Inflammatory marker trajectories associated with frailty and ageing in a 20-year longitudinal study.

OBJECTIVE: The aim of this exploratory study was to investigate the development of low-grade inflammation during ageing and its relationship with frailty. METHODS: The trajectories of 18 inflammatory markers measured in blood samples, collected at 5-year intervals over a period of 20 years from 144 individuals aged 65-75 years at the study endpoint, were related to the degree of frailty later in life. RESULTS: IFN-γ-related markers and platelet activation markers were found to change in synchrony. Chronically elevated levels of IL-6 pathway markers, such as CRP and sIL-6R, were associated with more frailty, poorer lung function and reduced physical strength. Being overweight was a possible driver of these associations. More and stronger associations were detected in women, such as a relation between increasing sCD14 levels and frailty, indicating a possible role for monocyte overactivation. Multivariate prediction of frailty confirmed the main results, but predictive accuracy was low. CONCLUSION: In summary, we documented temporal changes in and between inflammatory markers in an ageing population over a period of 20 years, and related these to clinically relevant health outcomes.

Limited effect of duration of CMV infection on adaptive immunity and frailty: insights from a 27-year-long longitudinal study.

OBJECTIVES: Cytomegalovirus infection is thought to affect the immune system and to impact general health during ageing. Higher CMV-specific antibody levels in the elderly are generally assumed to reflect experienced viral reactivation during life. Furthermore, high levels of terminally differentiated and CMV-specific T cells are hallmarks of CMV infection, which are thought to expand over time, a process also referred to as memory inflation. METHODS: We studied CMV-specific antibody levels over ~ 27 years in 268 individuals (aged 60-89 years at study endpoint), and to link duration of CMV infection to T-cell numbers, CMV-specific T-cell functions, frailty and cardiovascular disease at study endpoint. RESULTS: In our study, 136/268 individuals were long-term CMV seropositive and 19 seroconverted during follow-up (seroconversion rate: 0.56%/year). CMV-specific antibody levels increased slightly over time. However, we did not find an association between duration of CMV infection and CMV-specific antibody levels at study endpoint. No clear association between duration of CMV infection and the size and function of the memory T-cell pool was observed. Elevated CMV-specific antibody levels were associated with the prevalence of cardiovascular disease but not with frailty. Age at CMV seroconversion was positively associated with CMV-specific antibody levels, memory CD4+ T-cell numbers and frailty. CONCLUSION: Cytomegalovirus-specific memory T cells develop shortly after CMV seroconversion but do not seem to further increase over time. Age-related effects other than duration of CMV infection seem to contribute to CMV-induced changes in the immune system. Although CMV-specific immunity is not evidently linked to frailty, it tends to associate with higher prevalence of cardiovascular disease.

Distinct macrophage phenotypes skewed by local granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) are associated with tissue destruction and intimal hyperplasia in giant cell arteritis.

OBJECTIVE: To determine the presence and spatial distribution of different macrophage phenotypes, governed by granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) skewing signals, in giant cell arteritis (GCA) lesions. METHODS: Temporal artery biopsies (TABs, n = 11) from treatment-naive GCA patients, aorta samples from GCA-related aneurysms (n = 10) and atherosclerosis (n = 10) were stained by immunohistochemistry targeting selected macrophage phenotypic markers, cytokines, matrix metalloproteinases (MMPs) and growth factors. In vitro macrophage differentiation (n = 10) followed by flow cytometry, Luminex assay and ELISA were performed to assess whether GM-CSF and M-CSF are drivers of macrophage phenotypic heterogeneity. RESULTS: A distinct spatial distribution pattern of macrophage phenotypes in TABs was identified. CD206+/MMP-9+ macrophages were located at the site of tissue destruction, whereas FRß+ macrophages were located in the inner intima of arteries with high degrees of intimal hyperplasia. Notably, this pattern was also observed in macrophage-rich areas in GCA aortas but not in atherosclerotic aortas. Flow cytometry showed that GM-CSF treatment highly upregulated CD206 expression, while FRß was expressed by M-CSF-skewed macrophages, only. Furthermore, localised expression of GM-CSF and M-CSF was detected, likely contributing to macrophage heterogeneity in the vascular wall. CONCLUSIONS: Our data document a distinct spatial distribution pattern of CD206+/MMP-9+ macrophages and FRß+ macrophages in GCA linked to tissue destruction and intimal proliferation, respectively. We suggest that these distinct macrophage phenotypes are skewed by sequential GM-CSF and M-CSF signals. Our study adds to a better understanding of the development and functional role of macrophage phenotypes in the pathogenesis of GCA and opens opportunities for the design of macrophage-targeted therapies.