, recruiting immune cells, and forming membrane attack complexes that can directly damage nerve cells and their supporting structures. This uncontrolled complement activity contributes to the persistent inflammation and neurodegeneration characteristic of progressive MS.
**Complement inhibition** aims to block or reduce this harmful cascade, thereby protecting nerve cells from further damage. By targeting specific components of the complement system, therapies can reduce the recruitment and activation of inflammatory cells such as microglia and macrophages within the CNS. This dampening of the immune response helps to slow down the progression of disability and tissue loss.
The complement system can be activated through several pathways, but in MS, the alternative and classical pathways are often implicated. Once triggered, complement proteins like C3a and C5a act as potent inflammatory mediators, increasing the permeability of the blood-brain barrier and attracting immune cells into the CNS. This leads to a vicious cycle of inflammation, demyelination, and axonal injury. Complement inhibition interrupts this cycle by preventing the formation of these inflammatory fragments and the membrane attack complex, which otherwise would cause direct cell lysis.
In addition to reducing inflammation, complement inhibition may also protect astrocytes and oligodendrocytes—cells critical for maintaining CNS homeostasis and myelin repair. For example, in related neuroinflammatory diseases such as neuromyelitis optica, complement-dependent cytotoxicity is a major driver of astrocyte damage. Although MS pathology is more complex, similar mechanisms involving complement-mediated injury are thought to contribute to progressive neurodegeneration.
Therapeutic strategies under investigation or in use include monoclonal antibodies and small molecules that block key complement proteins or their receptors. These treatments aim to selectively inhibit harmful complement activation without compromising its essential role in host defense. By doing so, complement inhibitors offer a promising approach to managing progressive MS, where traditional anti-inflammatory therapies have limited efficacy.
In summary, complement inhibition in progressive MS serves to reduce chronic inflammation and neurodegeneration by blocking the destructive effects of complement activation within the CNS. This approach targets a fundamental immune mechanism driving disease progression, offering hope for slowing disability accumulation in patients with progressive forms of MS.
