A gut feeling about arthritis

The gut microbiota of patients recently diagnosed with rheumatoid arthritis is enriched in microbes belonging to the Prevotella genus

Immunological Goings-on in Visceral Adipose Tissue

Chronic, low-grade inflammation of visceral adipose tissue, and systemically, is a critical link between recent strikingly parallel rises in the incidence of obesity and type 2 diabetes. Macrophages have been recognized for some time to be critical participants in obesity-induced inflammation of adipose tissue. Of late, a score of other cell types of the innate and adaptive arms of the immune system have been suggested to play a positive or negative role in adipose tissue infiltrates. This piece reviews the existing data on these new participants; discusses experimental uncertainties, inconsistencies, and complexities; and puts forward a minimalist synthetic scheme

An Assessment of Primary Care Physician Shortages in Mississippi

According to the Department of Health and Human Services, there are Health Professional Shortage Areas in all states and territories of the United States.\u27 Since fewer students graduating from medical school are choosing primary care, it is imperative that future graduates in the field know which regions are in greatest need of primary care physicians. In a joint effort with the Mississippi Rural Physicians Scholarship Program and the Sally McDonnell Barksdale Honors College, this thesis used data obtained from the Mississippi Department of Health, the United States Census Bureau, the Mississippi State Medical Association, and the Mississippi State Board of Medical Licensure to research primary care physician shortages per specialty in each of the 82 Mississippi counties and to calculate each county’s relative need for primary care physicians. For the purposes of this thesis, the primary care specialties considered were family/general practice, internal medicine, obstetrics and gynecology, and pediatrics. Both the primary care physician to population rates and average and median physician ages per county and for each specialty were used to calculate indices of care that compare each county’s relative need for primary care physicians. Results showed that for overall primary care physicians and for those in family practice, relatively more counties had lower scores on their indices of care, while for those in obstetrics and gynecology, over half of the counties received the worst score, indicating that there were no physicians practicing obstetrics and gynecology in the county. These results are primarily intended to serve as a tool by which the Mississippi Rural Physicians Scholarship Program may direct its graduates to areas in need of their services

A revival of the B cell paradigm for rheumatoid arthritis pathogenesis?

Dominant paradigms for the understanding of rheumatoid arthritis (RA) pathogenesis have changed over the years. A predominant role of B lymphocytes, and perhaps of the rheumatoid factor they produced, was initially invoked. In more recent years, recognition of antigens in the joint by T cells sparking an inflammatory cascade has been a more favored interpretation. Here, we re-examine some of the arguments that underpin this proposed role of joint T cells, in light of recent results from transgenic mice in which a self-reactive T-cell receptor provokes disease, but from outside the joint and indirectly via B lymphocytes and immunoglobulins

Differences between personality traits of DCS intake and carrier workers, their goodness of job fit, and its effect on job satisfaction

The purpose of this study was to determine if there is a different personality trait between Department of Children\u27s Services, intake and carrier workers. If there is a difference, does it effect job satisfaction when the worker is placed in a position that is not compatible with their personality trait

The AKT–mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells

CD4+Foxp3+ regulatory T (T reg) cells play an essential role in maintaining immunological tolerance via their suppressive function on conventional CD4+ T (Tconv) cells. Repertoire studies suggest that distinct T cell receptor signaling pathways lead to T reg differentiation, but the signals that regulate T reg specification are largely unknown. We identify AKT as a strong repressor of entry into the T reg phenotype in vitro and in vivo. A constitutively active allele of AKT substantially diminished TGF-β–induced Foxp3 expression in a kinase-dependent manner and via a rapamycin-sensitive pathway, implicating the AKT–mammalian target of rapamycin axis. The observed impairment in Foxp3 induction was part of a broad dampening of the typical T reg transcriptional signature. Expression of active AKT at a stage before Foxp3 turn on during normal T reg differentiation in the thymus selectively impaired differentiation of CD4+Foxp3+ cells without any alteration in the positive selection of Tconv. Activated AKT, in contrast, did not affect established Foxp3 expression in T reg cells. These results place AKT at a nexus of signaling pathways whose proper activation has a strong and broad impact on the onset of T reg specification

TCR-based lineage tracing: no evidence for conversion of conventional into regulatory T cells in response to a natural self-antigen in pancreatic islets

Foxp3-expressing regulatory T (T reg) cells derive primarily from selection in the thymus. Yet conversion of mature conventional CD4+ T (T conv) cell lymphocytes can be achieved in several conditions, such as transforming growth factor β treatment, homeostatic expansion, or chronic exposure to low-dose antigen. Such conversion might provide a means to generate peripheral tolerance by “converting” potentially damaging T cells that react to self-antigens. We tested this hypothesis in mice transgenic for the BDC2.5 T cell receptor (TCR), which is representative of a diabetogenic specificity that is naturally present in NOD mice and reactive against a pancreatic self-antigen. In the thymus, before any exposure to antigen, clonotype-positive T reg and T conv cells express a second TCRα chain derived from endogenous loci. High-throughput single-cell sequencing of secondary TCRs of the Vα2 family showed their joining CDR3α regions to be very different in T reg and T conv cell thymocytes. These specific CDR3α motifs, thus, provided a “tag” with which to test the actual impact of T conv to T reg cell conversion in response to peripheral self-antigen; should the autoreactive clonotypic TCR induce T conv to T reg cell conversion upon encounter of cognate antigen in the pancreas or draining lymph node, one would expect to detect tag CDR3α motifs from T conv cells in the T reg cell populations. Sequencing large numbers of peripheral BDC+Vα2+ cells showed that little to no conversion occurs in response to this pancreatic autoantigen

Aire's Partners in the Molecular Control of Immunological Tolerance

SummaryAire induces the expression of a battery of peripheral-tissue self-antigens (PTAs) in thymic stromal cells, promoting the clonal deletion of differentiating T cells that recognize them. Just how Aire targets and induces PTA transcripts remains largely undefined. Screening via Aire-targeted coimmunoprecipitation followed by mass spectrometry, and validating by multiple RNAi-mediated knockdown approaches, we identified a large set of proteins that associate with Aire. They fall into four major functional classes: nuclear transport, chromatin binding/structure, transcription and pre-mRNA processing. One set of Aire interactions centered on DNA protein kinase and a group of proteins it partners with to resolve DNA double-stranded breaks or promote transcriptional elongation. Another set of interactions was focused on the pre-mRNA splicing and maturation machinery, potentially explaining the markedly more effective processing of PTA transcripts in the presence of Aire. These findings suggest a model to explain Aire's widespread targeting and induction of weakly transcribed chromatin regions.PaperCli

Number of T Reg Cells That Differentiate Does Not Increase upon Encounter of Agonist Ligand on Thymic Epithelial Cells

It has been reported that the differentiation of CD4+CD25+ regulatory T cells (T reg cells) can be induced by agonist peptide/major histocompatibility complex ligands in the thymus. Exploiting a transgenic mouse line wherein expression of a particular T cell epitope can be controlled temporally and quantitatively, we found that diversion of differentiating thymocytes into the FoxP3 T reg cell pathway by this agonist ligand was essentially nonexistent. However, CD4+CD25+ thymocytes were much less sensitive than their CD4+CD25− companions, by two to three orders of magnitude, to agonist-induced clonal deletion, such that their proportion increased, giving the false impression of induced differentiation. To account for these and prior observations, one can propose that differentiation along the CD4+CD25+ pathway is induced by cues other than recognition of self-agonist cues, which are poorly read by thymocytes, whose T cell receptors are conducive to selection toward the conventional CD4+CD25− lineage. Thus, selective survival, rather than induced differentiation, may explain the apparent enrichment observed here and in previous studies