Serum levels of IL-2, IL-1 alpha, TNF-alpha, and soluble receptor of IL-2 in HIV-1-infected patients.

Serum levels of the interleukins (IL-1 alpha, IL-2), tumor necrosis factor-alpha (TNF-alpha), and soluble receptor of IL-2 (sIL-2R) were studied by enzyme-linked immunosorbent assay (ELISA) in 12 normal healthy controls and 52 HIV-1 seropositive patients. Results indicated that: (1) sIL-2R levels were significantly increased in most HIV-1 seropositive patients. This increase appeared to be correlated with low CD4 cell counts and with the presence of detectable levels of p25 antigen. Furthermore, initially high levels of sIL-2R appeared to be correlated with progression of disease. (2) IL-2 levels were found to be increased in about 43% of asymptomatic carriers (ASY) and subjects with lymphoadenopathy-associated syndrome (LAS) compared with 12% in the case of AIDS-related complex (ARC) and AIDS patients. (3) There was a positive correlation between serum levels of TNF-alpha and IL-1 alpha in nearly all patients. Detectable levels of both cytokines were found in 34% of ASY and LAS patients and only rarely were detectable in ARC and AIDS patients. (4) Sixteen patients in whom progression of disease was observed were studied initially and at the moment they upstaged. No significant modification of serum levels of the three cytokines and sIL-2R studied could be evidenced. It was concluded that sIL-2R could be a useful marker of disease activity and progression, though a prospective study is necessary. For IL-2, IL-1 alpha, and TNF-alpha, this study indicated the presence of variable alterations in serum levels in HIV-1-infected patients.     

High plasma levels of soluble fas in HIV type 1-infected subjects are not normalized during highly active antiretroviral therapy

Plasma levels of soluble Fas (sFas) are elevated in human immunodeficiency virus type 1 (HIV-1) infection, indicating dysregulation of the Fas apoptosis pathway and chronic immune activation. We performed a retrospective study to investigate the effects of HAART on plasma levels of sFas. A cross-sectional study of 27 drug-naive infected subjects and 49 patients under antiretroviral treatment showed that plasma levels of sFas were higher in HIV-1-infected subjects than in 52 HIV-1-negative controls, independently of the treatment status. In a longitudinal study of 69 patients undergoing HAART, we observed a minimal, but significant decrease in sFas plasma levels after 1 year of therapy. Levels of sFas, however, remained still higher than physiologic values. Patients undergoing HAART were further classified as nonresponders or responders on the basis of viremia suppression; no significant changes in plasma levels of sFas were observed between the two groups. These findings show that 1 year of HAART has a minor effect on the sFas levels in plasma. Long-term HAART may be required to normalize the dysregulation of the Fas apoptotic pathway and the persistent immune activation initiated by HIV-1.     

Short communication: decreasing soluble CD30 and increasing IFN-gamma plasma levels are indicators of effective highly active antiretroviral therapy

It was previously reported that without highly active antiretroviral therapy (HAART), secretion of Th1 cytokines and antiviral IFN-gamma in HIV-infected patients is decreased, whereas the production of Th2 cytokines, proinflammatory cytokines, and TNF-alpha is increased. We studied the effect of HAART on Th1-, Th2-, and monocyte-derived cytokines, and on the Th2-type immune response marker soluble (s)CD30 in HIV-1-infected hemophilia patients. Viral Load (VL), CD4+ lymphocyte counts, and plasma levels of sIL-1RA, IL-2, sIL-2R, IL-3, IL-4, IL-6, sIL-6R, IL-7, IL-10, TNF-alpha, TGF-beta2, IFN-gamma, and sCD30 were measured in 18 patients who received HAART. Nine patients were initially treatment-naive and were monitored after the initiation of HAART. sCD30 median levels were significantly higher in treatment-naive patients than in patients who were on HAART (77 vs. 30 U/ml, p = 0.005). A strong association was observed between sCD30 and VL (r = 0.85, p = 0.004). After the initiation of HAART, sCD30 levels decreased and remained low (at 1 year, 38; at 2 years, 41 U/ml; p = 0.012 and p = 0.021, respectively, as compared to baseline level) and this was accompanied by a decrease in VL and monocyte-derived IL-6 and an increase in CD4+ lymphocyte counts and Th1-derived IFN-gamma. One year after the initiation of HAART a strong inverse correlation was observed between IFN-gamma and VL (r = -0.83, p = 0.006). In contrast to sCD30 and IFN-gamma, CD4 counts and plasma IL-6 did not correlate with VL at any time. Our data suggest that decreasing sCD30 and increasing IFN-gamma plasma levels are indicators of effective HAART treatment and CD4 Th1 cell recovery in HIV-infected patients.     

Soluble intercellular adhesion molecule-1 (sICAM-1) and soluble interleukin-2 receptors (sIL-2R) in scleroderma skin

In order to investigate whether soluble intercellular adhesion molecule- 1 (sICAM-1) and soluble interleukin-2 receptors (sIL-2R) were present in scleroderma skin, and to compare their levels to concentrations measured in plasma and clinical parameters, we examined suction blister fluid and plasma from 13 patients with systemic sclerosis and 11 healthy volunteers. Suction blisters and biopsies were from the transition zone between normal skin and scleroderma, and uninvolved abdominal skin. The levels of sICAM-1 and sIL-2R were significantly increased in both plasma and suction blister fluid from systemic sclerosis patients compared with healthy volunteers. ICAM-1 was localized to vessels and perivascular mononuclear infiltrates by immunohistochemical methods. IL-2R was expressed by CD3-positive cells. The elevated levels of sICAM-1 and sIL-2R in suction blister fluid point towards activation of endothelial cells and T cells in both the transition zone and uninvolved skin of systemic sclerosis patients.      

Soluble intercellular adhesion molecule-1 (ICAM-1), CD4, CD8 and interleukin-2 receptor in patients with Beh?et's disease and Vogt-Koyanagi-Harada's disease.

OBJECTIVES: In a search for serum markers of disease activity in uveitis, we measured the levels of the soluble form of ICAM-1 (sICAM-1), CD4 (sCD4), CD8 (sCD8) and interleukin-2 receptor (sIL-2R) in the serum of patients with Beh?et's disease (BD) and Vogt-Koyanagi-Harada's disease (VKH). METHODS: The study population consisted of 20 patients with active BD (treated with tacrolimus), 15 patients with inactive BD, 24 patients with VKH [20 of them successfully treated with systemic corticosteroids (cured group) and 4 of them with two or more episodes of uveitis after withdrawal of systemic steroid (recurrence group)], and 20 normal individuals. The levels of serum sICAM-1, sCD4, sCD8 and sIL-2R were measured by sandwich ELISA. RESULTS: Sera from patients with BD in the convalescent stage showed significantly higher levels of sICAM-1 than those in the acute stage. Patients with active BD in both stages or VKH in the acute stage had significantly higher levels of serum sCD4 and sIL-2R than the controls. The levels of sCD8 in patients with both diseases in both stages differed significantly compared to the controls. No difference was noted in the pattern of decline of these soluble markers after treatment in the cured and recurrence groups of VKH patients. A positive correlation was found between the serum levels of sCD4 and sIL-2R in patients with both diseases in the acute stage. CONCLUSIONS: The results suggest that these soluble markers may represent potentially useful parameters to monitor disease activity or chronic inflammation in certain types of autoimmune uveitis.     

Soluble adhesion molecules and cytokines in patients with myasthenia gravis treated by plasma exchange

Plasma exchange (PE) is an effective therapeutic method used in patients with myasthenia gravis (MG) refractory to common therapy and/or with life-threatening respiratory complications. Except for acetylcholine receptor antibodies (AChRAbs), some other inflammatory mediators possibly activated in MG may also be removed during PE. Serum levels of soluble adhesion molecules (sICAM-1 and sVCAM-1), IL-6 and soluble receptors for IL-2 (sIL-2R), IL-6 (sIL-6R) and TNF alpha (sTNF-R II) were measured in 20 MG patients assigned to treatment with PE. On the basis of the serum levels of AChRAb the patients were subdivided into 2 groups (8 patients with low AChRAb, 12 patients with high AChRAb). Soluble adhesion molecules and cytokines were measured before the first and last PE, at the end of the first PE and in the samples of plasma filtrate obtained during the first PE. Before the first PE patients with MG had higher serum levels of sICAM-1, sVCAM-1, sIL-2R and sTNF-R II than controls. Both after the first PE and during the course of PE, a substantial decrease in serum levels of AChRAb, sICAM-1 and sVCAM-1 was recorded. However, serum levels of sIL-2R and sTNF-R II were not significantly influenced by either a single treatment or during the course of PE. There were high levels of AChRAb, soluble adhesion molecules and soluble cytokine receptors in plasma filtrates too. Patients with high circulating AChRAb had higher serum levels of sICAM-1 and sVCAM-1 than patients with low AChRAb. Increased serum levels of soluble adhesion molecules and soluble cytokine receptors in patients with MG suggest some systemic activation of the immune response which is more pronounced in patients with high circulating AChRAb. PE led to the decrease in serum AChRAb and soluble adhesion molecules due to their effective filtration but, on the other hand, serum levels of soluble cytokine receptors were not influenced by PE, in spite of their effective filtration which is probably counteracted by their increased production, possibly stimulated by the contact of the blood with the synthetic membrane.     

Plasma bioavailable interleukin-6 is elevated in human immunodeficiency virus-infected patients who experience herpesvirus-associated immune restoration disease after start of highly active antiretroviral therapy

This study compared plasma bioavailable interleukin (IL)-6 levels in 3 groups: human immunodeficiency virus (HIV)-infected patients who had a human herpesvirus (HHV)-associated immune restoration disease (IRD) during highly active antiretroviral therapy (HAART); patients who experienced an IRD initiated by Mycobacterium avium complex, hepatitis C virus, or human papillomavirus; and control patients who had uneventful immune reconstitution. Total IL-6, soluble IL-6 receptor (sIL-6R), and soluble gp130 were measured by ELISA, and levels of free IL-6 and sIL-6/IL-6R complex were modeled mathematically. Persons who had an HHV-associated IRD had increased plasma bioavailable IL-6 before HAART, compared with patients who experienced a non-HHV-associated IRD and with control patients, and their plasma bioavailable IL-6 increased progressively over 3-4 years of treatment. Increased IL-6 production may be a feature of HAART-induced restoration of immune responses to HHV infections and may have long-term immunopathologic consequences.     

High effectiveness of efavirenz-based highly active antiretroviral therapy in HIV-1-infected patients with fewer than 100 CD4 cells/microl and opportunistic diseases: the EfaVIP Study (Efavirenz in Very Immunosuppressed Patients)

We evaluated the therapeutic outcomes of all antiretroviral-naive HIV-1-infected patients with fewer than 100 CD4 cells/microl, who received efavirenz-based highly active antiretroviral therapy (HAART). Sixty-one percent suffered AIDS-defining diseases, and after a median follow-up of 45 weeks there were three deaths and five AIDS-related conditions (two relapses, three new). Efavirenz-based HAART was found to be effective in profoundly immunosuppressed HIV-1-infected patients.     

Cytokines and adhesion molecules in patients with polymyalgia rheumatica

Serum levels of interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1ra), tumour necrosis factor alpha (TNF-alpha), IL-6, soluble IL-6 receptor (sIL-6R), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble E-selectin were measured in 15 patients with newly diagnosed polymyalgia rheumatica (PMR) before and after 3 months of corticosteroid therapy. Both IL-6 and IL-1ra were significantly increased in untreated PMR and remained elevated compared with controls during therapy, although significantly only for sIL-1ra. sICAM-1 was raised in 12/15 (87%) patients at diagnosis and remained high in 10/14 (71%) patients; soluble E-selectin levels were initially raised in 6/15 (40%) patients and decreased with therapy in those with the highest levels. IL-6, IL-1ra and sICAM-1 are sensitive indicators of continuing immunological activation in PMR; the advantages of these markers in assessing the response to therapy should be investigated in a longitudinal study.      

Impaired systemic cell-mediated immunity and increased susceptibility to acute respiratory tract infections in patients with COPD

Although it has been reported that chronic obstructive pulmonary disease (COPD) is frequently associated with systemic immune disturbances, negative impact of these disturbances on the increased prevalence of acute respiratory tract infections (aRTIs) has remained unclear. We evaluated circulating levels of interferon-gamma (IFN-gamma), soluble interleukin-2 receptor (sIL-2R), neopterin, and soluble intercellular adhesion molecule-1 (sICAM-1) in 35 clinically stable patients with COPD and in 22 age-matched healthy controls, since these molecules are considered to reflect the in vivo status of systemic cell-mediated immunity (CMI). We found that circulating levels of sIL-2R (1.52+/-1.25 vs. 0.97+/-0.48 ng/ml; P<0.05), neopterin (7.23+/-4.24 vs. 4.95+/-1.52 nmol/l; P<0.05), and sICAM-1 (665+/-302 vs. 328+/-164 ng/ml; P<0.0001), but not IFN-gamma (7.55+/-4.72 vs. 6.65+/-1.13 pg/ml; P=NS) were significantly higher in patients with COPD than in the controls. Importantly, follow-up study for 12 months demonstrated that patients in subgroup with relatively higher circulating levels of sIL-2R (2.20+/-1.44 ng/ml, n=18) had significantly higher risk of developing aRTIs (P=0.0204) than those in subgroup with relatively lower circulating levels of sIL-2R (0.80+/-0.23 ng/ml, n=17). These results may suggest that impaired systemic CMI observed in COPD patients is associated with the increased susceptibility to aRTIs in these patients.     

Immunological response to highly active antiretroviral therapy in children with clinically stable HIV-1 infection

We studied changes in 60 immunological parameters after the administration of highly active antiretroviral therapy (HAART) in 192 clinically stable antiretroviral drug-experienced HIV-1-infected children 4 months-17 years old. The studied immunological parameters included standard lymphocyte subsets and lymphocyte surface markers of maturation and activation. The most significant changes during the 48-week study period were seen for CD8(+), CD8(+)CD62L(+)CD45RA(+), CD8(+)CD38(+)HLA-DR(+), and CD4(+) T cell percentages (P < .0001 for all parameters). These changes suggest that significant decreases in the expression of activation markers and increases in the expression of naive markers in the CD8(+) T cell population may be related to better virologic control in these HIV-1-infected children, who had relatively stable immune function at the initiation of HAART. At week 44 of HAART, the major immunological parameters in these HIV-1-infected children moved from baseline values to about halfway to two-thirds of the way toward the values in healthy, uninfected children.     

Immunological predictors of survival in HIV type 2-infected rural villagers in Guinea-Bissau

We investigated the association between beta2-microglobulin, neopterin, serum levels of soluble urokinase-type plasminogen activator receptor (suPAR), CD4 count, and plasma viremia with survival in 133 HIV-2-infected villagers and 160 controls living in rural Guinea-Bissau. Subjects were recruited in 1991 and visited at home every 3-6 months until 1998. Median beta2-microglobulin, neopterin, and suPAR were significantly higher and CD4% significantly lower among HIV-2-infected individuals than controls. Thirty-one HIV-2-infected individuals died and 7 were lost to follow-up. beta2-Microglobulin, CD4%, and plasma viral load were associated independently with survival in multivariate analyses. Neopterin and suPAR did not reach statistical significance. These findings suggest that immune activation is central to the pathogenesis of HIV. They also have important implications for resource-poor settings where CD4 count and plasma viral load are unaffordable.     

Immune activation in patients infected with HIV type 1 and maintaining suppression of viral replication by highly active antiretroviral therapy

Immune activation associated with HIV infection declines after highly active antiretroviral therapy (HAART), but may persist or recur in some patients. It is not clear whether this reflects a resurgence of HIV replication or another cause of immune activation, such as inflammatory reactions to opportunistic pathogens (immune restoration disease [IRD]). Here, we studied plasma and cellular immune activation markers in adult HIV-1 patients who had received HAART for >12 months and maintained plasma HIV RNA levels of <400 copies/ml for >6 months. Plasma interleukin 1 receptor antagonist and tumor necrosis factor receptor I levels were similar in patients and HIV-negative control subjects, but the highest levels occurred mainly in patients with a history of IRD. In contrast, expression of HLA-DR and CD38 on monocytes and of HLA-DR on CD8(+) T cells was higher in patients than in control subjects. Thus, cellular markers of immune activation are abnormal in some patients with a good virological response to HAART, and abnormalities of plasma immune activation markers correlate with a history of IRD.     

艾滋病的高效抗逆转录病毒治疗、疗效观察及其对免疫功能的影响

目的 为探讨艾滋病高效抗逆转录病毒治疗、疗效观察及其对免疫功能的影响.方法 应用HAART疗法对4例有严重免疫功能低下的HIV/AIDS病人进行治疗.结果 所有病人在治疗4周HIV复制被明显抑制,血浆病毒载量平均下降1.99log/ml(0.73～2.46log/ml),CD_8~ 、CD_4~ 细胞和血浆IL-2浓度在4～12周后持续性显著增高,上升幅度分别为67.2%,103.0%,255.1%,而血浆sIL-2R、IL-6、TNF-α、sTNFR-I、Neopterin浓度在治疗4～12周后持续下降至正常水平或以下.HAART治疗后各因素变化间的相关性分析显示,CD_4~ 细胞数与CD_8~ 、CD_3~ 细胞和血浆IL-2浓度之间,血浆病毒载量与sIL-2R、IL-6、TNF-α、sTNFR-I、Neopterin之间,sTNFR-I和Neopterin与sIL-2R、IL-6、TNF-α之间均存在明显正直线相关性;而CD_4~ 细胞数与血浆病毒载量、sIL-2R、sTNFR-I、Neopterin之间.以及IL-2和sIL-2R之间则有明显负直线相关性.结论 抗病毒治疗效果、病毒复制和免疫活化间具有密切关系,HAART治疗能快速有效地抑制HIV-1的复制,纠正机体免疫功能紊乱和重建免疫功能;外周血CD_4~ 细胞数、血浆病毒载量、IL-2、sIL-2R、TNF-α、sTNFR-I、Neopterin的浓度变化可以作为HAART治疗效果评价的重要指标.     

Normalisation of cerebrospinal fluid biomarkers parallels improvement of neurological symptoms following HAART in HIV dementia – case report

Background  

Since the introduction of HAART the incidence of HIV dementia has declined and HAART seems to improve neurocognitive function in patients with HIV dementia. Currently, HIV dementia develops mainly in patients without effective treatment, though it has also been described in patients on HAART and milder HIV-associated neuropsychological impairment is still frequent among HIV-1 infected patients regardless of HAART. Elevated cerebrospinal fluid (CSF) levels of markers of neural injury and immune activation have been found in HIV dementia, but neither of those, nor CSF HIV-1 RNA levels have been proven useful as diagnostic or prognostic pseudomarkers in HIV dementia.     

Circulating intercellular adhesion molecule 1 in rheumatoid arthritis — Relationship to systemic vasculitis and microvascular injury in nailfold capillary microscopy

Summary Intercellular adhesion molecule-1 (ICAM-1) is a membrane bound molecule that plays an important role in the pathogenic inflammatory responses observed in vasculitis. The aim of this study was to determine whether levels of soluble ICAM-1 sICAM-1) shedding into the circulation reflect the vascular injury found in nailfold capillaroscopy as well as systemic vasculitis in RA patients. We determined serum levels of sICAM-1 and soluble interleukin-2 receptor (sIL-2R) by an enzyme-linked immunosorbent assay in 79 RA patients. Serum level of sICAM-1 were significantly increased in RA patients compared to 30 healthy controls. RA patients with clinical signs of systemic vasculitis showed significantly higher levels of sICAM-1 than those without vascular involvement. Although no significant correlation between sICAM-1 levels and the capillaroscopy findings were found, 75% of the patients with severe vascular changes in capillaroscopy exceeded normal sICAM-1 cut off value. Serum sICAM-1 concentrations correlated significantly with the erythrocyte sedimentation rate and serum sIL-2R, but not with the duration of RA, radiological stages, Ritchie index, age or type of treatment. These findings suggest that increased levels of sICAM-1 in serum of RA patients reflect systemic vascular involvement rather than a local vascular injury.     

Plasma soluble interleukin-2 receptor in patients with primary myelofibrosis

Summary Using an enzyme-linked immunosorbant assay (ELISA) test, the level of soluble Tac peptide, one chain of the human interleukin-2 receptor, was measured in the plasma of 26 patients with primary myelofibrosis (MF), seven patients with polycythaemia vera and 11 normal controls. The plasma soluble interleukin-2 receptor (sIL-2R) was found to be significantly elevated in patients with primary MF compared to polycythaemia vera or controls ( P <0·01), while the plasma sIL-2R of patients with polycythaemia vera also was found to be significantly elevated compared to controls ( P <0·01). The significantly elevated value of sIL-2R seen in primary MF may be secondary to T cell activation resulting from autoimmune phenomena, and myeloblast activation with release of sIL-2R may also be a contributing factor. In primary MF, plasma sIL-2R levels were also found to be correlated to survival, circulating blast cell counts, and thrombocytopenia, but not to white blood cell counts, LDH levels, degree of marrow fibrosis, or degree of splenomegaly. Patients with primary MF with higher titre of plasma sIL-2R had a shorter survival. Further studies involving more patients and longer follow-up may substantiate that plasma sIL-2R is an important prognostic indicator in primary MF.     

Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies

OBJECTIVE: To estimate the prognosis over 5 years of HIV-1-infected, treatment-naive patients starting HAART, taking into account the immunological and virological response to therapy. DESIGN: A collaborative analysis of data from 12 cohorts in Europe and North America on 20,379 adults who started HAART between 1995 and 2003. METHODS: Parametric survival models were used to predict the cumulative incidence at 5 years of a new AIDS-defining event or death, and death alone, first from the start of HAART and second from 6 months after the start of HAART. Data were analysed by intention-to-continue-treatment, ignoring treatment changes and interruptions. RESULTS: During 61 798 person-years of follow-up, 1005 patients died and an additional 1303 developed AIDS. A total of 10 046 (49%) patients started HAART either with a CD4 cell count of less than 200 cells/microl or with a diagnosis of AIDS. The 5-year risk of AIDS or death (death alone) from the start of HAART ranged from 5.6 to 77% (1.8-65%), depending on age, CD4 cell count, HIV-1-RNA level, clinical stage, and history of injection drug use. From 6 months the corresponding figures were 4.1-99% for AIDS or death and 1.3-96% for death alone. CONCLUSION: On the basis of data collected routinely in HIV care, prognostic models with high discriminatory power over 5 years were developed for patients starting HAART in industrialized countries. A risk calculator that produces estimates for progression rates at years 1 to 5 after starting HAART is available from www.art-cohort-collaboration.org.     

高血压脑出血病人脑脊液sICAM-1与sIL-6R的对比观察

目的对比观察高血压脑出血急性期不同时间脑脊液(CSF)可溶性细胞间黏附分子(sICAM-1)和可溶性白细胞介素6受体(sIL-6R)及白细胞介素6(IL-6)的变化与继发性脑损伤的关系.方法采用酶联免疫吸附试验(ELISA)测定20例(对照组)和15例高血压脑出血病人CSF中sICAM-1、sIL-6R、IL-6含量变化.结果高血压脑出血后第1天CSF sICAM-1、sIL-6R、IL-6含量升高已达高峰.sICAM-1在出血后5 d～7 d明显下降,但仍高于正常对照,而sIL-6R和IL-6虽有下降,但仍维持在较高水平,两者之间呈正相关(P＜0.001),而sICAM-1与sIL-6R含量变化无明显相关(P＞0.05).结论 sICAM-1、sIL-6R和IL-6参与高血压脑出血的免疫和炎症反应过程,与继发性脑损伤程度有关,sICAM-1与sIL-6R和IL-6调节机制可能不同.