Anti-CD4 autoantibodies and screening for anti-idiotypic antibodies to anti-CD4 monoclonal antibodies in HIV-seropositive people.

The cell-surface antigen CD4 is the major receptor for HIV. Anti-CD4 autoantibodies and anti-idiotypic antibodies to murine monoclonal anti-CD4 antibodies have been described in HIV-infected people. Ninety-seven sera from HIV-infected people at all stages of disease were examined for the presence of anti-idiotypic antibodies to three anti-CD4 monoclonal antibodies. None were found. The same sera were screened for antibodies reactive with soluble CD4, and five (5.2%) were positive. These antibodies did not recognize native CD4, and it is thought unlikely that they arise as anti-idiotypes to anti-gp120 antibodies.

Antibody-dependent cell-mediated cytotoxicity: comparison between HTLV-I and HIV-1 assays.

This study confirms the presence of detectable antibody-dependent cell-mediated cytotoxicity (ADCC) towards both HTLV-I- and HIV-1-infected cell lines, mediated by normal donor peripheral blood mononuclear cells and either by antibody from adult T-cell lymphoma and tropical spastic paraparesis patients (HTLV-I) or by antibody from sera of patients with persistent generalized lymphadenopathy, AIDS-related complex, AIDS and asymptomatic patients seropositive for HIV-1 infection. A comparison of ADCC towards these two retroviruses, under carefully controlled laboratory conditions, indicates major differences between the capacity of HTLV-I-seropositive sera and HIV-1-seropositive sera to mediate ADCC. In all cases, HIV sera showed low-titre ADCC, in contrast to the high titre (greater than 1:800,000) ADCC mediated by HTLV-I-positive sera. Both sets of sera showed the prozone phenomenon, and heat inactivation may abolish ADCC towards HIV-1-infected cells. Quantitation of surface antigen expression on HTLV-I- and HIV-1-infected cell lines indicated the presence of easily detectable amounts of virus-specific antigen. We conclude that, in contrast to some previous reports, ADCC mediated by HIV-1-specific immunoglobulin G (IgG) antibody is rather weak and of low titre when compared with HTLV-I ADCC. This is true for all cell lines and HIV-1 virus isolate combinations tested.

The relevance of HIV env/CD4 interactions to the pathogenesis of acquired immune deficiency syndrome.

The survey of the characteristics of HIV infection implicates the binding of HIV env to the CD4 receptor as the principal cause of the resulting immunodeficiency. There is evidence that such binding selectively impairs self-recognition. The resulting immunodeficiency syndrome has the characteristics of graft vs. host disease, consistent with chronic allogeneic and semiallogeneic GVHD in mouse-models. since these syndromes are believed to result from triggering the established immunoregulatory mechanisms necessary to maintain self-tolerance, vaccination to prevent AIDS should aim to correct the inability of the HIV host mount an immune response against CD4 binding epitopes on HIV gp120, preferably without exposing the vaccine to intact envelope glycoprotein. Since the AIDS syndrome is probably a defect in net-work immunoregulation, the most appropriate target for therapy and for vaccination is the idiotype of anti-CD4 antibodies that block CD4/env interaction.

Immunofluorescence analysis of normal and malignant lymphoid tissues with selected combination of antisera.

Tissue sections stained with combinations of antisera labeled with different fluorochromes (i.e., conventional antisera to human immunoglobulin classes, T lymphocyte antigens, and Ia-like p28,33 antigens used in various double combinations with each other or with different mouse monoclonal antibodies) allow the identification of the different areas of lymph nodes in serial sections and provide great flexibility as well as precision in the analysis of the distribution and relationship of normal and malignant cells. Lymphoid microenvironments in the thymus and the paracortical areas of lymph nodes are described. The close association of T lymphocytes and nonlymphoid cells expressing large amounts of Ia-like antigens (such as interdigitating reticular cells and endothelium) may be relevant for the understanding of immunoregulatory disorders such as dermatopathic and angioimmunoblastic lymphadenopathies and some malignancies (e.g., mycosis fungoides) were the expression of Ia-like antigens on non-T cells seems to be abnormally abundant. The analysis of immunoglobulin and membrane marker expression of normal and malignant B cells and their relation to T cells can also be related to the histology of the disease. These studies are clinically useful for the classification of childhood lymphomas, the differential diagnosis of anaplastic carcinomas and lymphomas, and in the study of the early stages of lymphomas.

HIV type 1 envelope glycoprotein 120 carboxy-terminal peptide-induced human T cell lines selectively suppress heterogeneous proliferative T cell responses to soluble antigens.

It has been proposed that the highly conserved human immunodeficiency virus type 1 (HIV-1) envelope gp120 carboxy-terminal sequence, TKAKRRVVEREKR (CT120), may represent a functional mimic of the human leukocyte antigen (HLA) class II DR beta-chain third hypervariable region (HVR3) sequence motif located at position 69-81. Presentation of this potentially pathogenic fragment by HLA class I and/or II molecules, in a manner analogous to the indirect pathway of allorecognition, may induce both widespread cellular activation and also break self-tolerance, resulting in the selective and progressive anti-self HLA class II-directed immune suppression, which is a central feature of HIV-1 infection and the associated acquired immune deficiency syndrome (AIDS). To investigate the functional role of the HIV-1 gp120 C-terminal fragment T cell lines (TCLs) were raised from three healthy HIV-1-seronegative subjects at low risk of HIV-1 exposure, by repeated stimulation with a short synthetic 13-mer CT120 peptide in vitro. Graded concentrations (10[3] to 5 x 10[4]) of CT120 TCLs suppressed the primary 6-day proliferation of autologous PBMCs in response to the soluble antigens tetanus toxoid (TT) and purified protein derivative (PPD). In contrast, CT120 TCLs demonstrated no suppressive effect on 3-day phytohemagglutinin (PHA), concanavalin A (ConA), and pokeweed mitogen (PWM) mitogenic responses. Fractionation of CT120 TCLs into highly purified CD4+ and CD8+ T cell subsets demonstrated that the CD8+ T cell fraction mediated the suppressor effector function. HLA restriction analysis revealed a complex pattern as both anti-HLA class II DR and anti-HLA class I (A, B, C) MAbs inhibited proliferation of oligoclonal CD8+ CT120 TCLs. Strategies aimed at specifically inhibiting such putative immunopathogenic HIV-1-encoded T cell epitopes may be an important consideration for development of future HIV-1 immunotherapy.

T lymphoblastic lymphoma with LEU-7 positive phenotype and unusual clinical course: a multiparameter study.

Immunologic phenotype studies were performed on cells and on frozen sections of involved tissue from a 20 year old female with typical T-cell lymphoblastic (convoluted) lymphoma. The cells demonstrated a thymic phenotype but in addition marked with Leu-7 (HNK-1)--an antibody reported to identify human natural killer/killer (NK/K) cells. Normal or neoplastic cells with this phenotype have not been previously reported. These findings support the existence of a thymic precursor for a T-cell subset of Leu-7 + cells. The unusual clinical response to therapy is another feature of this unique case.

B- and T-cell subsets in follicular centroblastic/centrocytic (cleaved follicular center cell) lymphoma: an immunohistologic analysis of 26 lymph nodes and three spleens.

Follicular centroblastic/centrocytic (CB/cc/F), or cleaved follicular center cell, lymphomas are known to contain admixtures of B cells and, often, numerous T cells. To analyze the presence and distribution of B and T cells and their subsets in CB/cc/F lymphomas, 26 lymph nodes and three spleens (from 24 patients) were studied with a panel of monoclonal antibodies and peanut lectin by the avidin-biotin immunoperoxidase technique on frozen sections. Immunoglobulin studies revealed monoclonal neoplastic follicles in most cases, although cells of the nondominant light chain were occasionally present. Rarely, the follicles showed both kappa and lambda light chains or were immunoglobulin-negative. Although monoclonal mantles were observed in only one case, more than half of the nodes demonstrated monoclonal interfollicular infiltrates. In most cases the phenotype of the follicular cells was similar to that of the predominant cells in the normal follicles. Interfollicular lymphomatous cells had variable phenotypes that, unlike the normal situation, sometimes resembled those in the follicles. Phenotypic variation was present within single neoplastic clones and sometimes suggested more mantle-like differentiation. Phenotypic changes were also observed in repeat biopsies. T cells, usually predominantly of the T-helper phenotype, were present in variable numbers in all cases. Although present in the neoplastic follicles, they were usually more common in the interfollicular areas. Six nodes and two spleens had definite rims composed predominantly of T cells around neoplastic follicles. Apparently "activated" (Tac-positive) T cells were often present and showed accentuation around the follicles in some cases. Thus, CB/cc/F lymphoma is a malignant lymphoma that closely resembles follicular hyperplasia but that also has distinctive features.

Heterogeneity of lymphoblastic malignancies in children.

Lymphocyte surface markers show that lymphoblastic lymphomata in children are a heterogeneous but related group of diseases. Lymphoblastic lymphomas of T cell type fall into at least three subgroups: (1) HTLA positive, E rosette negative, TdT positive phenotype, with characteristically high levels of TdT and some associated expression of C-ALL antigen on a small proportion of cells. (2) E rosette positive lymphoblasts with intermediate range of TdT positivity, and which express antigens specific for thymic cortical lymphocytes. (3) E rosette positive and C3d positive T lymphoblasts with low levels of TdT enzyme. B lymphoblastic lymphomas show a major subgroup characterised by surface IgM expression, with or without detectable cytoplasmic IgM, and which may express ALL antigen. A minor subgroup of B lymphoblastic disease, of predominantly nodal presentation, expresses surface IgM with some expression of C3d receptors. Therefore at least 3 T cell, and 2 B cell subgroups of lymphoblastic lymphoma can be described.

Cell receptor studies on seven cases of diffuse histiocytic malignant lymphoma (reticulum cell sarcoma).

Expression of B and T lymphocyte receptors has been studied in seven cases of reticulum cell sarcoma. In one case, surface receptors and tests of phagocytic function demonstrated the histiocytic origin of the neoplastic cells. In four cases, tumour cells expressed both B and T lymphocyte markers (two cases) or showed a normal pattern of expression of B and T lymphocyte markers. In the other two cases, lymphocyte receptors were not detected, and there was no evidence of phagocytic function: this class of receptor-silent tumours is of uncertain pathogenesis. The significance of these observations is discussed.

Normal values for the different classes of venous blood mononuclear cells defined by monoclonal antibodies.

We present the data obtained from routine quantitation of normal venous blood mononuclear cells using 19 monoclonal antibodies against defined mononuclear cell surface antigens. The results indicate different values for percentage and absolute numbers of T lymphocytes and of T lymphocyte subsets depending on the monoclonal antibodies used to quantify these populations. In most instances the total number of identified cells was significantly less than the total number of recovered blood mononuclear cells, which suggests the existence in blood of a null cell population. Evidence is advanced to support previous observations that at least a proportion of this population is of B cell lineage, expressing cytoplasmic immunoglobulin but lacking other class or lineage specific markers. The value of a diverse monoclonal panel in routine quantitation of peripheral blood mononuclear cells is discussed.

How HIV-1 lentivirus causes immune deficiency disease.

Human immunodeficiency virus (HIV-1) associated immune deficiency has the characteristics of chronic graft versus host disease (GVHD) caused by human leukocyte antigen (HLA) class 2 incompatibility. The envelope glycoprotein fragment TKAKRRVVEREKR mimics HLA class 1 C molecules serologically, and also mimics an immune regulatory T cell epitope, in the region of amino acids 67 to 71, within the HLA DR beta chain. This beta chain alloepitopic region (between amino acids 67 to 80) furnishes peptides predicted to bind optimally to HLA class 1 B alleles. The hypothesis predicts that viral parameters, such as viral load, and clinical parameters, such as rate of progress to acquired immune deficiency syndrome (AIDS) and severity of the associated immune deficient state, are linked to the HLA B and HLA DR beta chain haplotype in infected patients. Immune suppression is caused by HLA class 1 B restricted CD8+ T cells which normally regulate HLA class 2 DR restricted antigen specific responses. The hypothesis further predicts the severity of immune deficiency to be linked to those HLA DR beta chain allotypes which express the amino-acid glutamine (Q) in position 70.

The immune system and lymphoma. (A commentary on the role of the immune system in experimental lymphomagenesis).

Normal immune responsiveness is compared with four main types of experimental lymphomagenesis. In these types of lymphoma, the proximal cause of lymphomagenesis can be identified as a specific class of the immunoregulatory defect. The adaptive differentiation of normal immunocytes to immunocompetence permits the specific activation by antigenic determinants through the requirement for cognate recognition of such epitopes in the presence of an actively maintained self-tolerant state. Defective control of immune responsiveness in lymphomagenesis permits lymphocyte activation by stimuli resulting from the acquisition of alterations or defects in the expression of normally invariant molecules present during adaptive differentiation. Target antigens include class I and II MHC, env glycoproteins, and framework determinants of T cell receptor or immunoglobulin idiotype. Features common to both normal immune responsiveness and to lymphomagenesis are immunocompetence of the cognate recognition process and specificity of the target immunocyte for the permitted immunogenic or lymphomagenic stimulus.