Does tuberculosis threaten our ageing populations?

BACKGROUND: The global population is ageing quickly and our understanding of age-related changes in the immune system suggest that the elderly will have less immunological protection from active tuberculosis (TB). DISCUSSION: Ongoing global surveillance of TB notifications shows increasing age of patients with active TB. This effect of age is compounded by changes to clinical manifestations of disease, confounding of diagnostic tests and increased rates of adverse reactions to antimicrobial treatment of TB. Future epidemiological surveillance, development of diagnostic tests and trials of treatment shortening should all include a focus on ageing people. More detailed surveillance of TB notifications in elderly people should be undertaken and carefully evaluated. Risk stratification will help target care for those in greatest need, particularly those with comorbidities or on immunosuppressive therapies. Novel diagnostics and treatment regimes should be designed specifically to be used in this cohort

Differential effects of anti-TNF therapies for inflammatory arthritides on immune responses to Mycobacterium tuberculosis

Tumour necrosis factor (TNF) antagonists have revolutionised the management of rheumatoid arthritis (RA) and other inflammatory diseases. This success is partly tempered by substantially increased risk of granulomatous infectious diseases, particularly tuberculosis (TB). In this thesis I sought new insights into the mechanisms by which TNF blockade leads to an increased incidence of TB. In a new analysis of data collected by the British Society of Rheumatology Biologics Registry, I confirmed that anti-TNF therapy leads to reactivation of latent TB infection, rather than increasing the risk of new TB infection, consistent with published literature. I derived and validated four separate context-specific transcriptional modules representing TNF inducible gene expression in macrophages, keratinocytes and whole blood. I used these modules to quantify TNF bioactivity in clinical samples from RA patients responding to anti TNF therapies or treated with methotrexate only. As expected, anti-TNF therapy was associated with attenuated expression of the TNF modules in whole blood following ex vivo stimulation. However, anti-TNF therapy had no effect on TNF module expression and therefore TNF function, at the site of acute cell mediated immune responses in vivo, modelled by the tuberculin skin test. These data are consistent with a model in which anti-TNF therapies do not reach sufficient concentration within tissues to block TNF responses in an acute inflammatory challenge. Rather, my data suggest that anti TNF therapies mediate their therapeutic and adverse effects by regulating TNF activity at foci of chronic inflammation or by alternative non-canonical pathways. Finally I tested the hypothesis that anti-TNF therapy may inhibit cellular restriction of mycobacteria in human macrophage cultures. Using an in vitro model of human monocyte-derived macrophages, I established a new method to quantify fluorescent mycobacterial load both inside and outside cells, and showed that TNF blockade in this model did not have a significant impact on mycobacterial growth

Works for Violin & Movement (scores)

Works for Violin & Movement music composition scores

Tumor necrosis Factor (TNF) Bioactivity at the site of an acute cell-Mediated immune response is Preserved in rheumatoid arthritis Patients responding to anti-TNF Therapy

The impact of anti-tumor necrosis factor (TNF) therapies on inducible TNF-dependent activity in humans has never been evaluated in vivo. We aimed to test the hypothesis that patients responding to anti-TNF treatments exhibit attenuated TNF-dependent immune responses at the site of an immune challenge. We developed and validated four context-specific TNF-inducible transcriptional signatures to quantify TNF bioactivity in transcriptomic data. In anti-TNF treated rheumatoid arthritis (RA) patients, we measured the expression of these biosignatures in blood, and in skin biopsies from the site of tuberculin skin tests (TSTs) as a human experimental model of multivariate cell-mediated immune responses. In blood, anti-TNF therapies attenuated TNF bioactivity following ex vivo stimulation. However, at the site of the TST, TNF-inducible gene expression and genome-wide transcriptional changes associated with cell-mediated immune responses were comparable to that of RA patients receiving methotrexate only. These data demonstrate that anti-TNF agents in RA patients do not inhibit inducible TNF activity at the site of an acute inflammatory challenge in vivo, as modeled by the TST. We hypothesize instead that their therapeutic effects are limited to regulating TNF activity in chronic inflammation or by alternative non-canonical pathways

Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response

In senescent cells, a DNA damage response drives not only irreversible loss of replicative capacity but also production and secretion of reactive oxygen species (ROS) and bioactive peptides including pro-inflammatory cytokines. This makes senescent cells a potential cause of tissue functional decline in aging. To our knowledge, we show here for the first time evidence suggesting that DNA damage induces a senescence like state in mature postmitotic neurons in vivo. About 40 80% of Purkinje neurons and 20–40% of cortical, hippocampal and peripheral neurons in the myenteric plexus from old C57Bl ⁄ 6 mice showed severe DNA damage, activated p38MAPkinase, high ROS production and oxidative damage, interleukin IL-6 production, heterochromatinization and senescence-associated b-galactosidase activity. Frequencies of these senescence-like neurons increased with age. Short term caloric restriction tended to decrease frequencies of positive cells. The phenotype was aggravated in brains of late-generation TERC) ⁄ ) mice with dysfunctional telomeres. It was fully rescued by loss of p21(CDKN1A) function in late- generation TERC) ⁄ )CDKN1A) ⁄ ) mice, indicating p21 as the necessary signal transducer between DNA damage response and senescence-like phenotype in neurons, as in senescing fibroblasts and other proliferation competent cells. We conclude that a senescence-like phenotype is possibly not restricted to proliferation-competent cells. Rather, dysfunctional telomeres and ⁄ or accumulated DNA damage can induce a DNA damage response leading to a phenotype in postmitotic neurons that resembles cell senescence in multiple features. Senescence-like neurons might be a source of oxidative and inflammatory stress and a contributor to brain aging

Tumor Necrosis Factor (TNF) Bioactivity at the Site of an Acute Cell-Mediated Immune Response Is Preserved in Rheumatoid Arthritis Patients Responding to Anti-TNF Therapy

The impact of anti-tumor necrosis factor (TNF) therapies on inducible TNF-dependent activity in humans has never been evaluated in vivo. We aimed to test the hypothesis that patients responding to anti-TNF treatments exhibit attenuated TNF-dependent immune responses at the site of an immune challenge. We developed and validated four context-specific TNF-inducible transcriptional signatures to quantify TNF bioactivity in transcriptomic data. In anti-TNF treated rheumatoid arthritis (RA) patients, we measured the expression of these biosignatures in blood, and in skin biopsies from the site of tuberculin skin tests (TSTs) as a human experimental model of multivariate cell-mediated immune responses. In blood, anti-TNF therapies attenuated TNF bioactivity following ex vivo stimulation. However, at the site of the TST, TNF-inducible gene expression and genome-wide transcriptional changes associated with cell-mediated immune responses were comparable to that of RA patients receiving methotrexate only. These data demonstrate that anti-TNF agents in RA patients do not inhibit inducible TNF activity at the site of an acute inflammatory challenge in vivo, as modeled by the TST. We hypothesize instead that their therapeutic effects are limited to regulating TNF activity in chronic inflammation or by alternative non-canonical pathways

Quantitative Characterization of the T Cell Receptor Repertoire of Naive and Memory subsets Using an Integrated experimental and Computational Pipeline Which Is Robust, economical, and Versatile

The T cell receptor (TCR) repertoire can provide a personalized biomarker for infectious and non-infectious diseases. We describe a protocol for amplifying, sequencing, and analyzing TCRs which is robust, sensitive, and versatile. The key experimental step is ligation of a single-stranded oligonucleotide to the 3′ end of the TCR cDNA. This allows amplification of all possible rearrangements using a single set of primers per locus. It also introduces a unique molecular identifier to label each starting cDNA molecule. This molecular identifier is used to correct for sequence errors and for effects of differential PCR amplification efficiency, thus producing more accurate measures of the true TCR frequency within the sample. This integrated experimental and computational pipeline is applied to the analysis of human memory and naive subpopulations, and results in consistent measures of diversity and inequality. After error correction, the distribution of TCR sequence abundance in all subpopulations followed a power law over a wide range of values. The power law exponent differed between naïve and memory populations, but was consistent between individuals. The integrated experimental and analysis pipeline we describe is appropriate to studies of T cell responses in a broad range of physiological and pathological contexts

EVALUATION OF DENTAL HEALTH EDUCATION IN A SCHOOL DENTAL CARE PROGRAM

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65546/1/j.1752-7325.1978.tb03715.x.pd

Immunopathogenesis of rheumatoid arthritis

Rheumatoid arthritis (RA) is the most common inflammatory arthropathy. The majority of evidence, derived from genetics, tissue analyses, models, and clinical studies, points to an immune-mediated etiology associated with stromal tissue dysregulation that together propogate chronic inflammation and articular destruction. A pre-RA phase lasting months to years may be characterized by the presence of circulating autoantibodies, increasing concentration and range of inflammatory cytokines and chemokines, and altered metabolism. Clinical disease onset comprises synovitis and systemic comorbidities affecting the vasculature, metabolism, and bone. Targeted immune therapeutics and aggressive treatment strategies have substantially improved clinical outcomes and informed pathogenetic understanding, but no cure as yet exists. Herein we review recent data that support intriguing models of disease pathogenesis. They allude to the possibility of restoration of immunologic homeostasis and thus a state of tolerance associated with drug-free remission. This target represents a bold vision for the future of RA therapeutics