The bone marrow (BM) plays a key role in the long‐term maintenance of immunological memory. However, the impact of aging on the production of survival factors for effector/memory T cells and plasma cells in the human BM has not been studied. We now show that the expression of molecules involved in the maintenance of immunological memory in the human BM changes with age. While IL‐15, which protects potentially harmful CD8+CD28− senescent T cells, increases, IL‐7 decreases. IL‐6, which may synergize with IL‐15, is also overexpressed. In contrast, a proliferation‐inducing ligand, a plasma cell survival factor, is reduced. IFN‐y, TNF, and ROS accumulate in the BM in old age. IL‐15 and IL‐6 expression are stimulated by IFN‐y and correlate with ROS levels in BM mononuclear cells. Both cytokines are reduced by incubation with the ROS scavengers N‐acetylcysteine and vitamin C. IL‐15 and IL‐6 are also overexpressed in the BM of superoxide dismutase 1 knockout mice compared to their WT counterparts. In summary, our results demonstrate the role of inflammation and oxidative stress in age‐related changes of immune cell survival factors in the BM, suggesting that antioxidants may be beneficial in counteracting immunosenescence by improving immunological memory in old age.

Between 1978 and 1997 all newborns in the Austrian province of Tyrol were reviewed regarding hip dysplasia and related surgery. This involved a mean of 8257 births per year (7766 to 8858). Two observation periods were determined: 1978 to 1982 (clinical examination alone) and 1993 to 1997 (clinical examination and universal ultrasound screening). A retrospective analysis compared the number and cost of interventions due to hip dysplasia in three patient age groups: A, 0 to < 1.5 years; B, ≥ 1.5 to < 15 years; and C, ≥ 15 to < 35 years. In group A, there was a decrease in hip reductions from a mean of 25.2 (SD 2.8) to 7.0 (SD 1.4) cases per year. In group B, operative procedures decreased from a mean of 17.8 (SD 3.5) to 2.6 (SD 1.3) per year. There was a 75.9% decrease in the total number of interventions for groups A and B. An increase of €57,000 in the overall cost per year for the second period (1993 to 1997) was seen, mainly due to the screening programme. However, there was a marked reduction in costs of all surgical and non-surgical treatments for dysplastic hips from €410,000 (1978 to 1982) to €117,000 (1993 to 1997). We believe the small proportional increase in costs of the universal ultrasound screening programme is justifiable as it was associated with a reduction in the number of non-surgical and surgical interventions. We therefore recommend universal hip ultrasound screening for neonates.

The BM is well understood to play a key role in plasma cell homing and survival in mice. In humans, BM plasma cells and their functions are less well characterized. In this study, we used paired bone biopsies from the femur shaft and blood samples from persons of different ages to analyze age-related changes of plasma and memory B cells. Our results demonstrated that plasma cells were mainly located in the BM, while a higher percentage of memory B cells was in the peripheral blood than in the BM. The frequency of plasma and memory B cells from both sources decreased with age, while immature and naïve B cells were unaffected. An age-related decline of tetanus-and diphtheria-specific BM plasma cells was observed, whereas influenza A-and cytomegalovirus-specific BM plasma cells were not affected. With the exception of cytomegalovirus, peripheral antibody concentrations correlated with BM plasma cells of the same specificity, but were independent of antigen-specific peripheral blood memory B cells. Our results demonstrate that the BM houses decreased numbers of plasma cells in old age. The number of cells of certain specificity may reflect the number and time point of previous antigen encounters and intrinsic age-related changes in the BM. Keywords: Aging r Bone marrow r Memory B cells r Plasma cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionImmunologic memory is a hallmark of the adaptive immune system. Previous studies indicate that the BM is a secondary lymphoid organ and a major reservoir of memory CD4 + and CD8 + T cells + population were significantly decreased in BMMCs in the older age group, whereas the percentages of immature and naïve B cells were similar in both age groups ( Fig. 2A and C). Similar results to BMMCs were observed for PBMCs (Fig. 2B and D). Functional characterization of BM plasma cells and PB memory B cells in old ageNext, we analyzed the impact of aging on the frequency of antigenspecific BM plasma cells, PB-derived memory B cells as well as on peripheral antibody concentrations. Tetanus and diphtheria represent antigens against which most of our donors had been immunized in the past, but for which natural exposure is unlikely. In contrast, influenza A is a pathogen which is encountered frequently by natural exposure and/or vaccination. Cytomegalovirus (CMV) is a persistent virus which during latent infection chronically stimulates immune responses. The frequencies of tetanus-and diphtheria-specific BM plasma cells correlated negatively with age ( Fig. 3A). In contrast, no correlation between influenza A-specific BM plasma cells and age was observed. The frequency of CMV-specific BM plasma cells did not change with age in persons with a positive serotype.To assess age-related alterations of PB-derived memory B cells of a certain specificity, isolated PBMCs were preactivated with pokeweed mitogen, ODN2006, and Staphylococcus aureus Cowan to stimulate antibody production. The percentage of antibodysecreting ce...

BackgroundCD4+ and CD8+ T cells reside in the human bone marrow (BM) and show a heightened activation state. However, only small sample sizes are available from sources such as the iliac crest. Larger samples can be obtained from the femur in the course of hip replacement surgery. It was therefore the goal of the present study to compare the phenotype and function of BM T cells from different sources from elderly persons and to investigate how femur derived bone marrow T cells can serve as a tool to gain a better understanding of the role of adaptive immune cells in the BM in old age.ResultsBone marrow mononuclear cells (BMMC) were isolated from either the iliac crest or the femur shaft. As expected the yield of mononuclear cells was higher from femur than from iliac crest samples. There were no phenotypic differences between BMMC from the two sources. Compared to PBMC, both BM sample types contained fewer naïve and more antigen experienced CD4+ as well as CD8+ T cells, which, in contrast to peripheral cells, expressed CD69. Cytokine production was also similar in T cells from both BM types. Larger sample sizes allowed the generation of T cell lines from femur derived bone marrow using non-specific as well as specific stimulation. The phenotype of T cell lines generated by stimulation with OKT-3 and IL-2 for two weeks was very similar to the one of ex vivo BM derived T cells. Such lines can be used for studies on the interaction of different types of BM cells as shown by co-culture experiments with BM derived stromal cells. Using CMVNLV specific T cell lines we additionally demonstrated that BM samples from the femur are suitable for the generation of antigen specific T cell lines, which can be used in studies on the clonal composition of antigen specific BM T cells.ConclusionIn conclusion, our results demonstrate that BMMC from the femur shaft are a useful tool for studies on the role of T cells in the BM in old age.