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PubMed1994

Neuroglial-specific factors and the regulation of retrovirus transcription.

Retroviruses have been implicated as causative agents of a variety of human diseases including malignancy, immune system dysfunction, and neurologic disorders. Despite the isolation of various retroviral agents from patients suffering from malignant neoplasias and neurologic disorders, only the human T-cell lymphotropic virus type I (HTLV-I) and the human immunodeficiency virus (HIV) have been definitively accepted as etiologic agents of human disease (Hjelle, 1991; Gessain and Gout, 1992; Rosenblatt, 1993). Because of their increasingly defined roles in disease progression, the replication of HTLV-I and HIV is an important focus for understanding the pathogenic processes resulting from viral infection. Of particular interest are the molecular mechanisms by which expression of retroviral genomes is regulated by their regulatory units, the long terminal repeats (LTR), in a manner specific to the cellular targets which they infect.

AIDS Dementia Complex↗

PubMedDate not supplied

Recurrent early pregnancy loss and consanguinity.

The present authors have studied the possible relationship between recurrent miscarriage and consanguinity in the Qatari population, where the prevalence of first cousin marriage is 47%. The maternal of three or more early pregnancy losses were compared with those of 92 non-consanguineous women from the same population and with the same obstetrical history, matched for maternal age. The retrospective investigation showed no difference in the rate of previous pregnancy loss and maternal disorders, including diabetes, thyroid dysfunction and immunity, abnormal uterine and ovarian anatomy or thrombophilia. There was also no evidence of familial clustering of recurrent miscarriage in both groups. The prospective study showed no difference in the rate of subsequent pregnancy loss and the median gestational age and fetal weight at delivery in ongoing pregnancies. The absence of a relationship between recurrent miscarriage and consanguinity in Qatar could be due to the particular characteristics of the native Qatari population, in which rare recessive genes are uncommon, or overall to the absence of an association between recurrent miscarriage and consanguinity.

Abortion, Habitual↗

PubMed2001

TCL1 oncogene expression in B cell subsets from lymphoid hyperplasia and distinct classes of B cell lymphoma.

Activation of the TCL1 oncogene has been implicated in T cell leukemias/lymphomas and recently was associated with AIDS diffuse large B cell lymphomas (AIDS-DLBCL). Also, in nonmalignant lymphoid tissues, antibody staining has shown that mantle zone B cells expressed abundant Tcl1 protein, whereas germinal center (GC; centrocytes and centroblasts) B cells showed markedly reduced expression. Here, we analyze isolated B cell subsets from hyperplastic tonsil to determine a more precise pattern of Tcl1 expression with development. We also examine multiple B cell lines and B lymphoma patient samples to determine whether different tumor classes retain or alter the developmental pattern of expression. We show that TCL1 expression is not affected by Epstein-Barr virus (EBV) infection and is high in naïve B cells, reduced in GC B cells, and absent in memory B cells and plasma cells. Human herpesvirus-8 infected primary effusion lymphomas (PEL) and multiple myelomas are uniformly TCL1 negative, whereas all other transformed B cell lines tested express moderate to abundant TCL1. This observation supports the hypothesis that PEL, like myeloma, usually arise from post-GC stages of B cell development. Tcl1 protein is also detected in most naïve/GC-derived B lymphoma patient samples (23 of 27 [85%] positive), whereas most post-GC-derived B lymphomas lack expression (10 of 41 [24%] positive). These data indicate that the pattern of Tcl1 expression is distinct between naïve/GC and post-GC-derived B lymphomas (P < 0.001) and that the developmental pattern of expression is largely retained. However, post-GC-derived AIDS-DLBCL express TCL1 at a frequency equivalent to naïve/GC-derived B lymphomas in immune-competent individuals (7 of 9 [78%] positive), suggesting that TCL1 down-regulation is adversely affected by severe immune system dysfunction. These findings demonstrate that TCL1 expression in B cell lymphoma usually reflects the stage of B cell development from which they derive, except in AIDS-related lymphomas.

B-Lymphocyte Subsets↗

PubMed1996

Identification of the murine beige gene by YAC complementation and positional cloning.

The beige mutation is a murine autosomal recessive disorder, resulting in hypopigmentation, bleeding and immune cell dysfunction. The gene defective in beige is thought to be a homologue of the gene for the human disorder Chediak-Higashi syndrome. We have identified the murine beige gene by in vitro complementation and positional cloning, and confirmed its identification by defining mutations in two independent mutant alleles. The sequence of the beige gene message shows strong nucleotide homology to multiple human ESTs, one or more of which may be associated with the Chediak-Higashi syndrome gene. The amino acid sequence of the Beige protein revealed a novel protein with significant amino acid homology to orphan proteins identified in Saccharomyces cerevisiae, Caenorhabditis elegans and humans.

Amino Acid Sequence↗

PubMed2000

Mercuric chloride activates the Src-family protein tyrosine kinase, Hck in myelomonocytic cells.

Hck is a member of the Src-family of protein tyrosine kinases that appears to function in mature leukocytes to communicate a number of extracellular signals including various cytokines. In this study we show that the thiol-reactive heavy metal, mercuric chloride (HgCl2) induces rapid and robust activation of tyrosine phosphorylation within human myelomonocytic cells. This increase in tyrosine-phosphorylated proteins requires the activity of Hck because both kinase inactive alleles of Hck and pharmacological inhibitors selective for the Src-family kinases are able to abrogate the cellular response to HgCl2. Furthermore, ectopic expression of Hck in murine fibroblasts is able to confer HgCl2 responsiveness, as indicated by an increase in tyrosine-phosphorylated proteins to a normally nonresponsive cell line. Concomitant with the activation of Hck, there is a physical association of Hck with another cytoplasmic protein tyrosine kinase, Syk. The ability of HgCl2 to activate Src-family kinases such as Hck in hematopoietic cells may help explain why exposure to the heavy metal is associated with immune system dysfunction in rodents as well as humans.

Blotting, Western↗

PubMed1998

Lymphoid cell infiltration during breast cancer growth: a syngeneic rat model.

The systematic study of potential alterations in lymphoid infiltrates during tumour growth is extremely limited in humans. Therefore, development of a model utilizing a spontaneously arising mammary adenocarcinoma in Dark Agouti rats was adopted for the study of the dynamics of lymphoid cell infiltration during tumour development. Syngeneic rats were inoculated with tumour cell suspensions and the tumours were resected from 5 to 15 days. Serial sections were immunohistochemically stained using a panel of monoclonal antibodies. Irrespective of tumour age, ED2 (macrophages) and W3/25 (CD4)-positive cells were the most prominent cell infiltrates in tumours. There were no significant differences in cell counts for any marker between 8-day and 15-day tumours. However, in 5-day tumours there were significantly fewer macrophages, OX19+ T cells, W3/25+ cells, OX8+ (CD8) cells and OX62+ dendritic cells. Interleukin-2 receptor alpha chain expression was low at all examined stages of tumour growth, indicating a lack of tumour infiltrating lymphocyte (TIL) activation and/or possible TIL anergy. B cell staining was absent in all tumours, negating the possibility of these cells mediating coregulatory signals for TIL activation in the micro-environment of established tumours. The results parallel previous immunohistochemical findings in humans, suggesting that a dysfunctional local immune response in breast cancer may be determined very early during tumour development.

Adenocarcinoma↗

PubMed2003

Principles of antiretroviral treatment of children and adolescents with human immunodeficiency virus infection.

Human immunodeficiency virus (HIV) infection requires life-long therapy to attain durable suppression of HIV replication and prevent or reverse HIV-related symptoms or immune system dysfunction. Combination therapy with 3 or more antiretroviral medications is currently widely recommended for treatment of children and adolescents with HIV infection. While potent regimens can initially reduce virus load to below assay quantitation limits in the majority of persons with HIV infection, 30% to 80% of children will have regimen failure and return of detectable plasma virus within 1 year. Adherence to therapy is critical to regimen success. Optimal treatment requires careful use of potent combinations of drugs, with attention to adherence, palatability, toxicity, and pharmacokinetics. Practitioners with experience caring for children and adolescents with HIV infection should be involved.

Adolescent↗

PubMed2003

Sexually transmitted diseases.

Sexually transmitted diseases (STDs) constitute a major health burden in the United States, causing pelvic inflammatory disease, ectopic pregnancy, infertility, chronic pelvic pain, genital lesions, genital neoplasms, adverse pregnancy outcomes, immune system dysfunction, liver disease, and even death. STDs disproportionately affect adolescents and young adults. Of the estimated 15 million STDs that occur annually each year in the United States, 4 million are among adolescents and 6 million among young adults. The current epidemic is complicated by the high asymptomatic carrier state associated with most STDs and the inadequate protection of condoms in preventing transmission. Sexually active individuals, particularly adolescents, must be educated on the ramifications of early onset of sexual activity and the health consequences of multiple sexual partners.

Acquired Immunodeficiency Syndrome↗

PubMed2002

Novel bacterial polar lipids containing ether-linked alkyl chains, the structures and biological properties of the four major glycolipids from Propionibacterium propionicum PCM 2431 (ATCC 14157T).

Propionibacterium propionicum belongs to the "acnes group" of propionibacteria, which is currently considered as clinically important because of its growing potential in infections, in particular with those connected with immune system dysfunctions. Propionibacteria are thought to be actinomycete-like microorganisms and may still cause diagnostic difficulties. The chloroform-methanol extracts of the cell mass of P. propionicum (type strain) gave in TLC analysis the characteristic glycolipid profile containing four major glycolipids, labeled G(1) through G(4). These polar lipids were found to be useful chemotaxonomic markers to differentiate P. propionicum from other cutaneous propionibacteria, in particular from strains of the acnes group. Glycolipids G(1)-G(4) were isolated and purified using gel-permeation chromatography, TLC, and high performance liquid chromatography, and their structures were elucidated by compositional and methylation analyses, specific chemical degradations, MALDI-TOF mass spectrometry, and (1)H NMR and (13)C NMR spectroscopy, including HMBC, TOCSY, HMQC, and NOESY experiments. Glycolipids G(2) and G(3) possess as backbone alpha-d-Glcp-(1 --> 3)-alpha-d-Glcp-(1 --> 1)-Gro (Gro, glycerol), in which position O-2 of the glycerol residue is acylated by a fatty acid (mainly C(15):0) while O-3 is substituted by an alkyl ether chain. In glycolipid G(3), an additional fatty acyl chain was linked to O-6 of the terminal glucose residue. Glycolipid G(4) was structurally related to G(2) but devoid of one glucose residue. Glycolipid G(1) was isolated in small amounts, and its structure was therefore deduced from MALDI-TOF-MS experiments alone, which revealed that it possessed the structure of G(2) but was lacking one fatty acid residue. In studies on the biological properties of P. propionicum glycolipids, the anti-P. propionicum rabbit antisera reacted in dot enzyme-immunoblotting test with G(2) and G(3). Glycolipid G(3) was able to induce the delayed type of hypersensitivity. The results indicated that these novel ether linkage-containing polar glycolipids are immunogenic and possibly active in hypersensitivity, and thus, in pathogenesis.

Carbohydrate Sequence↗

PubMed1995

Update on pharmacotherapy of systemic lupus erythematosus.

Established and novel approaches to the pharmacologic management of systemic lupus erythematosus (SLE) are described. SLE is a chronic, multiple-organ-system inflammatory disorder associated with immune system dysfunction. Autoantibodies are produced that react with self-antigens, notably cell membranes and nuclear and cytoplasmic constituents. There are many clinical manifestations, including arthritis, arthralgia, myalgia, skin changes, photosensitivity reactions, fever, anemia, thrombocytopenia, proteinuria, and renal, CNS, and cardiopulmonary involvement. The disease characteristically fluctuates between remission and relapse. Survival has been improving because of new drug treatments and better diagnostic and serologic tests. Minor manifestations can be treated with less toxic agents, such as nonsteroidal anti-inflammatory drugs, sunscreens, topical and intralesional corticosteroids, and antimalarials. Aggressive therapy with high-dose corticosteroids or immunosuppressants is necessary in patients with worsening renal function (lupus nephritis). CNS lupus has responded to various degrees to dexamethasone, methylprednisolone, and cyclophosphamide. Other therapeutic options include methotrexate in corticosteroid-resistant SLE and cyclosporine. The use of monoclonal antibodies is under intensive study. As mortality due to SLE decreases, complications like cardiovascular problems are becoming more prominent; patients may require antihypertensives, cholesterol-lowering drugs, and hypoglycemic agents. The complexity and chronicity of SLE have led to diverse pharmacotherapeutic strategies based on the organ systems involved. Immunologic research may ultimately bring patients greater relief.

Female↗

PubMed1995

Zidovudine treatment prolongs survival and decreases virus load in the central nervous system of rhesus macaques infected perinatally with simian immunodeficiency virus.

To assess the potential therapeutic effects of zidovudine, rhesus macaques were inoculated with simian immunodeficiency virus (SIV) strain SMM/B670 at birth and infused either continuously or intermittently with zidovudine for 6-7 months. Zidovudine did not prevent infection but did significantly increase survival time, which was associated with lower serum p26 viral core antigen levels, a lower virus burden in the cerebrospinal fluid (CSF), and lower CSF quinolinic acid levels than in untreated monkeys. Two of 5 infected, untreated monkeys developed motor impairment within 6 months following infection, whereas motor impairments did not occur in infected, zidovudine-treated monkeys until after the drug was discontinued. Zidovudine treatment was well tolerated by rhesus infants with minimal, transient side effects. These results demonstrate that zidovudine treatment significantly decreases virus load within the central nervous system (CNS) and delays the onset of CNS dysfunction and immune disease in rhesus monkeys perinatally infected with SIV.

Animals↗

PubMed1995

Cytokine secretion by macrophages in the rat testis.

The rat testis contains a large population of resident macrophages, the physiological roles of which are yet to be established. To investigate the functional capacity of these cells, we have analyzed the secretion of the cytokines interleukin (IL)-1, IL-6, tumor necrosis factor alpha (TNF alpha), and granulocyte macrophage-colony stimulating factor (GM-CSF) by isolated testicular macrophages (TMs) and, for comparison, by isolated rat peritoneal macrophages (PMs). Cells were cultured for 48 h in serum-free medium alone or with lipopolysaccharide (LPS, 10 micrograms/ml) and/or recombinant interferon-gamma (rIFN gamma, 200 U/ml). Specific bioassays were used to measure cytokines in the media collected from cultures. Basal production of IL-1, TNF alpha, and IL-6 by TMs and PMs were similar, but TMs produced 8-fold greater levels of GM-CSF than did PMs. LPS, alone or in combination with IFN gamma, significantly enhanced the secretion of all cytokines by PMs (340-840% increase). LPS alone had little effect on TM secretion except to reduce GM-CSF levels some 4-fold. The addition of LPS and IFN gamma increased IL-1, IL-6, and TNF alpha levels (200-750% increase) and reduced GM-CSF levels to 45% of basal levels. Treatment of cultures with indomethacin to minimize prostaglandin production enhanced the LPS-induced effects in both cell types. Expression of the mRNA for each cytokine in cultures of testicular and peritoneal macrophages, as well as in intact testis, was confirmed by reverse transcription polymerase chain reaction. These studies indicate that macrophages resident within the rat testis have a novel cytokine secretion profile and an altered responsiveness to inflammatory activators compared with macrophages from the peritoneal cavity. This may be important in physiological processes in the testis and may contribute to the dysfunctional afferent immune activity thought to underlie the immunologically privileged status of the testes.

Animals↗

PubMed1998

Structure-based design of peptides that recognize the CD4 binding domain of HIV-1 gp120.

DESIGN: Envelope protein-specific antiviral peptides, called mucibodies, that can specifically recognize and bind to the surface unit protein gp120 of HIV-1 were designed. The initial mucibody binding target was the V3 loop of HIV-1 gp120. Here, the gp120-CD4 binding domain was chosen as the site of mucibody binding. The CD4 binding domain of gp120 is known to be a conformational epitope and is involved in the earliest events of viral entry into many cells. METHODS: The design of the mucibody antivirals was based on previous observations that antibody complementarity determining regions (CDR) are generally similar to the repeating loops or knob structures found in the 20-residue tandem repeat domain of human mucin MUC1. The heavy chain CDR3 from the bacteriophage display antibody b12 was used to construct two mucibodies, b12-CDR1 and b12-26. RESULTS: Peptides corresponding to three tandem repeats were shown to bind directly to the CD4 binding domain of HIV-1 gp120 in a solid-phase enzyme-linked immunosorbent assay. These mucibody peptides also disrupted the gp120-CD4 interaction in a solution-phase inhibition assay. Finally, mucibodies neutralized primary and laboratory macrophage-tropic isolates of HIV-1. CONCLUSIONS: There is a potential for medical use of these peptides as topical vaginal microbicides in preventing HIV-1 transmission during sexual contact. These results also suggest that multivalent, non-immunogenic binding proteins of virtually any specificity could be constructed for use in therapeutic applications involving infectious diseases and immune system dysfunction.

Anti-HIV Agents↗

PubMed2000

Stat proteins play a role in tumor necrosis factor alpha gene expression.

Trauma produces dysfunction in immunity, which appears to be partially related to alterations in the cytokine response. Signal transducer and activator of transcription proteins (STATs) mediate activation of several cytokine genes. However, the effect of STAT proteins on tumor necrosis factor-alpha (TNFalpha) activation is not fully defined. We identified binding sites for STAT 3 and STAT 5/6 within the promoter region of TNFalpha and hypothesize that alterations in these sites would affect TNFalpha expression. The TNFalpha promoter was inserted into the luciferase reporter vector, and binding sites for STAT 3, STAT 5/6, and activator protein-1 (AP-1) were mutated using site-directed mutagenesis. Murine macrophages were transfected with the resultant plasmids, then incubated with and without lipopolysaccharide (LPS) or IFNalpha. Gene expression was measured by dual luciferase assay. Mutation of the STAT 3 binding site was associated with decreased LPS-inducible activity. Mutation of the AP-1 and STAT 5/6 consensus binding sites alone had no effect on TNFalpha expression. However, combined mutation of both STAT 5/6 and AP-1 was associated with increased LPS-inducible activity. Mutations of the STAT binding sites in the promoter region of TNFalpha affect TNFalpha gene expression. These results suggest a regulatory role for STATs in TNF gene transcription.

Animals↗

PubMedDate not supplied

What does the future hold for irritable bowel syndrome and the functional gastrointestinal disorders?

Our understanding of irritable bowel syndrome and the functional GI disorders has grown considerably over the last 15 years. In part this relates changes in their classification and definition from being due solely to motility disturbances, to being symptom based (eg, Rome criteria). This opened the door to the study of many other factors that contribute to the clinical expression of these disorders, including visceral hypersensitivity, sensitization, altered mucosal immunity, and dysfunction in brain-gut regulatory processes. New knowledge has been gained in areas of genetics, central nervous system and enteric nervous system neurotransmitters of motility, sensitivity and secretion, the effect of altered mucosal inflammation on cytokine and paracrine activation, and neural sensitization, postinfectious disorders, the influence of psychologic stress on gut functioning via alterations in regulatory pathways (eg, hypothalamic-pituitary adrenal axis, or pain regulatory system like the cingulate cortex), improved accuracy of diagnosis using Rome II criteria plus "red flags" the institution of behavioral treatments, and the use of new pharmacologic treatments both at the gut and brain level. Future research will improve upon this new knowledge via basic and translational studies of neuropeptide signaling with new neurotransmitters, new knowledge on the mechanisms for central nervous system-enteric nervous system communication and dysfunction, and more advanced clinical research on education, communication skills and their effects on outcome, genetics, pharmacogenetics and genetic epidemiology, better understanding as to how certain psychosocial domains (eg, catastrophizing, abuse) affect symptom behavior and outcome, newer pharmacologic treatments, and the use of combined pharmacologic and behavioral treatment packages. I am pleased to have the opportunity to provide a personal perspective on what the future will be for irritable bowel syndrome and the other functional GI disorders. Having been involved in this field for almost 30 years, I have been fortunate to witness tremendous changes. The focus of this presentation is to address the advances that have recently occurred that set the stage for proposing future research to help move the field along and ultimately to help our patients.

Biomedical Research↗

PubMed2005

Effect of a novel inducible nitric oxide synthase inhibitor in prevention of rat chronic aortic rejections.

BACKGROUND: Cytotoxic nitric oxide (NO) is produced during ischemia-reperfusion injury and acute and chronic rejection in allografts by expression of inducible (i) NO synthase (NOS). Therefore, continuous inhibition of iNOS may prevent early graft dysfunction and immune injury (rejection) and consequently improve graft survival. FR260330 is a potent and selective inhibitor of iNOS activity that works by preventing iNOS monomers from dimerization. In this study, the authors evaluated the effect of FR260330 in prevention of chronic rejection in a model of rat aortic allografts. METHODS: Male Lewis (LEW, RT1l) rats received male ACI (RT1a) aorta allografts or LEW aorta isografts. Fourteen groups (n > or = 6) were involved in this study. FR260330, tacrolimus, or both were administered orally for 14 or 90 days, according to protocol. The degree of intimal proliferation of graft aorta was determined by a computerized image system. RESULTS: Both low and high doses of FR260330- or tacrolimus-treated grafts showed significantly decreased intima/(intima+media) ratios at day 90 compared with placebo controls. Combination therapy of low-dose FR260330 with low-dose tacrolimus produced a significant decrease of intima/(intima+media) ratios with intact endothelium compared with placebo controls. Anti-alpha-actin immunohistochemical staining demonstrated that one of the mechanisms of intimal proliferation is related to migration of vascular smooth muscle cells. CONCLUSIONS: A selective inhibitor of NOS, FR260330 plays a protective role in chronic aortic allograft rejection in the rat. Combination therapy of low-dose FR260330 with tacrolimus produces significant protection of immune injury and may serve to improve long-term graft survival and function.

Actins↗

PubMed2026

Associations between granulysin and ovarian endometriosis: A 2-sample Mendelian randomization study.

Endometriosis (EMS) is a chronic inflammatory disease defined by the presence of endometrial-like tissue outside the uterine cavity. Ovarian EMS is considered the most prevalent disease phenotype. However, the causal relationship between granulysin and ovarian EMS remains unclear. We investigate the potential causal relationship between granulysin and ovarian EMS using a 2-sample Mendelian randomization analysis. Genome-wide association study data for granulysin and ovarian EMS were obtained from publicly available online databases. A 2-sample Mendelian randomization analysis was conducted using the inverse-variance weighted method. The causal effect was further validated through weighted median and MR-Egger regression analyses, and a leave-one-out sensitivity analysis was performed. The odds ratio and its 95% confidence interval were used to evaluate the causal relationship between granulysin and the risk of ovarian EMS. Our findings suggest a direct causal relationship between granulysin expression and ovarian EMS. The inverse-variance weighted analysis revealed that a 1-standard deviation increase in granulysin was associated with a 10.7% reduction in the risk of ovarian EMS (odd ratio = 0.892, 95% confidence interval: 0.824-0.966, P = .004). There may exist a negative causal relationship between granulysin expression and ovarian EMS.

Female↗

PubMed1982

Epidermal Langerhans cell involvement in cutaneous lupus erythematosus.

Epidermal Langerhans cells (LCs) possess surface markers and functional attributes which identify them as being of macrophage/monocyte lineage, and recent evidence documents their participation in certain immune process which occur in skin. To assess the role of LCs in lupus erythematosus (LE), a disease in which immune system dysfunction predominates, human epidermis from patients with cutaneous LE was studied with 3 LC surface markers: ATPase activity, HLA-DR and OKT-6 antigens. Suction blister top epidermal skin biopsies from patients with 3 clinical types of cutaneous LE exhibited similar features: LCs were less dendritic, they were more irregularly distributed, and they were present in fewer numbers when compared with those in adjacent normal skin. These changes contrasted with those observed in diseases with similar lichenoid histopathological features. LCs appeared increased in number in lichen planus. LCs in skin lesions from one patient with dermatomyositis exhibited similar morphologic alterations, but surface densities and distributions were preserved. Disaggregated epidermal cells from skin lesions of patients with cutaneous LE induced allogeneic lymphocyte proliferation as efficiently as did cells from nonlesional skin, indicating that the morphologic alterations observed were not associated with a decreased alloantigen presenting capacity. These studies have demonstrated that epidermal LC populations in 3 clinical types of cutaneous LE are perturbed in a manner not seen in 2 other lichenoid skin diseases, although these changes were not associated with an altered capacity of such cells to stimulate proliferation by allogeneic lymphocytes.

Adenosine Triphosphatases↗