Costimulation of CD4+ and CD8+ T cells through CD26: the ADA-binding epitope is not essential for complete signaling.

It was previously shown that CD26 (DPP IV, EC 3.4.14.5) is a binding site for adenosine deaminase (ADA, EC 3.5.4.4) on T cells and that costimulation by some anti-CD26 monoclonal antibodies (mAbs) and anti-CD3 induces CD4+ T cell proliferation. The CD26 epitopes involved in costimulation, the precise sequence of the events preceding proliferation, and the response of CD8+ compared with CD4+ T cells to CD26 were not extensively studied. We therefore compared the effects of the novel TA5.9 anti-CD26 mAb, recognizing an ADA-binding epitope, and the clearly distinct anti-Ta1 reference anti-CD26 mAb for their costimulatory properties in various T cell subsets. Both purified CD4+ and CD8+ T cells proliferated upon costimulation with anti-CD3 and either anti-CD26 mAb, but anti-TA5.9 mAb induced a more potent response than anti-Ta1. Either anti-CD26 mAb, together with anti-CD3, caused a similar sequential up-regulation of CD69, CD25 (IL-2R alpha), and CD71 (transferrin receptor) expression on CD4+ and CD8+ T cells. The activation markers appeared faster on the CD45R0+ than on the CD45R0- subsets. After costimulation, CD4+ T cell cultures contained significant amounts of the Th1 cytokines IL-2, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha). In CD8+ T cell cultures relatively more IFN-gamma and TNF-alpha but almost no IL-2 was measured after triggering of CD3 and CD26. Our data demonstrate that the recognition of the ADA-binding epitope is not a prerequisite for the costimulatory capacity of anti-CD26 mAbs. Both CD4+ and CD8+ T cells and their CD45R0- and CD45R0+ subsets are sensitive to various aspects of activation via CD26, but the magnitude and/or kinetics differ according to the anti-CD26 used and the T cell subset studied.

Immunological comparison of HIV-1-, HIV-2- and dually-reactive women delivering in Abidjan, Côte d'Ivoire.

OBJECTIVES: To compare the basic immunological changes induced by HIV-1 and HIV-2 infection and to assess the immune status of subjects serologically reactive to both HIV-1 and HIV-2 (dually-reactive). DESIGN: Immune parameters were studied cross-sectionally in women delivering in Abidjan, Côte d'Ivoire, West Africa, where HIV-1 and HIV-2 are endemic. In this area, a significant number of sera from infected individuals are reactive to both HIV-1 and HIV-2. SUBJECTS AND METHODS: Two hundred and twenty-eight women delivering in a major maternity clinic were screened for HIV-1 and HIV-2 using an enzyme-linked immunosorbent assay. Seropositivity was confirmed by Western blot. The immune parameters studied were CD4+ and CD8+ lymphocyte subsets, immunoglobulin (Ig) serum levels, neopterin and beta 2-microglobulin (beta 2M) serum levels. RESULTS: Similar but less pronounced immune changes were present in HIV-2-reactive subjects compared with HIV-1- and dually-reactive subjects. The observed differences between the HIV-seropositive groups could not be explained by differences in age or disease stage but paralleled differences in the frequency of persistent generalized lymphadenopathy (PGL). The intermediate immune profile of HIV-2-reactives (between seronegatives and HIV-1- and dually-reactives) was most clearly reflected by the number of CD8+ lymphocytes, the CD4:CD8 ratio and the IgG serum level. Median neopterin and beta 2M levels, though significantly increased in all HIV-seropositive groups, did not differ significantly between HIV-2-, HIV-1- and dually-reactives. CONCLUSIONS: HIV-2 infection is associated with typical HIV-related immunological changes. Immunologically, dually-reactives resemble HIV-1-reactives more closely than HIV-2-reactive subjects.

A useful method for determining class-specific rheumatoid factors with computerized analyses of data.

A simple and sensitive enzyme-linked immunosorbent assay (ELISA) was developed to determine rheumatoid factors (RFs) of IgG, IgA and IgM class. Standardisation was performed with a standard reference serum for IgM-RF, calibrated according to the WHO preparation, and with the serum of a patient containing high levels of IgA- and IgG-RF. The sigmoidal shaped calibration curve was fitted with a computerized four parameter logistic model with simplified mathematical computations. This method provided to be more accurate for measuring RF levels, as judged by the smaller residuals, than logit or log-linear transformations. The considerable reduction in processing time, which is obtained by the computerized analysis of data, makes this method of class-specific RF determination suitable for routine analysis.

Renal disease in chronic experimental Trypanosoma gambiense infections.

Two recently isolated stocks of Trypanosoma brucei gambiense of human origin gave rise to a moderate to severe proliferative or membranoproliferative glomerulonephritis in 40 or 44 NMRI and C57BL/6J mice infected for 7-22 weeks. Extensive granular deposits of C3, IgG1 and IgG3 were found in the mesangium, together with smaller quantities of IgG2a, IgG2b, and IgM. No trypanosomal antigen could be detected in the deposits though specific anti-trypanosoma antibodies were found in kidney eluates. By electron microscopy, a conspicuous proliferation of mesangial and endothelial cells was observed and electron-dense deposits were seen in a mesangial and subepithelial localization. With one of these trypanosome stocks, four of seven Wistar rats infected for 9-15 weeks developed morphologically similar glomerular lesions. Four other trypanosome stocks did not evoke renal alterations in 17 other rats infected for 13-56 weeks. Experimental infection in mice or rats appears to be a suitable model for the study of renal disease in chronic African sleeping sickness.

HIV antigen detection in circulating immune complexes.

Various methods were evaluated for their effectiveness in releasing HIV antigen (Ag) from artificial immune complexes (IC) and from IC present in serum from HIV antibody (Ab) positive subjects. The most effective methods for recovering HIV Ag from IC were those which included a denaturation step to prevent reassociation of Ag with Ab. IC precipitation in 2.5% polyethylene glycol followed by acid treatment with 1 M glycine.HCl (pH 2) for 10 min at 70 degrees C in the presence of 0.05% SDS gave very satisfactory results. With this method, IC were detected in sera from HIV antibody positive Caucasian subjects at all stages of infection. After HIV IC dissociation, HIV Ag was detected in a significant number (8/17 or 47%) of asymptomatic subjects. IC were most prevalent during the late stages of infection. A substantial increase in HIV Ag positivity was also observed in 20 Senegalese HIV Ab positive sera. After HIV IC dissociation HIV antigen detection increased from 2/20 to 12/20. The relevance of IC detection is discussed.

Spontaneous glomerular basement membrane changes in the golden Syrian hamster (Mesocricetus auratus): a light and electron microscope study.

Changes in apparently healthy hamsters, consistent with proteinuria, are reported, but no IgG deposits or amyloid in the glomeruli were detected. Further investigation is required into the significance and the aetiology of these, as yet, obscure alterations.

[Urinary bilharziasis]. / La bilharziose urinaire.

A short account is given of present views on urinary schistosomiasis or bilharziasis. The incidence of infections is increasing in endemic areas of Africa and the near east, as a consequence of irrigation programs and hydroelectric power development. Urinary schistosomiasis is a disease of children and young adults. The serious consequences, obstructive uropathy due to more or less irreversible ureteral lesions, and cancer of the bladder, less directly related to the infection, appear but later in life. Diagnosis is still based on parasitology and serology but ultrasonography has proven to be an important means to evaluate the extent of lesions of the urinary tract, especially in developing countries. Praziquantel was a major development in the medical treatment and cures easily the infection. Some irreversible consequences have however to be treated surgically. Schistosomiasis is still an important cause of morbidity and mortality in medically backward endemic countries. The control of the disease aims at reducing morbidity and mortality, consequences of the infection, rather than to avoid infection itself. It is based on mass treatment of school age children, together with focal molluscacides at places where people have contacts with water. Vaccination will be available in the near future and will be a welcome addition to other control measures, but will not be able to interrupt transmission on its own. Only economic development will solve in the long term this social African problem.

[Epidemiology of Kaposi's sarcoma in Africa]. / Epidémiologie du sarcome de Kaposi en Afrique.

The epidemiology of Kaposi's sarcoma in Africa south of the Sahara is reviewed. The disease is characterized by its high incidence in natives only and by the presence of the lymphadenopathic form of children with fast evolution, but is otherwise not very different from the classical form. Incidence increases with age. The mean younger age of patients is a consequence of the demographic structure. The disease prevails always in males even, though to a lesser extent, in children. Maximal incidence is observed in the center of the continent and decreases at distance from the equator. No defined risk factor has been identified, geographical, tribal or socio-economical. Associations to other malignancies, especially lymphomas, appear uncommon in Africa, but might be underestimated. The three main clinical forms of the disease are probably epidemiologically different and the infantile form could be related to some unidentified immunosuppressive factor. The disease appears ancient in Africa and not directly related to the present A.I.D.S. epidemic, though a recent increase in aggressive Kaposi's sarcoma cases may be associated with it.

The prevalence of intestinal parasites in two suburbs of Kinshasa (Zaire) and their relation to domestic water supplies.

The prevalence of common intestinal nematodes (Ascaris, Trichuris and hookworms) and protozoa (Entamoeba coli, E. histolytica, Giardia, Trichomonas) was compared in two suburbs of Kinshasa, one provided with piped water and the other one with wells. Pit latrines were used in both places. No significant differences were observed for the worms, but the prevalence of the four common protozoa was approximately twice as high in the community without piped water supply. It is concluded that providing piped water has some impact on the transmission of potentially pathogenic intestinal protozoa, but no influence, at least on the short run, on intestinal worms. Infections with Giardia and Trichomonas were significantly associated.

Kaposi's sarcoma in Zaire.

Kaposi's sarcoma (KS) was recognized in 1948 in Zaire, where it has probably always been endemic. In 1957 a relative frequency of KS of 9% of all biopsied cancers was found. There are fluctuations in incidence within the country, with a higher incidence in the east, where it was estimated in 1960 at about 5-10 cases per 100 000 per year in males, with a relative frequency of 14% of all malignant male tumours and a M/F ratio higher than 10/1. More recently KS accounted for roughly 17% in males and 2% in females of all malignant biopsied tumours in north-east Zaire (1969-1983). In 2 years (1982-1983), 26 male and 5 female KS cases were histologically confirmed in an area of eastern Zaire with a population of roughly 300 000 people. It has been suggested, on the basis of this high incidence of KS and of the recent identification of African AIDS cases, that the hypothetical transmissible agent in AIDS might originate from Central Africa. The frequency of KS in African AIDS cases was low (16%) as compared to that in the USA. The M/F ratio of AIDS was 6/4 and that of AIDS-associated KS 1/1. AIDS-associated cases occurred in young adults and were generalized and fulminating. African KS occurs at a younger modal age than in Caucasians, which is the combined result of increasing incidence with age and of the high proportion of young people in the population in Africa but not of a higher risk for younger male adults, as in AIDS.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of IgM-rheumatoid factor interference in the determination of total serum IgE and IgE-containing circulating immune complexes.

IgM-rheumatoid factor (RF) interference in the determination of total serum IgE and IgE-containing circulating immune complexes (IgE-CIC) was studied by inhibition experiments in vitro comparing a new ELISA technique free of IgM-RF interference with more widely used RIA methods. It was shown that a considerable overestimation of the IgE content in CIC can exist when high levels of IgM-RF are present in the same serum. The clinical part of this study revealed a dramatic fall in prevalence of IgE-CIC in patients with rheumatoid arthritis (RA) with the ELISA technique, compared with the more conventional RIA method (respectively 1/20 compared to 12/20 positive for IgE-CIC). In these patients, there was a good correlation between the level of IgM-RF and the amount of IgE detected in the CIC by the RIA method (r = 0.87) whereas the RF-interference free ELISA method showed no correlation between these two parameters (r = 0.06). Total serum IgE determination with a solid phase RIA was also influenced by IgM-RF interference, whereas the PRIST method was not affected by the presence of IgM-RF. In conclusion, in patients with rheumatic diseases, IgE-assays using polyclonal rabbit or sheep anti-IgE antibodies are not appropriate and monoclonal anti-IgE antibodies that have been proved not to interfere with IgM-RF should be advocated.

Autoantibodies to intermediate filaments in experimental infections with Trypanosoma brucei gambiense.

Sera from rats with chronic Trypanosoma brucei gambiense infection were tested for autoantibodies by an indirect immunofluorescence assay. All the sera contained IgM autoantibodies which reacted with blood vessel walls. On cultured vascular smooth muscle cells positive sera reacted with cytoplasmic filaments which were rearranged into perinuclear coils of filaments in colcemid-pretreated smooth muscle cells. These observations strongly suggest that the cytoplasmic autoantigens are intermediate filaments (I.F.). It is probable that the anti-intermediate filament autoantibodies result from polyclonal lymphocyte activation, since in rats experimentally infected with T.b. gambiense the appearance of these autoantibodies occurs already 1 week post-infection.

Schistosoma mansoni: impaired clearance of model immune complexes consisting of circulating anodic antigen and monoclonal IgG1 in infected mice.

The clearance of schistosome-specific model immune complexes (IC) consisting of circulating anodic antigen (CAA), a gut-associated excretory-secretory antigen, and radiolabeled monoclonal antibody (IgG1) was investigated in mice with a light and heavy Schistosoma mansoni infection and in noninfected control animals. The size analysis of the in vitro prepared and injected IC, as determined by density gradient centrifugation, revealed a wide peak at 11S. In infected animals the injected IC were cleared at a significantly lower rate than in control mice. This was attributed to a decreased uptake of IC by the liver in infected mice. In heavily infected mice, 30 min after injection of 11S IC, 8S, 11S, and greater than 11S IC were present in the serum, whereas only small 8S IC were detected in the serum of lightly infected animals and noninfected controls. Immune complexes were also present in the serum of heavily infected mice 30 min after injection of antibody and were detectable as 11S and greater than 11S IC. The importance of this study is twofold. First, these results show that schistosome-specific monoclonal antibodies can be used in the production of model immune complexes applicable in clearance studies. Second, our findings might be of importance when the possible pathogenicity of circulating IC in schistosomiasis is considered.

Neutrophil activation by IgE-containing circulating immune complexes of patients with connective tissue diseases.

In an earlier study, we reported IgE-containing circulating immune complexes (CICs) in 66.6% of the patients with rheumatoid arthritis who were studied, especially in those with extra-articular manifestations. The present study was undertaken to examine the possible role of these immune complexes in inflammatory cell activation. Twelve patients with classic or definite rheumatoid arthritis, two with primary Sjögren's syndrome, and three patients with systemic lupus erythematosus were studied. Of these 17 patients, 10 were IgE-containing CIC positive, and seven patients were IgE-containing CIC negative. Polyethylene glycol-precipitated IgE-containing CICs and IgG-containing CICs of these patients were coated on plastic wells and incubated with suspensions of neutrophils. As a parameter of cell activation, superoxide release (SOR) was measured by cytochrome C reduction in the supernatant after 30, 60, and 90 minutes. There was a significant SOR up to 38% of the zymosan control when IgE-containing CICs were incubated with neutrophils. Furthermore, there was a significant correlation between the level of IgE-containing CICs and the amount of SOR, but not between the level of IgG-containing CICs and the amount of SOR. These results suggest a possible role for IgE-containing CICs in the activation of inflammatory cells in connective tissue diseases.

HLA studies of endemic African Kaposi's sarcoma patients and matched controls: no association with HLA-DR5.

In the search for a genetic factor involved in the etiology of Kaposi's sarcoma, several studies have recently focused on a significantly increased HLA determinant, DR5, as well as a decreased DR3, among patients with both the classical and the AIDS-related form of Kaposi's sarcoma. To test the consistency of this phenomenon, we analysed the frequencies of HLA immunogenetic markers in 23 histologically confirmed Kaposi's sarcoma patients from Central Africa, where this tumor is endemic, and a local sex- and tribe-matched control group. No definite association was observed for any of the HLA antigens, including DR5 and DR3. We were not able to support the hypothesis that the same HLA-associated immune susceptibility factors are involved in all types of Kaposi's sarcoma.

Experimental infections of laboratory rodents with recently isolated stocks of Trypanosoma brucei gambiense. 2. Histopathological investigations.

Histopathological findings on brain, heart, liver, and spleen of albino rats and white mice, infected with different stocks of Trypanosoma brucei gambiense of human origin are presented. Classical brain lesions, including chronic inflammation of the choroid plexuses, were observed in all infected animals, the severity of which increased with the chronicity of the disease. Parasite stocks which gave rise to a less acute course of the disease more often induced myocarditis, while brain lesions were less pronounced, suggesting that virulence of the parasites is more closely related to the advent of myocarditis than to the appearance of brain lesions. Liver lesions were not obvious. In spleens, a variable and often very pronounced degree of lymphoid hyperplasia was observed.

Effect of partial portal vein ligation on immune glomerular deposits in Schistosoma mansoni-infected mice.

Portosystemic collateral circulation was induced in mice infected or not with Schistosoma mansoni by partial ligation of the portal vein. The effects on immune glomerular deposits were assessed and compared to findings in unoperated infected, sham-operated and normal animals. Mesangial immune deposits of IgM, IgA, IgG and C3 were found by immunofluorescence significantly more frequently in operated than in unoperated infected mice. Schistosomal antigen was demonstrated in 5 animals out of 38 infected ones, 4 of the 5 having been operated. The results suggest that portosystemic collateral circulation might be an important factor in the genesis of schistosomal glomerulopathy, perhaps by diversion of antigens or complexes from the Kupffer cells. The high percentage of glomerular immune deposits found in uninfected ligated animals (71-4%) suggests furthermore that non-specific immune factors possibly of intestinal origin could be involved.

Immunohistochemical characterization of the mononuclear cells in the brain of the rat with an experimental chronic Trypanosoma brucei gambiense infection.

The distribution of T-cell subsets, B cells, and class II MHC antigens was examined within the CNS of rats chronically infected with Trypanosoma brucei gambiense, using appropriate mouse monoclonal antibodies. The mononuclear infiltrates of the leptomeninges and the perivascular areas (Virchow-Robin spaces) were composed of IgM-producing plasma cells and Mott cells and T-helper/inducer cells. Cells defined phenotypically as suppressor/cytotoxic T cells were rare. Anti-Ia reactive cells were also abundant in these inflammatory lesions and in the white matter, representing Ia-expressing neuroglial cells, B cells, activated T cells, and macrophages. The Ia-positive neuroglial cells, possibly acting as accessory cells, associated with numerous T-helper/inducer cells and cells from the B-cell lineage, suggest that a T-dependent B-cell immune response can be initiated within the CNS of rats with a chronic T. b. gambiense infection.

Schistosomicidal effects of Pavetta owariensis and Harrisonia abyssinica in mice infected with Schistosoma mansoni.

The schistosomicidal properties of ethanol and acetone extracts of Pavetta owariensis and an ethanol extract of Harrisonia abyssinica were assessed in mice infected with Schistosoma mansoni. Spleen weight, number of adult worms and eggs and size of liver granulomas were the main parameters studied. All P. owariensis extracts containing proanthocyanins were shown to cause a reduction in size of periovular granuloma formation in the liver. This effect was most pronounced with ethanol extracts of both "white bark" and "red bark" varieties of the plant. Acetone extracts of P. owariensis "red bark" variety, containing the highest concentration of proanthocyanins, caused a marked reduction of egg numbers in the liver and intestine whereas the ethanol extract of H. abyssinica proved to be inactive.

The implantation of sepharose beads in mouse livers as an aid in the study of hepatic schistosomal fibrosis.

An experimental model of schistosomal portal fibrosis is described. Sepharose beads the size of schistosome eggs, loaded or not with soluble egg antigen (SEA) from Schistosoma mansoni, are injected into the coecal vein of C3H/Sn mice and become embolized in the liver. Only SEA-coated beads evoke a granulomatous reaction; this is enhanced by simultaneous priming of the mice with spleen cells from Schistosoma mansoni-infected syngeneic animals. The fibrosis, which ensues around the beads, is stable and is much more evident after priming. Preliminary collagen tissue immunotyping reveals the presence of collagen deposits of types I and III collagen. Type IV collagen remains unchanged in the portal tracts. The model appears to be well suited for studies of the pathogenesis of portal fibrosis.