Seth Mark Berney

Inhibition of Platelet Adherence to Brain Microvasculature Protects against Severe Plasmodium berghei Malaria

ABSTRACT Some patients with Plasmodium falciparum infections develop cerebral malaria, acute respiratory distress, and shock and ultimately die even though drug therapy has eliminated the parasite from the blood, suggesting that a systemic inflammatory response contributes to malarial pathogenesis. Plasmodium berghei-infected mice are a well-recognized model of severe malaria (experimental severe malaria [ESM]), and infected mice exhibit a systemic inflammatory response. Because platelets are proposed to contribute to ESM and other systemic inflammatory responses, we determined whether platelet adherence contributes to experimental malarial pathogenesis. Indeed, a significant (P < 0.005) increase in the number of rolling and adherent platelets was observed by intravital microscopy in brain venules of P. berghei-infected mice compared with the number in uninfected controls. P-selectin- or ICAM-1-deficient mice exhibit increased survival after P. berghei infection. We observed a significant (P < 0.0001) reduction in the morbidity of mice injected with anti-CD41 (αIIb or gpIIb) monoclonal antibody on day 1 of P. berghei infection compared with the morbidity of infected controls injected with rat immunoglobulin G. Additionally, platelet rolling and adhesion in brain venules were reduced in P. berghei mice lacking either P-selectin or ICAM-1 or when the platelets were coated with anti-CD41 monoclonal antibody. Unlike other inflammatory conditions, we did not detect platelet-leukocyte interactions during P. berghei malaria. Because (i) leukocyte adhesion is not markedly altered in the absence of P-selectin or ICAM-1 and (ii) CD41 is not an adhesion molecule for parasitized erythrocytes, these findings support the hypothesis that inhibition of platelet adhesion to the brain microvasculature protects against development of malarial pathogenesis.

Intercellular adhesion molecule 1 is important for the development of severe experimental malaria but is not required for leukocyte adhesion in the brain

Plasmodium berghei-infected mice, a well-recognized model of experimental cerebral malaria (ECM), exhibit a systemic inflammatory response. Most investigators hypothesize that leukocytes bind to endothelial cells via intercellular adhesion molecule 1 (ICAM-1), which causes endothelial damage, increased microvascular permeability, and, ultimately, death. ICAM-1 -deficient mice on an ECM-susceptible C57BL/6 background were significantly (p = .04) protected from P. berghei mortality compared with ICAM-1 intact controls. ICAM-1 expression assessed by the dual radiolabeled monoclonal antibody technique was increased in the brain and lung in C57BL/6 mice on day 6 of P. berghei infection compared with uninfected controls (5.3-fold, p = .0003 for brain and 1.8-fold, p = .04 for lung). The increase in ICAM-1 expression coincided with significant (p < .05) increases in microvascular permeability in the brain and lung. In contrast to the hypothesized role for ICAM-1, in vivo analysis by intravital microscopy of leukocyte rolling and adhesion in brain microvasculature of mice revealed markedly increased levels of leukocyte rolling and adhesion in ICAM-1-deficient mice on day 6 of P. berghei infection compared with uninfected controls. In addition, ICAM-1 expression and microvascular permeability were increased in infected ECM-resistant BALB/c mice compared with uninfected BALB/c controls. These results collectively indicate that although ICAM-1 contributes to the mortality of experimental malaria, it is not sufficient for the development of severe experimental malaria. In addition, ICAM-1 expressed on the endothelium or on leukocytes is not required for leukocyte rolling or adhesion to the brain microvasculature of mice during P. berghei malaria. Leukocyte rolling and adhesion in the brain vasculature during P berghei malaria use different ligands than observed during inflammation in other vascular beds.

P-selectin contributes to severe experimental malaria but is not required for leukocyte adhesion to brain microvasculature.

ABSTRACT Plasmodium berghei-infected mice, a well-recognized model of experimental cerebral malaria (ECM), exhibit many of the hallmarks of a systemic inflammatory response, with organ damage in brain, lung, and kidneys. Identification of the molecules mediating pathogenesis of the inflammatory response, such as leukocyte adhesion, may lead to new therapies. Indeed, mice lacking the cell adhesion molecule P-selectin were significantly (P = 0.005) protected from death due to P. berghei malaria compared with C57BL/6 controls despite similar parasitemia (P = 0.6) being found in both groups of mice. P-selectin levels assessed by the quantitative dual radiolabeled monoclonal antibody technique increased significantly (P < 0.05) in several organs in C57BL/6 mice infected with P. berghei, supporting the concept of a systemic inflammatory response mediating malarial pathogenesis. Intravital microscopic analysis of the brain microvasculature demonstrated significant (P < 0.001) leukocyte rolling and adhesion in brain venules of P. berghei-infected mice compared with those found in uninfected controls. The maximum leukocyte adhesion occurred on day 6 of P. berghei infection, when the mice become moribund and exhibit marked vascular leakage into the brain, lung, and heart. However, P-selectin levels were significantly (P < 0.005) increased in brain, lung, and kidneys during P. berghei malaria in ECM-resistant BALB/c mice compared with those found in uninfected BALB/c controls, indicating that increased P-selectin alone is not sufficient to mediate malarial pathogenesis. Leukocyte adhesion to brain microvessels of P-selectin-deficient mice with P. berghei malaria was similar to that observed in control mice. Collectively, these results indicate that P-selectin is important for the development of malarial pathogenesis but is not required for leukocyte adhesion in brain.

Pulmonary hypertension in a patient with adult-onset Stills disease.

Pulmonary manifestations of adult-onset Still’s disease (AOSD) include aseptic pneumonitis, pleural effusions, rarely acute respiratory distress syndrome, and restrictive lung disease. Pulmonary arterial hypertension (PAH) occurs with several rheumatologic diseases, however, has only been reported once in AOSD. We describe a 29-year-old woman with a 9-year history of AOSD, who developed PAH without any other obvious cause. Therefore, we conclude that this is likely a result of pulmonary vascular changes related to AOSD.

ICAM-3 (CD50) cross-linking augments signaling in CD3-activated peripheral human T lymphocytes.

ICAM‐3 is a pan‐hematopoietic, constitutive adhesion molecule. ICAM‐3 binds to LFA‐1 on antigen‐presenting cells (APC) stabilizing the T cell‐APC interaction, facilitating signaling through the CD3/TCR complex. However, recent evidence using cultured and transformed T cells suggests ICAM‐3 may also function in signaling. Because ICAM‐3 is constitutively expressed on resting T cells, we postulated that signaling through ICAM‐3 in resting T cells represents an important costimulatory mechanism in these cells. In purified resting human T cells, cross‐linking both ICAM‐3 and CD3 with plate‐bound antibodies resulted in a marked increase in cell size (consistent with blastogenesis), synergistically increased surface expression of CD25 and CD69, and increased T cell metabolism. Similarly, concomitant ICAM‐3 and CD3 stimulation significantly (P < 0.001) increased resting human T cell phosphatidylinositol hydrolysis and phospholipase C‐γ1 phosphorylation. These results indicate that ICAM‐3 augments signaling through CD3, functioning as a costimulatory molecule for resting T cells in the initial activation step. J. Leukoc. Biol. 65: 867–874; 1999.

Wegener granulomatosis: a case report and update.

Wegener granulomatosis (WG) is a systemic disease of unknown etiology characterized by necrotizing granulomatous inflammation, tissue necrosis, and variable degrees of vasculitis in small and medium-sized blood vessels. The classic clinical pattern is a triad involving the upper airways, lungs and kidneys. Ninety percent of patients present with symptoms involving the upper and/or lower airways, and 80% will eventually develop renal disease. WG should be suspected in any patient with progressive or unresponsive sinus disease, glomerulonephritis, pulmonary hemorrhage, mononeuritis multiplex or unexplained multisystem disease. Before the routine use of glucocorticoids and cyclophosphamide, the one year mortality was 82%. However in 1973, Fauci and Wolf discovered that daily prednisone and cyclophosphamide induced complete remission in 75% of patients. The continued use of prednisone and cyclophosphamide for 1 year past remission leads to marked improvement in more than 90% of patients; however, is also associated with serious toxicities. Depending on the disease severity, current treatments employ induction with short-term cyclophosphamide followed by less toxic agents such as methotrexate to maintain disease remission. Although it is a rare disorder, it is pertinent to internists because it is a multisystem disease that presents in a variety of ways. We describe a 63-year-old white male with WG who presented with progressively worsening headaches, bilateral eye redness, epistaxis, hemoptysis and an unintentional 20 pound weight loss, and review the current treatment recommendations.

Impact of treatment with infliximab on anticyclic citrullinated peptide antibody and rheumatoid factor in patients with rheumatoid arthritis

Objective: To investigate the impact of infliximab treatment on anticyclic citrullinated peptide (anti-CCP) antibody and rheumatoid factor (RF) levels in patients with rheumatoid arthritis (RA). Methods: Sera from 33 RA patients receiving infliximab and disease modifying antirheumatic drugs were tested for anti-CCP antibody, IgA-, IgG- and IgM-RF using a commercially available semiquantitative ELISA at baseline, 30 and 54 weeks after treatment. Results: The serum levels of anti-CCP antibody and IgA-RF decreased significantly after 30 weeks (P = 0.002 and 0.024); however, the decrease was not significant at week 54 (P = 0.147 and 0.207). The decrease in IgG-RF level was not significant at 30 and 54 weeks (P = 0.059 and 0.097). IgM-RF levels, however decreased significantly at 30 and 54 weeks (P = 0.002 and 0.004). A strong correlation between anti-CCP and IgA-, IgG- and IgM-RF was observed at baseline (rs = 0.48, 0.43, 0.65, P = <0.05) and after infliximab treatment at 30 (rs = 0.45, 0.46, 0.62, P = <0.05) and 54(rs = 0.49, 0.45, 0.60, P = <0.05) weeks. Conclusion: Treatment with infliximab results in decreased anti-CCP antibody and IgA-RF early in the course of therapy that is not sustained. IgM-RF declines and remains decreased for at least 54 weeks. Investigations in larger cohorts of RA patients (especially early RA) with longer follow-up are needed to assess the impact of specific therapeutic interventions on anti-CCP antibody and RF levels and the relationship of their levels to disease activity.

CD2 (OKT11) augments CD3-mediated intracellular signaling events in human T lymphocytes.

CD5 is expressed on thymocytes, all mature T cells, and a subset of mature B cells, and probably contributes to T-cell–B-cell adhesion. We assessed whether CD5-crosslinking by mAb augments T-cell stimulation. Plate-bound anti-CD5 or anti-CD3 mAb alone had no effect on any of the assessed activation parameters of resting T cells. However, concomitant signaling through both CD5 and CD3 by plate-bound antibodies resulted in marked increases in T-cell surface CD69 expression and T-cell metabolism, as assessed by the T cells ability to reduce 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxylmethoxyphenyl)-2-(4-sulphophenyl)-2H-tetrazolium (MTS) to formazen. In addition, simultaneous cross-linking of CD5 and CD3 caused a significant (p < 0.001) increase in phosphatidylinositol hydrolysis in resting T cells compared to stimulation with anti-CD3 mAb alone or anti-CD3 mAb plus anti-CD5 isotype control antibody. These results indicate that CD5 augments signaling through CD3 and consequently functions as a costimulatory molecule for resting T cells.

269 INCIDENCE OF CANCER IS INCREASED IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS: A CASE CONTROL STUDY IN HALF A MILLION VETERANS

Objective To investigate the association of systemic lupus erythematosus (SLE) with cancer in the veteran population. Background Previous studies have suggested an increased risk of cancer among patients with lupus erythematosus. Methods and Materials A retrospective cross sectional case control study was conducted using data from the VSN 16 VA database of 484,226 VA patients, 615 (0.13%) of whom had diagnosis of systemic lupus (ICD-9 code of 710.0). Logistic regression analysis was done to adjust for covariates including age, race, and gender. Statistical tests were conducted at a 5% level of significance. Results Diagnosis of SLE was determined to have a significant association with the diagnosis of any cancer in general and specifically skin cancer. Patients with lupus have a risk of developing cancer at 1.73 times the risk of non-lupus patients. The risk for skin cancer development among lupus patients was 1.53 times the risk of non-lupus patients. (table) Table Cancer Proportions and Cancer Odds between Patients with Lupus (PL) and Non-lupus Patients (PNL) Discussion This study shows a positive correlation between lupus erythematosus and the development of cancer in the veteran population. This may reflect either decreased immune surveillance of neoplasms, increased systemic and cutaneous inflammation thus promoting gene rearrangements or increased susceptibility to neoplasm causing viral infections. Our data should be evaluated with caution, given the limitations of the population, the database and this being a case control study. However, the large size of the database was felt to limit the effect of these factors. Conclusion Patients with SLE have an increased incidence of cancer in general and skin cancer in particular.

270 INCIDENCE OF CANCER IS INCREASED IN PATIENTS WITH PROGRESSIVE SYSTEMIC SCLEROSIS: A CASE CONTROL STUDY IN HALF A MILLION VETERANS

Objective To investigate the association of progressive systemic sclerosis (PSS) with cancer in the veteran population. Background Previous studies have suggested an increased risk of cancer among patients with PSS. Methods and Materials A retrospective cross sectional case control study was conducted using data from the VSN 16 VA database from 1998 to 2004. Multivariate logistic regression analysis was done to adjust for covariates including smoking, age, race, and gender. Statistical tests were conducted at a 5% level of significance. Results A total of 484,226 veterans were studied, 203 (0.04%) of whom had PSS. The diagnosis of PSS was determined to have a significant association with the diagnosis of any cancer, lung and skin cancers. PSS patients have a risk of developing cancer at 1.61 times the risk of non-PSS patients. The risk for skin and lung cancers among PSS patients is respectively 1.82 and 2.35 times the risk among non-PSS patients. (table) Table Comparison of Cancer Proportions and Cancer Odds between PSS and Non‐PSS (NPSS) Patients Discussion This study shows a positive correlation between PSS and the incidence of cancer in the veteran population. It has been suggested that lung cancer in PSS may arise in previously damaged or fibrotic lung. Our data should be evaluated with caution, given the limitations of the population, the database, and this being a case control study. However, the large size of the database was felt to limit the effect of these factors. Conclusion Patients with PSS have an increased incidence of cancer in general and lung and skin cancer in particular.