IMMUNOSENESCENCE AND ITS IMPACT ON MEDICAL PRACTICE. A NEW LOOK AT AN OLD PROBLEM.

Introdução:O envelhecimento é um processo complexo que influencia todos os sistemas do corpo humano e seu impacto no sistema imune é chamado Imunosenescência. Essa condição é resultado de várias modulações imunológicas causadas por interações entre fatores genéticos e ambientais e é responsável por importantes condições clínicas em indivíduos idosos como alta prevalência de doenças infecciosas e autoimunes, neoplasias e menor eficácia de vacinas. Objetivo: Nesta revisão serão discutidos os problemas clínicos mais comuns na população idosa relacionados a Imunosenescência, e os novos achados da ciência básica relevantes a este tópico. Conclusão: A melhor compreensão da Imunosenescência é importante para prevenção de doenças comuns relacionadas à idade e para a promoção de um envelhecimento saudável.Background: Ageing is a very complex process that modulates all the organ systems of the human body, and its impact on the immune system is called Immunosenescence. This condition is the result of several immune modulations due to genetic and environmental interactions and is responsible for important clinical conditions in elderly subjects, such as a higher incidence of infectious and autoimmune diseases, neoplasias and decreased vaccine efficacy. Objective: In this current review we will discuss the most common clinical problems in the elderly population related to Immunosenescence and new findings in basic science relevant to this topic. Conclusion: A better understanding of Imunosenescence is important to prevention of common age related diseases and for the promotion of healthy ageing

A Distinct Macrophage Subset Mediating Tissue Destruction and Neovascularization in Giant Cell Arteritis:Implication of the YKL-40/Interleukin-13 Receptor alpha 2 Axis

OBJECTIVE: Macrophages mediate inflammation, angiogenesis and tissue destruction in giant cell arteritis (GCA). Serum levels of the macrophage-associated protein YKL-40 (chitinase-3 like-1), previously linked to angiogenesis and tissue remodeling, remain elevated in GCA despite glucocorticoid treatment. Here, we aimed to investigate the contribution of YKL-40 to vasculopathy in GCA. METHODS: Immunohistochemistry was performed on GCA temporal artery biopsies (TABs; n=12) and aortas (n=10) for detection of YKL-40, its receptor IL-13Rα2, macrophage markers PU.1 and CD206, and the tissue-destructive protein MMP-9. Ten non-inflamed TABs served as controls. In vitro experiments with GM-CSF- or M-CSF-skewed monocyte-derived macrophages (GM-MØs or M-MØs) were conducted to study the dynamics of YKL-40 production. Next, silencing RNA (siRNA)-mediated knock-down of YKL-40 in GM-MØs was performed to study its effect on MMP-9 production. Finally, the angiogenic potential of YKL-40 was investigated by tube formation experiments using human microvascular endothelial cells (HMVECs). RESULTS: YKL-40 was abundantly expressed by a CD206+MMP-9+ macrophage subset in inflamed TABs and aortas. GM-MØs of GCA patients, but not of healthy controls, released significantly higher levels of YKL-40, compared to M-MØs. In inflamed TABs, IL-13Rα2 was expressed by macrophages and endothelial cells. Functionally, knock-down of YKL-40 led to a 10-50% reduction in MMP-9 production by macrophages, whereas exposure of HMVECS to YKL-40 led to significantly increased tube formation. CONCLUSION: In GCA, a GM-CSF-skewed, CD206+MMP9+ macrophage subset expresses high levels of YKL-40 which may stimulate tissue destruction and angiogenesis through IL-13Rα2 signaling. Targeting YKL-40 or GM-CSF may inhibit macrophages that are currently insufficiently suppressed by glucocorticoids

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.</p

Differential effects of Cytomegalovirus carriage on the immune phenotype of middle-aged males and females

The elderly population is more susceptible to infections as a result of an altered immune response, commonly referred to as immunosenescence. Cytomegalovirus (CMV)-infection associated changes in blood lymphocytes are known to impact this process, but the interaction with gender remains unclear. Therefore, we analysed the effects and interaction of gender and CMV on the absolute numbers of a comprehensive set of naive and memory T- and B-cell subsets in people between 50 and 65 years of age. Enumeration and characterisation of lymphocyte subsets by flow cytometry was performed on fresh whole blood samples from 255 middle-aged persons. CMV-IgG serostatus was determined by ELISA. Gender was a major factor affecting immune cell numbers. CMV infection was mainly associated with an expansion of late-differentiated T-cell subsets. CMV+ males carried lower numbers of total CD4+, CD4+ central memory (CM) and follicular helper T-cells than females and CMV- males. Moreover, CMV+ males had significantly lower numbers of regulatory T (Treg)-cells and memory B-cells than CMV+ females. We here demonstrate an interaction between the effects of CMV infection and gender on T- and B-cells in middle-aged individuals. These differential effects on adaptive immunity between males and females may have implications for vaccination strategies at middle-age

Exposure to Candida albicans Polarizes a T-Cell Driven Arthritis Model towards Th17 Responses, Resulting in a More Destructive Arthritis

BACKGROUND: Fungal components have been shown very effective in generating Th17 responses. We investigated whether exposure to a minute amount of C. albicans in the arthritic joint altered the local cytokine environment, leading to enhanced Th17 expansion and resulting in a more destructive arthritis. METHODOLOGY: Chronic SCW arthritis was induced by repeated injection with Streptococcus pyogenes (SCW) cell wall fragments into the knee joint of C57Bl/6 mice, alone or in combination with the yeast of C. albicans or Zymosan A. During the chronic phase of the arthritis, the cytokine levels, mRNA expression and histopathological analysis of the joints were performed. To investigate the phenotype of the IL-17 producing T-cells, synovial cells were isolated and analyzed by flowcytometry. PRINCIPAL FINDINGS: Intra-articular injection of either Zymosan A or C. albicans on top of the SCW injection both resulted in enhanced joint swelling and inflammation compared to the normal SCW group. However, only the addition of C. albicans during SCW arthritis resulted in severe chondrocyte death and enhanced destruction of cartilage and bone. Additionally, exposure to C. albicans led to increased IL-17 in the arthritic joint, which was accompanied by an increased synovial mRNA expression of T-bet and RORgammaT. Moreover, the C. albicans-injected mice had significantly more Th17 cells in the synovium, of which a large population also produced IFN-gamma. CONCLUSION: This study clearly shows that minute amounts of fungal components, like C. albicans, are very potent in interfering with the local cytokine environment in an arthritic joint, thereby polarizing arthritis towards a more destructive phenotype

Mucosal-associated invariant T cells in patients with axial spondyloarthritis

Background: Several studies implicate Th17-cells and its cytokine (IL-17) in disease pathogenesis of spondyloarthritis (SpA), with available evidence supporting a pathogenic role of CD8+ T-cells. However, data on the involvement of CD8+ mucosal-associated invariant T-cells (MAIT) and their phenotypic characterization and inflammatory function including IL-17 and Granzyme A production in a homogenous population of SpA-patients with primarily axial disease (axSpA) are lacking. Objectives: Quantify and characterize the phenotype and function of circulating CD8+MAIT-cells in axSpA-patients with primarily axial disease. Methods: Blood samples were obtained from 41 axSpA-patients and 30 age- and sex-matched healthy controls (HC). Numbers and percentages of MAIT-cells (defined as CD3+CD8+CD161highTCRVα7.2+) were determined, and production of IL-17 and Granzyme A (GrzA) by MAIT-cells were examined by flow cytometry upon in vitro stimulation. Serum IgG specific for CMV was measured by ELISA. Results: No significant differences in numbers and percentages of circulating MAIT-cells were found between axSpA-patients and HCr zijn meer resultaten de centrale memory CD8 T cellen. cellen van patirculating MAIT cells. Further phenotypic analysis revealed a significant decrease in numbers of central memory MAIT-cells of axSpA-patients compared to HC. The decrease in central memory MAIT-cells in axSpA patients was not attributed to an alteration in CD8 T-cell numbers, but correlated inversely with serum CMV-IgG titers. Production of IL-17 by MAIT-cells was comparable between axSpA-patients and HC, whereas a significant decrease in the production of GrzA by MAIT-cells from axSpA-patients was observed. Conclusions: The decrease in cytotoxic capability of circulating MAIT-cells in axSpA-patients might implicate that these cell types migrate to the inflamed tissue and therefore associate with the axial disease pathogenesis

<i>Candida albicans</i> and Zymosan A aggravate the inflammation in the chronic SCW model.

<p>On days 0, 7, 14, and 21, streptococcal cell wall (SCW) fragments were injected intra-articularly (i.a.) into the knee joint. Joint swelling (ratio of ^{99 m}Tc uptake in the treated right knee joint to that in the untreated left knee joint) were determined 1 day after every injection (A) and during the chronic phase of the model on day 28 (B; n=6 mice/group). In addition, the inflammatory cell influx (C) on histological slides was quantified on day 28. H&E stained frontal knee sections (original magnification 100×) (D) are shown (n=8 mice/group. Values are the mean ± SEM; ns=non significant, * P<0.05, ** P<0.01, *** P<0.001, by One-way ANOVA.</p

Co-exposure to <i>C. albicans</i> induces Th17 cells in the joint.

<p>The mRNA expression of T-bet, GATA-3, RORγT and FOXP3 in synovial biopsies of the knee joints (n=3 mice/group) were measured by QPCR (A) The mRNA expression of IFNy, IL-17A, IL-17F, IL-21, IL-22 and IL-10 are shown (B). The knee joint synovium was dissected and prepared for enzymatic digestion. The cells were incubated with PMA/ionomycine and Golgiplug for 5 hours before flowcytometric analysis (n=6 mice/group) and stained for CD3, IL-17, and IFN-γ. Representative dot plots of the isolated cells gated on CD3+ are shown (C). The mean percentage of isolated IFN-γ and IL-17 producing T cells (CD3+ population) are shown (D). Results are mean ± SEM; ns=non significant *=P<0.05, **=P<0.01, by one-way ANOVA.</p

Exposure to <i>C. albicans</i> increases the cartilage destruction and bone erosion during chronic SCW arthritis.

<p>Analysis of destructive parameters after 4 relapsing flares of arthritis. On day 28, knee joints (n=8/group) were harvested for histological assessment. Knee joint sections were stained using Safranin O to determine the degree of proteoglycan (PG) depletion. H&E staining was used to score the degree of chondrocyte death, cartilage surface erosion and bone erosion (A). QPCR analysis of destructive related genes was performed on synovial biopsies (n=3/group) of day 22, one day after the last injection (B). Representative images of arthritic knee joints showing immunohistochemical staining for VDIPEN after the 4 repeated injections (day 28) (C). Besides, the quantitative measurement of VDIPEN expression (percentage of positively stained area) in the cartilage of the 3 groups of mice (n=8/group) was analyzed. Values are the mean ± SEM; ns=non significant * P<0.05, ** P<0.01, *** P<0.001, by One-way ANOVA.</p