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PubMed2005

Phenotypic, functional, and kinetic parameters associated with apparent T-cell control of human immunodeficiency virus replication in individuals with and without antiretroviral treatment.

The human immunodeficiency virus (HIV)-mediated immune response may be beneficial or harmful, depending on the balance between expansion of HIV-specific T cells and the level of generalized immune activation. The current study utilizes multicolor cytokine flow cytometry to study HIV-specific T cells and T-cell activation in 179 chronically infected individuals at various stages of HIV disease, including those with low-level viremia in the absence of therapy ("controllers"), low-level drug-resistant viremia in the presence of therapy (partial controllers on antiretroviral therapy [PCAT]), and high-level viremia ("noncontrollers"). Compared to noncontrollers, controllers exhibited higher frequencies of HIV-specific interleukin-2-positive gamma interferon-positive (IL-2(+) IFN-gamma(+)) CD4(+) T cells. The presence of HIV-specific CD4(+) IL-2(+) T cells was associated with low levels of proliferating T cells within the less-differentiated T-cell subpopulations (defined by CD45RA, CCR7, CD27, and CD28). Despite prior history of progressive disease, PCAT patients exhibited many immunologic characteristics seen in controllers, including high frequencies of IL-2(+) IFN-gamma(+) CD4(+) T cells. Measures of immune activation were lower in all CD8(+) T-cell subsets in controllers and PCAT compared to noncontrollers. Thus, control of HIV replication is associated with high levels of HIV-specific IL-2(+) and IFN-gamma(+) CD4(+) T cells and low levels of T-cell activation. This immunologic state is one where the host responds to HIV by expanding but not exhausting HIV-specific T cells while maintaining a relatively quiescent immune system. Despite a history of advanced HIV disease, a subset of individuals with multidrug-resistant HIV exhibit an immunologic profile comparable to that of controllers, suggesting that functional immunity can be reconstituted with partially suppressive highly active antiretroviral therapy.

Adult↗

PubMed2006

Simian immunodeficiency virus SIVagm.sab infection of Caribbean African green monkeys: a new model for the study of SIV pathogenesis in natural hosts.

Caribbean-born African green monkeys (AGMs) were classified as Chlorocebus sabaeus by cytochrome b sequencing. Guided by these phylogenetic analyses, we developed a new model for the study of simian immunodeficiency virus (SIV) infection in natural hosts by inoculating Caribbean AGMs with their species-specific SIVagm.sab. SIVagm.sab replicated efficiently in Caribbean AGM peripheral blood mononuclear cells in vitro. During SIVagm.sab primary infection of six Caribbean AGMs, the virus replicated at high levels, with peak viral loads (VLs) of 10(7) to 10(8) copies/ml occurring by day 8 to 10 postinfection (p.i.). Set-point values of up to 2 x 10(5) copies/ml were reached by day 42 p.i. and maintained throughout follow-up (through day 450 p.i.). CD4(+) T-cell counts in the blood showed a transient depletion at the peak of VL, and then returned to near preinfection values by day 28 p.i. and remained relatively stable during the chronic infection. Preservation of CD4 T cells was also found in lymph nodes (LNs) of chronic SIVagm.sab-infected Caribbean AGMs. No activation of CD4(+) T cells was detected in the periphery in SIV-infected Caribbean AGMs. These virological and immunological profiles from peripheral blood and LNs were identical to those previously reported in African-born AGMs infected with the same viral strain (SIVagm.sab92018). Due to these similarities, we conclude that Caribbean AGMs are a useful alternative to AGMs of African origin as a model for the study of SIV infection in natural African hosts.

Animals↗

PubMed2005

Lupus thrombocytopenia: clinical implications and prognostic significance.

OBJECTIVES: To clarify clinical manifestations, association with disease activity, and prognostic impact of thrombocytopenia using simple and reliable indices. METHODS: 632 patients were reviewed retrospectively. Fifty patients with thrombocytopenia were included as cases and matched with 100 control patients. Clinical manifestations at first thrombocytopenic episode were recorded. Classification criteria at diagnosis, basic immunological profiles, disease activity (ECLAM), and end organ damage (SLICC) were recorded. RESULTS: 29/50 (58%) had thrombocytopenia at diagnosis of lupus. Haemorrhagic manifestations were associated with the degree of thrombocytopenia (p<0.001). Anticardiolipin antibodies were not related to the degree of thrombocytopenia or the severity of haemorrhagic manifestations. Megakaryocytes were normal or increased in 26/28 (93%) bone marrow specimens, indicating peripheral platelet destruction. Patients with high disease activity were more thrombocytopenic than controls (OR = 2.61, 95% CI 1.13 to 5.96, p = 0.009). Patients with low C3 or CH50 were more likely to be thrombocytopenic (OR = 2.36, 95% CI 1.05 to 5.26, p = 0.029). Median SLICC for lupus patients with thrombocytopenia was 2 (range 0-11) compared with 1 (range 0-12) for controls (p<0.001). No deaths occurred during thrombocytopenic episodes. CONCLUSIONS: Thrombocytopenia is not directly associated with end organ damage and mortality, but defines a subgroup of patients with higher morbidity and is thus a major complication of systemic lupus erythematosus, affecting overall prognosis.

Adult↗

PubMed1996

Effect of HLA type and hypocomplementaemia on the expression of parvovirus arthritis: one year follow up of an outbreak.

OBJECTIVES: To determine the effect of HLA type and hypocomplementaemia on the duration and severity of joint involvement in parvovirus infection (HPV). METHODS: Forty seven patients were selected on a geographical basis from 83 with proven HPV infection during an outbreak that occurred in Oxfordshire in 1993. They were contacted by questionnaire a year later. Thirty five patients were available for examination and blood sampling. Subjects were typed for HLA-DRB1 alleles and HLA-B27 status. Immunological profiles, including C3 and C4 complement components, were determined. RESULTS: Joint symptoms occurred in all patients. They resolved within a week in 12 patients and persisted beyond one year in 19. On review, none had a picture of rheumatoid arthritis, but three patients had developed carpal tunnel syndrome. Decreased C4 was found in four. The HLA frequencies were similar to those in controls; however, joint symptoms persisted for more than one week in all HLA-DR4 positive patients (p = 0.009). There was no relation between the severity of joint symptoms and either HLA type, or hypocomplementaemia. CONCLUSIONS: Joint symptoms are common in parvovirus infection and the presence of HLA-DR4 may be associated with persistence of joint symptoms beyond one week. This study revealed no evidence of progression to rheumatoid arthritis.

Adult↗

PubMed1997

Subgroups of primary Sjögren's syndrome. Sjögren's syndrome in male and paediatric Greek patients.

OBJECTIVES: To describe the clinical and serological findings in male and paediatric Sjögren's syndrome (SS) patients. PATIENTS AND METHODS: Using the European criteria for the diagnosis of SS 12 male and 13 paediatric patients were identified and compared with those of 30 consecutive unselected adult female SS patients. RESULTS: The mean (SD) age of paediatric patients was 9.4 (2.2) years, ranging from 6 to 14 years. Recurrent parotid gland enlargement was the initial clinical manifestation in the majority of the children with a statistical significance compared with male (p < 0.01) and with female patients (p < 0.0001). Sicca manifestations were the most common clinical symptoms in male and female patients at disease onset. The systemic manifestations were similar among the three groups except that men showed lower frequency of arthritis (p < 0.05) and Raynaud's phenomenon (p < 0.05) compared with women. No differences were found among the immunological profile of children and female patients, while male patients had a lower frequency of antinuclear antibodies (p < 0.025) and antibodies to Ro(SSA) nuclear antigens (p < 0.025) compared with women. CONCLUSION: Primary SS is rare in children and men in Greece. Recurrent parotid gland enlargement is the most common clinical finding at disease onset in children. Male patients seem to have less systemic manifestations and lower frequency of autoantibodies.

Adolescent↗

PubMed1977

Keratoconus and coexisting atopic disease.

The association of keratoconus and atopic disease has been reported on several occasions but the only controlled clinical study that has so far been published found no evidence to support this view. Since it is now known that atopy is often associated with changes in various immunoglobulins, particularly IgE, it was considered desirable to determine the immunological profiles of a large series of keratoconus cases in order to seek evidence for coexistence of the two conditions in one individual. In this study of 182 cases of keratoconus a definite history of atopy was found in 35% compared with 12% in the matched control group. The serum IgE was significantly raised (P less than 0.001) in keratoconus and markedly so in those cases with associated atopic disease. Serum levels of IgG and IgM were also raised, but contrary to the findings of other observers IgA levels were normal. These findings suggest that atopic traits are more common in patients with keratoconus than in general ophthalmic patients.

Female↗

PubMed2003

Spatial vision in visually asymptomatic subjects at high risk for multiple sclerosis.

OBJECTIVE: To investigate the state of spatial vision in visually asymptomatic subjects at high risk for multiple sclerosis. METHODS: Fifteen subjects suffering a first neurological episode suggestive of multiple sclerosis in clinical presentation, immunological profile, and magnetic resonance imaging, were examined with a new, sensitive test of spatial vision, rarebit perimetry. None had symptoms or signs of optic neuropathy. RESULTS: Results of rarebit perimetry were significantly worse than those of 15 age matched normal controls (p=0.01); seven patients (47%) were outside normal limits. One patient only obtained abnormal results in high pass resolution perimetry. CONCLUSIONS: Rarebit perimetry may help to close the sensitivity gap between clinical examinations and neuroimaging.

Acute Disease↗

PubMed1993

Acquired C1 inhibitor deficiency with lymphoma causing recurrent angioedema.

A 52 year old man who developed recurrent, massive and generalized angioedema for the first time during adult life was found to have an acquired deficiency of C1q esterase inhibitor (C1 INH) in association with a B cell lymphoma producing a paraprotein. He had low levels of C4 and C1 INH during the attacks which returned to normal after the successful treatment of lymphoma. An underlying lymphoproliferative disease should always be considered in adult patients with this immunological profile, recurrent angioedema and a negative family history.

Angioedema↗

PubMedDate not supplied

Clinical patterns of diffuse parenchymal lung disease in Kuwait: a prospective study.

OBJECTIVE: To report our experience of the clinicopathological patterns of diffuse parenchymal lung disease (DPLD). SUBJECTS AND METHODS: Over a 4-year period, 75 patients (41 males, 34 females), aged 13-76 years, who were referred to Mubarak Al-Kabeer and the Chest Diseases Hospitals, Kuwait with a diagnosis of diffuse lung disease, were included in the study. After a comprehensive history and physical examination, further investigations were done, including hematological and immunological profiles, sputum and bronchoalveolar lavage fluid examination, chest radiograph, high resolution computed tomography (HRCT), pulmonary function test and lung biopsy. RESULTS: Of the 75 patients 60 (80%) were over 40 years of age. The duration of symptoms in 34 patients (45%) was less than 6 months and longer than 1 year in 28 (37.7%) patients. Twenty-five of the patients were cigarette smokers. The mean forced lung capacity (FVC), total lung capacity and diffusing capacity for carbon monoxide were less than 60% of the predicted values in most patients. There was a significant difference in mean FVC value between smokers and nonsmokers (p < 0.05). The HRCT findings were at an advanced stage in 65 patients, with additional honeycombing in 21 of the 65 patients. Idiopathic pulmonary fibrosis was the most common cause of DPLD, occurring in 52 patients, followed by sarcoidosis and collagen vascular diseases. CONCLUSION: DPLD was observed predominantly in middle aged and elderly patients, due probably to increasing industrialization in the country. The role of cigarette smoking as a contributory factor remains unclear.

Adult↗

PubMed2004

SARS in newborns and children.

The severe acute respiratory syndrome (SARS) is a highly contagious infection caused by a newly discovered strain of coronavirus (SARS-CoV). Infants born to pregnant women with SARS did not appear to acquire the infection through vertical transmission. Some newborn infants, however, developed severe intrauterine growth retardation and life-threatening gastrointestinal complications. It is now known that the clinical course and prognosis are different between paediatric and adult SARS patients. Young children (< 12 years), in general, run a less aggressive clinical course than do teenage and adult patients. Thus far, no fatalities have been reported in the paediatric age group (< or =18 years). This review describes the current understanding of the clinical manifestations, diagnostic tests, immunological profiles, patient management and outcomes of SARS-CoV infection in the paediatric population.

Adolescent↗

PubMed1990

Serial peritoneal macrophage function studies in new and established continuous ambulatory peritoneal dialysis patients.

Peritoneal macrophages (PM) perform first-line defense activity against peritonitis, the most important complication in continuous ambulatory peritoneal dialysis (CAPD) therapy. Our longitudinal study has compared the PM function in 20 uremic patients during periods free of peritonitis since they started CAPD therapy in January 1987. The results showed that at the initiation of CAPD, there was a higher bactericidal activity, phagocytosis index, H2O2 production and interleukin-1 (IL-1), gamma-interferon (IFN-gamma) and tumor necrosis factor (TNF) production ability and MHC expression. As time went on, these progressively decreased, and by 9 months after CAPD therapy had started they were significantly lower than at the beginning. During the 1.5-year follow-up period, there was a significantly increased peritonitis rate in the period 6 months after the beginning of CAPD than in the period before the 6th month (88.3 vs. 11.7% respectively; p less than 0.001). These results indicate that PM of new CAPD patients have a more active function than those of established patients. The established patients had a greater risk of peritonitis. A comparison of the immunological profiles of PM from patients who had a peritonitis history shows that phagocytosis index, bactericidal activity and IL-1 and TNF production of PM were significantly decreased during the period free of peritonitis. This result suggests that these parameters may serve as an indicator in developing peritonitis.

Blood Bactericidal Activity↗

PubMed1994

Circulating leukocyte-endothelial adhesion molecules in IgA nephropathy.

There is accumulating evidence that leukocyte-endothelial adhesion molecules are important in inflammatory injury in being involved in the primary step of entrapment and migration of leukocytes to the site of inflammation. We have used an antigen capture ELISA to measure the levels of circulating intercellular adhesion molecule-1 (cVCAM-1), vascular cell adhesion molecule-1 (cVCAM-1) and E selectin (cE selectin) in the peripheral blood of 33 patients with IgA nephropathy (IgAN) during clinical quiescence and 24 healthy controls. The serum levels of cICAM-1 and E selectin in IgA-nephritic patients were not different from that of healthy controls but the cVCAM-1 level was significantly elevated in IgAN despite a lack of clinical activity (p = 0.008). The differential rise of circulating leukocyte-endothelial adhesion molecules in IgAN probably reflects the origins and nature of these molecules as well as the specific immunological profile of IgAN. There was no correlation between the levels of these three circulating adhesion molecules. When the patients with IgA nephropathy were stratified according to the severity of their glomerular and interstitial lesions, there was an apparent increase in cE selectin and cVCAM-1 associated with increased histopathologic grading. The changes in endothelial adhesion molecules during clinical exacerbation were studied in 10 patients. Coinciding with synpharyngitic macrohematuria, there was a significant rise of cVCAM-1 and cE selectin (p = 0.046 and p = 0.016, respectively) but no similar rise was observed in cICAM-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Adhesion↗

PubMed1986

1985 Kreshover lecture. Molecular factors influencing neutrophil defects in periodontal disease.

Major advances in our understanding of the role of the neutrophil in host defense against periodontal organisms have been made through studies of localized juvenile periodontitis (LJP). Several lines of evidence suggest that LJP is an infectious process closely associated with Actinobacillus (Haemophilus) actinomycetemomitans as a causative agent, although other organisms may also participate. The immunologic profile of LJP patients suggests that a cell-associated neutrophil locomotory dysfunction is a key underlying immunodeficiency resulting in increased susceptibility to periodontal infection. In addition, LJP patients often exhibit cervical lymphadenopathy and IgG-hypergammaglobulinemia, and a markedly elevated antibody response to the infecting organism, A. actinomycetemcomitans, is found in the serum and crevicular fluid of most patients. Evaluation of the locomotory properties of LJP neutrophils shows that random migration and chemokinesis are normal; however, about 70% of the LJP patients suffer from a defect in chemotaxis, with their neutrophils responding poorly to bacterial chemotactic factors, synthetic chemotactic peptides, and complement fragments (C5a). Depressed chemotaxis of LJP neutrophils is paralleled by their reduced capacity to bind the synthetic chemotactic peptide N-formylmethionylleucylphenylalanine (FMLP), as well as C5a. Furthermore, there is a reduction in the amount of glycoprotein 110, a neutrophil membrane matrix component and differentiation antigen which is associated with FMLP- and possibly also C5a-mediated chemotaxis. Reduction of C5a and of FMLP ligand binding, decreased expression of GP-110, and reduced neutrophil chemotaxis are consistent with a stem cell maturation error in LJP patients. This is further supported by studies demonstrating increased expression of CR2, the C3d/EBV receptor, on peripheral blood neutrophils of LJP patients. CR2 receptors are normally present on immature human neutrophils but are lost during the maturation process. These alterations in neutrophil surface components and their reduced chemotaxis may result from a genetically determined abnormality. Studies demonstrating the familial nature of both the neutrophil chemotactic disorder and the clinical entity represented by localized juvenile periodontitis point to a strong role for genetic determinants in the disease which affect neutrophil surface receptors.

Aggressive Periodontitis↗

PubMed1992

Combined zidovudine and interferon-alpha 2a therapy in children with acquired immune deficiency syndrome.

A study was carried out in five children with acquired immune deficiency syndrome to assess the effect of combined zidovudine/interferon-alpha 2a therapy with that of zidovudine given alone on immunological profiles and plasma zidovudine concentrations. Immunoglobulins A, G and M, total and absolute CD4 lymphocyte counts, and p24 antigen concentrations did not differ significantly when children were treated with 300 mg/m2 zidovudine given orally once every 12 h, or with 150 mg/m2 zidovudine plus 1.5 or 3 MIU interferon-alpha 2a given intramuscularly three times weekly. Peak plasma zidovudine concentrations were significantly (P less than 0.05) lower when combined treatment with 150 mg/m2 zidovudine/1.5 MIU interferon-alpha 2a was administered compared with 300 mg/m2 zidovudine alone, or combined 150 mg/m2 zidovudine/3 MIU interferon-alpha 2a. The results suggest that combination zidovudine/interferon-alpha 2a therapy may be more efficacious than zidovudine alone and that the normal zidovudine dose may be reduced if interferon-alpha 2a is given in addition, thus reducing the side-effects associated with zidovudine.

Acquired Immunodeficiency Syndrome↗

PubMed2004

Decreased nasal tolerance to allergic asthma in mice fed an amino acid-based protein-free diet.

Intranasal (i.n.) administration of soluble proteins induces a state of specific unresponsiveness to subsequent immunization, known as nasal tolerance. It is thought that newborns are less susceptible to nasal tolerance induction. Recently, we have shown that feeding adult animals with a protein-free diet (Aa) resulted in their arrest at an immature immunological profile. Here, we examined the effects of the Aa diet on the development of nasal tolerance to ovalbumin (OVA) in a murine model of allergic asthma. Nasal OVA administration suppressed almost totally the OVA-induced asthma-like responses (airway eosinophilia, type 2 cytokine production, and OVA-specific IgE antibodies) in chow- or casein-fed BALB/c mice. In contrast, in Aa-fed animals the suppression of asthma-like responses by nasal OVA was partial, being effective in suppressing airway eosinophilia, but not airway type 2 cytokine or OVA-specific IgE response. We conclude that animals fed the Aa diet are more resistant to the induction of nasal tolerance. Our animal model may mimic the features of the immune system of human infants.

Amino Acids↗

PubMed2006

Early prediction of sepsis-induced disseminated intravascular coagulation with interleukin-10, interleukin-6, and RANTES in preterm infants.

BACKGROUND: The progression to disseminated intravascular coagulation (DIC) in infected very low birth weight (VLBW; <1500 g) infants is difficult to predict with precision at the onset of sepsis. We investigated the immunologic profiles of preterm infants with sepsis, using chemokine and cytokine measurements to predict the development of sepsis-induced DIC at the onset of infection. METHODS: We measured a panel of chemokines and cytokines at 0 and 24 h after clinical presentation in VLBW infants with suspected infection requiring full sepsis screening. The chemokines measured were interleukin (IL)-8, interferon-gamma-inducible protein-10 (IP-10), monokine induced by interferon-gamma, monocyte chemoattractant protein-1, and regulated upon activation normal T-cell expressed and secreted (RANTES), and the cytokines were IL-6, IL-10, and tumor necrosis factor-alpha. RESULTS: Of 195 episodes of suspected clinical sepsis investigated, 62 were culture-confirmed septicemia or necrotizing enterocolitis (28 of these infants developed DIC), 22 were culture-negative clinical infections, and 111 involved noninfected episodes. All studied inflammatory mediators except RANTES showed significantly greater up-regulation in culture-positive infected infants than in noninfected infants at 0 and 24 h, whereas RANTES showed significant down-regulation. The model that used plasma IL-10 (>208 ng/L), IL-6 (>168 ng/L), and RANTES (<3110 ng/L) at 0 h had sensitivity, specificity, and positive and negative predictive values of 100%, 97%, 85%, and 100%, respectively, for identifying infected patients who subsequently developed DIC. CONCLUSIONS: IL-10, IL-6, and RANTES measured at clinical presentation sensitively and accurately predicted the development of DIC in severely infected infants. This information could be vital for early and effective treatment of neonatal sepsis.

Chemokine CCL5↗

PubMed2003

Detection of multiple cytokines by protein arrays from cell lysate and tissue lysate.

Previously we demonstrated that multiple cytokines could be simultaneously detected using an antibody-based protein array system with high sensitivity and specificity from conditioned medium and serum. Here, we created a higher density array system to simultaneously detect 35 cytokines from cell lysates and tissue lysates. This assay combines the advantages of the specificity of enzyme-linked immunosorbent assays (ELISA), sensitivity of enhanced chemiluminescence (ECL), and high-throughput of microspot. In this system, capture antibodies dissolved in methanol were spotted onto polyvinylidene difluoride (PVDF) membranes. The membranes were then incubated with tissue lysates or cell lysates. After removing unbound proteins by extensive washing, the membranes were exposed to horseradish peroxidase (HRP)-conjugated antibody(ies). The signals were visualized with an ECL system. High specificity, sensitivity, and accuracy of this approach were demonstrated. This approach can be used in any general laboratory setting without any sophisticated equipment. It should be feasible to extend this concept to develop a high-throughput protein array system. Combining nitrocellulose membrane-based and PVDF membrane-based approaches, the human cytokine array system can be applied to detect multiple cytokine expression from cell lysate, tissue lysate, serum, plasma, and conditioned medium. Future applications of this new approach include direct protein expression profiling, immunological disease diagnostics, and discovery of new biomarkers.

Biomarkers↗

PubMed2003

The imidazoquinolines and their place in the therapy of cutaneous disease.

The imidazoquinolines arose from efforts to develop a nucleoside analogue. Although molecularly similar to nucleosides, the imidazoquinolines did not have nucleoside-like activity. However, the imidazoquinolines induced immune modulatory cytokines, in part, because of their ability to activate toll receptors (TLR)s. Imiquimod, the first FDA-approved imidazoquinoline, has been marketed as a 5% cream, which is approved for the therapy of genital warts. The advantage of imiquimod therapy over other therapies for genital warts is the decrease in recurrence rate with the establishment of an adaptive immunological response or immunological memory/surveillance response. As tumours and viral infections are handled similarly by the immune system, there has been great interest in the use of topical imiquimod for the treatment of cutaneous neoplasms, particularly non-melanoma skin cancers. Future efforts in imidazoquinoline research is focused around the development of analogues with modifications in the immunological profiles, potency and penetration parameters that better focus these new analogues for the therapy of specific intracellular infections and neoplasms, as well as the development of imidazoquinolines for conditions related either directly or indirectly to patterns of immune dysregulation.

Aminoquinolines↗