Cellular and humoral autoreactivity in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a morbid, refractory lung disorder with an unknown pathogenesis. To investigate potential adaptive immune mechanisms in IPF, we compared phenotypes and effector functions of peripheral CD4 T cells, autoantibody production, and proliferative responses of pulmonary hilar lymph node CD4 T cells to autologous lung extracts from afflicted patients and normals. Our results show that greater proportions of peripheral CD4 T lymphocytes in IPF subjects expressed MHC class II and CD154 (CD40L), and they more frequently elaborated TGF-beta1, IL-10, and TNF-alpha. Abnormal CD4 T cell clonal expansions were found in all IPF patients, and 82% of these subjects also had IgG autoantibodies against cellular Ags. IPF lung extracts stimulated proliferations of autologous CD4 T cells, unlike preparations from normals or those with other lung diseases, and the IPF proliferative responses were enhanced by repeated cycles of stimulation. Thus, CD4 T cells from IPF patients have characteristics typical of cell-mediated pathologic responses, including augmented effector functions, provision of facultative help for autoantibody production, oligoclonal expansions, and proliferations driven by an Ag present in diseased tissues. Recognition that an autoreactive immune process is present in IPF can productively focus efforts toward identifying the responsible Ag, and implementing more effective therapies.     

Volume of white matter hyperintensities in healthy adults: Contribution of age, vascular risk factors, and inflammation-related genetic variants

Aging is associated with appearance of white matter hyperintensities (WMH) on MRI scans. Vascular risk and inflammation, which increase with age, may contribute to white matter deterioration and proliferation of WMH. We investigated whether circulating biomarkers and genetic variants associated with elevated vascular risk and inflammation are associated with WMH volume in healthy adults (144 volunteers, 44-77 years of age). We examined association of WMH volume with age, sex, hypertension, circulating levels of total plasma homocysteine (tHcy), cholesterol (low-density lipoprotein), and C-reactive protein (CRP), and four polymorphisms related to vascular risk and inflammation: Apolipoprotein ε (ApoE ε2,3,4), Angiotensin-Converting Enzyme insertion/deletion (ACE I/D), methylenetetrahydrofolate reductase (MTHFR) C677T, C-reactive protein (CRP)-286C>A>T, and interleukin-1β (IL-1β) C-511T. We found that larger WMH volume was associated with advanced age, hypertension, and elevated levels of homocysteine and CRP but not with low-density lipoprotein levels. Homozygotes for IL-1β-511T allele and carriers of CRP-286T allele that are associated with increased inflammatory response had larger WMH than the other allelic combinations. Carriers of the APOE ε2 allele had larger frontal WMH than ε3 homozygotes and ε4 carriers did. Thus, in healthy adults, who are free of neurological and vascular disease, genetic variants that promote inflammation and elevated levels of vascular risk biomarkers can contribute to brain abnormalities. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

Joint Models for Time-to-Event Data and Longitudinal Biomarkers of High Dimension

Statistics in Biosciences - Joint models for longitudinal biomarkers and time-to-event data are widely used in longitudinal studies. Many joint modeling approaches have been proposed to handle...     

In vivo administration of BL-3050: highly stable engineered PON1-HDL complexes

Background  

Serum paraoxonase (PON1) is a high density lipoprotein (HDL)-associated enzyme involved in organophosphate (OP) degradation and prevention of atherosclerosis. PON1 comprises a potential candidate for in vivo therapeutics, as an anti-atherogenic agent, and for detoxification of pesticides and nerve agents. Because human PON1 exhibits limited stability, engineered, recombinant PON1 (rePON1) variants that were designed for higher reactivity, solubility, stability, and bacterial expression, are candidates for treatment. This work addresses the feasibility of in vivo administration of rePON1, and its HDL complex, as a potentially therapeutic agent dubbed BL-3050.     

Angiotensin II directly increases rabbit renal brush-border membrane sodium transport: Presence of local signal transduction system

Summary In the present study, we have examined the direct actions of angiotensin II (AII) in rabbit renal brush border membrane (BBM) where binding sites for AII exist. Addition of AII (10^–11–10^–7 m) was found to stimulate²²Na^– uptake by the isolated BBM vesicles directly. AII did not affect the Na⁺-dependent BBM glucose uptake, and the effect of AII on BBM²²Na⁺ uptake was inhibited by amiloride, suggesting the involvement of Na⁺/H⁺ exchange mechanism. BBM proton permeability as assessed by acridine orange quenching was not affected by AII, indicating the direct effect of AII on Na⁺/H⁺ antiport system.In search of the signal transduction mechanism, it was found that AII activated BBM phospholipase A₂ (PLA) and that BBM contains a 42-kDa guanine nucleotide-binding regulatory protein (G-protein) that underwent pertussis toxin (PTX)-catalyzed ADP-ribosylation. Addition of GTP potentiated, while GDP-ßS or PTX abolished, the effects of AII on BBM PLA and²²Na⁺ uptake, suggesting the involvement of G-protein in AII's actions. On the other hand, inhibition of PLA by mepacrine prevented AII's effect on BBM²²Na⁺ uptake, and activation of PLA by mellitin or addition of arachidonic acid similarly enhanced BBM²²Na⁺ uptake, suggesting the role of PLA activation in mediating AII's effect on BBM²²Na⁺ uptake.In summary, results of the present study show a direct stimulatory effect of AII on BBM Na⁺/H⁺ antiport system, and suggest the presence of a local signal transduction system involving G-protein mediated PLA activation.     

Helicobacter pylori: the Middle East scenario.

A review of Helicobacter pylori in the Middle East is presented. Prevalence studies have been performed in asymptomatic population groups from Algeria, Israel, Saudi Arabia and Turkey. These showed that the prevalence of H. pylori is similar to that of the developing countries of the world with a high level of infection in childhood (40 to 70 percent), which increases with age to 85 to 90 percent. Israel, however, has a low prevalence in children (10 percent), but there is a rapid rise in the second decade of life to 39 percent, reaching 79 percent in those over 60 years old. The prevalence rates were higher in those living in communal settlements (72 percent) than in urban dwellers (65 percent). The infection rates were higher in persons of Mediterranean and Asian origin (89 percent) compared to those of Western European/North American origin (57 percent). The prevalence rate of H. pylori infection in patients undergoing endoscopy for upper gastrointestinal symptoms has now been reported from many Middle Eastern countries, including Egypt, Iran, Israel, Oman, Saudi Arabia, the United Arab Emirates and Yemen. These studies showed that patients with gastritis and peptic ulcer disease had similar rates of infection as reported from Europe, United States and Africa (71 to 92 percent). However, patients with non-ulcer dyspepsia had higher rates of infection (61 to 89 percent). The H. pylori scenario from the prevalence rates, treatment protocols and responses to treatment does not differ very much from other developing areas of the world.     

Reduction of information redundancy in the ascending auditory pathway

Information processing by a sensory system is reflected in the changes in stimulus representation along its successive processing stages. We measured information content and stimulus-induced redundancy in the neural responses to a set of natural sounds in three successive stations of the auditory pathway-inferior colliculus (IC), auditory thalamus (MGB), and primary auditory cortex (A1). Information about stimulus identity was somewhat reduced in single A1 and MGB neurons relative to single IC neurons, when information is measured using spike counts, latency, or temporal spiking patterns. However, most of this difference was due to differences in firing rates. On the other hand, IC neurons were substantially more redundant than A1 and MGB neurons. IC redundancy was largely related to frequency selectivity. Redundancy reduction may be a generic organization principle of neural systems, allowing for easier readout of the identity of complex stimuli in A1 relative to IC.     

Diabetes modulates differentially creatine kinase-specific activity responsiveness to estradiol-17beta and to raloxifene in rat organs

Diabetes mellitus increases the risk for CVD in women. While there is considerable evidence suggesting beneficial effects of estrogen on decreasing lipid peroxidation, atherosclerotic processes, and cardiovascular diseases, diabetes negates most estrogen protective effects as well as the skeletal protective effects of estrogens, which are not discernable in diabetic women. In the present study, we examined the in vivo effects of estradiol-17beta (E2), on creatine kinase (CK)-specific activity, in estrogen-responsive organs from healthy and diabetic rats. Healthy or diabetic (streptozotocin-induced) female rats were injected with either E2 (10-50 microg/rat) or raloxifene (Ral; 500-1,000 microg/rat). Twenty-four hours following the injection, animals were sacrificed; their organs removed and assayed for CK-specific activity. CK-specific activity in different organs [Left ventricle of heart (Lv), uterus (Ut), aorta (Ao), para uterine adipose tissue (Ad), epiphyseal cartilage (Ep), and diaphyseal bone (Di)] from healthy animals, was stimulated with increased doses of E2, with maximum at 20 microg/rat. Age-matched diabetic female rats exhibited a remarkable decreased response to E2 in all organs except Ut. In contrast, the response to Ral was not altered in diabetic rats. Similar results were observed in organs from ovariectomized female rats (Ovx), healthy or diabetic. These results support our previous in vitro findings, demonstrating that hyperglycemia decreases CK response to E2 but not to Ral in cultured human vascular and bone cells. In summary, diabetes mellitus decreases CK response to E2 but not that of Ral in skeletal and vascular tissues. The decreased response to E2 detected in organs derived from diabetic rats might be due to changes in nuclear and/or membrane estrogen receptors and/or other genomic and non-genomic pathways, as was shown in in vitro cellular models.     

MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis

Background

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disease associated with substantial morbidity and mortality. The objective of this study was to determine whether there is a peripheral blood protein signature in IPF and whether components of this signature may serve as biomarkers for disease presence and progression.

Methods and Findings

We analyzed the concentrations of 49 proteins in the plasma of 74 patients with IPF and in the plasma of 53 control individuals. We identified a combinatorial signature of five proteins—MMP7, MMP1, MMP8, IGFBP1, and TNFRSF1A—that was sufficient to distinguish patients from controls with a sensitivity of 98.6% (95% confidence interval [CI] 92.7%–100%) and specificity of 98.1% (95% CI 89.9%–100%). Increases in MMP1 and MMP7 were also observed in lung tissue and bronchoalveolar lavage fluid obtained from IPF patients. MMP7 and MMP1 plasma concentrations were not increased in patients with chronic obstructive pulmonary disease or sarcoidosis and distinguished IPF compared to subacute/chronic hypersensitivity pneumonitis, a disease that may mimic IPF, with a sensitivity of 96.3% (95% CI 81.0%–100%) and specificity of 87.2% (95% CI 72.6%–95.7%). We verified our results in an independent validation cohort composed of patients with IPF, familial pulmonary fibrosis, subclinical interstitial lung disease (ILD), as well as with control individuals. MMP7 and MMP1 concentrations were significantly higher in IPF patients compared to controls in this cohort. Furthermore, MMP7 concentrations were elevated in patients with subclinical ILD and negatively correlated with percent predicted forced vital capacity (FVC%) and percent predicted carbon monoxide diffusing capacity (DL_CO%).

Conclusions

Our experiments provide the first evidence for a peripheral blood protein signature in IPF to our knowledge. The two main components of this signature, MMP7 and MMP1, are overexpressed in the lung microenvironment and distinguish IPF from other chronic lung diseases. Additionally, increased MMP7 concentration may be indicative of asymptomatic ILD and reflect disease progression.