Valeria Ramaglia

Overall research program. My research program bridges immunology and neurology. Specifically, my overarching goal is to ascertain novel roles for the innate immune system – particularly the complement system – in health and disease, to identify biofluids biomarkers that can help segregate people with increased risk of developing neurodegeneration and to test the potential of established or novel anti-complement agents to prevent, halt or reverse neurological disability. The increasing list of FDA-approved complement therapeutics for several neurological and non-neurological diseases makes complement therapy a real option for patients, giving this research obvious translational value in taking the generated knowledge into the clinic.

Background, rationale and significance of my research program.

For many years, the brain was thought to be ‘sealed’ from the rest of the body’s immune system. We now appreciate that communication between immune cells and brain-resident cells is not a one-way street; we have learned that specialized pockets in the brain are not immunoprivileged; and we know that immune components can even be produced by brain-resident cells. For instance, key immune proteins known as ‘complement’ are produced by brain-resident cells and can be activated within the brains of people with autoimmune or neurodegenerative diseases. However, the triggers and consequences of complement activation in the brain are not fully understood. On one hand complement may help clear cellular debris while on the other hand it could promote neuroinflammation and drive disease progression. My research goal is to uncover new roles for complement in the brain during health, neuroinflammation and neurodegeneration, particularly in the context of multiple sclerosis and traumatic brain injury.

My research program spans over three main themes:

• Neuroinflammation. My lab aims to understand the cellular and molecular mechanism of brain pathology in people with progressive multiple sclerosis. There are no effective treatments for progressive multiple sclerosis. The so-called “tertiary lymphoid tissues” (TLT) form in the leptomeninges overlaying the multiple sclerosis brain. These TLT represent a form of compartmentalized inflammation that has been associated, but not causally connected, with grey matter demyelination and neurodegeneration. Using a mouse model system that induces TLT and cortical injury in response to an adoptive transfer of encephalogenic Th17 cells and post-mortem human tissue from people with progressive multiple sclerosis, my lab investigates the cellular and molecular mechanisms that lead to grey matter damage with a particular focus on the role of the complement system.

• Neurodegeneration. My lab aims to understand the cellular and molecular changes caused by brain trauma. Traumatic brain injuries, even mild, can have serious consequences including an increased risk of neurodegeneration later in life. Identifying what sets up the injured brain for neurodegeneration will identify therapeutic targets to prevent or delay neurodegeneration in people at risk. We have leads that post-traumatic complement activation is a candidate risk factor. Following up on these leads, we plan to reveal the source, the cellular target, the molecular signalling and the functional consequences of complement activation in the brain at steady-state and after traumatic injury.

• Biomarkers. In the context of multiple sclerosis, serum/radiological biomarkers of TLT and grey matter injury are lacking. Therefore, it is challenging to identify patient populations that may benefit from therapies targeting the TLT, making clinical trials extremely difficult to interpret. By dissecting the cellular and molecular circuitry that operate at leptomeningeal TLT we aim to discover a cerebrospinal fluid (CSF) signature of TLT that can be used to segregate patients experiencing compartmentalized inflammation. This work aims to a personalized medicine approach that has the potential to identify appropriate patient populations that are more responsive to drugs targeting TLT.  In the context of traumatic brain injury, we lack biomarkers that can segregate which trauma patients are at risk of neurodegeneration later in life. People who suffer from brain trauma may be particularly amenable to early disease-modifying treatment. Identifying which patients may benefit from a certain therapy, or pin-pointing a timeframe when such therapy may be appropriate, would be invaluable in guiding clinicians to decide whether and when a specific drug might be effective. Measuring levels of an identified biomarker may also aid diagnosis, assessment of prognosis, and help in the monitoring of treatment response. A role for complement as biomarker will be explored.

Approach of research.

The approach of my research integrates analyses of post-mortem human brain tissue, biofluids from living patients, and functional studies in animal models, using genetic tools alongside multi-parameter flow cytometry, Imaging Mass Cytometry, proteomics, and single-cell RNA sequencing—offering a powerful platform to advance our understanding of immune-mediated brain pathology.

Lab culture.

I aim to cultivate a lab culture that prioritizes and celebrates equity and diversity, including the support of careers for women and underrepresented minorities in science.