ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity

The role of specialized follicular helper T (T_FH) cells in the germinal center has become well recognized, but it is less clear how effector T cells govern the extrafollicular response, the dominant pathway of high-affinity, isotype-switched autoantibody production in the MRL/MpJ-Fas^lpr (MRL^lpr) mouse model of lupus. MRL^lpr mice lacking the Icos gene have impaired extrafollicular differentiation of immunoglobulin (Ig) G⁺ plasma cells accompanied by defects in CXC chemokine receptor (CXCR) 4 expression, interleukin (IL) 21 secretion, and B cell helper function in CD4 T cells. These phenotypes reflect the selective loss of a population of T cells marked by down-regulation of P-selectin glycoprotein ligand 1 (PSGL-1; also known as CD162). PSGL-1^lo T cells from MRL^lpr mice express CXCR4, localize to extrafollicular sites, and uniquely mediate IgG production through IL-21 and CD40L. In other autoimmune strains, PSGL-1^lo T cells are also abundant but may exhibit either a follicular or extrafollicular phenotype. Our findings define an anatomically distinct extrafollicular population of cells that regulates plasma cell differentiation in chronic autoimmunity, indicating that specialized humoral effector T cells akin to T_FH cells can occur outside the follicle.     

Deficiency of the cyclin kinase inhibitor p21(WAF-1/CIP-1) promotes apoptosis of activated/memory T cells and inhibits spontaneous systemic autoimmunity

A characteristic feature of systemic lupus erythematosus is the accumulation of activated/memory T and B cells. These G0/G1-arrested cells express high levels of cyclin-dependent kinase inhibitors such as p21, are resistant to proliferation and apoptosis, and produce large amounts of proinflammatory cytokines. Herein, we show that ablation of p21 in lupus-prone mice allows these cells to reenter the cell cycle and undergo apoptosis, leading to autoimmune disease reduction. Absence of p21 resulted in enhanced Fas/FasL-mediated activation-induced T cell death, increased activation of procaspases 8 and 3, and loss of mitochondrial transmembrane potential. Increased apoptosis was also associated with p53 up-regulation and a modest shift in the ratio of Bax/Bcl-2 toward the proapoptotic Bax. Proliferation and apoptosis of B cells were also increased in p21-/- lupus mice. Thus, modulation of the cell cycle pathway may be a novel approach to reduce apoptosis-resistant pathogenic lymphocytes and to ameliorate systemic autoimmunity.     

Outcome of pulmonary function in Lemierre's disease-associated acute respiratory distress syndrome

Pulmonary function in acute respiratory distress syndrome (ARDS) survivors typically returns to normal with the exception of a persistent reduction in carbon monoxide diffusion capacity (DL(co)). Septic thrombophlebitis of the internal jugular vein, (Lemierre's syndrome or postanginal sepsis) is a well-described, albeit uncommon cause of ARDS in which metastatic pulmonary thromboemboli precipitate respiratory failure requiring ventilatory support. We describe convalescent pulmonary function in two survivors of Lemierre's disease-associated ARDS, suggesting that the subset of Lemierre's syndrome induced ARDS survivors have an excellent long-term pulmonary prognosis.     

Intrinsic reduced susceptibility of serotype 6 Streptococcus pyogenes to fluoroquinolone antibiotics

BACKGROUND: Fluoroquinolone resistance is common in Staphylococcus aureus, is increasing in Streptococcus pneumoniae, and is reported in Streptococcus pyogenes. METHODS: We surveyed 384 clinical isolates of S. pyogenes, isolated during 2002-2003, for susceptibility to ciprofloxacin. We performed nucleotide sequencing of the parC and gyrA genes and determined the M/emm type for selected isolates. Additionally, we analyzed M/emm type 6 S. pyogenes isolated during 1918-2003 from diverse locations. RESULTS: Of the survey isolates, 10.9% had reduced zones of inhibition to ciprofloxacin in the disk-diffusion test and had elevated minimum inhibitory concentrations to other fluoroquinolones, compared with those of fully susceptible isolates. Of the resistant isolates, 90.5% were M/emm type 6, and all sequenced M/emm type 6 isolates contained a serine-to-alanine substitution at position 79 in parC. Strikingly, the same findings were also present in macrolide-resistant isolates from a recent outbreak of S. pyogenes infection in Pittsburgh and in the Lancefield reference strain of M type 6, which was isolated in 1918, decades before the development of fluoroquinolone antibiotics. CONCLUSION: M/emm type 6 S. pyogenes has intrinsic reduced susceptibility to fluoroquinolones, as a result of a polymorphism in parC. This finding was also demonstrated in erythromycin-resistant M/emm type 6 S. pyogenes, which raises concern for the emergence of multidrug-resistant S. pyogenes.     

Emerging swine zoonoses

The majority of emerging infectious diseases are zoonotic in origin. Swine represent a potential reservoir for many novel pathogens and may transmit these to humans via direct contact with live animals (such as swine farmers and large animal veterinarians), or to the general human population via contaminated meat. We review recent emerging microbes associated with swine and discuss public health implications.     

Evaluation of venous thromboembolism risk following hospitalization

A better understanding of the relationship between outpatient venous thromboembolism (VTE) and prior hospitalization is needed including data regarding the utilization of inpatient pharmacologic VTE prophylaxis and its effect on outpatient venous thromboembolic risk. The primary objective was to assess the association between development of outpatient VTE and inpatient hospitalization within the previous 90 days. Additional outcome measures included describing patients who received pharmacologic anticoagulation during hospitalization and identification of factors independently associated with VTE. Case patients in this matched case–control study were diagnosed with an outpatient deep vein thrombosis or pulmonary embolus between January 2005 and December 2007 and were matched on age with up to five to patients who were seen for an outpatient health maintenance visit but had no VTE during the same time frame as their matched case. Information collected from electronic administrative databases and patient medical records included health services utilization, medication use, medical diagnoses, and patient demographic information. Of 2190 cases, 560 patients (25.6%) compared to 151 (1.4%) of 10,942 control patients were hospitalized in the previous 90 days (P < 0.001). Among hospitalized patients, 53.5% of cases and 47.0% of controls received an anticoagulant during hospitalization (P = 0.186). Factors associated with a VTE diagnosis included hospitalization for a surgical, medical, or orthopedic indication in the previous 90 days, younger age, longer hospitalization, cancer and an elevated Chronic Disease Score. Conclusions: A strong association exists between outpatient VTE diagnosis and hospitalization and gaps in pharmacologic prophylaxis utilization during hospitalization are evident.     

De novo generation of white adipocytes from the myeloid lineage via mesenchymal intermediates is age,adipose depot,and gender specific

It is generally assumed that white adipocytes arise from resident adipose tissue mesenchymal progenitor cells. We challenge this paradigm by defining a hematopoietic origin for both the de novo development of a subset of white adipocytes in adults and a previously uncharacterized adipose tissue resident mesenchymal progenitor population. Lineage and cytogenetic analysis revealed that bone marrow progenitor (BMP)-derived adipocytes and adipocyte progenitors arise from hematopoietic cells via the myeloid lineage in the absence of cell fusion. Global gene expression analysis indicated that the BMP-derived fat cells are bona fide adipocytes but differ from conventional white or brown adipocytes in decreased expression of genes involved in mitochondrial biogenesis and lipid oxidation, and increased inflammatory gene expression. The BMP-derived adipocytes accumulate with age, occur in higher numbers in visceral than in subcutaneous fat, and in female versus male mice. BMP-derived adipocytes may, therefore, account in part for adipose depot heterogeneity and detrimental changes in adipose metabolism and inflammation with aging and adiposity.