Investigating innate immune signalling in Gulf War Illness and blast‑related TBI

This project explores whether persistent changes in innate immune signalling contribute to long‑term symptoms in veterans with Gulf War Illness and blast‑related traumatic brain injury.

It focuses on myeloid‑derived suppressor cells and their cytokine activity, alongside upstream HMGB1–P2X7–NLRP3 signalling. By comparing immune markers in affected and healthy groups, the study aims to identify measurable biological differences behind chronic post‑deployment conditions.

Understanding long‑term health impacts on veterans

Long‑term health problems following military service - including Gulf War Illness and blast‑related traumatic brain injury - remain poorly understood, even though they affect many veterans. Persistent symptoms such as fatigue, pain and cognitive difficulties often lack clear biological explanations, which makes diagnosis, treatment and support harder.

This research tackles that gap by examining immune‑signalling mechanisms, particularly the role of myeloid‑derived suppressor cells and the HMGB1–P2X7–NLRP3 pathway, in chronic inflammation. By identifying measurable biological differences, the project strengthens scientific understanding, supports fairer recognition of veteran health conditions, and informs future research, clinical practice and policy to improve long‑term care and wellbeing.

This project is distinctive in its focus on the HMGB1–P2X7–NLRP3 innate immune‑signalling pathway in living veterans with Gulf War Illness and blast‑related traumatic brain injury - an area that has not been systematically explored. It centres on myeloid‑derived suppressor cells and their cytokine activity, linking upstream danger signalling to downstream immune regulation.

By analysing peripheral blood using integrated approaches - including flow cytometry, inflammasome assays and cytokine profiling - the study provides a minimally invasive but comprehensive assessment of immune function. Comparing multiple veteran cohorts with healthy controls helps identify shared and condition‑specific mechanisms. This approach addresses a critical gap in understanding upstream immune processes and offers new insights into chronic inflammation behind persistent post‑deployment symptoms.

Background and rationale

Many veterans experience persistent symptoms years after deployment, including fatigue, chronic pain and cognitive difficulties. Despite extensive research, the biological mechanisms behind these long‑term conditions - particularly Gulf War Illness and blast‑related traumatic brain injury - remain poorly understood. Evidence suggests that chronic neuroinflammation and immune dysregulation may play a role, but the upstream signalling pathways driving these processes are still unclear.

Research aims and objectives

This project investigates whether persistent activation of innate immune signalling contributes to long‑term symptoms in affected veterans. It focuses on the HMGB1–P2X7–NLRP3 pathway and its relationship with myeloid‑derived suppressor cells (MDSCs) and cytokine activity.

Key objectives:

• Assess activation of the HMGB1–P2X7–NLRP3 signalling pathway
• Evaluate cytokine production
• Characterise MDSC populations in peripheral blood
• Compare findings across Gulf War Illness, blast‑related TBI and healthy military controls

Methodology

This cross‑sectional observational study involves a single visit per participant.

Data collection includes:

• Informed consent and a symptom questionnaire
• Peripheral blood sampling via venepuncture

Laboratory techniques:

• Flow cytometry to assess immune cell populations and P2X7 receptor expression
• Inflammasome activation assays to measure IL‑1β and IL‑18 release
• ELISA to quantify circulating HMGB1 and cytokines

This integrated approach provides a detailed, minimally invasive assessment of immune signalling.

Innovation and contribution

This project is among the first to investigate upstream innate immune signalling in living veterans, linking danger‑associated molecular signalling (HMGB1) with inflammasome activation and MDSC‑mediated immune regulation. By combining multiple immunological techniques and comparing distinct veteran cohorts, it addresses a critical gap in understanding chronic inflammatory mechanisms.

Expected impact

The research aims to identify measurable biological differences associated with persistent post‑deployment symptoms.

Findings may:

• Advance understanding of chronic inflammation in veteran health
• Inform future biomedical and translational research
• Support improved clinical recognition and long‑term care strategies

(self‑funded PhD)