Angioimmunoblastic lymphadenopathy with dysproteinemia in homosexual men with acquired immune deficiency syndrome

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is a well-described clinicopathologic entity that tends to occur in older persons. A recently described syndrome, the acquired immunodeficiency syndrome (AIDS), occurring predominantly in young homosexual men, shows considerable clinical overlap with AILD. We studied two cases clinically typical of AIDS in which lymph node biopsies revealed AILD.     

Precipitable immune complexes in healthy homosexual men, acquired immune deficiency syndrome and the related lymphadenopathy syndrome.

Increased levels of 3% PEG precipitable circulating immune complexes (CIC) were found in healthy homosexual men, in homosexual patients with the acquired immune deficiency syndrome (AIDS), and in the AIDS related lymphadenopathy syndrome (LAS). The degree of CIC elevation increases from healthy homosexual men to LAS and AIDS. Patients suffering from AIDS associated with opportunistic infections had a more pronounced increase in CIC than patients with AIDS associated Kaposi's sarcoma. In LAS and AIDS the amount of CIC correlated with the degree of inversion of the T4/T8 lymphocyte ratio, whereas in healthy homosexual men with increased levels of CIC the T4/T8 ratio was not significantly altered. Laser nephelometric partial components analysis revealed that these complexes were of a complement poor subtype with low component levels of C4, C1q and C3c. IgM and IgG were found to be the major components. It is suggested that these CIC might represent a marker of the total antigenic burden of the immune system. Possibly, they are of prognostic and monitoring value for clinical handling of patients at risk for AIDS.     

Interleukin 2 augmentation of the defective natural killer cell activity in patients with primary Sjögren''s syndrome.

BALB/c mice are highly susceptible to Leishmania major infection and develop a disseminated lethal disease. Previous experiments indicate that during infection the spleen is heavily populated with large mononuclear cells containing amastigotes. Morphologically these cells resemble undifferentiated monocytes and granulocytes. In this study we examined myelopoiesis in BALB/c and C57BL/6 (resistant) mice during infection with L. major. The number of macrophage-granulocyte precursors in the spleen of infected BALB/c mice, determined by colony forming units in soft-agar cultures (cfu-c), increased steadily to a level of about 60 times that of normal sex- and age-matched controls. In C57BL/6 mice, spleen cfu-c peaked at about 1 month post-infection (four times that of normal controls) and declined thereafter to about two times normal levels. The number of cfu-c in the bone marrow did not change significantly in either strain during the infection. Colony stimulating activity (CSA) was found in supernates of cultures of adherent cells from the spleen of infected BALB/c mice. Under the same conditions, CSA was non-detectable in supernates of nonadherent spleen cells of infected mice, and those of adherent or nonadherent spleen cells of control animals. A possible role of undifferentiated macrophage-granulocytes in the exquisite susceptibility of BALB/c mice to L. major infection is discussed.     

Interleukin 2 enhances natural killer cell activity through induction of gamma interferon

Highly purified interleukin 2 (IL 2), free of interferon activity, enhanced natural killer (NK) cell activity against tumor cells in mouse spleen cell cultures and in human peripheral lymphocyte cultures in a manner similar to that of interferon (IFN). We determined that IL 2 enhanced NK activity indirectly in a cascade manner by the induction of gamma IFN (IFN-gamma) in the cultures, which actually mediated the enhanced killing. Accordingly, lymphocyte cultures treated with IL 2 alone produced 10 to 100 U of IFN per ml in 6 to 24 h of culture. The IFN was typed as IFN-gamma by specific antibodies. Specific antibodies either to natural IFN-gamma or to a synthetic peptide corresponding to the human IFN-gamma N-terminal amino acids, when added to cultures treated with IL 2, completely blocked IL 2 enhancement of NK cell activity for both the mouse and human systems. IL 2-induced proliferation was not affected by the antibodies. Thus, the enhancement of NK cell activity by IL 2 is completely mediated by IL 2-induced IFN-gamma. The findings clearly indicate a cascade effect whereby one lymphokine (IL 2) induces the production of another. The latter lymphokine (IFN-gamma) then mediates an important biological effect (natural killing).     

Effect of lymphokines on natural killer cytotoxicity in patients with high risk of developing the acquired immune deficiency syndrome

Regulation of natural killer (NK) activity of peripheral blood mononuclear cells (PBMC) from patients with the acquired immune deficiency syndrome (AIDS) and from individuals at high risk of developing AIDS (R-AIDS) was studied. The response of untreated PBMC to the interferon inducer polyinosinic polycytidilic acid (Poly I:C) was lower in AIDS and R-AIDS than in normal controls and PBMC from R-AIDS were more susceptible to stimulation with lymphokine rich supernatants (Con A-SN, PHA-SN, lectin free IL-2) than AIDS and normal controls. To determine the role of the different T lymphocyte subsets in the regulation of NK activity, PBMC were selectively treated with monoclonal non-cytotoxic anti-Leu 2a and anti-Leu 3a antibodies and then stimulated with lymphokine rich supernatants. These results indicate that the effect of crude supernatants was the combination of opposite effects. Leu 2a-blocked R-AIDS-PBMC enhanced NK cytotoxicity when exposed to IL-2 rich supernatants whereas Leu 3a-blocked R-AIDS-PBMC suppressed the cytotoxic reaction.     

Evaluation of natural killer cell activity in patients with persistent generalized lymphadenopathy and acquired immunodeficiency syndrome

Natural killer (NK) cell activity was quantitated using 51Cr release from the human erythroleukemia cell line K562 in 39 heterosexual males, 60 asymptomatic homosexuals, 39 patients with persistent generalized lymphadenopathy (PGL), and 16 patients with acquired immunodeficiency syndrome (AIDS). PGL and AIDS patients showed a slight decrease in NK cell activity compared to control groups. Absolute numbers of Leu 11a-positive cells were decreased in PGL and AIDS patients, and this decrease correlated with a decrease in absolute number of both the T4+ and T8+ cell subsets. Autologous plasma inhibited NK cell activity in 48% of asymptomatic homosexuals, 63% of PGL patients, and 63% of AIDS patients, but in none of the heterosexual controls. NK cell responses in fetal calf serum, normal human plasma, or autologous plasma showed no correlation with absolute numbers of T4+ cells, or with T4/T8 ratio. We conclude that NK cell responses are not of prime importance in the pathogenesis of PGL and AIDS.     

Alterations in cytotoxic and phenotypic subsets of natural killer cells in acquired immune deficiency syndrome (AIDS)

Testing of cytotoxic function using a panel of natural killer (NK)-sensitive target cells, including a unique herpes simplex virus-infected Raji-cell target, was performed in conjunction with phenotypic cell analysis by dual-color flow cytometry to characterize the NK system. Subjects included in the study were at risk for or infected with the etiologic agent of the acquired immune deficiency syndrome (AIDS), human immunodeficiency virus (HIV). A generalized defect in NK function was temporally correlated with disease manifestations, as evidenced by deficient NK lytic function in patients with AIDS and AIDS-related complex (ARC). Healthy at-risk subjects, including those seropositive for HIV, exhibited robust NK-cell function. Phenotypic analysis revealed that normal proportions of the NK-associated CD16⁺ (Leu11) Leu7^– and CD16⁺(Leu11)Leu7⁺ lymphocyte subsets were maintained throughout the clinical progression of HIV infection. However, the proportion and numbers of cells of the CD8⁺(Leu2)Leu7⁺ subset were increased in AIDS, ARC, and healthy at-risk subjects, including those seronegative for HIV. These results are consistent with a qualitative defect in the NK system in AIDS, perhaps secondary to CD4-cell depletion and a concomitant lack of essential accessory factors. The elevation in CD8⁺(Leu2)/Leu7⁺ cells is not solely the result of HIV infection and may be a general response to viruses and/or other antigenic stimulation.     

A case comparison of acquired immune deficiency syndrome (AIDS) in homosexual males with spindle-endothelial cell abnormalities and with recrudescent melioidosis

The AIDS syndrome includes cases of biopsy-proven Kaposi's sarcoma in persons under 60 years of age, or biopsy- or culture-proven Pneumocystis carinii pneumonia, or either of the life-threatening opportunistic infections in young previously healthy persons with no underlying cause of immunodeficiency (Center for Disease Control criteria). Here we described the first case of AIDS with early Kaposi's sarcoma-like lesions in homosexual male drug addict and have compared the clinical and laboratory findings with those of another homosexual male having recrudescent melioidosis due to Pseudomonas pseudomallei.     

A boy with X-linked hyper-IgM syndrome and natural killer cell deficiency

We present a boy with hyper-IgM syndrome with a previously not reported mutation in the CD40 ligand gene. He also had a concomitant natural killer (NK) cell deficiency. He had no CD56⁺ or CD16⁺ cells and no NK activity as determined in 4 h chromium release cytotoxicity assay. After 5 days in culture with IL-2-containing medium, however, his peripheral blood mononuclear cells lysed both NK-sensitive and NK-resistant targets, showing that he had lymphokine-activated killer cell precursors in the circulation. Due to the associated neutropenia, he was treated with granulocyte colony-stimulating factor (G-CSF) and responded well. In the same period we observed a transient increase in the number of NK cells. Isolated NK cell deficiencies are extremely rare. We suggest that the defect in our patient is part of the hyper-IgM syndrome, probably representing the phenotype of the new mutation described. Thus, it is possible that both the neutropenia and the NK cell deficiency are due to lack of growth-promoting signals normally delivered by the CD40 ligand.     

In vivo augmentation of natural killer cell activity by Candida albicans

We determined in vivo effects of Candida albicans (CA) on murine natural killer (NK) cell activity. C3H mice were treated with heat-killed CA and splenic NK cell activity assayed at 2, 7, 30 and 50 days post treatment. A single injection of CA caused enhancement of splenic NK activity as measured in a 4 h 51Cr-release assay. Peak NK activity was detected at day 7 and persisted for up to 30 days, after which it declined to control values at 50 days. Augmentation of NK activity by CA resulted from enhanced lytic effects of NK cells, which was independent of effector cell binding capacity. Moreover, enhanced NK activity was associated with an increase in the proliferative response to CA antigen and in splenic cellularity when compared to saline injected controls. Thus, CA seems to act as an immunomodulator causing an augmentation of NK cell activity. Since other biological response modifiers (BRMs) do not show the same strength of augmentation, CA could be used as a new BRM having possible anticancer effects.     

T4 cell receptor distortion in acquired immune deficiency syndrome

Among the possible affects of the HIV virus on T-cells in Acquired Immune Deficiency Syndrome is the cell membrane distortion of the T4 cell protein receptor for Genetically Related Macrophage Factor (GRF). The integrity of this specific T-cell receptor takes on profound significance due to its relationship to soluble antigen. Alpha-tocopheral has been shown to assist in the maintenance of cell membrane structure and may have application in a strategy of membrane restoration. Adoptive Transfer, a method of immune cell alteration applicable in anti-tumor therapy, may play a role in the mechanics of such a strategy.     

The acquired immune deficiency syndrome.

Liposomes prepared with human LS174T colon tumour cell membranes induce specific primary xenogeneic immune responses in BALB/c splenocytes in vitro. Characterization of the adjuvant role of these liposomes was accomplished by determining the effect on immune induction of several modifications on the liposomal carrier. The results showed that the carrier effect of liposomes was mediated primarily by tumour antigens exposed on the outer surface. Trypsin treatment of the liposomes eliminated 95% of the surface protein and significantly (P less than 0.05) reduced the ability of liposomes to induce cytotoxic splenocytes. The generation of cytolytic activity with liposomes was dose-dependent, with a 10 micrograms protein threshold and a maximal response at 100 micrograms. 'Rigid' liposomes were shown to be significantly (P less than 0.05) more efficacious than fluid liposomes in inducing cytotoxicity. In addition, the data indicate that the xenogeneic cell-mediated immunity exhibits identical classes of effector cells as found in murine-murine reactions. Lymphocytes bearing the THY-1, Lyt-1 and Lyt-2 surface markers were necessary for immune induction. The role of Lyt-123 subpopulation was suggested by the inability to achieve normal cytolytic levels by reconstitution with Lyt-1 plus Lyt-2 cells. Adherent cells were, as expected, necessary for the generation of primary immunity. Indeed, the interaction of I-A+ adherent cells with liposomes for at least 8 h was required to generate subsequent maximal T cell cytotoxic activity. The phenotype of the cytotoxic effector cell was Thy-1+, Lyt-2+, and I-Ad-. If this were an allo-or syngeneic, and not a xenogeneic system, this study would be of less interest. However, when coupled with the known molecular homologies between murine and human lymphocyte antigens, these results suggest that the concept of cross species major histocompatibility complex (MHC) restriction is tenable. Thus the liposome is not only an effective antigen carrier, but also a functional adjuvant for in vitro induced cell-mediated immunity.     

Anergy and acquired immune deficiency syndrome

Human immunodeficiency virus (HIV), the retrovirus associated with acquired immune deficiency syndrome (AIDS), acts as a super-antigen by binding to the variable region of the beta (Vβ) chain of T-cell receptor (TCR). It’s binding to CD4 molecules and chemokine receptors induces a spectrum of immune abnormalities including ‘a state of anergy’ in the host. This state is due to a defective function of T-helper cell-1 (Th-1), a reduction in production of lymphokines required for signal transduction, an impaired cytotoxic cell activation and a decrease in antigen presenting function of monocyte-macrophage cell lineage. These immune abnormalities form the basis for severe opportunistic infections and malignancies in the host. Malnutrition, micronutrient abnormalities, concomitant infections and genetic factors, etc., are some of the compounding co-factors that further contribute to ‘the state of anergy’.     

Cryptosporidiosis in the acquired immune deficiency syndrome

Cryptosporidiosis was found in a patient with the acquired immune deficiency syndrome. The microbiological and morphological features of this newly recognized opportunistic infection are distinctive and diagnostic.     

Lymphocyte-reactive antibodies in acquired immune deficiency syndrome

Antilymphocyte antibodies were studied using the Terasaki microcytotoxicity technique in 21 gay patients including 7 with Kaposi's sarcoma, 5 with opportunistic infection, and 9 with lymphadenopathy syndrome. A significant increase in lymphocyte-reactive antibody was noted in 61% of this group. Similar studies using serum from 25 apparently healthy gay males showed lymphocytotoxic antibody in only one instance. When isolated T-cell subsets (OKT4+ or OKT8+) were utilized, a few sera from acquired immune deficiency syndrome (AIDS) patients apparently showed preferential killing for helper-inducer or suppressor-cytotoxic T-cell subsets, however, this showed no correlation with T-cell phenotypic profiles of OKT4 or OKT8+ cells in concurrent peripheral blood studies. When isolated normal OKT4 or OKT8 T-cell subsets were treated with complement and AIDS serum showing apparent T-cell subset specificity and treated T cells added to B cells, macrophages, and OKT4 or OKT8 cells cultured with pokeweed mitogen, no discernible effect on either help or suppression of IgG or IgM synthesis was recorded.     

Myelodysplasia in the acquired immune deficiency syndrome

Certain new hematologic findings in eight homosexual or bisexual patients with the acquired immune deficiency syndrome (AIDS) are presented. All eight patients manifested a normochromic, normocytic anemia, and six of eight had granulocytopenia during their hospitalization. The other two had low-normal granulocyte counts. Bone marrow examination showed normocellular or hypercellular marrows with increased myeloid: erythroid ratios and increased numbers of megakaryocytes. All patients had abnormalities in maturation of all cell lines, most prominent in the granulocytic series. This constellation of features is similar to the findings in the myelodysplastic syndromes (preleukemia). The authors suggest that myelodysplasia in patients with AIDS results in ineffective hematopoiesis and contributes to the peripheral blood cytopenias found in these patients. Myelodysplasia could be a direct or indirect effect of human T-lymphotropic retrovirus-III (HTLV-III).     

Detection of coronavirus-like particles in homosexual men with acquired immunodeficiency and related lymphadenopathy syndrome

Summary Coronavirus-like particles were identified by electronmicroscopy in the feces of homosexual men. The particles banded at a density of 1.21 g/ml after cesium chloride density gradient centrifugation. To determine whether the presence of this virus might be related to clinical symptoms, several patient groups were studied prospectively. In 8 of 16 (50%) homosexual males with acquired immunodeficiency syndrome (AIDS) or unexplained lymphadenopathy syndrome (LAS), coronavirus particles were found. In contrast, such particles were found in none of 18 heterosexual controls and in only 3 of 20 homosexual males without AIDS or LAS. Thus, coronavirus excretion correlated significantly (2<0.01) with the clinical diagnosis of AIDS or with syndromes belonging to the AIDS-related complex. In addition, such particles identified in the serum of one patient with LAS and diarrhea suggest invasion and systemic spread of the agent and underline that this virus behaves differently from common cold human coronaviruses.Abbreviations AIDS acquired immune Deficiency syndrome - LAS unexplained, generalized lymphadenopathy syndrome - sp. species - EM electronmicroscopy - rIFN A recombinant leukocyte A Interferon - CVLP coronavirus-like particles - CsCl cesium chloride