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PubMed2004

Immunologic aspects of chronic fatigue syndrome. Report on a Research Symposium convened by The CFIDS Association of America and co-sponsored by the US Centers for Disease Control and Prevention and the National Institutes of Health.

Chronic fatigue syndrome (CFS) is a serious health concern affecting over 800,000 Americans of all ages, races, socioeconomic groups and genders. The etiology and pathophysiology of CFS are unknown, yet studies have suggested an involvement of the immune system. A symposium was organized in October 2001 to explore the possibility of an association between immune dysfunction and CFS, with special emphasis on the interactions between immune dysfunction and other abnormalities noted in the neuroendocrine and autonomic nervous systems of individuals with CFS. This paper represents the consensus of the panel of experts who participated in this meeting. Data suggest that persons with CFS manifest changes in immune responses that fall outside normative ranges, but current research does not provide definitive evidence on whether these immune abnormalities are a cause or result of the illness. It has become clear that CFS cannot be understood based on single measurements of immune, endocrine, cardiovascular, or autonomic nervous system dysfunction. This panel encourages a new emphasis on multidisciplinary research into CFS.

Autonomic Nervous System↗
PubMed2005

TNF regulates leukocyte-endothelial cell interactions and microvascular dysfunction during immune complex-mediated inflammation.

1. The aim of this study was to assess directly the role of TNF in immune complex-induced leukocyte-endothelial cell interactions and microvascular dysfunction. 2. Intravital microscopy was used to examine immune complex-induced leukocyte rolling, adhesion and emigration and microvascular permeability in cremasteric postcapillary venules in wild-type and TNF(-/-) mice. The reverse passive Arthus (RPA) reaction was used to localize immune complex formation to the cremaster muscle. 3. In wild-type mice, immune complex deposition induced a reduction in leukocyte rolling velocity and increases in leukocyte adhesion and emigration. In TNF(-/-) mice, the immune complex-induced reduction in leukocyte rolling velocity was significantly attenuated, and leukocyte adhesion and emigration were also significantly reduced relative to responses in wild-type mice. 4. The alterations in TNF(-/-) mice were associated with decreased expression of endothelial P-selectin and VCAM-1, and an absence of E-selectin-dependent rolling normally seen in wild-type mice at the peak of the response. In addition, the level of immune complex-induced microvascular permeability was attenuated in TNF(-/-) mice. 5. These findings demonstrate that in immune complex-induced inflammation, TNF promotes leukocyte rolling and adhesive interactions, and entry of leukocytes into sites of immune complex deposition, in part via the increased expression and/or function of endothelial P-selectin, E-selectin and VCAM-1. In addition, this increase in leukocyte recruitment mediated by TNF correlates directly with an increase in microvascular injury.

Animals↗
PubMed1993

Murine complement-mediated immune clearance dysfunction is associated with the lymphoproliferative (lpr) gene.

Using a branched series model of immune clearance and an iterative curve fitting process, we have previously demonstrated abnormal in vivo clearance of opsonized erythrocytes in autoimmune MRL-lpr/lpr mice. This technique allows simultaneous evaluation of four rate constants governing both complement- and Fc-mediated clearance; i.e., complement-mediated sequestration (k1), C3b deactivation and release (k2), complement-dependent phagocytosis (k4), and Fc gamma-mediated sequestration and phagocytosis (k3). To evaluate genetic factors which may contribute to abnormal clearance in MRL-lpr/lpr mice, serial clearance studies were performed in congenic MRL-(+/+) mice, as well as in several mouse strains homozygous for the lymphoproliferative gene; i.e., BALB/c-lpr/lpr and C57BL/6-lpr/lpr mice. Rate data were obtained from mice 3 months through 12-18 months of age, and mean rate constant values compared to control BALB/c and/or C57BL/6 mice. Clearance of opsonized cells in MRL-lpr/lpr mice was characterized by both abnormal complement and Fc gamma receptor function with decreased complement-mediated sequestration, complement-dependent phagocytosis, and Fc gamma-mediated sequestration and phagocytosis. In contrast, abnormal clearance in congenic MRL-(+/+) mice was characterized by decreased Fc gamma-mediated sequestration and phagocytosis (P < 0.0001) only. Both complement-mediated sequestration and complement-dependent phagocytosis were significantly decreased in BALB/c-lpr/lpr and C57BL/6-lpr/lpr mice (P < 0.0001), with the pattern and magnitude of abnormal complement clearance kinetics similar to that occurring in MRL-lpr/lpr mice and contrasting with normal complement-mediated clearance in control BALB/c and C57BL/6 mice. Since decreased complement-mediated clearance was observed in three differing strains of mice homozygous for the lymphoproliferative gene, these data suggest that clearance of opsonized cells in mice is in part genetically determined, and that there may be a specific association between complement-mediated clearance dysfunction and the murine lymphoproliferative gene.

Animals↗
PubMed2005

Intradermal reactions to purified protein derivative in patients with diabetes mellitus.

Diabetes mellitus is known to adversely affect the immune system. Immune dysfunction is also associated with the etiology of diabetes mellitus. Immune dysfunction is associated with diminished chemotactic, phagocytic and monocyte activity. There is also increased T-cell activity. All these are associated with acute hyperglycemia. We investigated the cellular arm of the immune system of patients with diabetes mellitus using intradermal reactions (IDR) to purified protein derivative (PPD). Both groups high blood glucose [HBG] vs. low blood glucose [LBG]) were homogeneous in terms of size and sex and average age (24. vs. 22.; 21 F vs 25 M; 56.5yrs. vs. 54.5 yrs.). The LBG had a greater average duration of diabetes (13.6 yrs vs. 9.3 yrs), which suggests an increased tendency to complications of diabetes mellitus. The results showed an average blood glucose and IDR (HBG vs. LBG) of 235.8 +/- 46.5 mg/dl vs. 144.3 +/- 26.7 mg/dl and 18.5 +/- 8.5 mm vs. 12.2 +/- 7.0 mm respectively. These results showed that IDR is significantly affected by hyperglycemia. This increased IDR may be a consequence of the synergy between interferon-gamma and tumor necrosis factor alpha which is a significant factor in diabetes. Also, there is an accentuation of this synergy following injection of PPD. It appears to be clear that IDR to PPD may be influenced by the diabetic state, especially acute hyperglycemia. However, it also appears that IDR to PPD may not be an adequate method for assessing cutaneous cell-mediated immunity.

Blood Glucose↗
PubMed1996

Effects of vaccination against different T cell receptors on maintenance of immune function during murine retrovirus infection.

Murine retrovirus infection causes an aberrant stimulation of several subsets of T helper 2 cells identified by their T cell receptors (TCR). C57BL/6 mice were treated with synthetic peptides based upon different human TCR V beta CDR1 sequences following experimental infection with the murine retrovirus. Previous studies established that retrovirally infected mice produced autoantibodies to certain of these peptides, and their administration after infection diminished many of the cytokine abnormalities induced by the virus. This study determined whether the complete 16-mer synthetic peptides modeling the V beta CDR1/FR3 were required, and whether admixture of autoantigenic peptides synergized immune preservation. Treatment with complete TCR pep beta 3 and pep V beta 5.2 peptide alone and combined largely prevented the retrovirus-induced reduction in B and T cell proliferation and Th1 cytokine secretion while suppressing excessive production of Th2 cytokines, which are stimulated by retrovirus infection. Treatment with overlapping short peptides corresponding to the N-terminal 11-mer and C-terminal 12-mer did not significantly prevent the immune dysfunction in retrovirus-infected mice. These data suggest that immune dysfunction and abnormal cytokine production, induced by murine retrovirus infection, were largely prevented by TCR V beta CDR1 peptides, and the complete CDR1 in association with the five residues from FR2 was required.

Amino Acid Sequence↗
PubMed2003

Immune reconstitution in HIV infection and its relationship to cancer.

HIV infection results in formidable immune dysfunction, widely affecting the immune system, but typified by T lymphopenia. This dysfunction includes a perturbed immune response to several persistent viruses that have a propensity to cause tumors. Effective control of HIV replication by highly active antiretroviral therapy (HAART) results in regeneration of the damaged immune system, and recent advances have allowed this immune reconstitution to be better defined. This article describes the immunodeficiency caused by HIV and the response of the immune system to HAART, with specific reference to the immune response to cancers associated with HIV infection.

HIV Infections↗
PubMed1995

Vitamin A deficiency results in a priming environment conducive for Th1 cell development.

Certain infections, like that with the human immunodeficiency virus-1, deplete vitamin A, and when vitamin A levels are low, immune dysfunctions establish susceptibility to further infection. Our research has focused on the immune dysfunctions that are a consequence of vitamin A deficiency and that predispose to further infection. We previously studied a helminth infection in mice, and showed that when vitamin A levels are low, the immune response develops a strong regulatory T cell imbalance with excessive T helper type-1 cell interferon (IFN)-gamma synthesis and insufficient T helper type-2 cell development and function. Here, we studied the T cell priming environment in vitamin A-deficient mice to learn how that priming environment might produce a regulatory T cell imbalance and consequently distort the ability of the immune system to respond to an infection. Our results show that during vitamin A deficiency, the priming environment included constitutive interleukin (IL)-12 and IFN-gamma transcripts, but it was devoid of constitutive IL-4 and IL-10 transcripts. Dietary all-trans-retinoic acid supplementation down-regulated the level of constitutive IL-12 and IFN-gamma transcripts. Furthermore, when T cells from naive vitamin A-deficient animals were stimulated through the T cell receptor, they produced excess IFN-gamma protein compared to T cells from control animals. In contrast, T cell stimulation failed to induce IL-4 or IL-10 secretion. The inducible IFN-gamma was largely from CD8+ T cells and all-trans-retinoic acid addition in vitro inhibited IFN-gamma production at the transcript level. Retinoic acid addition in vitro also decreased natural killer cell IFN-gamma synthesis at the transcript level. Taken together, the distorted constitutive and inducible cytokine gene expression patterns that occurred when vitamin A levels were low would be expected strongly to favor T helper type-1 development and limit T helper type-2 cell growth and differentiation, thereby limiting the animal's humoral immune response capability.

Animals↗
PubMed1996

Melatonin administration following hemorrhagic shock decreases mortality from subsequent septic challenge.

Melatonin administration has been reported to have beneficial effects on immune function in some clinical studies and in several animal models of immune dysfunction. Furthermore, recent studies suggest beneficial effects of melatonin on depressed immune function following trauma-hemorrhage. Nonetheless, it remains unknown whether this hormone has any salutary effects on survival following hemorrhagic shock and subsequent septic challenge. Male C3H/HeN mice were bled to and maintained at a mean arterial blood pressure of 35 +/- 5 mm Hg for 90 min, adequately resuscitated, and 48 hr thereafter subjected to sepsis (cecal ligation and puncture; CLP). Melatonin-treated mice received either short-term treatment on Days 1 and 2 after hemorrhage or continuous treatment throughout the study. Treatment with vehicle (10% ethanol in normal saline) or melatonin (10 mg/kg body weight) was administered daily starting in the evening of the day of hemorrhage/sham-operation. Short-term melatonin administration after hemorrhage significantly improved survival in animals subjected to septic challenge. Continuous melatonin treatment did not improve survival, as compared to vehicle-treated mice subjected to shock and CLP. Moreover, continuous melatonin treatment in sham-operated animals significantly increased mortality compared to short-term-treated and vehicle-treated animals. While the mechanisms of the differential effects of melatonin administration are yet to be clearly defined, this study, nonetheless, demonstrates the salutary effects of short-term melatonin administration in the treatment of immune dysfunction following hemorrhagic shock.

Animals↗
PubMed1996

Monocyte and blood interleukin-12 levels in patients with obstructive jaundice.

Patients with obstructive jaundice have an increased incidence of peri-operative complications and immune dysfunction. This study was to investigate interleukin (IL)-12 (a cellular immunity stimulant), levels in jaundiced patients. 23 jaundiced patients and 17 controls were studied. There was significantly increased monocyte IL-12 production in jaundice, as measured by an ELISA, compared with that in controls (p < 0.01 by Mann-Whitney U test). A similar increase is seen in both benign and malignant jaundice. There was no difference between plasma IL-12 levels in the two groups. It is concluded that in jaundice, monocytes have a significantly increased capacity to release IL-12. This suggests that IL-12 may play a role in the immune dysfunction in jaundiced patients.

Cholestasis↗
PubMedDate not supplied

Fungal infections in the immunocompromised host.

With the increased number of immunocompromised patients there has been a concomitant increase in patient morbidity and mortality due to fungi. The etiologic microorganisms vary depending upon the type of immune dysfunction. Patients with malignancies and chemotherapy-induced neutropenia commonly are infected with Candida and Aspergillus. Other ubiquitous fungi such as Rhizopus, Fusarium, and Trichosporon are more frequently implicated as agents of disease in these patients. Patients with cell-mediated immune dysfunction such as acquired immune deficiency syndrome (AIDS) are susceptible to mucocutaneous candidiasis and pulmonary and disseminated cryptococcosis. Histoplasmosis and coccidioidomycosis have been particularly lethal infections in AIDS patients. Contributing factors such as broad-spectrum antibiotic use, intravenous catheterization, malnutrition, hyperalimentation, multiple surgical procedures and/or trauma, and steroids used either singly or in combination may also predispose patients to invasive fungal disease. Definitive diagnosis is often difficult to establish and usually requires invasive biopsy. Delay of culture results due to the time required to process specimens and to allow the fungus to grow also contributes to the poor results of therapy. Biopsy of skin lesions represents a useful technique for making a diagnosis. Recent advances in antifungal therapeutics promise to change the current approach to treatment for several of the mycoses. The availability of new oral azoles with spectra of activity that include aspergillosis and cryptococcosis, which currently require treatment with parenteral amphotericin B, may prove practical for prolonged oral therapy of otherwise lethal mycoses.

Antifungal Agents↗
PubMedDate not supplied

Heterogeneity of immune markers in hemophagocytic lymphohistiocytosis: comparative study of 9 familial and 14 familial inheritance-unproved cases.

PURPOSE: Although immune dysfunction is suspected in patients with hemophagocytic lymphohistiocytosis (HLH), the difference between immune dysfunction in patients with familial erythrophagocytic lymphohistiocytosis (FEL) and familial inheritance-unproved lymphohistiocytosis (FIU) remains unknown. The aim of this study was to determine useful markers to distinguish patients with FEL from those with FIU. PATIENTS AND METHODS: Clinical features and laboratory findings, especially natural killer (NK) cell activity and the relative frequencies of peripheral blood mononuclear cell (PBMC) subsets, and serum levels of interferon-gamma and soluble interleukin-2 receptor were compared in 9 patients with FEL and 14 age-matched patients with FIU. Twenty-seven healthy infants served as controls. The treatment and outcome were also compared for patients with FEL and FIU. RESULTS: Comparison between patients with FEL and FIU revealed significantly lower NK activity in those with FEL (p = 0.03) but failed to show any significant differences in PBMC subsets, except that the percentage of CD3+ T cells was higher in patients with FEL (p = 0.02). CD4- and CD8-dominant phenotypes were characteristic findings in both groups of patients, although increased CD19+ B cells were restricted to patients with FIU. NK activity was deficient (< 5%) in four of the seven patients with FEL tested but in only one of eight patients with FIU. By comparison to values for age-matched controls, the percentages of CD3+, CD3+DR+ and CD45RO+ PBMCs in patients with FEL were significantly high (p < 0.05) and those of CD19+ and CD45RA+ subsets were lower than normal. Among patients with FIU, PBMC subsets included significantly reduced CD3+, CD4+, CD45RA+, and CD4+CD45RA+. In this small series, the outcome of patients with FEL and FIU treated with chemotherapy was not significantly different at the time of evaluation. CONCLUSIONS: These results indicate considerable immune heterogeneity among patients with HLH younger than 2 years. Although NK activity was useful but not diagnostic, determination of PBMC subsets and patterns of cytokine expression was not helpful in distinguishing patients with FEL from those with FIU, suggesting that the immune responses characteristic of these diseases may reflect different triggering factors, including viruses. The impact of this immune heterogeneity on patients' outcome remains to be determined.

Antigens, CD↗
PubMed1996

Inhibition of T and B cell proliferation by titanium, cobalt, and chromium: role of IL-2 and IL-6.

The mechanism by which an increased risk of prosthetic infection is induced in patients with total joint arthroplasties is poorly understood. The adverse effects of metallic corrosion products of a prosthesis on host defense mechanisms, particularly immune response and release of immunoregulatory cytokines, remain largely unknown. Titanium, cobalt, and chromium are the materials most often used for joint implantation. Therefore, this study was aimed at investigating the cytotoxicity of titanium, cobalt, and chromium and whether these metals affect T and B cell proliferation and the release of cytokines by human peripheral blood mononuclear cells (PBMC) in vitro. Metal cytotoxicity was not observed judging by cell viability and cell injury after PBMC was extensively exposed to the metals. Phytohemagglutinin (PHA)-induced T cell proliferation and lipopolysaccharide-induced B cell proliferation were significantly inhibited by titanium, chromium, and cobalt. The release of IL-2 and IL-6 by PHA-stimulated PBMC was significantly inhibited by titanium, chromium, and cobalt. Titanium did not alter IFN-gamma production, whereas chromium and cobalt significantly reduced IFN-gamma release by PHA-stimulated PBMC. The addition of IL-2 and IL-6 significantly restored the metal-induced inhibition of T cell and B cell proliferation, respectively. This study sheds light on how the metals impair immune response and cytokine release, suggesting that patients with an extensive exposure to the metals may develop immune dysfunctions. The compromised immune response induced by the metals might significantly contribute to an increased risk of infection in patients with joint prostheses.

B-Lymphocytes↗
PubMed1991

External ocular herpesvirus infections in immunodeficiency.

Infections of the eye with members of the herpes family of viruses (e.g. HSV, CMV, VZV) are frequent manifestations of acquired and inherited defects in cell mediated immunity. Herpesvirus infections in the immunocompromised may reflect frequent viral reactivation from the latent state, as well as extensive productive infection of ocular structures following reactivation or primary infection. A review of experimental and clinical studies of both acquired and inherited immune dysfunction implicates specific immune mechanisms influencing the establishment of latency, viral reactivation and the control of active viral replication in ocular tissues.

Herpes Zoster↗
PubMed1996

Differential patterns of serum biomarkers of immune activation in human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis, and adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) and human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are associated with differing patterns of immune dysfunction. Biomarkers of immune activation may correlate with perturbations of immune function associated with these diseases. We conducted a pilot cross-sectional study to assess four candidate biomarkers of immune activation. beta 2-microglobulin, neopterin, tryptophan, and kynurenine levels were assayed in stored sera from asymptomatic, human T-cell leukemia virus type I (HTL V-I)-seronegative (HTLV-I-) and HTLV-I-seropositive (HTLV-I+) individuals, and ATL and HAM/TSP patients previously enrolled in seroepidemiological studies in Jamaica. Mean levels of beta 2-microglobulin, neopterin, and kynurenine were significantly elevated among ATL patients compared to the other study groups. Mean tryptophan levels were significantly lower among ATL and HAM/TSP patients than HTLV-I- and HTLV-I+ groups. No significant differences in biomarkers were found between the HTLV-I- and HTLV-I+ groups. Among HAM/TSP patients, a significant association was found between elevated neopterin levels and symptoms of less than 4 years duration. In Cox proportional hazards regression modeling, neopterin and tryptophan were found to be independent predictors of survival among ATL patients. This study demonstrates a differential pattern of biomarkers of immune activation among ATL and HAM/TSP patients compared to HTLV-I- and HTLV-I+ individuals. Neopterin and tryptophan may be useful clinical indicators of disease severity and prognosis among HAM/TSP and ATL patients.

Adult↗
PubMed1993

Activation of alveolar macrophages in asymptomatic HIV-infected individuals.

After the initial infection with HIV, there is evidence of immune dysfunction despite an apparent normal clinical state. In the context that the lung is a major site affected by opportunistic infection during the progression of this immune dysfunction, and that some components of the immune system are activated during early HIV infection, we hypothesized that there may be activation of alveolar macrophages (AM), a key component of the pulmonary host defense system, during the asymptomatic phase of HIV infection. Compared to normals, in HIV-infected individuals the class II MHC molecules DR, DQ, and DP were all expressed more frequently and in greater cell surface density on AM (p < 0.03, all comparisons), and there was increased spontaneous release of superoxide anion (O2-.) by AM (p < 0.002). To gain insight into whether the activation of the AM was an inherent property of the cells or dependent on the in vivo milieu, AM were evaluated after 24 h in culture for O2-. release. In contrast to the findings in fresh AM, after 24 h in culture, O2-. release by HIV AM was not different from normals (p > 0.7), suggesting that these AM had been activated in vivo. To assess whether IFN-gamma could be mediating these effects, mRNA levels of the IP-10 gene (a gene specifically induced by increased concentrations of IFN-gamma) were quantified in AM. Strikingly, the IP-10 gene was expressed only in AM of HIV-seropositive individuals, suggesting the AM had been exposed to IFN-gamma in vivo. Overall, these observations are consistent with the concept that the HIV-seropositive state is associated with activation of AM, in part due to local exposure to IFN-gamma.

Adult↗
PubMed1998

Glucocorticoids protect against suppression of T cell responses in a murine model of acute ethanol exposure and thermal injury by regulating IL-6.

Previous reports by this laboratory demonstrated that acute alcohol exposure combined with a 15% body surface area dorsal scald injury results in significant reductions in delayed-type hypersensitivity (DTH) and splenocyte proliferative responses compared to either insult alone. Previous studies by this lab have also shown that these defects are mediated, in part, by increased production of interleukin-6 (IL-6). Because both alcohol exposure and thermal injury are known to modulate glucocorticoid (CORT) levels, and CORT regulates IL-6 gene expression, the relationship between circulating CORT and IL-6 production in burn + ethanol mice was examined. At 24 and 48 h post-burn, a positive correlation existed between circulating CORT levels and measurements of cellular immune function. Administration of exogenous CORT to burn + ethanol-treated mice resulted in significant restoration (to 60% of control) of DTH and splenocyte proliferative responses. This restoration was concomitant with a down-regulation of circulating and macrophage-derived IL-6. The specificity of CORT in modulating these responses was tested by assessing cellular immune function and IL-6 levels after glucocorticoid receptor blockade with RU486. Taken together, these data strongly suggest that under normal circumstances CORT protects burned mice from severe immune dysfunction, a protection that is not afforded to burn + ethanol-treated mice. Furthermore, the immune dysfunction observed in burn + ethanol mice may be due to a lack of glucocorticoid attenuation of IL-6.

Animals↗
PubMed2002

[Immunopathogenesis of severe wounds and traumas: possibilities of immune correction].

The authors describe the present-day views on the nature of immune dysfunctions in severe traumas. Based on personal clinical experiences and literature data the authors discuss the role of immune dysfunctions in pathogenesis of the traumatic disease. Special attention is given to the role of the immune system in the development of the life-threatening condition: polyorganic insufficiency whose formation mainly results from disorganization and functional failure of the system of immune reactivity. Clinical investigations have shown high effectiveness of early administration for severe wounds and traumas of a new means of immunocorrection--yeast recombinant interleukin-2 of man (preparation Roncoleukin). The administration of this immunocorrector in complex schemes of intensive therapy of the victims was shown to prevent the development of severe pyo-septic pathology and perfectly change the course of the traumatic disease.

Adult↗