The effect of ageing on immunity; chronic inflammation; trauma; stress and immunity
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.
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.
Hazeldine J, Hampson P, Opoku FA, Foster M, 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 46:975-984.
Pollock RD, Carter S, Velloso CP, Duggal NA, Lord JM, Lazarus NR, Harridge SR (2015) An investigation into the relationship between age and physiological function in highly active older adults. J Physiol 593:657-680.
LordJM, MidwinterMJ, BelliA, BrohiK, KovacsEJ, KoendermanL, KubesP, ChenY-F, LilfordRJ (2014) The systemic immune response to trauma: an overview of pathophysiology and treatment. Lancet 384:1455-1465.
Hazeldine J, Hampson P, Lord JM (2014) The impact of trauma on neutrophil function. Injury doi:10.1016/j.injury.2014.06.021.
Sapey E, Greenwood H, Walton G, Mann E, Love A, Aaronson N, Insall RH, Stockley RA, Lord JM (2014) Phosphoinositide 3 kinase inhibition restores neutrophil accuracy in the elderly: towards targeted treatments for immunesenescence. Blood 123:239-248.
Baylis D, Ntani G, Edwards MH, Syddall HE, Bartlett DB, Dennison EM, Martin-Ruiz C, von Zglinicki T, Kuh D, Lord JM, Sayer AA, Cooper CF (2014) Inflammation, telomere length and grip strength: a 10 year longitudinal study. Calcified Tissue Int 95:54-63.
Duggal NA, Upton JA, Phillips AC, Sapey E, Lord JM (2013)An age-related numerical and functional deficit in CD19+CD24hiCD38hi B cells is associated with an increase in systemic autoimmunity. Aging Cell 12:873-881.
Duggal NA, Upton JA, Phillips AC, Hampson P, Lord JM (2013). Depressive symptoms are associated with reduced neutrophil superoxide generation in hip fracture patients. Brain Behavior Immunity 33:173-182.
Phillips AC, Upton JA, Duggal NA, Carroll D, Lord JM (2013).New onset depression following hip fracture is associated with increased physical frailty in older adults: the role of the cortisol:dehydroepiandrosterone sulphate ratio. BMC Geriatrics 13:60.
Hazeldine J, Hampson P, Lord JM (2012) Reduced release and binding of perforin at the immunological synapse underlies the age-related decline in Natural Killer cell cytotoxicity. Aging Cell 11:751-759.
Bartlett DB, Firth CM, Phillips AC, Moss P, Baylis D, Syddall H, Sayer AA, Cooper C, Lord JM (2012). The age-related increase in low grade systemic inflammation (Inflammaging) is not driven by cytomegalovirus infection. Aging Cell 11:912-915.
Baylis D, Bartlett DB, Syddall HE, Ntani G, Gale CR, Cooper C, Lord JM, Sayer AA (2013) Immune-endocrine biomarkers as predictors of frailty and mortality: a ten year longitudinal study in community dwelling older people AGE 35:963-971.
Jansen JO, Lord JM, Thickett D, Midwinter MJ, McAuley DF and Gao F (2013). Statins and Trauma: a systematic review. Crit Care 17:227.
Wang K, Hampson P, Hazeldine J, Kryštof V, Strnad M, Pechan P, Lord JM (2012) Cyclin-Dependent Kinase 9 activity regulates neutrophil spontaneous apoptosis. PLoS ONE 7(1): e30128. doi:10.1371/journal.pone.0030128.
Khanfer R, Lord JM, Phillips AC (2011) Neutrophil function and cortisol:DHEAS ratio in bereaved older adults. Brain Behavior and Immunity. 25:1182-1186.
Radford DJ, Wang K, McNelis JC, Taylor AE, Hechenberger G, Hofmann J, Chahal H, Arlt W and Lord JM (2010) Dehydroepiandrosterone sulfate directly activates protein kinase C-β to increase human neutrophil superoxide generation. Mol Endocrinol. 24:813-821.
Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM(2010). Aging of the innate immune system. Current Opinion Immunol. 22:507-513.