• Fellow of the Academy of Medical Sciences 2015
• PhD Biological Sciences 1983
• BSc (Hons) Human Biology 1979

Janet Lord began her research career in the field of diabetes, gaining a PhD from the University of Aston in 1983 researching the link between obesity, diabetes and ageing. She went on to investigate signalling pathways involved in regulating insulin secretion, working with Steve Ashcroft at Oxford University, revealing the key role played by protein kinase C in this process. She returned to Birmingham and was awarded a Royal Society University Fellowship in 1989, allowing her to set up her own group looking at cell signalling in immune cells and its dysregulation in disease. She was promoted to the chair in immune cell biology in 2004.

She has made seminal contributions to the field of apoptosis, defining the PKC isoenzyme PKC-delta as an apoptotic lamin kinase and showing for the first time that the very short lifespan of neutrophils was due to their ability to activate death receptor signalling pathways in the absence of death receptor ligation. Her research has identified several novel therapeutic targets based upon the induction of apoptosis, most notably members of the PKC family.

In the last decade she has become interested in the effect of ageing and stress upon neutrophil function, including how innate immunity is regulated by the endocrine system. In 2010 she showed for the first time that the major adrenal steroid dehydroepiandrosterone sulphate was able to enhance neutrophil bactericidal function, revealing a biological function for this hormone distinct from its role as a precursor for the androgen DHEA. Her work suggests that a lack of this hormone in old age results in older adults being more susceptible to the immune suppressive effects of the stress hormone cortisol after physical stress such as hip fracture or the emotional stress of a bereavement.

Professor Lord and her team now focus upon characterising signaling pathways that regulate innate immune cell function and migration, with a special interest in the role dysregulation of these functions plays in human ageing. She has recently shown that PI3 kinase delta is constitutively active in neutrophils from older donors and that inhibiting this enzyme corrects this age-related defect in chemotaxis. Moreover, reduced migratory dynamics contributes to the systemic inflammation seen in old age and this may contribute to many age-related characteristics including sarcopaenia. This knowledge is used to develop novel therapies in three main areas; Immune senescence (loss of immune function with ageing), chronic inflammatory disease (Rheumatoid Arthritis) and physical frailty.

Teaching Programmes

• MSc Musculoskeletal Ageing and Health (Course Director)
• MSc Immunology and Immunotherapy
• BSc Medical Science, final year module: The Biology of Ageing
• MBChB

Professor Lord supervises doctoral research students in the following areas:

• The mechanisms underlying reduced immune function in ageing.
• Lifestyle factors (exercise, diet, sleep) influencing immune function in old age
• Stress (trauma) and Immunity
• The inflammatory response to trauma
• Mechanisms underlying age, disease and trauma related muscle loss (sarcopaenia)

If you are interesting in studying any of these subject areas please contact Professor Lord on the contact details above, or for any general doctoral research enquiries, please email: dr@contacts.bham.ac.uk  or call +44 (0)121 414 5005.
For a full list of available Doctoral Research opportunities, please visit our Doctoral Research programme listings.

Opportunities for PhD projects with Prof Lord are also listed on www.findaphd.com when available.

RESEARCH THEMES

The effect of ageing on immunity; chronic inflammation; trauma;  stress and immunity 

RESEARCH ACTIVITY

Immune senescence and frailty
As humans age they become more susceptible to infectious diseases (especially bacterial infections), inflammatory disease, autoimmune disease and have poorer responses to vaccinations. Although ageing is a complex process, these data suggest that immune function may be reduced during ageing and will contribute to the increased morbidity of the elderly. Professor Lord’s team has shown that neutrophil function declines with age, specifically that neutrophil phagocytosis of bacteria is reduced by almost half and also that neutrophil migration accuracy is reduced. The latter is important as inefficient migration leads to excess tissue damage as the cell migrates towards a site of infection and this may explain why older people are frailer after infection.  The team are now testing interventions to improve neutrophil migration and reduce mortality in patients with pneumonia.

Prof Lord’s studies also aim to determine if stress accelerates this loss of neutrophil function and makes the elderly more susceptible to infection and physical frailty. The research so far has shown that after hip-fracture or bereavement, the loss of neutrophil function is dramatically increased and almost half of hip fracture patients succumbed to serious bacterial infections. Importantly this work has revealed that this may be mediated by an excess of the immune suppressive stress hormone cortisol and a lack of the immune enhancing counter stress hormone dehydroepiandrosterone (DHEA). A raised cortisol:DHEAS ratio was also associated with poor physical function (frailty) up to 6 months after hip fracture. Professor Lord is now seeking funding to try and supplement hip fracture patients with DHEA to see if the number of infections in these patients can be reduced.

More recently the team associated with the MRC-ARUK Centre for Musculoskeletal Ageing Research have been studying older adults who have been physically very active all of their lives to determine how much of physical and immune ageing is due to increased inactivity with old age. So far this research has revealed that sarcopenia did not occur in these adults, but other aspects of ageing such as a decline in lung function did. The team are now examining immune function in these adults.

Chronic inflammatory disease
During an immune response inflammatory cells, including T cells and neutrophils, are recruited to sites of infection to help to clear pathogens. Once the site is rendered sterile these same cells must be removed efficiently to avoid non-specific attacks on healthy tissue. This is achieved in part by their death by apoptosis and removal by macrophages. Professor Lord and colleagues has shown that this process is dysregulated in chronic inflammatory diseases such as Rheumatoid arthritis, leading to the accumulation of inflammatory cells and destruction of healthy tissue by cells such as neutrophils. The group has identified signals from stromally derived cytokines (type 1 Interferon and GM-CSF) as regulators of neutrophil survival and stromal fibroblasts are now recognised as rational targets in rheumatoid arthritis.

This work has now progressed to consider the role of immunesenescence in the development of RA. Previous work by researchers in the US has shown that patients with established RA show features of accelerated immune ageing and Prof Lord has revealed that regulatory B cells, which play a role in preventing autoimmunity, are reduced with age. The team are now working with Prof Karim Raza to determine if immunesenescence appears in the very earliest stages of RA and could be a driver of pathology rather than a consequence.

Trauma
Major trauma is accompanied by a significant systemic inflammatory response (SIRS) accompanied by a compensatory anti-inflammatory response (CARS), however there is also major immuneparesis which leaves the patient at risk of infections and sepsis. In addition, both the endocrine (increased cortisol:DHEAS ratio) and inflammatory response promote a catabolic response which combined with immobility leads to dramatic loss of muscle. For the elderly patient that presents problems as the ability to restore muscle mass and strength is compromised with age. Prof Lords team in the SRMRC are following the inflammatory and endocrine response to trauma in young and elderly patients with the aim to develop intervention to improve immunity and reduce muscle loss and frailty after trauma.

• Section editor for the journal Aging Cell

Lara J, Cooper R, Nissan J, Ginty AT, Khaw K-T, Deary IJ, Lord JM, Kuh D and Mathers JC (2015) A proposed panel of biomarkers of healthy ageing. BMC Medicine 13:222

Hazeldine J, Hampson P, Opoku FA, Foster M and Lord JM (2015) N-formyl peptides drive mitochondrial damage associated molecular pattern induced neutrophil activation through ERK1/2 and P38 MAP Kinase signalling pathways. Injury 46:975-84

Pollock RD, Carter S, Velloso CP, Duggal NA, Lord JM, Lazarus NR and Harridge SD (2015) An investigation into the relationship between age and physiological function in highly active older adults. J Physiol 593(3):657-80

Lord JM, Midwinter MJ, Chen YF, Belli A, Brohi K, Kovacs EJ, Koenderman L, Kubes P and Lilford RJ (2014) The systemic immune response to trauma: an overview of pathophysiology and treatment. Lancet 384(9952):1455-65

Sapey E, Greenwood H, Walton G, Mann E, Love A, Aaronson N, Insall RH, Stockley RA and Lord JM (2014) Phosphoinositide 3 kinase inhibition restores neutrophil accuracy in the elderly:  towards targeted treatments for immunesenescence. Blood 123(2):239-48

Hazeldine J, Harris P, Chapple IL, Grant M, Greenwood H, Livesey A, Sapey E and Lord JM (2014) Impaired neutrophil extracellular trap formation: a novel defect in the innate immune system of aged individuals. Aging Cell 13:690-8

Baylis D, Ntani G, Edwards MH, Syddall HE, Bartlett DB, Dennison EM, Martin-Ruiz C, von Zglinicki T,  Kuh D, Lord JM, Aihie Sayer A and Cooper C (2014) Inflammation, telomere length and grip strength: a 10 year longitudinal study. Calcified Tissue Int 95(1):54-63

Duggal NA, Upton JA, Phillips AC, Sapey E and Lord JM (2013) An age-related numerical and functional deficit in CD19⁺CD24^hiCD38^hi B cells is associated with an increase in systemic autoimmunity. Aging Cell 12(5):873-81