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Mycobacterium avium complex (MAC) is the most common cause of disseminated bacterial infection in patients with acquired immune deficiency syndrome (AIDS) and macrophage dysfunction is important both in the pathogenesis of AIDS- and MAC-infection. 1,25-Dihydroxyvitamin D3 (1,25D), the active metabolite of vitamin D, has a number of effects on cell types of the immune system including monocytes/macrophages. The present study was designed to investigate whether 1,25D supplementation in vitro could modulate MAC replication in macrophages from HIV-infected patients. It was therefore of particular interest to examine whether the effect of 1,25D differs between cells from HIV-infected patients and healthy control subjects. After 3 and 7 days of infection, 1,25D supplementation increased numbers of bacteria in cells from control subjects. In contrast, there was no change or even a decrease in numbers of bacteria in cells from HIV-infected patients. These findings suggest that HIV infection may significantly modulate the macrophage response to 1,25D stimulation, and that 1,25D may have inhibitory effects on MAC replication in macrophages from HIV-infected patients.

Cyclic AMP-dependent protein kinase A (PKA) type I has been established as an acute inhibitor of T cell activation. For this reason, we investigated the possible role of PKA type I in HIV-induced T cell dysfunction. T cells from HIV-infected patients have increased levels of cAMP and are more sensitive to inhibition by cAMP analog than are normal T cells. A PKA type I-selective antagonist increases the impaired proliferation of T cells from HIV-infected patients to normal or subnormal levels (up to 2.8-fold). Follow-up of patients after initiation of highly active antiretroviral treatment revealed that a majority of patients have a persistent T cell dysfunction that is normalized by incubation of T cells with Rp-8-Br-cAMPS. These observations imply that increased activation of PKA type I may contribute to the progressive T cell dysfunction in HIV infection and that PKA type I may be a potential target for immunomodulating therapy.

RANTES has been found to suppress human immunodeficiency virus type 1 (HIV-1) replication. To further elucidate the role of this chemokine in HIV-1 infection, RANTES levels were analyzed in serum and platelet-free plasma (PFP) in 53 HIV-1-infected patients and 20 controls. RANTES levels were significantly elevated in both serum and PFP in all clinical stages of HIV-1 infection, with the highest levels in CDC groups A and B. In longitudinal testing, the progressors were characterized by a pronounced decline in serum levels over time; the nonprogressors, however, had only a slight reduction or an increase in RANTES levels. During 16 weeks of indinavir therapy, there was an increase in circulating RANTES levels and enhanced release of RANTES from stimulated CD8+ lymphocytes. The decline in RANTES levels along with disease progression is compatible with RANTES having a beneficial role in HIV-1-infected patients. The increase in RANTES levels during protease inhibitor-containing regimens may represent a previously unrecognized immunologic effect of such therapy.

Background: Immunologic and inflammatory responses appear to play a pathogenic role in the development of congestive heart failure (CHF). Activation and migration of leukocytes to areas of inflammation are important factors in these immunologic responses. Because the C-C chemokines are potent chemoattractants of monocytes and lymphocytes and can modulate other functions of these cells (eg, generation of reactive oxygen species), we measured circulating levels of three C-C chemokines in CHF., Methods and Results: Levels of macrophage chemoattractant protein-1 (MCP-1), macrophage inflammatory protein- 1alpha (MIP-1alpha), and RANTES (regulated on activation normally T-cell expressed and secreted) were measured by enzyme immunoassays in 44 patients with CHF and 21 healthy control subjects. CHF patients had significantly elevated levels of all chemokines with the highest levels in New York Heart Association class IV, and MCP-1 and MIP-1alpha levels were significantly inversely correlated with left ventricular ejection fraction. Elevated C-C chemokine levels were found independent of the cause of the heart failure, but MCP-1 levels were particularly raised in patients with coronary artery disease. Studies on cells isolated from peripheral blood suggested that platelets, CD3+ lymphocytes, and in particular, monocytes, might contribute to the elevated C-C chemokine levels in CHF. The increased MCP-1 levels in CHF were correlated with increased monocyte activity reflected in an enhancing effect of serum from CHF patients on O2-generation in monocytes, which was inhibited by neutralizing antibodies against MCP-1., Conclusions: This first demonstration of increased circulating levels of C-C chemokines in CHF with particularly high levels in patients with severe disease may represent previously unrecognized pathogenic factors in CHF.

Patients with advanced human immunodeficiency virus (HIV) infection are susceptible to infections with Mycobacterium avium complex (MAC). Interleukin (IL)-10 may impair immunity to MAC; therefore, the effect of different MAC preparations on IL-10 production was examined in mononuclear cell cultures from HIV-infected patients. IL-10 levels in cultures for 26 patients were higher than those in 20 control cultures. The highest IL-10 levels were found in cultures from patients with the most advanced HIV disease. Monocytes were the major IL-10 producers, while little IL-10 could be attributed to Th2 lymphocytes. Cultures for patients produced reduced levels of tumor necrosis factor-alpha and normal levels of IL-12; the production of these cytokines increased after neutralization of IL-10. Circulating IL-10 was higher in HIV-infected patients than in controls, with the highest levels in the AIDS group. Elevated monocyte/macrophage-derived IL-10 production may contribute to the high susceptibility to MAC infection seen in patients with advanced HIV disease.

Recent reports suggest a role for immunologic and inflammatory processes in the pathogenesis of congestive heart failure (CHF) and accelerated coronary artery disease (CAD) after heart transplantation (HT). The interaction between endothelial cells, leukocytes, and platelets involving various adhesion molecules may be of particular importance. We therefore measured serum levels of soluble(s) vascular cell adhesion molecule-1 (VCAM-1), sP-selectin, and sE-selectin in 34 patients with severe CHF (23 with CAD and 11 with idiopathic dilated cardiomyopathy) and in 20 healthy controls. Twenty of the patients were followed with serial measurements of these circulating adhesion molecules (CAMs) for up to 2 years after HT. Levels of all 3 CAMs were significantly elevated in patients with CHF compared with controls irrespective of the etiology of heart failure, with particularly high concentrations of sVCAM-1. After HT, different patterns in CAMs were found over time. Whereas there was a normalization of sE-selectin levels after HT, concentrations of sVCAM-1 also declined, but without normalization. In contrast, sP-selectin levels were persistently elevated, with the highest concentrations at the end of the study period. The persistent elevation of sP-selectin and the lack of normalization of sVCAM-1 levels were associated with persistently raised serum levels of tumor necrosis factor-alpha, and these findings were not related to either acute episodes of allograft rejection or intercurrent infections. These results support the notion that immunologic and inflammatory processes are important features of CHF. Furthermore, the persistently elevated levels of CAMs and tumor necrosis factor-alpha found up to 2 years after HT may reflect a state of persistent immune activation in these patients, possibly involved in the development of CAD after HT.

Liver transplantation was performed in a patient with primary hypogammaglobulinaemia, chronic hepatitis C and hepatic failure. The immediate posttransplant period was uncomplicated. Owing to a stricture of the choledochojejunostomy the patient was reoperated with construction of a hepaticojejunostomy 11 months posttransplant. The patient remained hepatitis C virus (HCV) RNA-positive, with high and increasing levels of HCV. Liver biopsies demonstrated the recurrence of HCV. 14 months after the transplantation the patient developed severe diarrhoea caused by Cryptosporidium parvum. The infection did not respond to available therapeutic measures. He deteriorated with development of liver failure and died 18 months after the transplantation. The present case report illustrates the difficulties associated with organ transplantation in patients with primary hypogammaglobulinaemia.

Besides their role in hemostasis, platelets are involved in inflammatory and immunological processes, and we hypothesize that platelet activation may play an immunopathogenetic role in HIV-1 infection. Blood was drawn from 15 controls and 20 HIV-1-infected patients with normal platelet counts, classified into groups of non-AIDS and AIDS. Platelet activation was detected using flow cytometry with mAbs against the release markers P-selectin and CD63, mAb against GPIb, and the probe annexin V detecting surface exposure of aminophospholipids. The amount of microvesicles was measured using mAb against GPIIIa. Compared to controls, blood samples from HIV-1-infected patients showed significantly enhanced levels of microvesicles and activated platelets as detected by their exposure of P-selectin, CD63, and aminophospholipids, as well as reduction in GPIb expression. Increased expression of P-selectin and amounts of microvesicles were most pronounced in advanced clinical and immunological disease. When studying the effect of HIV-1 protease inhibitor therapy (indinavir) on platelet activation, we found that concomitant with a profound decrease in plasma viral load, there was a near normalization of several of the parameters reflecting enhanced platelet activation. Finally, we demonstrated that platelets may be an important source of the chemokine RANTES in HIV-1-infected patients. Although both unstimulated and SFLLRN-stimulated platelets from asymptomatic patients had enhanced release of RANTES, platelets from AIDS patients were characterized by markedly enhanced spontaneous, but decreased SFLLRN-stimulated release of this chemokine. Taken together, these results, which demonstrate for the first time increased platelet activation in HIV-1-infected patients with normal platelet counts, may represent a previously unrecognized immunopathogenic factor in HIV-1 infection.

The effect of a single bolus injection (0.4 g/kg) of intravenous immunoglobulin (IVIG) on the tumor necrosis factor (TNF) system in human immunodeficiency virus type 1 (HIV-1)-infected patients was investigated. At 140 h after infusion, there was a significant decrease in levels of TNF-alpha and a significant increase in levels of soluble TNF receptors (sTNFR) in both plasma and lipopolysaccharide-stimulated peripheral blood mononuclear cells (PBMC). A rapid (within 1 h) decline in expression of membrane-bound TNF-alpha and p55-TNFR on PBMC persisted throughout the study. In contrast, there was an increased expression of membrane-bound p75-TNFR after 140 h. IVIG administration also resulted in significantly increased numbers of circulating CD4 lymphocytes, correlated with down-regulation of TNF-alpha activity in PBMC supernatants. Thus, down-regulation of the abnormally increased TNF-alpha activity may be achieved by IVIG administration. Studies evaluating the possible therapeutic role of long-term TNF-alpha suppression by IVIG may be warranted in HIV-1-infected patients.

The correlation of persistent tumor necrosis factor-alpha (TNF-alpha) activation with disease progression in patients infected with human immunodeficiency virus type 1 (HIV-1), suggests a role for TNF-alpha in the pathogenesis of HIV-1 infection. In the present study, we examined by flow cytometry the expression of membrane-bound (m) components of the TNF system in 33 HIV-1-infected patients and 12 healthy controls. While peripheral blood mononuclear cells (PBMC) from asymptomatic and symptomatic non-acquired immune deficiency syndrome (AIDS) patients showed a significantly increased percentage of mTNF-alpha+ and mTNF receptor (TNFR)+ cells compared with controls, this was not found in the AIDS group. Compared with healthy controls, AIDS patients had a significantly decreased percentage of both monocytes and lymphocytes expressing p75-TNFR. PBMC from AIDS patients showed a higher p75-TNFR mRNA level and a higher spontaneous release of soluble p75-TNFR than healthy individuals, suggesting enhanced cell surface turnover of this TNFR. The low expression of TNFRs on both lymphocytes and monocytes in the AIDS group was associated with high numbers of HIV-1 RNA copies in plasma, low numbers of CD4+ lymphocytes, and high serum levels of soluble TNFRs. AIDS patients had a decreased percentage of CD8+ lymphocytes expressing TNFRs compared with healthy controls. In contrast, these patients, as well as symptomatic non-AIDS patients, had an increased percentage of TNF-alpha+ and TNFRs+ cells among remaining CD4+ lymphocytes. The pattern of abnormalities seen in AIDS patients suggests a role for persistent activation of the TNF system in the accelerated CD4+ lymphocyte destruction, the enhanced HIV-1 replication, and the markedly impaired antimicrobial defense in advanced HIV-1-related disease.

Based on previous studies from our group, we hypothesized that enhanced oxidative stress in association with a persistent immune activation may be important in both the immunopathogenesis and certain clinical manifestations in a subgroup of patients with common variable immunodeficiency (CVI). To explore this hypothesis further, we examined plasma levels of lipid peroxidation, antioxidant vitamins and redox status of various thiol species in 20 CVI patients and 16 healthy control subjects. We found significantly higher malondialdehyde (MDA) levels in plasma from CVI patients than in healthy control subjects. Furthermore, in a subgroup of CVI patients characterized by persistent immune activation in vivo (CVIHyper), we found significantly decreased levels of vitamin E and beta-carotene. In the CVI patients, there was a significant inverse correlation between MDA levels and levels of vitamin E and beta-carotene. Finally, we found a marked elevation in plasma levels of reduced homocysteine in the CVI group, but no corresponding rise in plasma levels of total homocysteine. In the CVI group, the high plasma levels of reduced homocysteine were significantly correlated with enhanced lipid peroxidation and low levels of vitamin E. The results of the present study further support a role for enhanced oxidative stress in the immunopathogenesis of CVI. Furthermore, our finding of markedly elevated plasma levels of reduced homocysteine in CVI patients without simultaneous elevation of other homocysteine species suggests that this disturbance in homocysteine metabolism may be related to enhanced oxidative stress.

Three Norwegians, a couple and their daughter, died from AIDS in 1976 after up to 10 years of clinical manifestations of HIV infection (Lindboe et al., 1986, Acta Pathol. Microbiol, Immunol. Scand. 94, 117-123; Frøland et al., 1988, Lancet i, 1344-1345). We here demonstrate the presence of HIV DNA in autopsy materials from the father and the daughter. In phylogenetic analysis, the obtained sequences of the HIV pol and vif genes clustered with the HIV-1 group O clade. The genotyping was confirmed by detection of antibodies against HIV-1 group O in blood samples from the father and the mother. That these and other early isolates of HIV-1 are very similar to the presently circulating viruses and not intermediates between the present subtypes, verifies that the latest common ancestor of HIV-1 existed long before the emergence of the present epidemic. The presence of HIV-1 group O 30 years ago suggests that the limited spread of these viruses, compared to HIV-1 group M viruses, is not due to a later emergence of the group O viruses.

In 12 patients with primary hypogammaglobulinaemia we investigated the in vivo effect of one bolus injection (400 mg/kg) of intravenous immunoglobulin (IVIG) on lymphocyte subsets and monocytes in peripheral blood, on plasma levels of soluble factors reflecting monocyte and lymphocyte activity and on lymphocyte proliferation and generation of reactive oxygen species (ROS) from monocytes analysed in vitro. Several immunological changes were induced by IVIG infusion. First, there was a significant decrease in CD4+/CD8+ lymphocyte ratio in peripheral blood, reflecting a significant increase in circulating numbers of CD8+ lymphocytes. Second, although there was no significant change in plasma levels of soluble CD8 antigen, there was a significant decrease in soluble CD8 antigen/CD8+ lymphocyte ratio, suggesting a down-regulation of CD8+ lymphocyte activity. Third, there was a significant increase in plasma levels of neopterin, suggesting in vivo activation of monocytes/macrophages. Fourth, the was a down-modulation of mitogen-stimulated lymphocyte proliferation in vitro, and this down-regulation was significantly correlated with the increase in plasma neopterin levels. Finally, there was a significant decrease in zymosan-stimulated, but not in phorbol myristate acetate-stimulated, ROS generation from monocytes as evaluated by nitroblue tetrazolium reduction. The ability of IVIG administration in vivo to down-modulate lymphocyte proliferation and ROS generation from monocytes in patients with persistent immune activation may be relevant for the clinical effects of IVIG in a variety of immune-mediated disorders.

Mutation pattern was characterized in the Bruton's tyrosine kinase gene (BTK) in 26 patients with X-linked agammaglobulinemia, the first described immunoglobulin deficiency, and was related to BTK expression. A total of 24 different mutations were identified. Most BTK mutations were found to result in premature termination of the translation product. Mutations were detected in most BTK exons with a predominance of frameshift and nonsense mutations in the 5' end of the gene and missense mutations in its 3' part, corresponding to the catalytic domain of the enzyme. Nonsense and frameshift mutations were associated with diminished levels of BTK mRNA expression, except for a frameshift mutation in exon 17 and two nonsense mutations in exon 2, indicating that these cases are not confined to penultimate exons. One amino acid substitution (R28H) was found in the pleckstrin homology domain's residue, which is mutated in mice bearing the X-linked immunodeficiency phenotype; another substitution (R307G) was identified in the src homology domain 2. All remaining amino acid substitutions were found in the catalytic domain of Btk.

The objective was to study the impact of exposure group on the progression rate to the acquired immunodeficiency syndrome (AIDS). 289 subjects in Oslo, Norway, infected with the human immunodeficiency syndrome (HIV) and without major clinical signs of HIV infection (102 intravenous drug users, 151 homosexual men and 36 heterosexually infected subjects) were recruited to the Oslo HIV Cohort Study from 1989 and followed until 1 January 1995. 15 (14.7%) of the intravenous drug users, 56 (37.1%) of the homosexual men and 5 (12.5%) of the heterosexually infected subjects developed AIDS during a mean time of 47 months (p < 0.001, log rank test). When controlling for possible confounding variables (age, number of CD4+ lymphocytes, antiviral therapy at study entry, gender and year of HIV diagnosis), the relative risk of AIDS progression was 2.2 [1.1-4.5, 95% confidence interval (CI)] for homosexual men and 0.5 (0.2-1.3, 95% CI) for heterosexually infected subjects as compared to intravenous drug users. In a subgroup with known time of seroconversion (n = 60), 47% (18/38) of the homosexual men, 20% (3/15) of the intravenous users and none (0/7) of the heterosexually infected subjects developed AIDS (p = 0.04, log rank test). The results suggest that homosexual men have more rapid progression to AIDS than intravenous drug users and heterosexually infected subjects.

We investigated the percentage of CD45RA+ and CD45RO+ T cells in peripheral blood and the intracellular glutathione redox balance in these lymphocyte subsets in patients with human immunodeficiency virus type 1 (HIV-1) infection and healthy controls. In HIV-1-infected patients there was a preferential depletion of CD45RA+CD4+ cells, which was most pronounced in symptomatic patients. In CD4+ lymphocytes from HIV-1-infected patients the glutathione abnormalities were clearly most pronounced in the CD45RA+ subset with a marked increase in level of oxidized glutathione and decreased ratio of reduced to total glutathione as the major characteristics. These abnormalities were shown in CD45RA+ CD4+ lymphocytes from both symptomatic and asymptomatic patients, whereas similar abnormalities in CD45RO+CD4+ cells were found only in symptomatic patients. The glutathione abnormalities in CD45RA+CD4+ lymphocytes were significantly correlated with low numbers of total CD4+ lymphocytes, decreased proportion of CD45RA+CD4+ lymphocytes, and raised serum levels of tumor necrosis factor-alpha. In the CD8+ lymphocytes a decrease in both proportion and absolute numbers of CD45RA+ cells was found, with markedly increased level of oxidized glutathione and decreased ratio of reduced to total glutathione in this subset. These findings suggest that glutathione redox disturbances in CD45RA+ T cells may be of pathogenic importance for the preferential depletion of this subset considered to represent naive T cells, during HIV-1 infection.

Adhesion molecules enabling leukocytes to communicate and adhere are essential for immunological and inflammatory responses. Circulating forms of these adhesion molecules are detected, although their influence on immunological functions is unknown. We have measured soluble levels of E-selectin, vascular adhesion molecules-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) in sera from 65 HIV-1-seropositive patients and controls. We found significantly higher levels of soluble VCAM-1 (sVCAM-1) and ICAM-1 (sICAM-1) in both symptomatic and asymptomatic HIV-1-infected patients than in controls (P <0.01). Both sICAM-1 and sVCAM-1 correlated to serum levels of neopterin (r = 0.40, P < 0.001; r = 0.46, P <0.001, respectively) and TNFalpha (r = 0.44, P < 0.01; r = 0.49, P < 0.001, respectively), while only sVCAM-1 correlated strongly to CD4+ lymphocyte count (r = -0.46, P < 0.001). Patients infected with Mycobacterium avium intracellular complex had significantly higher levels of sVCAM-1 and sICAM-1 than other AIDS patients (P < 0.05), while patients with cytomegalovirus disease had significantly lower levels both of sE-selectin and sICAM-1 (P < 0.05) than other AIDS patients. In conclusion, we found abnormal levels of circulating adhesion molecules in both symptomatic and asymptomatic HIV-1 infection including AIDS. The correlation to other parameters and clinical events may implicate involvement of circulating adhesion molecules in the immunopathogenesis of HIV-1 infection.

The active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D), has been shown to induce monocyte-to-macrophage maturation in vitro as well as monocytic differentiation of bone marrow precursors and monocytic leukaemic cell lines. In this study we assessed whether 1,25D could improve the maturation defect we have previously demonstrated in monocytes from AIDS patients. In vitro growth and maturation of monocytes from 10 controls, 15 asymptomatic HIV positives (CDC group II or III) and 13 symptomatic HIV positives (CDC group IV) was examined by assessing cellular morphology, differentiation, adherence and protein content. Cells were cultured for 10 days with or without addition of 1,25D at a concentration of 100 pg/ml. In addition, patients were monitored clinically and by immunological parameters and HIV p24 antigen in serum. The present study showed that addition of 1,25D significantly improved the growth and maturation in both patient and control groups. There was a significant negative correlation between response to 1,25D and CD4+ lymphocyte count in blood in HIV-infected patients. A greater response to 1,25D was seen in monocytes from patients with advanced immunodeficiency and symptomatic disease than in monocytes from asymptomatic patients. However, in the most advanced cases of HIV infection with serious ongoing opportunistic infections the response to 1,25D was very poor, possibly reflecting profound and incorrigible dysfunction of monocytes.

The proportion of T-cell receptor gamma/delta+ cells and the CD4/CD8 ratio relative to all CD3+ intraepithelial lymphocytes (IEL) were determined by immunofluorescence in duodenal mucosa of late-stage (mostly CDC IVC1/D) subjects (n = 21) infected with human immunodeficiency virus type 1 (HIV-1). The gamma/delta fraction (median, 14.2%; range, 1.7 to 59.8%) was increased (P < 0.03) compared with that in HIV- controls (n = 11; median 2.8%; range, 0.3 to 38%). Also, the number of gamma/delta+ IEL per mucosal unit was increased (P < 0.05) in the HIV+ subjects (median, 11.1/U) compared with the controls (3.2/U). Approximately 100% of the gamma/delta+ IEL were CD8-, and most expressed the Vdelta1vJdelta1-encoded epitope (median, 90.9%). The total number of CD3+ IEL tended to be lower than in the controls (67.4 versus 72.9/U). Both the epithelium and the lamina propria contained mainly CD8+ T cells, the median ratios of CD4+ T cells being 1 and 7.6%, respectively. This result accorded with the reduced CD4 cell number in blood (median, 18 X 10(6)/liter). The HIV+ subjects had increased serum levels of neopterin and beta2-microglobulin (both P < 0.0001), probably reflecting immunostimulation. Serum neopterin and beta2-microglobulin were inversely related to duodenal gamma/delta IEL, particularly in the premortal group (r = -0.97 and r = -0.58, respectively). The increased gamma/delta IEL might reflect enhanced intestinal protection in late-phase HIV infection. Short survival expectancy (<7 months) was associated not only with high levels of neopterin and beta2-microglobulin but also with a reduced number of duodenal gamma/delta+ cells (P < 0.03).

Impaired immune responses in patients with carcinoma of cardia or oesophagus have previously been reported. However, we do not know whether resectability correlates with specific immunological variables. Immunological assessment was performed in 35 such cancer patients including measurement of total T cells (CD3+) and T cell subsets (CD4+ and CD8+), NK cells (CD16+) and B cells (CD19+) in blood. In vitro lymphocyte responses to phytohemagglutinin (PHA) separated from peripheral blood were quantitated. The numbers in peripheral blood of both total T cells (CD3+) and B lymphocytes (CD19+) were significantly lower in the inoperable patients compared to resected patients (P < 0.01). The number of NK cells (CD16+) was, however, not significantly lower in the inoperable patients compared to the patients operated for cure. Lymphocyte responses to PHA in vitro were similar in resectable and non-resectable patients, but significantly lower in inoperable patients compared to the controls (P < 0.01). In conclusion, resectability in carcinoma of cardia or oesophagus is associated with changes in both T (CD3+) and B (CD19+) cell subsets.

Oxidative stress has been suggested to be an important factor in the immunopathogenesis of human immunodeficiency virus (HIV) infection. Reduced plasma thiols may lead to production of reactive oxygen species, thus contributing to the oxidative stress. We quantified the total, reduced, and protein-bound forms of the thiols homocysteine, cysteine, cysteinylglycine, and methionine in plasma from 21 HIV-infected patients and 15 healthy control subjects and compared the results with clinical and immunologic indexes. The HIV-infected patients had significantly higher concentrations of reduced homocysteine in plasma compared with control subjects. No significant differences in reduced homocysteine concentrations were noted when asymptomatic and symptomatic HIV-infected patients were compared, and we did not find any relation between reduced homocysteine concentrations and other markers of immunodeficiency. The HIV-infected patients had normal total homocysteine concentrations. The reduced cysteinylglycine concentration tended to be elevated in the patient group. No differences between HIV-infected patients and control subjects were found for reduced or total cysteine. Compared with control subjects, the HIV-infected patients had lower concentrations of methionine in plasma, and a significant correlation was found between low concentrations of methionine and low CD4+ lymphocyte counts in blood. Elevated concentrations of reduced homocysteine could possibly contribute to formation of reactive oxygen species, leading to accelerated immunologic deterioration and increased HIV replication.

In patients with common variable immunodeficiency (CVI), we have previously defined a subgroup of patients (CVIHyper) characterized by decreased numbers of CD4+ lymphocytes in peripheral blood, splenomegaly, and persistent immune activation in vivo, particularly of monocytes/macrophages. To further characterize this hyperactivity, parameters of activation of the tumor necrosis factor (TNF) system (TNF alpha and soluble TNF receptors [sTNFRs]) were measured in 24 patients with CVI and 20 healthy controls. Patients with CVI had significantly higher serum levels of TNF alpha and both types of sTNFRs, with the highest levels in the CVIHyper subgroup. In vitro, peripheral blood mononuclear cells (PBMC) and purified monocytes from CVIHyper patients spontaneously released significantly higher levels, and, after lipopolysaccharide (LPS) stimulation, significantly lower levels of TNF alpha and soluble p75-TNFR than cells from both other CVI patients and healthy controls. CVIHyper patients also had significantly higher TNF alpha:sTNFRs ratios in both serum and in unstimulated PMBC supernatants. The present study demonstrates persistent in vivo activation of the TNF system in CVI, particularly in the CVIHyper subgroup. This activation may contribute to the pathogenesis of both clinical and immunologic manifestations in CVI.

Disseminated Mycobacterium avium complex (MAC) infection is associated with considerable morbidity and mortality in patients with AIDS. Because both tumor necrosis factor-alpha (TNF-alpha) and 1,25-dihydroxyvitamin D3 (1,25D) may be involved in the normal control of MAC infection, these parameters were studied in AIDS patients with disseminated MAC infection. Of 53 AIDS patients studied, 24 had no clinical events, 11 had disseminated MAC infection, and 18 had other clinical events. Patients with disseminated MAC infection had significantly higher serum levels of both TNF-alpha and soluble TNF receptors compared with other AIDS patients; almost half of the MAC-infected patients had TNF bioactivity in serum. MAC-infected patients also had severely decreased serum 1,25D levels compared with all other AIDS patients. The activation of the TNF system was significantly correlated with the degree of 1,25D deficiency. These findings may reflect interaction between vitamin D and the TNF system in the pathophysiology of disseminated MAC infection in AIDS.

Background: Recombinant interferon remains the cornerstone of treatment of chronic hepatitis C virus (HCV) infection. Still, evaluation of treatment on the basis of response indicators and long-term effect of the treatment raises several questions., Methods: Seventy-four patients with chronic HCV infection were randomized to a high (3 MIU, 3/7 days) or low (1 MIU, 3/7 days) dose of recombinant interferon-alpha-2b for 48 weeks after a 4-week course of 3 MIU, 3/7 days. Response to treatment was assessed by means of liver enzymes (transaminases), HCV RNA, and liver histology., Results: The higher maintenance dose was associated with a significantly higher rate of sustained alanine aminotransferase (ALAT) response (45% versus 19%) and with a significantly better chance of becoming HCV RNA-negative during therapy (47% versus 23%). In the high maintenance dose group 14 of the 29 (48%) patients with available HCV RNA data were negative at the 3-month follow-up, compared with 4 of 27 (15%) in the low maintenance dose group. Significantly more patients had improved liver biopsy findings after interferon in the high maintenance dose group (79%) than in the low maintenance dose group (36%). There was a close correlation between ALAT response and HCV RNA response. Of 17 patients who were HCV RNA-negative 3 months after the end of treatment, 10 remained HCV RNA-negative 2-4 years later., Conclusion: The study demonstrates a higher response rate as assessed by biochemistry, HCV RNA, and liver histology in the higher dose group.

The clinical course of infectious diseases depends on the complicated interaction between the microorganism and the immune system of the host. The vast amount of knowledge acquired during recent years in the field of immunology will probably lead to new ways of treating infectious diseases by selective immunomodulation. In this paper, we review some newer aspects of host defence mechanisms of relevance to immunomodulation of infectious diseases. The cytokine network, apoptosis, superantigens, and oxidative stress are all discussed with reference to various infectious diseases. Furthermore, the possible role of physical and psychological stress in the immunopathogenesis of infectious disease is discussed in the light of the interplay between the immune system and the neuroendocrine system.

We have previously shown chronic immune activation and enhanced generation of reactive oxygen species in common variable immunodeficiency (CVI). In the present study, we examined levels of glutathione, the dominant intracellular thiol, that play an important protective role against oxidative and inflammatory stress in plasma and in monocytes and lymphocyte subsets in 20 CVI patients and in 16 healthy controls. CD4+ lymphocytes from CVI patients had significantly lower levels of both total and reduced glutathione as well as a lower ratio of reduced to total glutathione compared with healthy controls. This decrease in glutathione levels in CD4+ lymphocytes was most pronounced in the CD45RA+ subset. Plasma levels of total glutathione were also significantly decreased in CVI. In contrast, monocytes from CVI patients exhibited increased levels of both total and reduced glutathione compared with blood donor monocytes. CVI patients had significantly raised serum levels of tumor necrosis factor alpha (TNF alpha) and TNF alpha concentration was strongly associated with glutathione depletion in CD4+ lymphocytes. Furthermore, the lowest levels of both total and reduced glutathione were found in a subgroup of CVI patients characterized by persistent immune activation in vivo, decreased numbers of CD4+ lymphocytes in peripheral blood, and splenomegaly. Finally, supplementation of cell cultures with glutathione-monoethyl ester did significantly enhance interleukin-2 production from peripheral blood mononuclear cells in CVI patients. These glutathione abnormalities in CVI indicate increased oxidative stress, particularly in CD4+ lymphocytes, and intracellular depletion of reduced glutathione of the demonstrated magnitude may have profound implications for CD4+ lymphocyte function and the immunodeficiency in CVI.

Seventeen patients with IgA deficiency, 13 subjects with selective IgA deficiency and 4 with a combined IgA and IgG2 deficiency, were assessed for serum levels of cytokines relevant for B cell differentiation. Transforming growth factor (TGF)-beta was quantified by bioassay and interleukin (IL)-4, IL-6, and IL-7 by immunoassay. The serum levels of TGF-beta were significantly lower in patients with IgA deficiency than in healthy blood donors. Of the patients with IgA deficiency, 4 had detectable IL-4 levels while 4 of the others had detectable IL-6 levels in serum. IL-4 and IL-6 were not detected in the controls. Serum IL-7 levels were similar in patients and controls. A significant, negative correlation was found between serum TGF-beta and the number of circulating B lymphocytes in the patients with IgA deficiency. No association was found between serum cytokine levels and the occurrence of infections at the time of study. Since TGF-beta has been implicated in IgA isotype switching in man, and our study demonstrates an association between low serum TGF-beta levels and IgA deficiency, dysregulation of TGF-beta might be a contributing factor in the pathogenesis of IgA deficiency.

We investigated the intracellular glutathione redox status in isolated lymphocyte subpopulations and monocytes in patients with human immunodeficiency virus type 1 (HIV-1) infection and in healthy controls. CD4+ lymphocytes from HIV-1-infected patients were primarily characterized by a substantial increase in oxidized glutathione levels and a considerable decrease in the ratio of reduced to total glutathione, in most cases below 0.5 in patients with symptomatic HIV-1 infection, rather than decreased levels of reduced glutathione. The increase in oxidized glutathione was strongly correlated with low numbers of CD4+ lymphocytes in peripheral blood and impaired stimulated interleukin-2 production and proliferation in peripheral blood mononuclear cells, which is compatible with an immunopathogenic role for these redox disturbances. The HIV-1-infected patients with the most advanced clinical and immunologic disease were also characterized by an increase in levels of reduced glutathione in monocytes, suggesting that the glutathione redox cycle may be differentially regulated in CD4+ lymphocytes and monocytes. We could not confirm previous reports suggesting cysteine deficiency as a major cause of disturbed glutathione homeostasis during HIV-1 infection. The demonstrated glutathione abnormalities were correlated with raised serum levels of tumor necrosis factor alpha. These findings suggest that a therapeutical approach, which can restore the glutathione redox dysbalance in CD4+ lymphocytes and decrease the inflammatory stress, may be worthwhile exploring in HIV-1 infection.

Primary antibody deficiencies are chronic conditions and the patients usually need lifelong replacement therapy with gammaglobulin to prevent or reduce infections. It has been shown that the gammaglobulin can be given safely as subcutaneous infusions, instead of intramuscular injections or intravenous infusions. The major aim of this multi-centre study was to investigate the perceptions of the subcutaneous method among patients using it, both in hospital settings and as self-infusions at home. The study included 152 patients: 89 women, 63 men, mean age 44 years (range 18-76). Data were collected by using questionnaires. The patients were found to have a strongly positive attitude towards receiving the replacement therapy as subcutaneous infusions, perceived the method as effective in preventing infections and wished to retain the treatment. However, the younger patients found the subcutaneous infusions more uncomfortable and were less determined to continue with the therapy as compared with the older individuals. The responsibility for self-infusions at home was accepted by the patients, leading to an increased independence from the health care personnel and to a feeling of flexibility and freedom. As these patients have a chronic disease and are in need of lifelong treatment, it is important to discuss the development of structured education and training programmes in which special emphasis is placed on the support of the younger patients. It is suggested that Orem's nursing model of self-care may serve as a conceptual framework for nurses working in this specific area of nursing care.

Thirty-three patients with AIDS were subjected to neuropsychological and immunological testing with semi-annual examinations over a two year period. No patient had signs of opportunistic infections or neoplasms in the CNS. Patients who were neuropsychologically impaired at the time of AIDS diagnosis (n = 12) survived for a significantly shorter period than did the non-impaired subjects (n = 21), and neuropsychological function at first test had a significant predictive value concerning survival time. The poor prognosis associated with impaired neuropsychological status was seen also in patients treated with zidovudine (ZDV). Of the 21 patients who started ZDV treatment shortly after the first neuropsychological examination, 12 were retested. Follow-up data showed that this group of patients had a significant improvement in neuropsychological functioning during the first 6 months. However, a decrease in performance was observed at second follow-up. In the group not treated with ZDV (n = 7), two initially normal patients developed signs of HIV-encephalopathy, while none of the initially normal ZDV-treated patients did so. This might suggest a prophylactic effect of ZDV on development of neuropsychological dysfunction. Changes in neuropsychological test results were correlated with changes in serum concentration of neopterin irrespective of ZDV treatment, suggesting that monocyte/macrophage activation may be involved in the pathogenesis of HIV-encephalopathy.

Immunoglobulins (IgG) as replacement therapy in primary antibody deficiencies can be given as intramuscular injections, or as intravenous or subcutaneous infusions. Our aims were to obtain information on the frequency of adverse systemic reactions during subcutaneous therapy, the occurrence and intensity of tissue reactions at the infusion sites, and serum IgG changes. Furthermore, we compared costs between the different replacement regimes. Our study included 165 patients (69 women, 96 men, aged 13-76 years) with primary hypogammaglobulinaemia or IgG-subclass deficiencies. Data were compiled from questionnaires filled in by the patients and from their medical records. 33,168 subcutaneous infusions (27,030 in home therapy) had been given. 106 (of which 16 were at home) adverse systemic reactions (100 mild, 6 moderate) were recorded in 28 patients (17%). No severe or anaphylactoid reactions occurred. Despite large immunoglobulin volumes given during 434 patient years (28,480 infusions), no signs have been found that indicate the transmission of hepatitis virus. Transient tissue reactions occurred at the infusion sites but were not troublesome to most patients and we found significant increases in mean serum IgG. The use of subcutaneous instead of intravenous infusions at home would reduce the yearly cost per patient for the health-care sector by US $10,100 in Sweden alone. We conclude that subcutaneous administration of IgG is a safe and convenient method of providing immunoglobulins. We were able to reach serum IgG concentrations similar to those by the intravenous therapy and we found that the method could also be used successfully in patients with previous severe or anaphylactoid reactions to intramuscular injections.

The relationships between serum levels of soluble tumor necrosis factor receptors (sTNFRs) and other prognostic and immunological parameters in different immunological subgroups of 64 HIV-1 infected patients were studied. In the patient group as a whole, the raised serum levels of sTNFRs were significantly inversely correlated to the numbers of CD4+ and CD8+ lymphocytes and significantly positively correlated with serum levels of neopterin, HIV-1 p24 antigen and the soluble CD8/CD8+ lymphocyte ratio. However, when the patients were classified into three separate immunological subgroups according to the numbers of CD4+ lymphocytes, only serum levels of neopterin were significantly correlated to levels of sTNFRs in all the defined immunological subgroups. These results indicate that HIV-1 infection is associated with a persistent and chronic immune activation in the TNF system manifested by raised serum levels of sTNFRs, which may reflect sustained activation of the immune system particularly in monocytes/macrophages. Further, these results confirm that, when comparing immunological and virological parameters in HIV-1 infection, different results may be obtained in different immunological subgroups of patients.

Background: In Scandinavia many patients with primary hypogammaglobulinemia contracted non-A, non-B hepatitis after intravenous treatment with an immune globulin product that was later found to contain a non-A, non-B hepatitis virus., Methods: We studied the prevalence and clinical course of hepatitis C virus (HCV) infection in a group of 55 Norwegian patients with primary hypogammaglobulinemia and investigated its association with the use of contaminated immune globulin. We used the polymerase chain reaction to detect HCV RNA and performed HCV genotyping. We also analyzed the responses to treatment with interferon., Results: Of 20 patients who received the contaminated immune globulin, 17 were seropositive for HCV RNA: In addition, 1 of 35 patients not exposed to the contaminated immune globulin was HCV RNA--positive. HCV genotype V was found in all 12 patients for whom genotyping was performed, but 8 patients also had genotype II or III, or both. All HCV RNA--positive patients had abnormal results on biochemical liver tests. All liver-biopsy specimens (from 15 patients) were abnormal, with portal inflammation, bile-duct damage, and focal necrosis. In six patients there was cirrhosis. Two patients died of liver failure. In 4 of the 10 patients treated with interferon there were complete, though transient, biochemical responses, but the follow-up biopsy specimens showed evidence of histologic progression. The poorest responses to interferon were among the patients with multiple HCV genotypes. All but one patient remained positive for HCV RNA:, Conclusions: In patients with primary hypogammaglobulinemia there was a high rate of HCV infection after treatment with contaminated immune globulin. In these immunocompromised patients HCV infection has a severe and rapidly progressive course, and responses to interferon are poor.

In order to study differences in risk of the development of AIDS in different groups of HIV infected subjects, 151 homosexual men, 110 intravenous drug users (IVDUs) and 36 heterosexually infected persons without major signs of HIV infection at entry to the study were enrolled in a cohort study. The mean follow-up time was 35 months. At the end of follow-up 40 subjects (13%) were diagnosed as having AIDS. This represented 20% (31/151) of the homosexual men, 7% (8/110) of the IVDUs and 3% (1/36) of the heterosexual subjects. The probability of being AIDS-free 36 months after entering the study was 0.88 (0.84-0.92, 95% CI) for the total study population, 0.83 (0.77-0.90) for the homosexual men, 0.92 (0.86-0.99) for IVDUs and 0.93 (0.91-1.0) for heterosexual subjects (p < 0.05, log rank test). In a Cox regression analysis, adjusting for CD4+ cell count at study entry, the relative risk of AIDS progression was 2.4 (1.1-5.2) for homosexual men and 0.3 (0.04-2.4) for heterosexual subjects, compared with IVDUs. The results demonstrate a higher risk of AIDS for homosexual men during the follow-up period.

We investigated the in vivo effects of one bolus injection (400 mg/kg) of intravenous immunoglobulin (IVIG) on a number of cytokines, soluble cytokine receptors, and interleukin-1 receptor antagonist (IL-1Ra) in plasma in 12 patients with primary hypogammaglobulinemia. A significant and rapid increase in plasma levels of IL-6, IL-8, and tumor necrosis factor alpha (TNF alpha) was seen within 1 hour after IVIG infusion. This increase was accompanied by a more prolonged elevation in levels of both types of soluble TNF receptors (sTNFRs), which remained elevated throughout the study period (44 hours) although they reached peak levels within 1 hour. After an initial increase in the ratio between TNF alpha and sTNFRs, this ratio decreased to values significantly lower than baseline values 20 and 44 hours postinfusion with approximately 600-fold molar excess of sTNFRs to TNF alpha (trimer). Although only a modest but statistically significant increase in plasma levels of IL-1 beta was seen, IVIG infusion was followed by a marked increase in plasma levels of IL-1Ra with 1,000-fold molar excess of IL-1Ra to IL-1 beta in some patients. The demonstrated effects of IVIG infusion on the cytokine network, particularly the induction of IL-1Ra and sTNFRs release, might be important for the therapeutic effects of IVIG in several immune-mediated disorders.

The calcium-binding myelomonocytic protein calprotectin (L1 protein) was quantified in serum from 51 patients with HIV infection and in 20 HIV-seronegative blood donors. Significantly elevated levels were found both in asymptomatic patients and in people with AIDS compared with controls. The calprotectin level was not related to ongoing or recent opportunistic infections. For patients with CD4+ counts above 50 x 10(6)/L, a significant negative correlation was found between serum calprotectin levels and the CD4+ counts. Serial samples from 24 patients during their first year of zidovudine (ZDV) treatment showed a further elevation of serum calprotectin during the first months of ZDV treatment, with a subsequent decline to pretreatment levels. A low calprotectin response during the first 6 months, determined as area under the curve, was associated with the occurrence of at least one AIDS-defining infection during the first year of antiviral treatment. Also, a low calprotectin maximal response during ZDV therapy was associated with short survival. Similar associations were not found for neopterin, beta 2-microglobulin, HIV p24 antigen, or CD4+ or CD8+ lymphocytes in blood. Our findings in a limited number of patients suggest that calprotectin levels may reflect immune activation and other immune mechanisms correlated with enhanced antimicrobial defense induced at least transiently by antiviral treatment.

The relationship between neuropsychological test performance and immunological parameters was studied in 52 HIV-positive patients within different stages of the infection. All subjects were neuropsychologically tested, the CD4+ and CD8+ lymphocyte count were measured in peripheral blood, and the concentration of neopterin and HIV-p24 antigen were measured in serum. Ten patients with AIDS were defined as neuropsychologically impaired. The CD8+ cell count was the only immunological parameter that could significantly discriminate between AIDS patients with and without neuropsychological impairment. For the total group, significant positive correlations were found between neuropsychological test results and the number of CD8+ and CD4+ lymphocytes, and significant negative correlations were observed between serum concentration of neopterin and neurocognitive function. Regression analyses showed that up to 51% of the variance in test performance could be explained by CD8+ cells and neopterin concentration. The possible role of CD8+ lymphocytes and neopterin in the pathogenesis of HIV-related CNS-dysfunction is discussed.

Monocyte and macrophage dysfunction may be important for both immunopathogenesis and clinical manifestations in subgroups of patients with primary hypogammaglobulinaemia. In the present study we examined the ability to generate reactive oxygen species (ROS) in isolated monocytes from these patients by two different methods: superoxide dismutase (SOD) inhibitable cytochrome c reduction by O2- and nitroblue tetrazolium (NBT) reduction. Monocyte from patients with common variable immunodeficiency (CVI) demonstrated significantly enhanced ROS generation both unstimulated and stimulated (unopsonized zymosan and phorbol myristate acetate (PMA)). The enhanced oxidative burst response in CVI patients was found both with and without serum containing medium. Furthermore, serum from CVI patients did significantly enhance the oxidative burst response in monocytes from healthy blood donors compared with the effect of control serum. The enhanced ROS generation in CVI patients was significantly correlated with elevated serum levels of neopterin, reduced numbers of CD4+ lymphocytes in peripheral blood and occurrence of splenomegaly. In contrast to the CVI group, monocytes from patients with X-linked agammaglobulinaemia (XLA) did not show enhanced ROS generation. The increased oxidative burst response in monocytes from CVI patients most probably reflects in vivo activation of these cells. Our observations indicate the presence of a subgroup of CVI patients characterized by chronic immune activation particularly of monocytes. The enhanced ROS generation might be involved in immunopathogenesis (e.g. T cell dysfunction) and in the pathogenesis of clinical manifestations (e.g. malignancies and autoimmune disorders) in these patients.

Vitamin D metabolites, immunologic, virologic, and clinical parameters, and survival time were determined in 22 asymptomatic human immunodeficiency virus (HIV)-infected patients (CDC stage II/III), 31 symptomatic HIV-infected patients (CDC stage IV), and 28 HIV-seronegative controls. Significantly lower serum levels of 1,25-vitamin D (1,25D) were found in symptomatic patients (median, 34 pg/mL; 25th-75th percentile, 21-45) compared with controls (49 pg/mL; 39-59) and asymptomatic patients (45 pg/mL; 42-50). In HIV-infected subjects, the serum level of 1,25D was positively correlated with CD4+ cell counts in peripheral blood (r = .35, P < .05) and negatively correlated with the level of serum neopterin (r = -.36, P < .01). HIV-infected patients with abnormally low 1,25D (< 25 pg/mL) also had shorter survival times than other HIV-infected subjects (P < .01). Low 1,25D levels did not appear to be related to vitamin D deficiency.

Serum immunoreactive interleukin (IL-)1 alpha, IL-4, IL-6 and tumor necrosis factor (TNF) alpha were measured in 42 patients with primary hypogammaglobulinemia (25 common variable immunodeficiency (CVI), 10 congenital hypogammaglobulinemia (CH), 7 X-linked agammaglobulinemia (XLA), and in 21 healthy controls. The cytokine levels were correlated to other immunological parameters including serum levels of neopterin and soluble CD8 (sCD8) antigen. IL-6 was detectable in 48% and IL-4 in 36% of the CVI patients, but in none of the controls. Seventy-five percent of the CVI patients with elevated IL-4 levels had detectable IL-6. In contrast, no patients in the XLA group and only three CH patients had detectable IL-4 or IL-6 levels. TNF alpha and IL-1 alpha were detected in only a few serum samples with no significant differences between patients and controls. In the CVI group elevated IL-6 levels were significantly associated to reduced numbers of CD4+ and CD19+ lymphocytes, elevated levels of neopterin and sCD8 antigen, and occurrence of splenomegaly and bronchiectasis. The raised IL-6 levels were confirmed in longitudinal testing, probably reflecting a characteristic immunological dysregulation in these patients. Cytokine alterations may play a role in the pathogenesis of the immunodeficiency and for the clinical manifestations in CVI patients. Alternatively, elevated cytokine levels may be only a marker of chronic immune activation, particularly in monocytes, possibly delineating a distinct subgroup of patients within the heterogeneous CVI group.

Two EIAs (Medgenix and Quantikine) and a bioassay were used to measure tumor necrosis factor-alpha (TNF alpha) in serum samples from 73 human immunodeficiency virus type 1 (HIV-1)-seropositive patients and in samples from 2 control groups. All clinical groups of HIV-1-infected patients, regardless of concurrent illness, had significantly elevated levels of both types of soluble TNF receptors (sTNFRs) and immunoreactive TNF alpha (Medgenix EIA), with the highest concentrations among the AIDS patients. These TNF parameters were significantly correlated with reduced CD4+ lymphocyte counts. Only a few HIV-1-infected patients had detectable TNF alpha levels measured by the Quantikine EIA. TNF alpha bioactivity was significantly raised only in the AIDS group. Serially measured sTNFRs, expressed as sTNFR slopes, were significantly associated with survival in the patient group. The raised levels of immunoreactive TNF alpha and sTNFRs strongly indicate activation of the TNF alpha system during HIV-1 infection. Levels increase with disease progression and degree of immunodeficiency; thus, serially measured sTNFRs may give useful prognostic information in HIV-1 infection.

Expression of the gamma/delta T cell receptor (TCR) on CD3+ intraepithelial lymphocytes (IELs) was studied by two-colour immunofluorescence in duodenal tissue sections from healthy (n = 6) or infection-prone (n = 7) subjects with selective IgA deficiency (IgAD), and subjects (n = 4) with combined IgAD and IgG subclass deficiency. TCR gamma/delta+ IEL proportions in selective IgAD subjects (median 6.3%, range 1.0-41%) and in those with combined deficiency (median 4.5%, range 1.2-33%) were well within the range (0.3-38%) for histologically normal controls (n = 11), but the healthy IgAD subgroup tended to show raised TCR gamma/delta+ IEL proportions (median 13.6%) compared with the other two subgroups. Also the number of TCR gamma/delta+ IELs per intestinal length unit was relatively high (median 13.9/mm) in the healthy IgAD subjects, and significantly raised (P < 0.03) compared with controls (median 3.2/mm). Paired staining revealed that most TCR gamma/delta+ IELs in both selective IgAD (98%) and combined deficiency (99%) were CD8-, and a large fraction (median 84% and 63%, respectively) expressed the V delta 1/J delta 1-encoded epitope. The total number of CD3+ IELs (mostly CD8+) was similar to controls. IgAD subjects, and especially the healthy subgroup, had significantly increased serum concentrations of soluble CD8 (P < 0.0002), neopterin (P < 0.005), and beta 2-microglobulin (P < 0.007), which was similar to our previous observations in common variable immunodeficiency, and probably reflected stimulation of cell-mediated immunity. In addition, the increased TCR gamma/delta+ IELs might reflect a component of compensatory surface protection in the healthy IgAD subgroup.

Expression of the gamma/delta T-cell receptor (TCR) on CD3+ intraepithelial lymphocytes (IEL) was studied in situ by two-color immunofluorescence on duodenal tissue sections from 34 infection-prone, adult patients with various types of primary hypogammaglobulinemia, classical Bruton's, Bruton-like or congenital, and common variable immunodeficiency. TCR gamma/delta+ IEL proportions (median 4.3%, range 0.3-43.3%) were within the range (0.3-38.3%) for histologically normal controls (n = 11), and there was no significant difference between the three patient categories. The total number of CD3+ IEL (mostly CD8+) per intestinal length unit was significantly higher (P < 0.004) in patients than in controls. In addition, TCR gamma/delta+ IEL per length unit, as well as TCR gamma/delta+ IEL proportions, were significantly increased (P < 0.008 and P < 0.05) in 14 patients with intestinal villous atrophy. Paired staining revealed that most (approximately 94%) TCR gamma/delta+ IEL in B-cell deficiency were CD8-, and a large fraction (approximately 67%) expressed the V delta 1/J delta 1-encoded epitope. No relationship was found between CD3+ or TCR gamma/delta+ IEL and the number of CD3+, CD4+, CD8+, and B lymphocytes or the CD4:CD8 ratio in peripheral blood. TCR gamma/delta+ IEL thus appeared to maintain a normal distribution in B-cell deficiency, except for being increased in patients with villous atrophy. Enhanced T-cell-mediated immunity, as possibly reflected by the numerical increase of CD3+ IEL, might compensate for a deficient mucosal B-cell system.

A group of asymptomatic HIV-infected patients (CDC II and III) was followed-up over a two year period with semi-annual neuropsychological testing. Of the total sample of 36 subjects, all were retested at test two (T2), 19 at test three (T3) and 13 at test four (T4). A subgroup of subjects was further tested on a simple and a complex task of reaction time. The CD4+ and CD8+ lymphocyte counts were measured in peripheral blood. According to our criteria, no patient could be defined as neuropsychologically impaired. A significant improvement in performance was found from T1 to T2 and from T2 to T3, with a leveling off between T3 and T4. No associations were observed between reaction time and changes in neuropsychological test results and immunological parameters. Our results indicate that neuropsychological impairment does not develop gradually in the asymptomatic stages of HIV-infection. Furthermore, measurements of reaction time do not seem to have any prognostic significance neither for neurocognitive function nor for immunological status as measured by us.

The level of the antifungal leukocyte protein calprotectin was determined in parotid saliva from 44 individuals with infection due to human immunodeficiency virus (HIV) and 19 healthy HIV-seronegative controls. Nine of the HIV-infected subjects suffered from oral candidiasis. Similar calprotectin levels were found in subjects with HIV infection as a whole group and in controls. When HIV-infected individuals with or without oral candidiasis were compared, the calprotectin level was significantly lower in the former group (67 micrograms/L vs. 216 micrograms/L). We suggest that calprotectin may play a role in the defense against oral candidal infections in HIV-infected patients, although several other antimicrobial factors also are probably operative.

A total of 24 asymptomatic HIV-infected patients (CDC II/III) and 27 HIV-negative controls were tested for speed of reaction and for general neuropsychological functioning. Reaction time was assessed with two computerized tests with differing levels of cognitive complexity. The results show that the asymptomatic HIV-positive patients have a significantly longer mean reaction time to simple and complex stimuli (SRT p < 0.001, CPT p < 0.05), and a significantly greater standard deviation (SD) (SRT-SD p < 0.005). No significant differences were observed on any of the clinical neuropsychological tests, or in the number of false positive (FP) or non-responses to stimuli (NR) from the CPT. The results indicate that asymptomatic HIV-infected patients are slower and have a greater intra-subject variability in speed using a simple test for reaction time. The difference is less pronounced when doing a more demanding cognitive task and not significant in a test of visuo-motor coordination or on other clinical neuropsychological tests. Emotional state or cognitive strategies affecting speed/accuracy trade-off do not account for the findings.

Serum neopterin levels were analysed in 43 patients with primary hypogammaglobulinaemia (25 common variable immunodeficiency (CVI), 12 congenital hypogammaglobulinaemia (CH), six X-linked hypogammaglobulinaemia (XLH)), and in 33 healthy controls. The neopterin values were correlated to lymphocyte subset counts in peripheral blood, lymphocyte mitogen responses and clinical and histological manifestations in the study group. Serum neopterin levels were significantly elevated in all subgroups of patients and particularly in the CVI groups where the highest concentrations were found (P less than 0.001, CVI versus controls). Furthermore, in CVI and CH patients elevated neopterin levels were strongly correlated to decreased number of CD4+ lymphocytes (rs = -0.61, P less than 0.005 and rs = -0.83, P less than 0.001, respectively). In the CVI group high neopterin levels were also significantly correlated to low number of circulatory B (CD19+) lymphocytes (rs = -0.58, P less than 0.05). Both patients with moderately and those with severely depressed lymphocyte mitogen responses had significantly higher neopterin levels than those with normal responses. In addition, high neopterin levels were significantly associated with the occurrence of splenomegaly and nodular intestinal lymphoid hyperplasia. The immunological findings were consistently observed in longitudinal testing, and appeared to be characteristic for the individual patient. High serum neopterin levels are thought to be a marker for hyperactivity in monocytes/macrophages, and dysfunction of these cells may therefore be associated with fundamental immune pathology in some subgroups of primary hypogammaglobulinaemia.