Cardiovascular Manifestations of Systemic Sclerosis: An Overview of Pathophysiology, Screening Modalities, and Treatment Options.

Systemic sclerosis, previously known as scleroderma, is a heterogeneous, systemic disease that is defined by its 3 pathological hallmarks: the production of autoantibodies, small vessel vasculopathy, and fibroblast dysfunction, leading to an increased deposition of extracellular matrix. We conducted a review of the available literature that covers the cardiovascular manifestations of SSc: electrical conduction abnormalities, pulmonary hypertension, pericardial disease, and atherosclerosis. Within each major category, we will discuss the definition, diagnostics, and available treatment options. Increased mortality from cardiovascular complications necessitates early screening and management. Annual screening with noninvasive modalities is encouraged. The current management of each complication generally follows the management algorithms of patients regardless of SSc status and is dependent on the severity of the patient's clinical presentation.

Cardiac Manifestations of Systemic Lupus Erythematous: An Overview of the Incidence, Risk Factors, Diagnostic Criteria, Pathophysiology and Treatment Options.

Systemic lupus erythematosus (SLE) is a complex connective tissue disease that can potentially affect every organ of the human body. In some cases, SLE may present with diverse cardiac manifestations including pericarditis, myocarditis, valvular disease, atherosclerosis, thrombosis, and arrhythmias. Heart disease in SLE is associated with increased morbidity and mortality. It is unclear whether traditional treatments for coronary artery disease significantly impact mortality in this population. Current therapeutic agents for SLE include glucocorticoids, hydroxychloroquine, mycophenolate mofetil, azathioprine, methotrexate, cyclophosphamide, and B cell-directed therapies. This article will provide a comprehensive review and update on this important disease state.

Pluripotent plasticity of stem cells and liver repopulation.

Different types of stem cells have a role in liver regeneration or fibrous repair during and after several liver diseases. Otherwise, the origin of hepatic and/or extra-hepatic stem cells in reactive liver repopulation is under controversy. The ability of the human body to self-repair and replace the cells and tissues of some organs is often evident. It has been estimated that complete renewal of liver tissue takes place in about a year. Replacement of lost liver tissues is accomplished by proliferation of mature hepatocytes, hepatic oval stem cells differentiation, and sinusoidal cells as support. Hepatic oval cells display a distinct phenotype and have been shown to be a bipotential progenitor of two types of epithelial cells found in the liver, hepatocytes, and bile ductular cells. In gastroenterology and hepatology, the first attempts to translate stem cell basic research into novel therapeutic strategies have been made for the treatment of several disorders, such as inflammatory bowel diseases, diabetes mellitus, celiachy, and acute or chronic hepatopaties. In the future, pluripotent plasticity of stem cells will open a variety of clinical application strategies for the treatment of tissue injuries, degenerated organs. The promise of liver stem cells lie in their potential to provide a continuous and readily available source of liver cells that can be used for gene therapy, cell transplant, bio-artificial liver-assisted devices, drug toxicology testing, and use as an in vitro model to understand the developmental biology of the liver.

Iron metabolism markers and haptoglobin phenotypes in susceptibility to HSV-1 or/and HSV-2 lesion relapses.

Different haptoglobin (Hp) phenotypes play a role in several pathologic processes including infectious diseases. In order to evaluate the role of iron storage and metabolism in susceptibility to herpetic manifestations, we studied the frequency of the Hp phenotypes and iron metabolism in patients affected by H. Simplex virus 1 or 2 (HSV-1 or HSV-2), compared with controls. Hp phenotype and iron metabolism were determined in 100 patients with recurrent HSV-1 or HSV-2 manifestations during the relapses, and in 110 healthy subjects. The frequencies of the three Hp phenotypes in the patient group compared to the control group were 18% versus 14.5% p = NS for Hp 1.1, 25% versus 40% p = 0.03 for Hp 2.2 and 57% versus 45.5% p = NS for Hp 2.1. All iron metabolism parameters tested showed significant differences between patients and controls; haemoglobin (Hb), ferritin, and serum iron were lower, while transferrin was higher in the patients than in controls. Reductions in iron availability may be a risk factor for relapsing lesions of HSV-1 or HSV-2. Hp 2.2 phenotype may offer some protection against the recurrence of Herpes labialis or genitalis manifestations.

Gout and hyperuricemia.

Hyperuricemia is an elevated uric acid level in blood. Gout is a common systemic metabolic disease characterized by deposition of monosodium urate monohydrate crystals with resultant acute intense inflammation of the involved joint. The clinical spectrum ranges from asymptomatic hyperuricemia to intermittent acute episodes of gouty arthritis to chronic tophaceous gout and chronic gouty arthropathy.

Mitochondria influence Fas expression in gp120-induced apoptosis of neuronal cells.

The human immunodeficiency virus-1 (HIV-1) destroys the immune system and also induces neurological disease culminating into dementia (HIV-associated dementia). Though the HIV viral protein gp120 induces apoptosis in neuronal cells, the mechanism of action is still poorly defined. Recent studies show that cells die during apoptosis by Fas aggregation aided by the mitochondrial proapoptotic proteins. Our studies show an increase in expression of Fas and its associated downstream proteins after treatment of the neuroblastoma cells, SH-SY5Y, with gp120. Fas and its associated death proteins, FADD and caspase-8 (DISC), are downregulated when treated with the caspase inhibitors. The results indicate that mitochondrial-death proteins like caspases may influence the upregulation of the death receptor Fas, and the inhibition of caspases prevents gp120-induced apoptosis.

Localized Scleroderma: A Clinical Review.

Localized scleroderma (LS) is characterized by excessive collagen deposition leading to thickening of the dermis, subcutaneous tissue or both. The outcome for most patients with localized scleroderma is directly related to the type and stage of the affected tissue. The major challenge for untreated patients is not increased mortality risk, rather deformity and growth defects from skin, muscle and bone abnormalities. Treatment is individualized to type and stage of the lesion and may include pharmacologic and non-pharmacologic therapies. Among the pharmacologic modalities, methotrexate with systemic glucocorticoids is currently the mainstay of treatment. More controlled trials are needed to determine the length of treatment and the maintenance dose of this combination therapy.

Antibody-mediated antigen sampling across intestinal epithelial barriers.

The epithelium of the gastrointestinal tract is the interface between luminal contents and the mucosal immune system. It must function as a selective barrier to limit penetration of antigens yet keep the mucosal immune system "informed" for the purpose of generating oral tolerance responses to food antigens or commensal organisms and host defense responses against pathogens. Alterations in epithelial barrier function have been proposed to play a significant role in gastrointestinal disease. In this review, we will discuss mechanisms of regulation of epithelial barrier function, and we will focus on the emerging understanding of how secreted immunoglobulins play a role in antigen-specific antigen sampling across the gastrointestinal epithelium.

Phenotypic diversity in delayed drug hypersensitivity: an immunologic explanation.

Drug hypersensitivity reactions are a significant cause of iatrogenic-induced illness. (They were originally classified as type IV hypersensitivity, to describe the tuberculin skin reaction.) It now appears that the T-cell directs the entire inflammatory cascade induced by delayed drug allergy. Delayed drug hypersensitivity, usually manifested in the skin, is triggered when drug-specific CD4+ and CD8+ T cells recognize drugs through their T-cell receptors in a process that is dependent on a major histocompatibility complex. Drugs stimulate T-cell receptors by either covalently binding to peptides or using their structural features to interact via a more direct approach. Immunohistochemical and functional analysis of drug-reactive T-cell clones has shown that the phenotypic pattern of delayed drug hypersensitivity depends on the cytokine pattern induced. For example, maculo-papular exanthema may be either TH-1 or TH-2 in nature, depending on whether they are interferon- g /tumor necrosis factor- a or interleukin-4, 5 and 13 driven. Bullous reactions to drugs (i.e., Stevens-Johnson syndrome or toxic epidermal necrolysis) are characterized by widespread keratinocyte apoptosis, a consequence of high CD8+ T-cell involvement and the molecular cytotoxicity of Fas, perforin and granzyme B. Pustular exanthema reactions to medications are stimulated via the T-cell release of IL-8 and granulocyte-monocyte colony-stimulating factor (GM-CSF). With better understanding of these unique inflammatory cascades, delayed type IV hypersensitivity reactions have been re-classified into four main subtypes: IVa (TH-1/monocyte directed), IVb (TH-2/eosinophil directed), IVc (CD8+/ Fas/perforin/Granzyme B directed) and IVd (IL-8/GM-CSF/neutrophil directed). Clinically, delayed hypersensitivity eruptions are often an overlap of cytokine pathways, with one preferential reaction dominating the final picture.

Stem cells: an alternative to organ transplantation in chronic, degenerative and infectious diseases?

Even in the absence of damage or illness mature animals need billions of new cells every single day of their lives in order to survive and renew circulating blood cells and intestinal and skin lining. This task is accomplished by undifferentiated cells residing in most adult organs. These cells are designated adult stem cells (ASC) since they represent the adult counterpart, present in almost every organ, of the embryonal stem cells (ES) from which the entire human body develops. Scientists first hypothesized the existence of stem cells over a century ago, and haematopoietic stem cells (HSC) have been exploited for the therapy of human diseases for two decades. Other types of stem cells also circulating in the bloodstream have been described. We briefly describe the potential uses of each of these types of cells, including autologous circulating stem cells, for disease therapy and in particular for the possible reversal of liver failure due to chronic hepatitis and/or cirrhosis.

Neurologic consequences of HIV infection in the era of HAART.

In this brief review, we present a summary of the clinical presentation of HIV-associated dementia (HAD), HAD in the highly active antiretroviral therapy (HAART) era, the immunopathogenesis of HAD, and the possible role of a recently described novel macrophage-derived protein in HAD. Different aspects of the clinical presentation of HAD will be reviewed as well as the results of recent autopsy studies demonstrating that although HAART dramatically decreased the incidence of opportunistic infections and malignancies in the central nervous system, it has reduced but not eliminated HIV encephalopathy. This suggests a direct cytopathic effect of HIV on neuronal tissue. Consequently, the immunopathogenesis of HAD and the role of neurotoxins produced by brain macrophages and microglial cells will be reviewed including the possible role of a recently cloned macrophage-derived proapoptotic factor, soluble HIV apoptotic protein (SHIVA) identified in our laboratory. HAART therapy reduces the incidence of opportunistic infections, the direct pathogenic effect of HIV, especially on neuronal tissue, may become of increasing importance.

Hydroxychloroquine in systemic lupus erythematosus and rheumatoid arthritis and its safety in pregnancy.

INTRODUCTION: The antimalarial drug hydroxychloroquine (HCQ) is widely used to treat various rheumatic diseases. Many autoimmune diseases occur in women of child-bearing age who may become pregnant while on therapy, which raises concerns regarding the teratogenicity of HCQ and its effect on the outcome of the pregnancy. There is a lack of data regarding the safety of HCQ during pregnancy. AREAS COVERED: In this review, the authors attempt to identify relevant publications by searching MEDLINE, Cochrane database, Ovid-Currents Clinical Medicine, Ovid-Embase:Drugs and Pharmacology, EBSCO, Web of Science and SCOPUS using the search terms HCQ and/or pregnancy. A basis for the mechanism of action of HCQ is provided. EXPERT OPINION: HCQ has been shown by numerous studies over the past 15 years to be efficacious in the treatment of autoimmune diseases, including systemic lupus erythematosus, discoid lupus erythematosus and rheumatoid arthritis. HCQ does not appear to be associated with any increased risk of congenital defects, spontaneous abortions, fetal death, prematurity or decreased numbers of live births in patients with autoimmune diseases. Therefore, in the author's opinion, HCQ is safe for the treatment of autoimmune diseases during pregnancy.

Systematic review of hydroxychloroquine use in pregnant patients with autoimmune diseases.

OBJECTIVE: The purpose of this study is to compare the incidence of congenital defects, spontaneous abortions, number of live births, fetal death and pre-maturity in women with autoimmune diseases taking HCQ during pregnancy. METHODS: The authors searched MEDLINE, Cochrane data base, Ovid-Currents Clinical Medicine, Ovid-Embase:Drugs and Pharmacology, EBSCO, Web of Science, and SCOPUS using the search terms HCQ and/or pregnancy. We attempted to identify all clinical trials from 1980 to 2007 regardless of language or publication status. We also searched Cochrane Central Library and http://www.Clinical trials.gov for clinical trials of HCQ and pregnancy. Data were extracted onto standardized forms and were confirmed. RESULTS: The odds ratio (OR) of congenital defects in live births of women taking HCQ during pregnancy was 0.66, 95% confidence intervals (CI) 0.25, 1.75. The OR of a live birth for women taking HCQ during pregnancy was 1.05 (95% CI 0.58, 1.93). The OR of spontaneous abortion in women taking HCQ during pregnancy was 0.92 (95% CI 0.49, 1.72). The OR of fetal deaths in women taking HCQ during pregnancy was 0.97 (95% CI 0.14, 6.54). The OR of pre-mature birth defined as birth before 37 weeks in women taking HCQ during pregnancy was 1.10 (95% CI 0.75, 1.61). CONCLUSION: HCQ is not associated with any increased risk of congenital defects, spontaneous abortions, fetal death, pre-maturity and decreased numbers of live births in patients with auto-immune diseases.

Toll-like receptors: new therapeutic targets for the treatment of atherosclerosis, acute coronary syndromes, and myocardial failure.

The toll-like receptors (TLRs) are a class of transmembrane molecules that have important functions in both innate and acquired immunity. As part of the body's normal immune defense against microbial pathogens, stimulation of these receptors will trigger the inflammatory response cascade and the release of cytokines. Activation of these receptors also plays a role in a variety of systemic inflammatory diseases such as asthma, sepsis, atherosclerosis, acute coronary artery disease, and left ventricular remodeling. Pharmacologic approaches to modify the actions of TLRs are now under consideration as potential treatments for inflammatory systemic diseases that include atherosclerosis. At the same time, it is essential to characterize the benefits and risks of modifying such an important part of the body's innate immune system.

Vaccines in development to prevent and treat atherosclerotic disease.

Coronary heart disease (CHD) remains the leading cause of death in the United States. Immune mechanisms have been recently proposed to play an important role in the development of atherosclerotic plaques in CHD. Heat shock proteins and oxidized low-density lipoprotein are proinflammatory substances that have been shown to have an important role in the pathogenesis of atherosclerosis, and are now targets for clinical vaccine development. In addition, a vaccine has been developed to inhibit cholesteryl ester transfer protein. It is now recognized that many medications used to combat plaque development and rupture have significant anti-inflammatory effects and these effects are critical for drug efficacy. The influenza vaccine is associated with an atheroprotective effect. In addition, a nicotine vaccine, an antiangiotensin vaccine, and an anti-obesity vaccine may play a therapeutic role in modifying known risk factors for the development of atherosclerosis and its complications. This article reviews these vaccines as possible additions to the armamentarium of atheroprotective treatment modalities.

Transcytosis of IgE-antigen complexes by CD23a in human intestinal epithelial cells and its role in food allergy.

BACKGROUND & AIMS: Secreted immunoglobulins play an integral role in host defense at mucosal surfaces, and recent evidence shows that IgG can participate in antigen sampling from the intestinal lumen. We examined whether IgE also could facilitate transepithelial antigen sampling. METHODS: Stool samples from food-allergic patients undergoing oral food challenge were analyzed for CD23 and food-specific IgE. CD23 isoform expression on primary human intestinal epithelial cells (IEC) was analyzed by polymerase chain reaction. The role of CD23 isoforms in transcytosis of antigen and IgE-antigen complexes was assessed using polarized human T84 cells retrovirally transfected with CD23a or CD23b. RESULTS: CD23 was expressed constitutively on IECs, and food-allergic patients had increased levels of soluble CD23 and food-specific IgE in the stool after challenge. CD23a, but not CD23b, was expressed by primary human IECs. We show in transcytosis assays that CD23a, but not CD23b, acts as a bidirectional transporter of IgE. In addition, specific IgE facilitated the uptake of antigen from the apical surface of an epithelial monolayer by diverting antigen from delivery to lysosomes. Finally, delivery of antigen-IgE complexes across the epithelial barrier could induce the degranulation of rat basophil leukemia cells transfected with the human high-affinity IgE receptor. CONCLUSIONS: These studies show that CD23a is expressed normally on human IECs, and in the presence of IgE can function as an antigen-sampling mechanism capable of activating subepithelial mast cells. IgE may serve as a secretory immunoglobulin that in concert with CD23 participates in food-induced pathophysiology of the gastrointestinal tract.

Impaired accessory cell function in a human dendritic cell line after human immunodeficiency virus infection.

We generated human dendritic cell (DC) hybridoma cell lines by fusing HGPRT-deficient promonocytic U937 cells with immature DCs obtained by culturing peripheral blood monocytes with interleukin-4 (IL-4; 1,000 U/ml) and granulocyte-macrophage colony-stimulating factor (100 U/ml) for 7 days and mature DCs by treatment with tumor necrosis factor alpha (12.5 microg/ml) for 3 days. Only one fusion with immature DCs was successful and yielded four cell lines--HB-1, HB-2, HB-3, and HB-9--with an overall fusion efficiency of 0.0015%. The cell lines were stable in long-term culture, displayed morphological features typical of DCs, and expressed distinct class I and class II molecules not present on U937 (A*031012, B*51011, Cw*0701, DRB3*01011 52, and DR5*01011). A representative cell line, HB-2, that expressed DC markers including CD83, CD80 and CD86 could be induced to produce IL-12 through CD40 stimulation. After human immunodeficiency virus (HIV) infection, there was impairment of antigen-presenting cell (APC) function, which was manifested by an inability to stimulate allogeneic T-cell responses. There was no change in expression of major histocompatibility complex class I and class II antigens, CD83, CD40, CD4, CD11c, CD80, CD86, CD54, and CD58, or IL-12 production in the HIV-infected HB-2 cells. The HIV-infected HB-2 cells induced T-cell apoptosis in the cocultures. T-cell proliferation could be partially restored by using ddI, indinivir, and blocking anti-gp120 and anti-IL-10 antibodies. Our data suggest that there are multiple mechanisms that DCs use to inhibit T-cell responses in HIV-infected patients. The HB-2 cell line could be a useful model system to study APC function in HIV-infected DCs.

Cdc2/cyclin B1 interacts with and modulates inositol 1,4,5-trisphosphate receptor (type 1) functions.

The resistance of inositol 1,4,5-trisphosphate receptor (IP3R)-deficient cells to multiple forms of apoptosis demonstrates the importance of IP3-gated calcium (Ca2+) release to cellular apoptosis. However, the specific upstream biochemical events leading to IP3-gated Ca2+ release during apoptosis induction are not known. We have shown previously that the cyclin-dependent kinase 1/cyclin B (cdk1/CyB or cdc2/CyB) complex phosphorylates IP3R1 in vitro and in vivo at Ser421 and Thr799. In this study, we show that: 1) the cdc2/CyB complex directly interacts with IP3R1 through Arg391, Arg441, and Arg871; 2) IP3R1 phosphorylation at Thr799 by the cdc2/CyB complex increases IP3 binding; and 3) cdc2/CyB phosphorylation increases IP3-gated Ca2+ release. Taken together, these results demonstrate that cdc2/CyB phosphorylation positively regulates IP3-gated Ca2+ signaling. In addition, identification of a CyB docking site(s) on IP3R1 demonstrates, for the first time, a direct interaction between a cell cycle component and an intracellular calcium release channel. Blocking this phosphorylation event with a specific peptide inhibitor(s) may constitute a new therapy for the treatment of several human immune disorders.

Induction of apoptosis by HIV-1-infected monocytic cells.

We have previously described a soluble 6000-Da peptide produced by an HIV-1-infected human macrophage cell line, clone 43(HIV), which induces apoptosis in T and B cells. We have identified this factor as the novel cDNA clone FL14676485 that encodes for the human hypothetical protein, FLJ21908. The FL14676485 cDNA clone was isolated from a 43(HIV) lambda ZAP Escherichia coli expression library and screened with a panel of rabbit and mouse anti-apoptotic Abs. We transfected the FL14676485 clone into Bosc cells and non-HIV-1-infected 43 cells. Western blot analysis of lysates from the FL14676485-transfected 43 cells and Bosc cells using anti-proapoptotic factor Abs revealed a protein with a molecular mass of 66 kDa corresponding to the size of the full-length gene product of the FL14676485 clone, while Western blot of the supernatant demonstrated a doublet of 46-kDa and 6000-Da peptide that corresponds to our previously described proapoptotic factor. Primary HIV-1(BaL)-infected monocytes also produce the FLJ21908 protein. Supernatants from these transfected cells induced apoptosis in PBMC, CD4(+), and CD8(+) T and B cells similar to the activity of our previously described proapoptotic factor. PCR analysis of 43 cells and 43(HIV) cells revealed a base pair fragment of 420 bp corresponding to the FL14676485 gene product in 43(HIV) cells, but not in 43 cells. The FLJ21908 protein induces apoptosis through activation of caspase-9 and caspase-3. We have further demonstrated that the FLJ21908 protein has apoptotic activity in the SH-SY5Y neuronal cell line and can be detected in brain and lymph tissue from HIV-1-infected patients who have AIDS dementia. The FLJ21908 protein may contribute to the apoptosis and dementia observed in AIDS patients.