One-hundred spleens from HIV-infected patients which were studied by conventional morphological and immunohistochemical methods exhibited alterations in lymphatic tissue as well as in the mononuclear phagocyte system (MPS); these were probably related directly to HIV infection of lymphocytes and MPS cells. There was ample evidence of impairment of macrophage activation, accompanied by decreased expression of functional markers and an enhanced reactivity with antibodies against S100 protein. This impairment of macrophage function is related to the particular morphology and aggressive clinical behaviour of some opportunistic infections in AIDS.

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

In situ immunophenotyping of lymphocytes/macrophages: grading of lymphadenopathy, staging and pathophysiology of HIV infection.

Histological changes in lymph nodes in HIV1-related lymphadenopathy were analysed in 106 lymph node biopsies and in lymph nodes of 140 autopsy cases. A classification system of five stages was established on the basis of histological and immunohistochemical studies. The analysis confirmed a close correlation between the progression of HIV1-related disease and our staging system. Although the classification is chiefly based on histological and immunohistochemical changes of the follicles, other frequently seen findings are included. Alterations in the interfollicular tissue, e.g. vascular proliferation and lymphocyte depletion, correspond to an increasing concentration of macrophages within this tissue. In HIV1 infection, the macrophages appear to produce high concentrations of angiogenic factors responsible for the frequent and sometimes extreme lymph node vascularization. Since the vascular proliferation can be subject to regression and sclerosis as seen in autopsy cases, the macrophages may lose the ability to produce large amounts of angiogenic factors in the final stage of the disease.

AIDS-Related Complex↗

PubMedDate not supplied

Pathophysiological mechanisms of HIV-induced defects in haematopoiesis: pathology of the bone marrow.

Bone marrow biopsies of 96 HIV1-infected patients were analysed histologically and by immuno- and enzyme histochemical techniques. Independently of the stage of disease, the bone marrow frequently exhibits hypercellularity and features of dysplastic haemopoiesis combined with mesenchymal alterations. In situ immunohistochemical analysis shows that there is a marked reduction in expression of the proliferation-associated nuclear antigen recognized by the Ki67 antibody. Comparison with non-infected controls reveals that there is a reduction in CD34+/myeloperoxidase-/naphthol AS-D chloroacetate- progenitor cells and an overproportional decrease in CD8+ lymphocytes in the bone marrow. Double staining revealed the presence of gag-coded HIV1 proteins in the above-mentioned CD34+ progenitor cells, in myelopoiesis cells, megakaryocytes and above all, in CD68+/acid phosphatase+ and alkaline phosphatase+ bone marrow reticular cells. From the latter results, it was concluded that HIV1-infected reticular cells may be disturbed in their ability to produce factors responsible for the short-range regulation of haemopoietic activity.

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

Growth patterns, inflammatory cells and prognosis in AIDS-associated Kaposi's sarcoma.

AIDS-associated cutaneous Kaposi's sarcomas (KS) in 35 patients were the subject of a histopathological and immunohistochemical study. Histologically, the tumours were classified as granulation-tissue-like (GR, n = 10), angioma-like (A, n = 11), angiosarcoma-like (AS, n = 9) and as spindle cell type (SP, n = 5). There was a distinct relationship between the main growth patterns of KS and the CD4+ peripheral blood lymphocyte (PBL) count. A decrease in numbers of CD4+ PBL was correlated with an increase in the frequency of AS and SP growth patterns. There were no correlations between growth pattern and concentrations of protein S100+, MT1+, CD45+ and MAK387+ tumour-associated inflammatory cells. When the GR type was grouped together with the A type, and the AS type with the SP type, statistically significant differences emerged for CD45+ and MT1+ tumour-associated cells, and for survival time, respectively. In all these instances, the GR/A group values were higher than those of the AS/SP group. Additionally, linear correlation analysis revealed an inverse relationship between the concentrations of CD4+ PBL and of protein S100+ tumour-associated inflammatory cells within the GR/A group. In contrast to what is observed with certain tumours of HIV-negative patients, this suggests that a high concentration of protein S100+ tumour-associated cells may indicate a worse prognosis in the GR/A group. The concentration of MAK387+ tumour-associated macrophages did not vary as a function of the growth patterns, even when they were grouped together as described above.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

Functional abnormalities of monocytes/macrophages in HIV1-infected patients as demonstrated by the skin window procedure.

Skin window (SW) tests were performed in ten HIV1-infected patients and in ten healthy volunteers. The chemotaxis of monocytes/macrophages is weakened in AIDS patients, since the number of monocytes/macrophages attracted by the SW stimulus decreases in HIV1-infected subjects during the observation time, whereas the number increases in control individuals. HLA-DR expression decreases faster in AIDS patients than in healthy volunteers. Giant cell formation occurs and disappears earlier in HIV1-infected patients than in healthy control individuals. The results suggest that, at least in part, the impairment of chemotaxis and other functional abnormalities of mononuclear phagocytes are caused by their accelerated aging in HIV1-infected patients.

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

Distinct antigen-induced cytokine pattern upon stimulation with antibody-complexed antigen consistent with a Th1-->Th2-shift.

The consequences of complexing an antigen with specific antibodies upon the antigen-induced immune response were studied with respect to secretion of interleukin-2 (IL2), interleukin-6 (IL6), interleukin-10 (IL10) and interferon-gamma (IFN gamma). We found that the tetanus toxoid antigen-induced cytokine pattern was mainly dependent on the antigen/antibody ratio. While tetanus toxoid antigen alone induced a typical Th1-like cytokine pattern with high levels of IL2 and IFN gamma, equivalent or antibody-excess immune complexes induced a marked secretion of IL6 and IL10 while failing to induce IL2 and IFN gamma secretion. As the cytokine pattern plays a crucial role in the development of specific immune responses towards infectious agents, our results indicate that immune complexes--typically occurring during the course of chronic infectious diseases--may play an important role in the modulation of immune responses. Since a shift from Th1 to Th2 immune responses has been discussed as a pathogenetic factor in HIV-induced immunodeficiency, the role of circulating immune complexes as a possible cause for this shift should be considered.

Adult↗

PubMedDate not supplied

Distribution and infection of Langerhans cells in the skin of HIV-infected healthy subjects and AIDS patients.

The in situ content of cells of the reticuloendothelial system and lymphatic cells was examined in the skin of eight symptom-free HIV-positive individuals, three AIDS patients and eleven healthy immunocompetent volunteers. The epidermis was obtained in vivo by the suction blister technique. The numbers of CD68+, CD3+, CD8+, CD25-(IL2R)+ and HLA-DR+ intraepidermal cells proved to be independent of the number of CD4+ peripheral blood lymphocytes. At the same time, the intraepidermal concentrations of these cells were generally low in symptom-free HIV-infected individuals. The strong inverse correlation between the number of epidermal Langerhans cells (LC) and the severity of immunodeficiency was quantitatively confirmed; an increase in LC in symptom-free HIV-infected individuals was found. Thus, the reduction in these cells which was observed in the epidermis of AIDS patients began at a significantly elevated level. In contrast to results from other studies, in AIDS patients, in the present study, the concentration of epidermal LC did not differ significantly from that of healthy immunocompetent volunteers. The immunohistochemical technique can be as effective as in situ hybridization for the detection of HIV in the skin. Our results suggest that the viral load of the skin is rather low in HIV-infected subjects. HIV was demonstrated in one cell of one AIDS case by in situ techniques and this result was confirmed by a polymerase chain reaction examination using the same amount of tissue as for the in situ techniques.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

In vitro analysis of HIV- and non-HIV-infected monocytes/macrophages from healthy subjects and patients with malignant tumours.

Phenotype and release of IL1 alpha, IL6 and TNF alpha were examined in monocytes derived from 14 healthy donors and 24 tumour patients in a long-term culture using immunohistochemical, RNA in situ hybridization and ELISA techniques. After stimulation with LPS and IFN-gamma, blood monocytes and resulting macrophages showed an overall decrease in cytokine release from the 6th to the 48th day of culture, both with and without HIV infection. HIV infection provided a strong stimulus for IL6 production and a weak stimulus for IL1 alpha production, whereas TNF alpha release decreased after HIV infection. Non-HIV-infected monocytes/macrophages from patients with malignancies showed significantly reduced cytokine production after stimulation, in comparison with monocytes/macrophages from healthy subjects. In vitro HIV infection of monocytes from tumour patients caused severe depression of cytokine production during the whole time of observation. In all experiments a parallel was observed between the extent of cytokine release and the presence of young/early inflammatory macrophages as identified by the antibody MAC387/27E10 in situ. In contrast, cytokine expression assessed semiquantitatively by immunohistochemical staining in situ showed discordant development, since it increased during long-term culture, while supernatant concentrations of cytokines declined. Simultaneously, significant cytokine RNA levels could be found in macrophages from the 6th to the 24th day of culture, as detected by in situ hybridization. After 48 days of culture, no more cytokine RNA was detectable, while macrophages continued to exhibit distinct immunohistochemical positivity for cytokine antibodies. From these results, it is concluded that macrophages kept in culture for a long period become inhibited in their secretion. HIV has an ambivalent effect on cytokine production in Mo/Mac, resulting in an increase in IL6 and IL1 as well as a decrease in TNF alpha production. Mo/Mac of non-HIV-infected tumour patients show significantly reduced cytokine production in comparison with Mo/Mac from healthy subjects. The sum of the HIV infection in vitro and the tumour burden results in a dramatic reduction in cytokine release in Mo/Mac. This finding may provide a possible explanation for the specific aggressive behaviour of non-Hodgkin's lymphoma and Hodgkin's disease in AIDS.

Antigens, Differentiation↗

PubMedDate not supplied

Cytokine expression of HIV-infected monocytes/macrophages at the single-cell level.

Monocytes of healthy donors were infected with HIV1 in vitro: 14-21 days after infection 50-70% of the cells produced p24 HIV1 antigen as detected with anti-p24 immunostaining; infected cultures showed enhanced secretion of interleukin-6 (IL6), interleukin-8 (IL8) and tumour necrosis factor alpha (TNF-alpha). The expression of cytokines on the single-cell level was further analysed by in situ hybridization using nonradioactive digoxigenin for detection. HIV1 (p24+) -producing cells were compared with non-HIV (p24-) -producing cells. All morphological subtypes of macrophages showed HIV production; no difference in cytokine expression was observed. Immunocytochemistry of HIV-infected and uninfected cultures also showed no difference in the pattern of IL1-beta, IL6, IL8 and TNF-alpha protein expression in the cells.

Cytokines↗

PubMedDate not supplied

Signs of Kupffer cell involvement in productive simian immunodeficiency virus infection in monkey liver.

The livers of 21 rhesus monkeys inoculated with SIVmac251 were examined at 4 days to 39 months after infection. SIV antigens were detected in the cytoplasm of Kupffer cells (KC), macrophages and lymphocytes in two-thirds of the livers tested. The number of cells containing viral proteins substantially increased during the development of the disease, and KC were the main cell type displaying SIV proteins at an advanced stage of infection. Mature and immature lentiviral particles were found in cytoplasmic vacuoles or associated with worm-like structures in KC, indicating that SIV replication could occur within resident liver macrophages. Another sign of the permissiveness of KC was the formation of multinucleated giant cells within the hepatic sinusoids. Some of these cells containing 3-6 nuclei still retained ultrastructural features of KC. Most of them contained a high quantity of viral particles. Numerous lymphocytes displaying signs of apoptosis were taken up by KC, especially at the beginning of infection. Hyperplasia and hypertrophy of KC were noted in the course of SIV disease in the liver. The present data indicate that KC can be infected in vivo and may serve as a reservoir for SIV during the progression of the disease.

Animals↗

PubMedDate not supplied

Familial erythrophagocytic lymphohistiocytosis (Farquhar's disease): involvement of the central nervous system.

The clinical course and the postmortal pathological findings in a female newborn showing parental consanguinity are presented. One week afterbirth, the infant developed fever, hepatosplenomegaly and polyserositis. Rapidly progressing immunodeficiency due to pancytopenia led to pneumonia and untreatable respiratory distress with fatal outcome after 2 weeks. Autopsy findings revealed multisystem lymphohistiocytic infiltration with marked erythrophagocytosis. Neuropathological findings included lymphohistiocytic leptomeningitis, perivascular cuffing by lymphohistiocytic infiltrations in the cerebral white matter, predominantly in subependymal location, and multifocal lymphohistiocytic infiltrations of the cerebral grey matter and the cervical spinal cord. Erythrophagocytosis was the histopathological hallmark at all sites. Regarding the fatal clinical course, the medical history of parental consanguinity and the histopathological features, postmortem diagnosis was familial erythrophagocytic lymphohistiocytosis (FEL, Farquhar's disease). The present case is discussed with focus on CNS involvement in FEL by reviewing the relevant literature.

Central Nervous System↗