Anthony W. O'Regan

Osteopontin: a key cytokine in cell-mediated and granulomatous inflammation.

Osteopontin (Opn) is a secreted adhesive, glycosylated phosphoprotein that contains the arginine‐glycine‐aspartic acid (RGD) cell‐binding sequence that is found in many extracellular matrix (ECM) proteins (for a review of Opn see References Denhardt & Guo 1993 ; Patarca et al. 1993 ; Rittling & Denhardt 1999 ). Since its initial description in 1979 as a secreted protein associated with malignant transformation, Opn has been independently discovered by investigators from diverse scientific disciplines, and has been associated with a remarkable range of pathologic responses. Opn is an important bone matrix protein, where it is thought to mediate adhesion of osteoclasts to resorbing bone. However, studies from the past decade have identified an alternative role for Opn as a key cytokine regulating tissue repair and inflammation. Recent work by our laboratory and that of others has underlined the importance of Opn as a pivotal cytokine in the cellular immune response. Despite this Opn is not well known to the immunologist. In this review we will focus on studies that pertain to the role of Opn in cell‐mediated and granulomatous inflammation.

Osteopontin (Eta-1) in cell-mediated immunity: teaching an old dog new tricks

Abstract Previously regarded as an adhesive bone matrix protein, recent studies suggest that osteopontin (Eta-1) is also a novel RGD-containing cytokine that regulates early cell-mediated immunity. Proteins related to the extracellular matrix may function as important modulators of immune responses.

IFN-γ induction of osteopontin expression in human monocytoid cells

Osteopontin (OPN) is an arginine-glycine-aspartate (RGD)-containing cytokine that increases macrophage expression of the Th1 cytokines interferon-gamma (IFN-gamma) and interleukin-12 (IL-12), and downregulates macrophage expression of IL-10. OPN has been implicated in the clearance of mycobacterial infection and in granuloma formation. We previously showed decreased OPN expression in the granulomas of patients with disseminated mycobacterial infection in the setting of mutation of the IFN-gamma receptor-1 (IFNGR-1). These data suggested that IFN-gamma critically regulates OPN expression during mycobacterial infection. Herein, we characterize the effect of IFN-gamma stimulation on OPN expression by human monocytoid cells. By Western blot, ELISA, and Northern blot analysis, IFN-gamma treatment of THP-1 cells was shown to induce OPN mRNA and protein expression in a time-dependent and dose-dependent manner. The human OPN promoter was amplified by PCR using human genomic DNA as a template and transfected into THP-1 cells. Compared with control, OPN promoter activity increased by 15-fold after treatment with IFN-gamma. Similar induction of OPN was seen in IFN-gamma-stimulated primary human blood monocytes. These data show that IFN-gamma stimulates OPN expression from monocytoid cells and suggest that OPN may function in a positive feedback loop in Th1 inflammation, increasing expression of IFN-gamma, which itself upregulates the OPN gene.

Patterns of Disease in Patients with Middle-Lobe Predominant Bronchiectasis

Background: Middle-lobe predominant bronchiectasis affecting the right middle-lobe and/or lingula (RMLP) is classically described in asthenic, elderly females with skeletal abnormalities or associated nontuberculous mycobacterial (NTM) infection. Objectives: We aimed to evaluate the frequency and clinical characteristics of patients with an RMLP phenotype in a cohort of newly diagnosed bronchiectasis patients and determine associations with disease severity. Methods: A retrospective observational cross-sectional cohort study of consecutive bronchiectasis patients in our institution was performed. Data were collected on baseline variables, microbiology status, lung function, and radiology according to the modified Bhalla score. Disease severity was assessed using bronchiectasis severity index (BSI) and FACED severity scores. Results: Of 81 patients (mean age [SD] 62.6 [12.4], females 55 [67.9%], BMI 26.9 [5.7%]), 20 (24.7%) had RMLP disease. These patients were significantly younger, female, and with lower BMIs than patients with the classical bronchiectasis phenotype (p = 0.03, 0.01, and p <0.01, respectively). Fewer symptoms of cough and daily sputum (p = 0.01 and <0.01), prior exacerbation frequency (p = 0.03), and higher baseline forced expiratory volume (p = 0.04) were noted. A higher incidence of NTM at diagnosis was demonstrated (p = 0.01). BSI and FACED severity scores in RMLP patients were significantly lower than their counterparts (both p < 0.001). Conclusions: The RMLP phenotype is associated with younger patients than classically described in the literature. An increased rate of NTM infection in this phenotype was noted, particularly in females, but much lower than previously described. Lung function and disease severity scores in this patient group are relatively normal, suggesting a milder phenotype in patients with this form of the disease.

What lies beneath

A 74-year-old male smoker was hospitalized for a transurethral resection of the prostate. A preoperative chest x-ray raised the suspicion of a finding that had been overlooked 6 months earlier.

The effect of unfractionated heparin on circulating lymphocyte counts and subsets in humans

Heparin is used for inhibition of blood clotting but also has effects on inflammation. Heparin has been reported to inhibit allergen or exercise-induced bronchospasm in asthma, and to reduce rectal bleeding and inflammation in patients with ulcerative colitis [1–3]. Animal studies with heparin in numerous models of inflammation and cellmediated immunity have shown similar anti-inflammatory activity [4–6]. Despite evidence that heparin interferes with leukocyte migration, and particularly the adhesion of leukocytes to endothelial cells and endothelial transmigration, the mechanism for its anti-inflammatory effects in humans is unknown [7–11]. We report that treatment with unfractionated heparin increases the number of circulating lymphocytes in humans. This effect appears to be specific for CD4+ T cell subsets. We suggest that the effect of heparin on T cell migration may be one mechanism by which heparin exerts an antiinflammatory effect.

P92 C reactive protein as a predictive indicator of treatment and disease progression in patients with sarcoidosis: a retrospective observational cohort study in the West of Ireland

Introduction C reactive protein (CRP) is an acute-phase protein synthesised in response to tissue damage or inflammation. Previous studies evaluating the role of CRP in sarcoidosis have focussed on disease monitoring. Adequate markers to determine predictors of progression in sarcoidosis are currently lacking. Objectives The aim of this retrospective observational study is to evaluate the utility and practical application of baseline serum CRP in predicting treatment indication and disease severity in a well-defined sarcoidosis population over a 26-year follow-up period. Methods We reviewed the clinical, biochemical, radiological and physiological findings in all confirmed sarcoidosis patients attending a regional referral centre between 1983 and 2009. Disease progression was defined in two ways: decline in lung function as per Hunninghake criteria (>15% reduction in baseline FEV1 % and/or >10% decline in baseline DLCO%); and radiological progression (defined as worsening stage of disease and/or development of bronchiectasis or cavitation). Indication for treatment was defined as need for corticosteroid treatment throughout duration of follow-up. Correlation coefficients and multiple logistic regression (MLR) analysis were performed to determine independent baseline variables relating to outcome. Results are expressed as OR, 95%-CIs and p-values. Results 328/409 (80.2%) of sarcoidosis patients were suitable for inclusion, 46.6% of whom had an abnormally elevated CRP at presentation. MLR analysis of presenting characteristics with baseline CRP showed strong associations with Löfgrens syndrome (p=0.002) and FVC % (p=0.009), consistent with previously published data. In terms of predicting outcomes, CRP was found to be an independent predictor of both radiological progression and physiological deterioration (p=0.026 and 0.048 respectively). Other independent indices for radiological progression were smoking status, Löfgrens syndrome and Scadding CXR stage at presentation (p=0.035, 0.002 and <0.001 respectively). DLCO % was shown to be a further independent predictor of physiological decline (p=0.015). Conclusion This is one of the largest clinical studies investigating the predictive influence of CRP in sarcoidosis. The data suggests a role for CRP as a predictive indicator of physiological deterioration and radiological progression. Therefore, a subset of chronic sarcoidosis patients with high baseline CRP at presentation may benefit from closer monitoring and extra attention to parameters of physiological and radiological decline.

Clinical problem-solving. Looking at the whole picture.

A 50-year-old woman presented with rapidly progressive shortness of breath. Five months earlier, she had received a diagnosis of invasive breast carcinoma and had undergone mastectomy. Her fifth cycle of chemotherapy was completed 10 days before presentation.