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PubMed2005

Inhibition of neutrophil function by the Kaposi's sarcoma-associated herpesvirus vOX2 protein.

Kaposi's sarcoma is multifactorial, involving Kaposi's sarcoma-associated herpesvirus (KSHV) infection and immune dysfunction. A KSHV protein (vOX2), fused with the Fc domain of human immunoglobulin G1 to create vOX2:Fc, suppressed neutrophil oxidative burst and inhibited the production of pro-inflammatory chemokines (IL-8 and monocyte chemoattractant protein 1) by monocyte/macrophage cells. vOX2:Fc suppressed the acute inflammatory response in mice in which neutrophil-mediated inflammation was induced by carrageenan. The data suggest that vOX2 can contribute to immune dysfunction and could have anti-inflammatory therapeutic potential.

Animals↗

PubMed2001

Nutrition and ageing.

The reviewed literature indicates that, even in industrialised countries, the nutrition of mature and aged subjects is often inadequate (because of deficiency or excess), which may lead to premature or pathological senescence. Recent nutritional research on ageing laboratory animals shows that dietary restriction may be the most effective procedure to achieve a long and disease-free life span, probably owing to a better protection against mitochondria-linked oxygen stress. Likewise, the experimental and clinical work from many laboratories, including our own, indicates that age-dependent changes in the cardiovascular and immune systems are linked to oxygen stress and that an adequate intake of dietary antioxidants may protect those systems against chronic degenerative syndromes in the physiopathology of which reactive oxygen species (ROS) play a key role. The extant data indicate that the antioxidant vitamins C and E are centrally involved in defending the above two systems against ROS attack. Moreover, recent research suggests that the glutathione-related thiolic antioxidants, thiazolidine carboxylic acid (thioproline) and N-acetylcysteine, as well as the phenolic liposoluble 'co-antioxidants' of Curcuma longa, may have a significant protective effect against age-related atherogenesis and immune dysfunction. Key messages from this paper are the following. (1) It is generally accepted that oxygen free radicals released in metabolic reactions play a key role in the physiopathology of 'normal ageing' and of many age-related degenerative diseases. (2) Consumption of adequate levels of antioxidants in the diet is essential in order to preserve health in old age. (3) A certain degree of protection against atherogenesis and immune dysfunction may be achieved by preventing vitamin E deficiency and an excessive oxidation of the glutathione-supported thiol pool.

Aged↗

PubMed2003

Melatonin rejuvenates degenerated thymus and redresses peripheral immune functions in aged mice.

The effect of melatonin on age-related thymic involution and peripheral immune dysfunctions was investigated. Exogenous melatonin was administered through the drinking water (15 microg/ml) of 22-month-old female C57BL mice for 60 consecutive days. Our results show that melatonin distinctly reversed the age-related thymic involution as revealed by the notable increase of thymus weight, total number of thymocytes and percentage of thymocytes at G2+S phases. More strikingly, spleen weight, total number of splenocytes and some peripheral immune capacity such as mitogen responsiveness and NK cell activity were also significantly recovered by 60 days of melatonin application in aged mice. Our findings demonstrate that even when the melatonin supplementation begins late in life, the age-related thymic involution and peripheral immune dysfunctions can be restored at least partially in old mice.

Aging↗

PubMed1996

Dysfunction of immune system and induction of autoantibodies to liver antigens by neonatal thymectomy in mice.

We examined the development of autoantibodies to liver proteins and hepatitis in BALB/c mice thymectomized 2 days after birth and attempted to characterized the immune function of these mice. Autoantibodies to crude liver proteins detected by ELISA were found in 21 (84%) of 25 mice thymectomized 2 days after birth. In these mice, sera of 11 animals showed reactivity with both liver specific proteins (LSP) and the second fraction of crude liver proteins; sera of 3 mice showed reactivity with only the second fraction but sera showed reactivity with only LSP. By Western-immunoblotting, sera of BALB/c mice which showed high autoantibody level to liver proteins detected a strong band around 150kD in the second fraction of crude liver proteins. Still more, hepatic inflammation; mononuclear cell infiltration in the portal area, was induced in mice with apparently high autoantibody level to crude liver proteins. These results in BALB/c mice corresponded with our previous reports which employed C3H/HeN mice. Next, we examined immune functions of mice thymectomized 2 days after birth. In thymectomized mice, the proportion of Thy-1, L3T4 and Lyt-2 positive cells (T cells) decreased and the proportion of B220 positive cells (B cells) increased. The proliferative response of lymph nodes lymphocytes cultured with mitomycin C-treated syngeneic spleen cells was lower, and the total IgG level in the sera was higher when compared with control normal mice. Anti-nuclear antibody (ANA) also appeared in the sera of thymectomized mice 2 days after birth. All these results suggest that the dysfunction of T cell and polyclonal activation of B cell were induced in neonatally thymectomized mice and resulted in the production of ANA and autoantibodies to liver proteins.

Animals↗

PubMed1993

Spleen and thymus cell subsets modified by long-term morphine administration and murine AIDS--II.

Intravenous heroin abusers suffer a great variety of infections, including AIDS (acquired immune deficiency syndrome). We developed an experimental mouse model to evaluate the long-term effect of in vivo morphine administration during retrovirus-induced immune dysfunction. Mice were treated daily for 11 weeks with increasing doses of morphine. Morphine treatment produced a decrease in body weight and spleen cell number. Murine retrovirus infection provoked an increase in body weight due to enlargement of lymphoid organs, and an increase in the percentage and absolute number of CD4+ and Mac 1+ cells. Interestingly, retrovirus-infected mice that were also morphine-treated did not show the increase in the relative proportion of Mac 1+ cells. Moreover, under the experimental conditions of protein-malnutrition and morphine treatment potentiation of immune dysfunction by murine retrovirus infection was investigated. Retrovirus infection-induced splenocyte proliferation was partially regulated by morphine treatment. Splenocytes from retrovirus-infected mice presented a higher percentage of IL-2R+ cells and, lower levels of sIL-2R in splenocyte supernatants. Mitogen-stimulated splenocytes had a lower production of interferon-gamma as well as an increase in the secretion of tumor necrosis factor-alpha. Thus morphine altered the immune system by down-regulating splenocyte proliferation, because retrovirus infection-induced splenocyte proliferation was partially regulated by morphine treatment. We also evaluated the effects of joint murine retrovirus infection and protein undernutrition on the thymus cell subsets. Retrovirus infection was associated with a decrease in the absolute number of Thy 1+, CD4+ and CD8+ cells per thymus with the CD8+ cell subset being the most affected. Moreover, retrovirus-infected mice presented a dramatic decrease in the percentage of double-positive (CD4+ CD8+) cells in the thymus as well as changes in its immunoarchitecture. While protein undernutrition alone did not produce further differences between infected versus non-infected, protein-undernourished, morphine treatment induced a greater decrease in thymocyte number than that seen in retrovirus- or morphine-treated animals alone.

Animals↗

PubMed1994

Loa loa: immunological responses during experimental infections in mandrills (Mandrillus sphinx).

Six intact, adult mandrills (Mandrillus sphinx) were infected with human-derived, diurnal Loa loa infective larvae. Microfilaremia, hematological, and immunological parameters were followed for 2-4 years. A major aim was to investigate the relationship between specific humoral immunity to microfilariae and microfilaremia and also to assess whether infection led to generalized immune dysfunction. Microfilaremia was similar to previous studies for 4 mandrills, with a prepatent period of 153.5 +/- 10.1 days, a peak of 34-1,798 mf/ml around Day 200, followed by a decline to low, persistent microfilaremia. One mandrill (No. 20) had a longer prepatent period and very low, but persistent, levels of microfilaremia, and one (No. 19) had gradually increasing levels which remained > 10,000 mf/ml for 3 years. To assess generalized immune perturbations several parameters were studied. There was neither generalized leukocytosis nor relative or absolute eosinophila. Serum Ig concentrations were measured from 0-600 days postinfection by radial immunodiffusion using a rabbit anti-mandrill Ig serum, and these were remarkably stable. Proliferative responses of peripheral blood mononuclear cells from these infected mandrills and noninfected controls showed no significant differences in the magnitude of proliferation after stimulation with a range of doses of PHA, PWM, or Concanavalin A. Thus, no evidence of generalized immune dysfunction was found in the peripheral blood. Serum IgG levels to soluble mf antigens were estimated by an indirect ELISA and all animals had maximal levels around Week 22 postinfection, at the time of maximum microfilaremia, and these decreased over the next 2-3 years in all mandrills except No. 19, in which levels remained fairly constant. Serum IgG levels to adult worm antigens showed a similar pattern but were not, or were only slightly, diminished late in infection. Antibody to mf sheath antigens were detected by indirect immunofluorescence and agglutination of live mf. Antibody to sheath antigens were never detected in mandrill 19 but were present from Week 8 postinfection to 2-4 weeks before patency in all the others. Anti-sheath antibodies were not detected in serum at later time points, i.e., postpatency, in any mandrill, even at time points when microfilaremia was < 1 mf/ml. The anti-sheath antibody was IgM and no anti-sheath IgG was detected. Ig was detected on the surface of circulating mf in 1 mandrill (No. 20). The appearance of these antibodies prior to maturation of the adults indicates that certain L4 or immature adult antigens cross-react with the surface of mf.(ABSTRACT TRUNCATED AT 400 WORDS)

Agglutination Tests↗

PubMed2006

Adult xanthogranulomatous disease of the orbit and ocular adnexa: new immunohistochemical findings and clinical review.

BACKGROUND/AIMS: Adult xanthogranulomatous disease involving the ocular tissues is rare and poorly understood. Adult onset xanthogranuloma (AOX), adult onset asthma and periocular xanthogranuloma (AAPOX), necrobiotic xanthogranuloma (NBX), and Erdheim-Chester disease (ECD) are the four syndromes within this disorder, which is diagnosed by characteristic histopathology. Experience with eight cases prompted a multi-institutional effort to study the histopathology, immunohistochemistry, clinical findings, and systemic associations in this disorder. METHODS: 22 cases, including histopathological slides, were compiled. Published reports were identified by an English language Medline search (1966-2005) and review of reference citations. Each case in this series and the literature was classified as one of four syndromes and then analysed for age onset, sex, skin xanthoma, orbital location, immune dysfunction, internal organ and bone lesions, treatment, and outcome. The histopathology in each of these cases was reviewed by two pathologists. Immunhistochemical stains (CD3, CD4, CD8, L26) were performed in 14 cases where unstained slides were available. RESULTS: 137 cases were compiled. There was no sex or age difference between syndromes. AOX, AAPOX, NBX affect the anterior orbit, ECD tends to be diffuse and intraconal. Skin lesions are found in all the syndromes. Immune dysfunction was noted in all cases of AAPOX and NBX; 11% of NBX and all ECD patients had internal organ disease. Treatment included surgery, corticosteroids, other chemotherapeutic agents, radiotherapy, and combinations of these. No AOX or AAPOX deaths occurred; 66% of ECD patients died. All 22 cases had xanthoma cells; most had Touton giant cells. Lymphocytes were present in all cases and occurred as aggregates (mostly in AAPOX) or diffuse populations mixed with fibroblasts (mostly in ECD). Immunohistochemistry revealed the majority of these to be CD8+. Necrosis was most marked in NBX. CONCLUSION: Adult xanthogranuloma of the orbit is rare, making prospective evaluation or meta-analysis impossible. The best treatment is unknown but seems to be with multiagent chemotherapy guided by histopathological, immunohistochemical, and systemic findings.

Adolescent↗

PubMed2006

Salivary gland function in HIV-infected patients treated with highly active antiretroviral therapy (HAART).

OBJECTIVE: This study was undertaken to determine if HAART alters salivary oral host defense in HIV(+) men. STUDY DESIGN: Whole, parotid, and submandibular/sublingual saliva was collected from 39 healthy men and 147 HIV(+) patients with mild to moderate immune dysfunction (69 treated with HAART [HAART(+)]; 78 not treated [HAART(-)]). Salivary flow rates, anticandidal activities, electrolytes, and antimicrobial/antifungal proteins were determined. RESULTS: While CD4(+) cell counts were not different between the HIV(+) groups, the median viral load for HAART(-) was 15 times greater than HAART(+). For both HAART groups, salivary yeast carriage rates and concentration were comparable and both showed similar reductions in salivary flow rates. Salivary anticandidal activities were not altered. Saliva composition of both HIV(+) groups was different from control, but only uric acid in parotid saliva of HAART(+) differed from HAART(-). CONCLUSIONS: HAART does not adversely affect inherent salivary oral host defense in HIV(+) patients with mild to moderate immune dysfunction.

Adult↗

PubMed2001

Trypanosoma cruzi-Induced Host Immune System Dysfunction: A Rationale for Parasite Immunosuppressive Factor(s) Encoding Gene Targeting.

An intense suppression of T cell proliferation to mitogens and to antigens is observed in a large number of parasitic infections. The impairment of T cell proliferation also occurred during the acute phase of Chagas' disease, caused by the intracellular protozoan parasite Trypanosoma cruzi. A wealth of evidence has accumulated that illustrates the ability of T. cruzi released molecules to influence directly a variety of diverse immunological functions. In this paper, we review the data concerning the immunoregulatory effects of T. cruzi Tc24 (a B cell activator antigen) and Tc52 (an immunosuppressive protein) released molecules on the host immune system. The gene targeting approach developed to further explore the biological function(s) of Tc52 molecule, revealed interesting unexpected functional properties. Indeed, in addition to its immunusuppressive activity a direct or indirect involvement of Tc52 gene product alone or in combination with other cellular components in T. cruzi differentiation control mechanisms have been evidenced. Moreover, targeted Tc52 replacement allowed the obtention of parasite mutants exhibiting low virulence in vitro and in vivo. Thus, the generation of a complete deficiency state of virulence factors by gene targeting should provide a means to assess the importance of these factors in the pathophysiological processes and disease progression. It is hoped that such approaches might allow rational design of tools to control T. cruzi infections.

Journal Article↗

PubMedDate not supplied

Diagnosis and management of acquired immune deficiency syndrome in intravenous drug users.

Acquired Immune Deficiency Syndrome (AIDS) is a clinical entity that is part of a spectrum of immune dysfunction found in specific high risk groups, among them intravenous drug users. In drug users AIDS almost always presents as an opportunistic infection, usually Pneumocystis carinii. The leading etiologic hypothesis is of a viral agent acting, it is possible, on a previously immunocompromised host. Recent research at hospitals affiliated with The Albert Einstein College of Medicine, where an unusually large proportion of AIDS patients are drug users, is described. Suggestions are advanced for the management of IV drug users with immune dysfunction.

Acquired Immunodeficiency Syndrome↗

PubMed1984

Interaction of African trypanosomes with the immune system.

African trypanosomes cause disease in man and domestic animals. The parasites have the ability to escape immune control by two means: by antigenic variation of the surface glycoprotein coat so that waves of variant parasites arise and by inducing a general immunosuppression affecting immune responses to the parasite as well as to parasite-unrelated antigens. The cellular basis of the immune dysfunction will be discussed in relation to a mouse model system - it is the result of proliferative stimuli to T- or B-cells which then become refractory to selection by antigen and normal control signals. Recent experiments have focused on macrophages as important direct target cells for parasite action. We have obtained no evidence for a parasite derived mitogen acting directly on B- or T-cells. In vitro cell proliferation is associated with accessory cells and relates only to T-cells. During infection, macrophages become activated with changes in receptor expression and mediator release, so that there is, for example, spontaneous IL-1 release (with a role in T- and possibly in B-cell proliferation) and several-fold increases in PGE2 secretion, with its immunosuppressive activities. We also find parasitaemia-associated release of alpha-beta and gamma interferon by various cells which in turn influences immune function. The active parasite component is associated with parasite membranes, but its nature has not been further defined. We proposed that the macrophage changes provide a general pathway causing immune dysfunction associated with many infections, be they parasitic or caused by other invading organisms.

Adjuvants, Immunologic↗

PubMed2000

Genetic linkage analysis of susceptibility to particle exposure in mice.

Particle-induced increases in respiratory morbidity and mortality have been observed worldwide in industrialized cities but the toxicologic mechanisms have not been elucidated. It is hypothesized that subpopulations including the elderly and individuals with cardiopulmonary disease are particularly at risk to the effects of exposure. Genetic background is another important host factor that may contribute to interindividual responsivity to particulate exposure. This study was designed to identify susceptibility loci for alveolar macrophage (AM) immune dysfunction induced by inhalation of sulfate-associated carbon particles in susceptible C57BL/6J and resistant C3H/ HeJ inbred mice. AMs were chosen for study because they represent an important component of host defense, and compromised host defense has been hypothesized to be an important factor in particle-induced respiratory morbidity. The quantitative phenotype for these studies was Fc receptor-mediated phagocytic function, an index of AM integrity. Analyses of macrophage dysfunction phenotypes of segregant and nonsegregant populations derived from these two strains indicate that two unlinked genes control susceptibility. A genome-wide linkage analysis of an intercross (F(2)) cohort identified significant and suggestive quantitative trait loci (QTLs) on chromosomes 17 and 11, respectively. Candidate susceptibility genes were identified for mice and humans by comparative mapping. Importantly, both QTLs overlap previously identified QTLs for susceptibility to another common pollutant, ozone. This is the first demonstration that genetic background is an important determinant of responsiveness to particle-induced immune dysfunction, and it has important implications for understanding the epidemiologic associations between particulates and morbidity and mortality.

Air Pollution↗

PubMed2006

Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells.

Active suppression of tumor-specific T lymphocytes can limit the efficacy of immune surveillance and immunotherapy. While tumor-recruited CD11b+ myeloid cells are known mediators of tumor-associated immune dysfunction, the true nature of these suppressive cells and the fine biochemical pathways governing their immunosuppressive activity remain elusive. Here we describe a population of circulating CD11b+IL-4 receptor alpha+ (CD11b+IL-4Ralpha+), inflammatory-type monocytes that is elicited by growing tumors and activated by IFN-gamma released from T lymphocytes. CD11b+IL-4Ralpha+ cells produced IL-13 and IFN-gamma and integrated the downstream signals of these cytokines to trigger the molecular pathways suppressing antigen-activated CD8+ T lymphocytes. Analogous immunosuppressive circuits were active in CD11b+ cells present within the tumor microenvironment. These suppressor cells challenge the current idea that tumor-conditioned immunosuppressive monocytes/macrophages are alternatively activated. Moreover, our data show how the inflammatory response elicited by tumors had detrimental effects on the adaptive immune system and suggest novel approaches for the treatment of tumor-induced immune dysfunctions.

Animals↗

PubMed1979

In vivo inactivation of erythrocyte S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine in adenosine deaminase-deficient patients.

The cytotoxic nucleoside 2'-deoxyadenosine is excreted in excessive amounts by individuals with genetic deficiency of adenosine deaminase, and may be in part responsible for the severe combined immune dysfunction from which they suffer. Earlier studies from this laboratory showed that 2'-deoxyadenosine causes the irreversible inactivation of the enzyme S-adenosylhomocysteine hydrolase by an active site-directed, "suicide-like" process. In this communication we have demonstrated similar inactivation of S-adenosylhomocysteine hydrolase in hemolysate and in intact erythrocytes, as well as a striking deficiency of S-adenosylhomocysteine hydrolase activity in the erythrocytes of three adenosine deaminase-deficient patients. In vivo suicide-like inactivation of S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine may contribute to the cytotoxicity of 2'-deoxyadenosine and to the immune dysfunction in adenosine deaminase deficiency.

Adenosine Deaminase↗

PubMed2000

Immunosenescence: potential causes and strategies for reversal.

Age-related deterioration in immune function has been recognized in many species. In humans the clinical manifestation of such immune dysfunction is age-related increases in the susceptibility to certain infections and in the incidence of some autoimmune disease and certain cancers. Laboratory investigations reveal age-related changes in the peripheral T cell pool, in the predominant phenotype, cytokine production profiles, signalling function and in replicative ability following stimulus with antigen, mitogens or anti-CD3 antibody. These changes in the properties of peripheral T cells are thought to be causally linked to an age-associated involution in the thymus. Our analysis reveals that thymic involution is due to a change in the thymic microenvironment linked to a reduction in the level of available interleukin 7. Treatment with interleukin 7 leads to a reversal of thymic atrophy with increased thymopoiesis. This provides the potential to reverse the immune dysfunction seen in the peripheral T cell pool by replacing old cells with new output generated in the thymus. Problems to overcome in order for such an experimental therapy to be successful require careful analysis in order to provide an optimal strategy to ensure that new T cell emigrants from the thymus have a broad range of specificities and are able to enter the peripheral T cell pool.

Aging↗

PubMed2004

Interferon-alpha in systemic lupus erythematosus.

PURPOSE OF REVIEW: To describe the lines of evidence supporting a significant role for interferon-alpha (IFNalpha) in the pathogenesis of systemic lupus erythematosus (SLE) and to propose potential mechanisms by which IFNalpha contributes to the autoimmunity and immune dysfunction of SLE. RECENT FINDINGS: Long-standing data indicating elevated levels of IFNalpha in the circulation of patients with SLE have recently been supplemented by reports from clinical practice, gene expression data, analysis of patient cells studied ex vivo, and studies of mechanisms of induction of IFNalpha production to provide complementary data strongly supporting a pathogenic role for IFNalpha in SLE. Recombinant IFNalpha, when administered as a therapy to patients with malignancy or hepatitis infection, can induce SLE. IFNalpha-regulated genes are highly expressed in SLE peripheral blood cells compared with cells from control subjects. Functional alterations of SLE mononuclear cells have been attributed to effects of IFNalpha. In addition, immune complexes bearing lupus autoantibodies and RNA or DNA have been shown to induce IFNalpha production. Finally, progress in understanding the role of Toll-like receptors (TLR) in the activation of the innate immune response has suggested potential mechanisms by which adjuvant-like factors act through TLR to induce IFNalpha as well as effective processing of self-antigens, resulting in activation of an adaptive immune response directed against self, as well as cytokine-mediated immune dysfunction. SUMMARY: Substantial evidence supports a significant role for IFNalpha in the pathogenesis of lupus. The IFNalpha pathway represents a promising target for therapeutic intervention in patients with SLE.

Animals↗

PubMed1992

Increased DNA strand breaks in mononuclear cells from patients with rheumatoid arthritis.

Immune dysfunction is linked with lymphocyte DNA metabolism. In particular, DNA damage may impair lymphocyte function and induce increased cell turnover; such changes are of relevance to the pathogenesis of rheumatoid arthritis. The rate of DNA unwinding in alkaline solution was used as a measure of the number of DNA strand breaks in mononuclear cells freshly isolated from peripheral blood. The rate of DNA unwinding was significantly increased in cells from patients with rheumatoid arthritis compared with those from healthy subjects and from patients with other autoimmune and connective tissue diseases. These findings support the hypothesis that DNA damage is increased in patients with rheumatoid arthritis and it is one factor contributing to immune dysfunction in this disease.

Adolescent↗

PubMed1993

Sex hormones and immune dysregulation in multiple myeloma.

A group of 49 multiple myeloma patients, 20 men and 29 women, were evaluated. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17 beta-oestradiol (E) and testosterone (T) serum concentrations have been detected by radioimmunoassay. Peripheral blood lymphocyte proliferation in response to phytohaemagglutinin (PHA), concanavalin A (ConA), recombinant interleukin-2 (rIL-2) and dextran sulphate (DxS) was investigated. Our findings provide evidence for two different patterns of sex hormone changes and immune dysfunctions presented differently by male and female multiple myeloma patients. In men increased FSH, LH and E concentrations and an augmented E to T ratio were associated with decreased lymphocyte blastogenic response to PHA, ConA and increased proliferation to rIL-2 and DxS. Female patients with multiple myeloma demonstrated normal values of FSH, LH and T, but a diminished E level and decreased E to T ratio correlated with a lymphocyte normal response to PHA and ConA and augmented blastogenesis to IL-2 and DxS. Our data, while admittedly preliminary, suffice to provide an indication of sex hormone changes in multiple myeloma patients, which could be responsible, at least in part, for the immune dysfunction observed in multiple myeloma.

Aged↗