The infectious etiology of vasculitis

Infectious agents have been implicated in the etiopathogenesis of various vasculitides via numerous and overlapping mechanisms including direct microbial invasion of endothelial cells, immune complex mediated vessel wall damage and stimulation of autoreactive B and/or T cells through molecular mimicry and superantigens. While the causative role of hepatitis B virus in polyarteritis nodosa and hepatitis C virus in mixed cryoglobulinemia is clearly established, evidence for the association of other infectious agents with vasculitis, including human immunodeficiency virus, parvovirus B19, cytomegalovirus, varicella zoster virus, Staphylococcus aureus, rickettsiaceae, Treponema pallidum and Borrelia burgdorferi, among numerous others, is accumulating. The spectrum of association of infectious agents; bacteria, viruses and parasites, with systemic vasculitides, will be reviewed herewith.     

Low Urine Secretion of Semaphorin3A in Lupus Patients with Proteinuria

Inflammation - Immune semaphorins are important in controlling both innate and adaptive immune responses. The regulatory role of semaphorin3A (sema3A) in systemic lupus erythematosus (SLE),...     

Clinical evaluation (phase I) of a combination of two human monoclonal antibodies to HBV: safety and antiviral properties

Treatment of chronic hepatitis B virus (HBV) infection with interferon alfa and lamivudine is characterized by lack of viral clearance, loss of response, or emergence of drug-resistant mutants. Thus, new and multiple drug approaches are needed. We have developed two fully human monoclonal antibodies, directed against different epitopes of hepatitis B surface antigen (HBsAg) that bind to all major HBV subtypes. A phase I clinical study was conducted to evaluate the safety, tolerability, and efficacy of a mixture of these two monoclonal antibodies, HBV-AB(XTL). A total of 27 chronic HBV patients were enrolled. In part A of the study 15 patients in 5 cohorts received a single intravenous infusion of antibodies with doses ranging from 0.26 mg (260 IU) to 40 mg (40,000 IU). All patients completed 16 weeks of follow-up. In the second part of the study (part B), 12 patients in 4 cohorts received 4 weekly infusions of 10, 20, 40, or 80 mg each of HBV-AB(XTL) and were followed for 4 additional weeks. Administration of antibodies was well tolerated. Patients administered doses at an Ab:Ag molar ratio of 1:2 to 1:20 showed a rapid and significant decrease in HBsAg to undetectable levels, with a corresponding reduction of HBV-DNA levels. In part B, HBV-AB(XTL) induced a significant reduction in both HBsAg and HBV-DNA levels repeatedly after administration. In conclusion, these data suggest that HBV-AB(XTL) binds HBV particles and reduces serum viral titers and HBsAg levels. HBV-AB(XTL) could be combined with other monotherapies that are currently used to treat HBV carriers.     

Increased C-reactive protein levels in the polycystic ovary syndrome: a marker of cardiovascular disease

The polycystic ovary syndrome (PCOS), one of the most common reproductive abnormalities, shares some components of the metabolic cardiovascular syndrome. Therefore, PCOS patients may represent the largest group of women at high risk for the development of early-onset cardiovascular disease (CVD) and/or diabetes. C-reactive protein (CRP) is a strong independent predictor of future CVD and/or stroke. Only one small published study has looked for such an association (17 PCOS patients vs. 15 controls). The objective of this study was to compare the levels of CRP and other risk factors of CVD in a large group of PCOS patients and controls. CRP measurements were undertaken in 116 PCOS patients and 94 body mass index-matched controls with regular menstrual cycles. Whereas 36.8% of the PCOS patients had CRP levels above 5 mg/liter, only 9.6% of the controls exhibited high CRP levels (P < 0.001). The mean +/- SD was 5.46 +/- 7.0 in the PCOS group vs. 2.04 +/- 1.9 mg/liter in the control (P < 0.001). The body mass index, white blood cell count, TSH, glucose, cholesterol, and homocysteine levels were not significantly different between the two groups. CRP levels are elevated in patients with PCOS and may be a marker of early cardiovascular risk in these patients. High CRP levels may explain why some PCOS women may possibly be at an increased risk for the development of early-onset CVD. Consequently, whether treatment regimens directed toward lowering CVD risk factors should be more aggressive for those PCOS women with increased CRP levels, awaits further clinical experience.     

Male sex coupled with articular manifestations cause a 4-fold increase in susceptibility to amyloidosis in patients with familial Mediterranean fever homozygous for the M694V-MEFV mutation

OBJECTIVE: Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by attacks of fever, serositis, and a predisposition to the development of amyloidosis. The wide clinical variability of the disease has been partly attributed to MEFV allelic heterogeneity and partly to the influence of additional genetic and/or environmental modifiers. Of these, male sex was found to influence disease penetrance and susceptibility to amyloidosis. We investigated the role of sex as an independent contributor to the phenotypic profile in FMF and further defined the factors affecting disease expression and severity. METHODS: A total of 124 patients with FMF who were all homozygous for the M694V mutation, including 47 patients with nephropathic amyloidosis, were identified. A detailed chart review and physical examination were undertaken to determine demographic characteristics, history, clinical manifestations, and treatment, and we calculated the disease severity score from the Tel-Hashomer key. RESULTS: A preponderance of male patients was documented (73:51; 1.4). The overall male:female ratio was significantly higher among patients with amyloidosis (32:15; 2.1) compared to patients without amyloidosis (41:36; 1.1). FMF severity scores, independently calculated for male and female patients, were equally high (9.5 +/- 3.0 and 9.7 +/- 2.8, respectively). The frequency of arthritic attacks, significantly higher in women than men (p = 0.015), remained notably higher in male FMF patients with amyloidosis compared to male FMF patients without amyloidosis (p = 0.002). Significant correlation between arthritis attacks and amyloidosis was found (R > 0.285, p < 0.001). CONCLUSION: Susceptibility to renal amyloidosis is influenced both by sex and the occurrence of joint attacks, acting as 2 MEFV independent factors (OR 2.37, 95% CI 1.06-5.26 and OR 3.27, 95% CI 1.23-8.68, respectively).     

Role of Ras signaling in erythroid differentiation of mouse fetal liver cells: functional analysis by a flow cytometry-based novel culture system

Ras signaling plays an important role in erythropoiesis. Its function has been extensively studied in erythroid and nonerythroid cell lines as well as in primary erythroblasts, but inconclusive results using conventional erythroid colony-forming unit (CFU-E) assays have been obtained concerning the role of Ras signaling in erythroid differentiation. Here we describe a novel culture system that supports terminal fetal liver erythroblast proliferation and differentiation and that closely recapitulates erythroid development in vivo. Erythroid differentiation is monitored step by step and quantitatively by a flow cytometry analysis; this analysis distinguishes CD71 and TER119 double-stained erythroblasts into different stages of differentiation. To study the role of Ras signaling in erythroid differentiation, different H-ras proteins were expressed in CFU-E progenitors and early erythroblasts with the use of a bicistronic retroviral system, and their effects on CFU-E colony formation and erythroid differentiation were analyzed. Only oncogenic H-ras, not dominant-negative H-ras, reduced CFU-E colony formation. Analysis of infected erythroblasts in our newly developed system showed that oncogenic H-ras blocks terminal erythroid differentiation, but not through promoting apoptosis of terminally differentiated erythroid cells. Rather, oncogenic H-ras promotes abnormal proliferation of CFU-E progenitors and early erythroblasts and supports their erythropoietin (Epo)-independent growth.