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PubMed2004

Thymalfasin: an immune system enhancer for the treatment of liver disease.

Thymalfasin (thymosin-alpha 1) is an immunomodulating agent able to enhance the Th1 immune response. It has been evaluated for its immunomodulatory activities and related therapeutic potential in several diseases, including chronic hepatitis B and C, AIDS, primary immunodeficiency diseases, depressed response to vaccination and cancer. The basis for effectiveness in these conditions is primarily through modulation of immunological responsiveness, as thymalfasin has been shown to have beneficial effects on numerous immune system parameters and to increase T-cell differentiation and maturation. Thymalfasin is responsible for reconstitution of immune function when thymic tissue is given back to thymectomized animals. In addition, thymalfasin has been shown to have efficacy in multiple experimental models of immune dysfunction, mainly, infectious diseases such as hepatitis (woodchuck) and influenza (mouse), and cancer such as melanoma (mouse) and colorectal carcinoma (rat) where thymalfasin has shown antitumor effects.

Amino Acid Sequence↗
PubMed2006

PCR/DGGE and 16S rRNA gene library analysis of the colonic microbiota of HLA-B27/beta2-microglobulin transgenic rats.

AIMS: To determine the phylogenetic composition of the colonic microbiota of transgenic (TG) HLA-B27 rats using 16S ribosomal RNA (rRNA) gene sequences obtained from denaturing gradient gel electrophoresis (DGGE) gels and sequences from a 16S rRNA gene library. METHODS AND RESULTS: Colonic microbiota of TG and nontransgenic (NT) rats harboured by 10-week-old and 6-month-old animals was screened using PCR/DGGE. Six months old TG rats had marked inflammation of the colon compared with 10-week-old TG and NT rats. The DGGE profiles of rats with inflamed colon were similar from rat to rat (Dice's Similarity Coefficient proximal colon 73%, distal colon 83%) whereas profiles from animals without inflammation were dissimilar (52-64%). Identifications of bacterial origins of 16S rRNA gene sequences obtained from DGGE gels (200 bp) and from 16S rRNA clones (450 bp) of the colonic microbiota of diseased rats gave sequences most closely phylogenetically affiliated with uncultured or unknown bacteria. CONCLUSIONS: PCR/DGGE was shown to be an effective method to compare the colonic microbiota composition of TG and NT rats relative to the progression of inflammatory disease. Sequencing of 16S rRNA gene fragments from DGGE gels or 16S rRNA gene clones from a random library showed that uncultured or unknown bacteria were most commonly detected by both methods. It can be concluded that it would be better in future studies to search for the antigens produced by the gut microbiota against which the dysfunctional immune system reacts rather than seek phylogenetic associations. SIGNIFICANCE AND IMPACT OF THE STUDY: PCR/DGGE can be used as a rapid initial screening method to compare the composition of bacterial communities of initially unknown composition that are associated with the development of intestinal disease.

Animals↗
PubMed1992

Food hypersensitivity and dietary management in atopic dermatitis.

Although immune dysfunction is known to play an integral role in the development of atopic dermatitis, no clear delineation of the underlying pathogenic mechanism(s) responsible for this disorder has been proposed. Several factors are known to trigger flares of atopic dermatitis. In the extrinsic form of this disorder, food and airborne allergens may provoke flares of eczema. Research implicating food hypersensitivity in the pathogenesis of atopic dermatitis includes studies of food allergen avoidance in newborn infants at high risk for atopic disease, investigations of children with blinded food challenges, and therapeutic trials of allergen-elimination diets. Taken together, these studies demonstrate a significant pathogenic role for food hypersensitivity in about one-third of children with atopic dermatitis.

Child, Preschool↗
PubMed2004

Validity of a self-reported history of a positive tuberculin skin test. A prospective study of drug users.

OBJECTIVE: To define the prevalence of and factors associated with having a negative purified protein derivative (PPD) among persons who self-report a prior positive PPD and to define the safety of repeat testing in such persons. DESIGN: Observational cohort study. SETTING: Methadone maintenance program with onsite primary care. PATIENTS/PARTICIPANTS: Current or former drug users enrolled in methadone maintenance treatment. INTERVENTIONS: Structured interview, tuberculin skin testing regardless of self-reported PPD status, and anergy testing. MEASUREMENTS AND MAIN RESULTS: Nearly one third (31%) of participants who self-reported a prior positive PPD had a negative measured PPD, despite receipt of a "booster" PPD. A single participant (0.5%) blistered in response to the PPD without lasting ill effect. Participants with PPD results discordant from their history were more likely to be HIV-seropositive and nonreactive to the anergy panel. The discordance rate among HIV-infected participants was 43%, and was largely attributable to immune dysfunction. Among HIV-seronegative participants, the discordance rate was 27%. Recent crack-cocaine use was independently associated with discordance in the absence of HIV infection. CONCLUSIONS: We confirmed that planting a PPD in patients who self-report a positive PPD history confers minimal risk. Substantial rates of discordance exist between self-reported history of a positive PPD and measured PPD status. Further research is needed to define the optimal management of PPD-negative patients who self-report a prior positive PPD and who have not received prior treatment for latent tuberculosis.

Adult↗
PubMed1990

Age-related decline in interleukin 2 production in response to influenza vaccine.

Articles in the recent literature document an abnormal antibody response in elderly persons to influenza vaccination. Several studies have presented evidence to show that immune dysfunction in aged mice and humans may be due to a defect in the production of interleukin 2 (IL2) by helper T cells (TH). Cultures of peripheral blood mononuclear cells (PBMC) were prepared from blood samples taken at eight weeks after vaccination (0.5 mL of Armand-Frappier, 15 micrograms/0.5 mL each of A/Taiwan/1/86, A/Leningrad/360/86, and B/Ann Arbor/1/86 administered in the fall of 1987) from a group of elderly men and a young control group. Peripheral blood mononuclear cells were frozen in 10% dimethyl sulfoxide (DMSO) until all the cells were cultured. After stimulation with a 1/320 dilution of the same influenza vaccine, cultures of PBMC from young controls showed a significantly greater increase in IL2 production than the cultures of PBMC from the elderly group of patients. This was statistically significant at both day 3 (P less than .01) and day 5 (P less than .05) of culture using the Mann-Whitney U test. Previous experiments that have shown defective IL2 production related to aging have used potent mitogens such as concanavalin A and phytohemagglutinin to stimulate TH. This study provides evidence that defective IL2 production may also occur in response to physiologic antigenic stimulation and may be one explanation for the reduced efficacy of influenza vaccination in elderly persons.

Aged↗
PubMed1997

Human cytomegalovirus infection of breast milk.

Human cytomegalovirus is the most common cause of congenital and perinatal infections throughout the world. Primary infection with human cytomegalovirus usually follows a benign course, but the virus remains latent or persistent in the host cell thereafter. Understanding the epidemiology of human cytomegalovirus is a key element in the development of strategies for prevention of infection. Although the actual sites of latency or persistence of human cytomegalovirus infections are still controversial, peripheral blood mononuclear cells and endothelial cells appear to be major sites of infection. Persistent infections caused by human cytomegalovirus could be augmented by a decrease in major histocompatibility complex expression as well as by virus-mediated immune dysfunction. It is possible that specific cellular interactions as well as production of several cytokines are necessary for the reactivation of human cytomegalovirus. Breast-fed infants are susceptible to human cytomegalovirus infection from breast milk. Human cytomegalovirus was isolated more frequently from breast milk at more than 1 month after delivery than from colostrum or early breast milk. Human cytomegalovirus DNA was also not detected in colostrum, but was found in breast milk samples 1 month after delivery. To clarify the role of milk cells and whey in vertical infection by breast feeding, we separated breast milk into milk cells and whey and examined each fraction. Human cytomegalovirus was isolated more frequently from milk whey samples than from cell samples. Human cytomegalovirus particle shedding into whey may be more important in vertical infection by breast milk than cell-to-cell transmission. The supernatant of colostrum did not exert an inhibitory effect on human cytomegalovirus-infected cells. Serum levels of cell free soluble interleukin-2 receptor of mothers with DNA-positive milk at 1 month after delivery were significantly higher than those of mothers with DNA-negative milk. It is likely that levels of factors such as soluble interleukin-2 receptor in serum are related to the reactivation of human cytomegalovirus which occurs locally in the mammary gland of the lactating mother after delivery. This minireview focuses on recent advances in the study of human cytomegalovirus infection of breast milk.

Antiviral Agents↗
PubMed1994

Role of lymphoid organs in the pathogenesis of human immunodeficiency virus (HIV) infection.

The pathogenic mechanisms of HIV disease are multifactorial and multi-phasic. The common denominator of the disease is the profound immunosuppression that occurs in the vast majority of infected patients. Studies in lymphoid tissues in HIV disease have provided considerable insight into the pathogenic processes involved from the earliest phases of infection through the advanced stages. Following primary infection, virus is disseminated throughout the body and seeds the lymphoid tissue where its replication is only incompletely suppressed and where a reservoir of virus is established. Extracellular virus is trapped within the FDC of the lymph node germinal centers and serves as a source of infection for cells which reside in or migrate through the lymph node throughout the course of infection even during the early and often prolonged asymptomatic period. Eventually, the architecture of the lymphoid tissue is destroyed, compounding the immune dysfunction that results from the depletion of CD4+ T cells. In this regard, the lymphoid tissue of LTNPs is relatively intact and viral burden and replication is considerably lower in the peripheral blood and lymph node mono-nuclear cells of LTNPs than in individuals whose disease progresses. Cytokines probably play a major role in the modulation of HIV expression in the milieu of the lymphoid tissue. Further understanding of the pathogenic mechanisms operative in the lymphoid tissues of HIV-infected individuals will have important implications in the design of therapeutic strategies involving both antiretroviral and immunomodulatory approaches.

Apoptosis↗
PubMed1996

The potential roles of endogenous retroviruses in autoimmunity.

Endogenous retroviruses (ERVs) are estimated to comprise up to 1% of human DNA. While the genome of many ERVs is interrupted by termination codons, deletions or frame shift mutations, some ERVs are transcriptionally active and recent studies reveal protein expression or particle formation by human ERVs. ERVs have been implicated as aetiological agents of autoimmune disease, because of their structural and sequence similarities to exogenous retroviruses associated with immune dysregulation and their tissue-specific or differentiation-dependent expression. In fact, retrovirus-like particles distinct from those of known exogenous retroviruses and immune responses to ERV proteins have been observed in autoimmune disease. Quantitatively or structurally aberrant expression of normally cryptic ERVs, induced by environmental or endogenous factors, could initiate autoimmunity through direct or indirect mechanisms. ERVs may lead to immune dysregulation as insertional mutagens or cis-regulatory elements of cellular genes involved in immune function. ERVs may also encode elements like tax in human T-lymphotrophic virus type I (HTLV-I) or tat in human immunodeficiency virus-I (HIV-I) that are capable of transactivating cellular genes. More directly, human ERV gene products themselves may be immunologically active, by analogy with the superantigen activity in the long terminal repeat (LTR) of mouse mammary tumour viruses (MMTV) and the non-specific immunosuppressive activity in mammalian type C retrovirus env protein. Alternatively, increased expression of an ERV protein, or expression of a novel ERV protein not expressed in the thymus during acquisition of immune tolerance, may lead to its perception as a neoantigen. Paraneoplastic syndromes raise the possibility that novel ERV-encoded epitopes expressed by a tumour elicit immunity to cross-reactive epitopes in normal tissues. Recombination events between different but related ERVs, to whose products the host is immunologically tolerant, may also generate new antigenic determinants. Frequently reported humoral immunity to exogenous retrovirus proteins in autoimmune disease could be elicited by cross-reactive ERV proteins. A review of the evidence implicating ERVs in immune dysfunction leads to the conclusion that direct molecular studies are likely to establish a pathogenic role for ERVs in autoimmune disease.

Animals↗
PubMed1993

Defective neutrophil function in workers occupationally exposed to lead.

Chemotaxis and nitroblue tetrazolium reduction were measured in peripheral blood neutrophils of workers occupationally exposed to lead. These two neutrophil functions were significantly reduced, as compared to controls, even in those workers with blood lead levels and urinary delta-aminolevulinic acid (ALA-U) concentrations below the currently accepted biological limit values of 60 micrograms/dl and 6 mg/l, respectively. The immunosuppressive effects of relatively low level lead absorption suggests that immune dysfunction may be a sensitive indicator of lead exposure.

Adolescent↗
PubMed2005

Double-stranded RNA-dependent protein kinase (PKR) is downregulated by phorbol ester.

The double-stranded RNA-dependent protein kinase (PKR) is one of the key mediators of interferon (IFN) action against certain viruses. PKR also plays an important role in signal transduction and immunomodulation. Understanding the regulation of PKR activity is important for the use of PKR as a tool to discover and develop novel therapeutics for viral infections, cancer and immune dysfunction. We found that phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC), decreased the level of autophosphorylated PKR in a dose- and time-dependent manner in IFN-treated mouse fibroblast cells. Polyinosinic-polycytidylic acid (poly I:C) treatment enhanced the activity of PKR induced by IFN, but did not overcome the PMA-induced reduction of PKR autophosphorylation. Western blot analysis with a monoclonal antibody to mouse PKR revealed that the decrease of PKR autophosphorylation in cells by PMA was a result of PKR protein degradation. Selective PKC inhibitors blocked the degradation of PKR stimulated by PMA, indicating that PKC activity was required for the effect. Furthermore, we also found that proteasome inhibitors prevented PMA-induced down regulation of PKR, indicating that an active proteasome is required. Our results identify a novel mechanism for the post-translational regulation of PKR.

Animals↗
PubMed2006

Mycobacterium tuberculosis secreted antigen (MTSA-10) modulates macrophage function by redox regulation of phosphatases.

Macrophages are the primary host cells for Mycobacterium tuberculosis (Mtb). Although macrophages can mount a strong inflammatory response to dispose of invading microbial pathogens, the immune dysfunction of the Mtb-infected macrophage constitutes the hallmark of mycobacterial pathogenesis. A 10-kDa, Mtb secretory antigen (MTSA-10), encoded by ORF Rv3874, is one of the predominant members of the 'region of difference 1' locus of Mtb genome that has been strongly implicated in mycobacterial virulence. In this study, we investigated the possible role of MTSA-10 in modulating the macrophage dysfunction in a mouse macrophage cell line J774.1. We found that recombinant MTSA-10 caused extensive protein dephosphorylation in J774.1 cells as revealed by two-dimensional gel electrophoresis analysis. We also observed that MTSA-10 treatment downregulated the reactive oxygen species levels in the cells leading to activation of cellular protein phosphatases putatively responsible for the dephosphorylation phenomenon. This implied a direct role of MTSA-10 in the disruption of host cell signaling, resulting in downregulation of transcription of several genes essential for macrophage function.

Animals↗
PubMed2001

Malassezia and Candida infections in bull terriers with lethal acrodermatitis.

In 12 cases of lethal acrodermatitis (LAD), four sampling techniques (brush, swab, scrape and adhesive tape strip) were used to study the distribution of yeasts in various body sites and these results were compared with those from five cases of atopic dermatitis and those of 10 normal dogs. Malassezia was frequently isolated from lesional and non-lesional skin and haircoat, footpads, nails and mucous membranes from dogs with either LAD or atopic dermatitis, although, generally, more Malassezia organisms were isolated from LAD cases. In normal dogs, Malassezia was most frequently recovered from the ear canal and the perianal skin. Candida was isolated frequently from dogs with LAD, but only a single isolate of this yeast was found in the other two groups. Fungal hyphae and pseudohyphae, probably Candida albicans, could be detected in samples collected from the nails and footpads of dogs with LAD. Both Malassezia and Candida could be isolated using all four sampling techniques. The MacKenzie (toothbrush) technique and adhesive tape strip cultures proved simple methods for the semiquantitative evaluation of yeasts. The high recovery rate of Malassezia and Candida from dogs with LAD is probably related to immune dysfunction, particularly T-cell dysfunction, known to be present in these dogs. C albicans infection may in part be responsible for the pathogenic changes of the nails and footpads commonly seen in cases of LAD.

Acrodermatitis↗
PubMed1989

Human retroviruses: their role in neoplasia and immunodeficiency.

Human retroviruses (HTLVs and HIVs) infect the cells of the immune system and cause mild-to-severe immune dysfunction. They are directly or indirectly responsible for associated neoplasia and central nervous system disorders. The study of these viruses is of great importance, not only because they cause grave illnesses like AIDS, neoplasias, and CNS disease, but also because they have the ability to exert such fine levels of gene regulatory control in their replication and expression. These studies will ultimately shed light on fundamental mechanisms of genetic control in human cells in their normal state and the alterations of these controls in neoplastic or immunologically aberrant states.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Cytokines and osteoporosis.

Bone remodeling is controlled by systemic factors such as parathyroid hormone (PTH), calcitonin (CT), and 1,25(OH)2 vitamin D and by local factors including cytokines and growth factors such as IL-1, IL-2, TNF alpha, TGF beta, IFN alpha, and IFN gamma. Derangement of such control mechanisms leading to an imbalance between osteoclastic bone resorption and osteoblastic bone formation could cause osteoporosis. Conditions associated with immune dysfunction such as aging, corticosteroid therapy, and rheumatoid arthritis are associated with osteoporosis, which is also more common in females than in males, like most of the autoimmune-collagen diseases. Peripheral lymphocyte subsets CD4/CD8 were higher in patients with senile osteoporosis than in the age-matched controls, and returned to normal after 1 month of 1 alpha(OH)vitamin D3 treatment. On multiple regression analysis of histomorphometric data and lymphocyte subsets, a negative correlation was found between CD4 lymphocytes and bone resorption. High CD4 is thus associated with a low level of osteoclastic bone resorption or low turnover osteoporosis. Plasma interferon reflecting macrophage function decreased with advance in age and increased in response to 1 alpha(OH)D3 treatment. As one of the immunoregulators, vitamin D tends to stimulate the macrophage-natural killer system and suppress the lymphocyte system, stimulating TGF beta and TNF alpha activity. Senile osteoporosis of low turnover thus appears to be associated with vitamin D deficiency, low macrophage function, high CD4 lymphocyte proportion, low IL-1 and high IL-2 activity, low IFN alpha and high IFN gamma activity, and low TGF beta and TNF alpha activity. Treatment with vitamin D derivatives tends to reverse these changes.

Aging↗
PubMed2002

Can antioxidant diet supplementation protect against age-related mitochondrial damage?

Harman's free radical theory of aging and our electron-microscopic finding of an age-related mitochondrial degeneration in the somatic tissues of the insect Drosophila melanogaster as well as in the fixed postmitotic Leydig and Sertoli cells of the mouse testis led us to propose a mitochondrial theory of aging, according to which metazoan senescence may be linked to oxygen stress-injury to the genome and membranes of the mitochondria of somatic differentiated cells. These concepts attract a great deal of attention, since, according to recent work, the mitochondrial damage caused by reactive oxygen species (ROS) and concomitant decline in ATP synthesis seem to play a key role not only in aging, but also in the fundamental cellular process of apoptosis. Although diet supplementation with antioxidants has not been able to increase consistently the species-characteristic maximum life span, it results in significant extension of the mean life span of laboratory animals. Moreover, diets containing high levels of antioxidants such as vitamins C and E seem able to reduce the risk of suffering age-related immune dysfunctions and arteriosclerosis. Presently, the focus of age-related antioxidant research is on compounds, such as deprenyl, coenzyme Q10, alpha-lipoic acid, and the glutathione-precursors thioproline and N-acetylcysteine, which may be able to neutralize the ROS at their sites of production in the mitochondria. Diet supplementation with these antioxidants may protect the mitochondria against respiration-linked oxygen stress, with preservation of the genomic and structural integrity of these energy-producing organelles and concomitant increase in functional life span.

Aging↗
PubMed1997

Prevalences of feline leukaemia virus and feline immunodeficiency virus infections in cats in Sydney.

OBJECTIVE: To determine prevalences of feline leukaemia virus (FeLV) and feline immunodeficiency virus (FIV) infections in 'healthy' cats that, through acute misadventure or other circumstance, were presented to veterinary practitioners. Prevalences of FeLV and FIV in this population were compared to those in a population of predominantly sick cats. DESIGN AND PROCEDURES: Serum specimens were obtained over a 2-year period from 200 cats older than 1 year of age presented to veterinary clinics for routine procedures, including cat fight injuries or abscesses, vehicular trauma, neutering, dental scaling, vaccination, grooming or boarding. An additional 894 sera were obtained over approximately the same period from specimens submitted by veterinarians to a private clinical pathology laboratory, mainly from sick cars suspected of having immune dysfunction, but including some sera from healthy cats being screened prior to FeLV vaccination. FIV antibody and FeLV antigen were detected in samples using commercial enzyme immunoassays. RESULTS: Amongst 200 'healthy' cats, the prevalence of FeLV infection was 0 to 2%, and the prevalence of FIV was 6.5 to 7.5%, depending on the stringency of the criteria used to define positivity. FIV infection was significantly more prevalent in cats which resided in an inner city environment (P = 0.013). Of the 894 serum specimens submitted to the laboratory by practitioners, 11/761 (1.4%) were FeLV positive, while 148/711 (20.8%) were FIV positive. The prevalence of FIV was significantly higher in these predominantly 'sick' cats than in cats seen for routine veterinary procedures (P < 0.00001), while there was no difference in the prevalence of FeLV (P = 0.75) CONCLUSIONS: The prevalence of FeLV and FIV in healthy cats may have been substantially overestimated in some previous Australian surveys. FeLV infection would appear to be a rare cause of disease in Australian cats. The higher prevalence of FIV positivity in sick as opposed to healthy cats infers that FIV infection contributes to the development of disease.

Animals↗
PubMedDate not supplied

Development of a device for removing a partial denture in a patient with scleroderma.

Scleroderma is a chronic disease that has been associated with immune dysfunction. One of the oral manifestations is microsomia, a result of collagen deposition in the perioral issues. The complexity of treating these patients includes limited mouth opening ability, and difficulty inserting and removing dentures due to finger deformity. This article will describe an appliance specially designed especially for scleroderma patients, which facilitates treatment of the patient with removable partial dentures (RPD).

Adult↗