Studies comparing chronologically "young" versus "old" humans document age-related decline of classical immunological functions. However, older adults aged ≥65 years have very heterogeneous health ...phenotypes. A significant number of them are functionally independent and are surviving well into their 8(th)-11(th) decade life, observations indicating that aging or old age is not synonymous with immune incompetence. While there are dramatic age-related changes in the immune system, not all of these changes may be considered detrimental. Here, we review evidences for novel immunologic processes that become elaborated with advancing age that complement preserved classical immune functions and promote immune homeostasis later in life. We propose that elaboration such of late life immunologic properties is indicative of beneficial immune remodeling that is an integral component of successful aging, an emerging physiologic construct associated with similar age-related physiologic adaptations underlying maintenance of physical and cognitive function. We suggest that a systems approach integrating immune, physical, and cognitive functions, rather than a strict immunodeficiency-minded approach, will be key towards innovations in clinical interventions to better promote protective immunity and functional independence among the elderly.
Systemic-onset juvenile idiopathic arthritis (SJIA) is a disease of unknown etiology with an unpredictable response to treatment. We examined two groups of patients to determine whether there are ...serum protein profiles reflective of active disease and predictive of response to therapy. The first group (n = 8) responded to conventional therapy. The second group (n = 15) responded to an experimental antibody to the IL-6 receptor (MRA). Paired sera from each patient were analyzed before and after treatment, using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). Despite the small number of patients, highly significant and consistent differences were observed before and after response to therapy in all patients. Of 282 spectral peaks identified, 23 had mean signal intensities significantly different (P < 0.001) before treatment and after response to treatment. The majority of these differences were observed regardless of whether patients responded to conventional therapy or to MRA. These peaks represent potential biomarkers of active disease. One such peak was identified as serum amyloid A, a known acute-phase reactant in SJIA, validating the SELDI-TOF MS platform as a useful technology in this context. Finally, profiles from serum samples obtained at the time of active disease were compared between the two patient groups. Nine peaks had mean signal intensities significantly different (P < 0.001) between active disease in patients who responded to conventional therapy and in patients who failed to respond, suggesting a possible profile predictive of response. Collectively, these data demonstrate the presence of serum proteomic profiles in SJIA that are reflective of active disease and suggest the feasibility of using the SELDI-TOF MS platform used as a tool for proteomic profiling and discovery of novel biomarkers in autoimmune diseases.
Replicative senescence of human T cells is characterized by the loss of CD28 expression, exemplified by the clonal expansion of CD28(null) T cells during repeated stimulation in vitro as well as in ...chronic inflammatory and infectious diseases and in the normal course of aging. Because CD28 is the major costimulatory receptor for the induction of T cell-mediated immunity, the mechanism(s) underlying CD28 loss is of paramount interest. Current models of replicative senescence involve protracted procedures to generate CD28(null) cells from CD28(+) precursors; hence, a T-cell line model was used to examine the dynamics of CD28 expression. Here, we show the versatility of the JT and Jtag cell lines in tracking CD28(null) <--> CD28(hi) phenotypic transitions. JT and Jtag cells were CD28(null) and CD28(lo), respectively, but expressed high levels of CD28 when exposed to phorbol 12-myristate 13-acetate. This was a result of the reconstitution of the CD28 gene transcriptional initiator (INR). Tumor necrosis factor-alpha reduced CD28 expression because of the inhibition of INR-driven transcription. Ligation of CD28 by an antibody or by CD80 also down-regulated CD28 transcription through the same mechanism, providing evidence that CD28 can generate a T cell receptor-independent signal with a unique biological outcome. Collectively, these data unequivocally demonstrate the critical role of the INR in the regulation of CD28 expression. T cell lines with transient expression of CD28 are invaluable in the dissection of the biochemical processes involved in the transactivation of the CD28 INR, the silencing of which is a key event in the ontogenesis of senescent T cells.
Abstract only
INTRODUCTION
Past research in disc biology has highlighted the beneficial effects of growth factors, such as BMPs and IGF‐1,
in vitro
. Based on this research, it was proposed that ...exogenous IGF‐1 be used as a therapy for intervertebral disc degeneration (IDD). In the aging research field, suppressing the IGF‐1‐mediated signaling pathway has consistently decreased the incidence of age‐related disorders and increased lifespan of mammals and rodents. One model using
PappA
knockout mice has shown decreasing IGF‐1 signaling leads to positive effects on aging and longevity. Active PappA protease cleaves IGF binding protein 4 (IGFBP4), releasing active IGF‐1 which can bind to its receptor and exert downstream signaling effects. When you genetically remove PappA, IGF‐1 stays bound to IGFBP4. Here, we examined the discs of aged
PAPPA−/−
mice versus wild type (WT) to determine whether there was an effect on age‐associated IDD.
METHODS
This study was conducted according to IACUC approved protocols at University of Pittsburgh. Genetic deletion of PAPP‐A protease in mice with a mixed C57BL/6‐129SV/E background was achieved by deletion of both alleles of PAPP‐A. Spine segments were harvested from
WT
and
PAPPA−
/
−
mice at 23 months. Disc proteoglycan content was assessed by safranin‐O‐histology and DMMB assay was used to quantify sulfated glycosaminoglycans (GAG) in lumbar NP tissue. Western blotting was performed to measure the disc aggrecan proteolytic fragments, and the catabolic markers MMP‐3 and ADAMTS‐4. Levels of disc cellular senescence (loss of lamin B1expression) was assessed by immunohistochemistry. Student’s t‐test was used to test significance between groups (p<0.05). Average values (n=4 mice) were shown with SEM.
RESULTS
Compared to WT,
PAPPA−
/
−
mice had decreased proteoglycan content and two times less disc GAG content (Figure
1
).
PAPPA−
/
−
mice also had significantly decreased aggrecan fragmentation and decreased protein levels of MMP‐3 and ADAMTS‐4 in their discs compared to WT mice (Figure
2
). Additionally, greater level of disc lamin B1 was seen in
PAPPA
−/− compared to WT mice, suggesting reduced disc cellular senescence in
PAPPA
−/− mice.
DISCUSSION
The role of IGF‐1 in disc health and aging is currently unresolved.
PAPPA
−/− mice have reduced matrix content but the aggrecan matrix present after aging appears to be less fragmented based on our findings. Lowered disc fragmentation corresponded to a decrease in disc catabolic factors MMP‐3 and ADAMTS‐4 protein in
PAPPA
−/− mice. Lamin B1 staining suggests there are less disc senescent cells in old
PAPPA
−/− mice compared to normally aged mice. Further studies are needed to determine the mechanism for the decreased disc catabolism and more full length aggrecan in aged
PAPPA
−/− mice compared to aged WT mice. Additionally, further studies should confirm whether young
PAPPA
−/− mice also have decreased GAG content or this loss occurs during the aging process.
SIGNIFICANCE
The results of this study suggest the net effect of IGF‐1 regarding both anabolic and catabolic effects must be examined to fully understand if IGF‐1 is beneficial for disc homeostasis during age‐associated IDD.
Support or Funding Information
R01‐AG044376‐01 & Ferguson Foundation Grant
Qualitative and quantitative results show decreased disc proteoglycan content, including aggrecan, in aged
PAPPA
−
/
− mice.
Figure 1
Despite less proteoglycan content, aged PAPPA −/− mice had less fragmented aggrecan and lower levels of catabolic markers, MMP‐3 and ADAMTS‐4 compared to aged WT mice.
Figure 2
Abstract
We reported previously that children with JIA carry senescent CD31+CD8+ T cells disproportionate with age. Such cells are inflammatory effectors via CD31-driven TCR-independent activation ...pathway. Here, we hypothesized that these T cells interact with non-hematopoietic cells in the synovial space to perpetuate joint inflammation. JIA patients medically indicated to undergo arthrocentesis were recruited. Synovial aspirates were screened by flow cytometry, and short-term cultures were established. Results showed two subsets of plastic-adherent fibrocyte-like cells (FLC). About 75% were procollagen-CD45-CD14- cells that variably expressed CD34. The other ~25% were procollagen+CD45+CD14+IL17RA+ CD34- FLC; a finding unlike similar cells reported for adult-onset rheumatoid arthritis. FLC exposed to rIL-17 and/or rTNFα induced production of MMPs that were reversed with corticosteroid, TNFi, anti-IL6R, or experimental NFkB inhibitors. Co-culture of FLC with autologous CD8 T cells resulted in production of the same array of MMPs and inflammatory cytokines that were partially blocked by neutralizing anti-CD31 antibody. These results suggest a FLC-CD8 T cell communication circuit in the maintenance of joint inflammation in JIA. Further understanding of the regulation and/or the consequences of this local cell-cell interaction could shed light into the systemic complications of this childhood disease that impose lifelong health burden. Supported by Nancy E Taylor Foundation and NIH.
Abstract
Pro-inflammatory cytokines in the blood and synovium are key actors in JIA pathology. We recently reported that JIA patients have an over abundance of prematurely senescent CD8+ T cells ...expressing CD31, an adhesion molecule expressed by granulocytes and endothelial cells. CD31 triggering alone is sufficient to activate such senescent T cells. This study examined whether cytokine profile in JIA may be derived from T cell activation through CD31 ligation independent of the TCR. Results showed a cytokine signature of JIA characterized by dominance of IL-6, IL-10 and TNFα. Notably, patients with oligoarticular JIA showed higher levels of IFNγ and IL-17 family cytokines than those with polyarticular JIA. All patients also had a novel subset of T cells deficient in CD4, CD8, and CD28, but expressing CD31. Cross-linking bioassays, using anti-CD31 or its ligand CD38, show high levels of induction of IL-2, IL-17, and IFNγ. This CD31-driven, TCR-independent cytokine production was also verified by using somatic T cell line mutants that lack TCR and TCR/CD3, respectively, but both are CD31+. The observed cytokine production was associated with the phosphorylation of the signaling substrates ZAP70, cAbl, and p65-NFΚB. TCR independent, CD31-driven induction of these cytokines suggests maladaptive T cell function in JIA. Further investigation on the relevance of IFNγ and IL-17 to disease activity, and the CD31 signaling pathway may allow for innovations in immunotherapy.
Abstract
CD56 is a classical marker of NK cells, but its direct relevance to the elaboration of NK cell effector function is not known. In two cohort studies of aging, we have found that high levels ...of CD56 expression on both NK cells and T cells are highly correlated with unimpaired cognitive and physical ability among older adults aged ≥65 years. In multivariate analysis of collated data on clinical and laboratory assessments of health and performance, we identified CD56 as a key immunologic predictor of successful aging, an emerging physiologic and clinical construct pertaining to the maintenance of functional independence in old age despite a history of disease and concurrent comorbid conditions. In biological assays using primary T and NK cells, and various immortalized T/NK cell lines, ligation of CD56 alone was sufficient to induce activation of NK cells, and of T cells in a TCR-independent manner. CD56 triggering effectively elicited expression of activation antigens such as CD69 and CD25, and the production of various cytokines including IL-2, IL-4, and IFN-γ. CD56-mediated activation of both T cells and NK cells involved LAT phosphorylation. Clearly, CD56 is a functional immune receptor capable of effecting proximal and distal cellular outcomes. TCR-independent CD56-driven activation of T cells in particular is consistent with the concept of beneficial immune remodeling that has been proposed to underlie healthy aging and long-term survivorship.
Objective
Juvenile dermatomyositis (DM) is an autoimmune disease of childhood characterized by lesions in skin and muscle that are populated by plasmacytoid dendritic cells (PDCs) and lymphocyte ...infiltrates. We undertook this study to examine the cellular composition, organization, and molecular milieu of the cellular infiltrates in muscle in juvenile DM and to correlate the infiltrates with clinical disease manifestations.
Methods
Since PDCs and lymphocyte foci express CCL19 and CCL21, we investigated for in situ formation of lymphoid microstructures that could be sites of extranodal immune activation.
Results
Analyses of muscle biopsy samples from children with new‐onset juvenile DM showed 3 categories of lesions: diffuse infiltrates, lymphocytic aggregates lacking follicle‐like organization, and follicle‐like structures. The last of these exhibited elements of classic lymphoid follicles, including networks of follicular dendritic cells and high endothelial venules. They also expressed high levels of CXCL13 and lymphotoxins known to support lymphoid organogenesis. There were also resident naive CD45RA+ T cells and maternally derived B cells and PDCs. Patients with diffuse infiltrates or lymphocytic aggregates were responsive to standard therapy with steroids and methotrexate, but those with follicle‐like structures tended to have severe disease that required additional agents such as intravenous Ig or rituximab.
Conclusion
These data suggest that lymphoneogenesis is a component of the early disease process in juvenile DM. Ectopic lymphoid structures could indicate a severe course of disease; their early detection could be a tool for disease management.
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