[A rare diagnosis: a case report of an isolated pulmonary valve endocarditis].
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Adult↗
Biomedical subjects
J L Pasquali
Publications and source records attributed to J L Pasquali.
[Pulmonary histiocytosis, then bronchiolo-alveolar cancer in HIV-1 infection].
INTRODUCTION: Langerhans cell pulmonary histiocytosis is a rare disease, primarily enhanced by smoking, and of unclear mechanism. OBSERVATION: A 42 year-old man, smoking 25 packs-years, was infected by a type 1 human immunodeficiency virus (HIV-1). He successively developed pulmonary emphysema, Langerhans cell pulmonary histiocytosis and alveolar bronchial carcinoma of the lower right pulmonary lobe, which was fatal. DISCUSSION: We discuss the concomitance of pulmonary histiocytosis and alveolar bronchial carcinoma, exceptional in the literature, and the eventual enhancing role of HIV-1 infection. The principal incriminating factor in pulmonary histiocytosis probably remains smoking, but the HIV-1 infection may have participated in the emergence of the neoplastic pathology.
Adenocarcinoma, Bronchiolo-Alveolar↗
Expansion of marginal zone B cells is not sufficient for the development of renal disease in NZBxNZW F1 mice.
The mechanisms which govern the production of autoantibodies and of tissue damage during systemic lupus (SLE) are still unclear. In the NZBxNZW F1 (BW) model of SLE glomerulonephritis, the activation and commitment of B cells are thought to play a major role in disease progression. Previous analysis has suggested that these mice have a substantial increase of marginal zone (MZ) B cells before the occurrence of the disease. Owing to the probable role of this B cell subset in autoantibody production, it was important to define the possible link between this abnormality and the occurrence of kidney damage. Using cytofluorometry analysis, we followed the splenic MZ B cell phenotype in different series of mice with shared autoimmune genetic background and histologically defined renal status. By comparing BW females and BW males, NZB and NZW mice, we confirm that BW mice have an increase in MZ B cells but this MZ B cells expansion is not directly linked to tissue lesions. Genetically modified BW female mice with a restricted repertoire of B and T cell antigen receptors, and which do not develop nephritis, exhibit the same increase of MZ B cells, suggesting that this increase does not depend on a specific set of antigens. Moreover, our analysis brings to light a pre-disease state in BW males, with autoantibody production and mesangial deposits.
Animals↗
[The immune system: new therapeutic targets].
Control of the immune reaction can become a major goal, particularly in patients with autoimmune diseases or who express alloreactivity after organ transplantation. The most important side effect of this control is an immunodeficiency, a consequence of the wide spectrum of activity of the treatment. Thus, in order to limit the infectious risks, it would appear reasonable to try to develop new more selective strategies. A better definition of the cellular and molecular mechanisms implicated in the initiation and effector phases of autoimmune diseases authorizes the development of new therapeutic approaches able to target precise points of the immune system. There are a large number of potential targets, mainly directed at orientating the cytokinic response toward an antiinflammatory profile, neutralizating proinflammatory cytokines or their receptors, inducing regulatory lymphocytes in order to normalize the state of T and B cell tolerance, and modulating cellular cooperation and lymphocytic homing by blocking adhesion molecules. Some of these new approaches have already been validated in autoimmune diseases, others will follow soon.
Animals↗
Blood coagulation disorders during primary cytomegalovirus infection.
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Adult↗
The clonal analysis of anticardiolipin antibodies in a single patient with primary antiphospholipid syndrome reveals an extreme antibody heterogeneity.
The mechanism underlying the prothrombotic state that characterizes the primary antiphospholipid syndrome proves to be difficult to define mainly because of the variety of the phospholipid and protein targets of antiphospholipid antibodies that have been described. Much of the debate is related to the use of polyclonal antibodies during the different antiphospholipid assays. To better describe the antiphospholipid antibodies, a strategy was designed to analyze the reactivity of each one antibody making up the polyclonal anticardiolipin activity, breaking down this reactivity at the clonal level. This was performed in a single patient with primary antiphospholipid syndrome by combining (1) the antigen-specific selection of single cells sorted by flow cytometry using structurally bilayered labeled anionic phospholipids and (2) the cloning of immunoglobulin (Ig) variable (V) region genes originating from individual IgG anticardiolipin-specific B cells by a single-cell polymerase chain reaction technique. The corresponding V regions were cloned in order to express human recombinant antibodies in insect cells by a baculovirus expression system. The molecular analysis, the fine specificity, and the protein cofactor dependency of the first 5 monoclonal IgG anticardiolipins are reported here. This clonal analysis reveals the extreme heterogeneity of these antibodies, which could account for the difficulties in the previous attempts to define the pathogenic antiphospholipid response. This approach should help to unravel the complex antiphospholipid immune response and the mechanism of the prothrombotic state associated with these antibodies, but it could also shed some light on their possible origins. (Blood. 2001;97:3820-3828)
Adult↗
Natural autoreactive B cells in transgenic mice reproduce an apparent paradox to the clonal tolerance theory.
Naturally occurring autoreactive B cells are thought to be physically eliminated or rendered functionally silent through different mechanisms of tolerance. However, multireactive low affinity natural autoantibody-producing B cells seem to escape these mechanisms in normal adults and could constitute the B cell pool from which pathological autoantibodies can emerge. To analyze this apparent paradox to the clonal tolerance theory, we have made two transgenic mouse lines (mu(k), mudelta(k)) producing a natural low affinity multireactive human autoantibody. These models enable us to test both the central tolerance mechanisms (reactivity with single-stranded DNA) and the peripheral tolerance mechanisms after Ag administration. Not only are the multireactive B cells not deleted in the bone marrow, they circulate and remain in the periphery even after the prolonged administration of Ag, the presence of membrane IgD increasing the number of mature autoreactive B cells. Self-reactive B cells are shown to be autoantigen ignorant both in vivo and in vitro, but they are not anergic because they can be easily activated through both B cell receptor-dependent and -independent pathways. Thus, these mouse lines reproduce an apparent paradox to the clonal tolerance theory meriting further investigation of the biological significance of this phenomenon.
Animals↗
Antiphospholipid antibodies and preeclampsia: a case-control study.
OBJECTIVE: To assess the association between the occurrence first of preeclampsia and antiphospholipid antibodies. METHODS: We conducted a prospective case-control study of 180 pregnant women with their first incidents of preeclampsia and no histories of thrombosis or systemic autoimmune diseases. Preeclampsia (n = 180) was defined as blood pressure (BP) at least 140/90 mmHg after 20 weeks' gestation and proteinuria at least 0.3 g per 24 hours. Two control subjects were matched to each case (n = 360). They were pregnant women without hypertension or proteinuria and without histories of thrombosis or systemic autoimmune disease. Lupus anticoagulant (activated partial thromboplastin time, diluted thromboplastin time, platelet neutralization procedure) and anticardiolipin antibodies (immunoenzymatic assays) were assessed in both groups, and the coagulation state (levels of thrombin-antithrombin III complexes, fragments 1 + 2 of prothrombin) was also evaluated. The analysis design was a sequential plan with 5% type I error and 95% power. RESULTS: There was no association between antiphospholipid antibodies and preeclampsia. The odds ratio for the association was 0.95 (95% confidence interval 0.45, 2.61). Antiphospholipid antibodies were detected in eight of 180 preeclamptic women and in 19 of 360 controls. In contrast, there was a clear, confirmed activation of coagulation during preeclampsia. CONCLUSION: Despite evidence of a prothrombotic state during preeclampsia, it is unlikely that antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies) represent risk factors for preeclampsia among women with no previous preeclampsia and no histories of thrombosis or systemic autoimmune disease.
Adult↗
Recombinant vaccinia viruses expressing immunoglobulin variable regions efficiently and selectively protect mice against tumoral B-cell growth.
The variable regions of the immunoglobulin (Ig) expressed on the surface of a malignant B cell can be considered tumor-specific antigens and, as such, could be targets for immunotherapeutic approaches. However, because until now the immunization procedures have been complex and have given only partial protection, it was necessary to find new methods of immunotherapy. Here, we present a successful method of vaccination against B-cell tumors in a murine model. We produced recombinant vaccinia viruses (rVV) expressing the heavy and the light chain of surface Ig of a patient's malignant B cells and we tested the ability of these rVV to protect immunized mice against tumor growth of transfectomas producing the same human Ig. The protection of the mice was complete and specific to the variable region of the immunizing heavy chain although specific lymphoproliferative and cytotoxic responses were not detectable in vitro. The protection was strictly dependent on the presence of CD4 T cells and asialo GM1+ cells. Furthermore, tumor protection clearly required gamma-interferon and was partially inhibited by blocking the Fas-Fas ligand interaction. We also show, in a murine syngeneic model, that rVV expressing a poorly mutated Ig protects against the growth of Ig-producing tumor.
Amino Acid Sequence↗
Salivary gland lymphomas in patients with Sjögren's syndrome may frequently develop from rheumatoid factor B cells.
OBJECTIVE: Patients with Sjögren's syndrome (SS) have an increased risk of developing monoclonal B cell non-Hodgkin's lymphomas (MNHL), which frequently occur in the salivary glands (SG). The transition from the benign lymphocyte infiltrate of the gland that characterizes SS to MNHL is not well understood. Previous sequence analyses of the expressed variable (V) region genes have supported the theory that the surface Ig (sIg) plays an important role in the initial expansion of nonmalignant B cell clones and in lymphomagenesis. However, the antigenic specificities of these B cells were unknown. We describe the specificities of the Ig expressed by 2 cases of MNHL that developed in the SG of 2 patients with SS. METHODS: The expressed V genes were amplified by polymerase chain reaction from biopsy specimens, sequenced, and subcloned into eukaryotic expression vectors. The constructs were transfected into P3X63-Ag8.653 cells to obtain 2 monoclonal cell lines, each secreting 1 of the sIg expressed by the MNHL. These IgM were tested by enzyme-linked immunosorbent assay and immunofluorescence against a panel of antigens potentially implicated in SS. RESULTS: Our main finding was that the Ig products of the neoplastic B cells were rheumatoid factors (RF). Contrary to expectations, they did not react with nuclear or cytoplasmic antigens, double-stranded DNA, self antigens commonly bound by natural autoantibodies, or SG tissue. CONCLUSION: Previous analyses of V gene use have provided indirect evidence that SG MNHL may frequently express RF. We demonstrate that this hypothesis is true in the 2 patients we studied. Large-scale studies will be needed to establish the exact frequency of RF specificity among SS-associated MNHL.
Aged↗
[Drug-addicted prisoners: seroprevalence of human immunodeficiency virus and hepatitis B and C virus soon after the marketing of buprenorphine].
PURPOSE: Considering the importance to public health and the frequency with which drug addicts are imprisoned, we studied the prevalence of human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), as well as drug addiction of patients admitted to the Elsau prison in Strasbourg (France). METHODS: The prospective study included all entering inmates from 1 September to 31 October 1997 (270 persons) to whom HIV, HBV and HCV blood tests were offered as well as a questionnaire on their drug addiction. RESULTS: Thirty-six percent of the entering inmates were drug addicts, of whom 1% were HIV positive, 11.2% HBV positive and 30% HCV positive, compared to, respectively, 0.6, 9.9 and 6.4% for non-drug addicts. Ninety-five of the 98 patients used several drugs, including buprenorphine for 53 patients. At the beginning of this study, buprenorphine had been available in France for 9 months. CONCLUSION: The results are to be taken seriously regarding the misuse of this product in this selected population (intravenous use, multiple drug use, dealing).
Adult↗
AIDS primary central nervous system lymphoma: molecular analysis of the expressed VH genes and possible implications for lymphomagenesis.
AIDS-associated primary central nervous system lymphomas are late events that have an extremely poor prognosis. Despite different hypotheses, the brain localization of these B cell lymphomas remains an enigma. To better define the cell origin of the lymphomas and the possible role of the B cell receptor (BCR) in the brain localization and/or in the oncogenic transformation, we analyzed the V region genes of the Ig heavy chain expressed by lymphoma cells in five randomly selected patients. After amplifying the rearranged VHDJH DNA by PCR, cloning, and sequencing of the amplified products, we observed that: 1) of the five lymphomas analyzed, four were clearly monoclonal; 2) there was no preferential use of one peculiar VH family or one peculiar segment of gene; 3) the mutation analysis showed that an Ag-driven process occurred in at least two cases, probably before the oncogenic event; and 4) there was no intraclonal variability, suggesting that the hypermutation mechanism is no longer efficient in these lymphoma B cells. Taken together, our results suggest that distinct Ags could be recognized by the BCR of the lymphoma cells in different patients and that, if the Ags are responsible for the brain localization of these B cells bearing mutated BCR, other factors must be involved in B cell transformations in primary central nervous system lymphoma.
Adult↗
[Rheumatoid factor: what could we learn from mature autoantibodies].
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Antibodies, Anti-Idiotypic↗
From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins.
Rheumatoid arthritis is a common and debilitating autoimmune disease whose cause and mechanism remain a mystery. We recently described a T cell receptor transgenic mouse model that spontaneously develops a disease with most of the clinical, histological, and immunological features of rheumatoid arthritis in humans. Disease development in K/BxN mice is initiated by systemic T cell self-reactivity; it requires T cells, as expected, but B cells are also needed, more surprisingly. Here, we have identified the role of B cells as the secretion of arthritogenic immunoglobulins. We suggest that a similar scenario may unfold in some other arthritis models and in human patients, beginning with pervasive T cell autoreactivity and ending in immunoglobulin-provoked joint destruction.
Adoptive Transfer↗
Terminal deoxynucleotidyl transferase deficiency reduces the incidence of autoimmune nephritis in (New Zealand Black x New Zealand White)F1 mice.
Terminal deoxynucleotidyl transferase (TdT) enzyme activity in lymphocytes generates diversity in the Ag receptor repertoires by adding template-independent N nucleotides and disrupting homology-directed rearrangements. The importance of this diversity in vivo and the significance of the suppression of TdT during fetal life remain uncertain. Previous studies have shown that in TdT knockout mice (TdT(0)) 1) the T cell repertoire is less peptide oriented; and 2) natural autoantibody, particularly anti-DNA autoantibodies, are less polyreactive, and their mean affinities are reduced. Consequently, the suppression of TdT during early T/B cell ontogeny may participate in controlling autoimmunity. To study the impact of TdT suppression in autoimmune-prone mice, we introduced the TdT null mutation into the (NZB x NZW)F1 (B/W) mouse strain. We show that TdT deficiency significantly reduces the incidence of autoimmune nephritis and prolongs survival compared with those in control mice. Surprisingly, the long-term survivor TdT(0) mice produced amounts of anti-ADN and anti-histone autoantibodies similar to those of their TdT+ littermates. However, these TdT(0) mice showed no evidence of renal inflammation, and the immune deposits were restricted to the mesangium, whereas basal membrane deposits were clearly correlated with overt renal disease. The present study supports the idea that the absence of TdT enzyme activity in lymphocytes protects mice against autoimmunity and could offer a therapeutic approach to autoimmune diseases. Moreover, our results may help to unravel the mechanisms of lupus nephritis.
Animals↗
[Soluble tumor necrosis factor receptors in patients with systemic lupus erythematosus].
OBJECTIVE: To study the variations of type II soluble receptors for tumor necrosis factor (sR-TNF) in patients with systemic lupus erythematosus and investigate their use in the clinical setting. PATIENTS AND METHODS: Twenty-six patients with systemic lupus were followed for a mean 3 years. sR-TNF and other immunological parameters (C reactive protein, anti-DNA antibodies, C3 and C4 complement fractions, soluble receptors for interleukin 2) were measured in sera at different points of the disease course. The systemic lupus activity measure (SLAM) was determined at each point, and confronted with the biology results. The study was cross sectional for the group and longitudinal for the patients. RESULTS: sR-TNF was the immunological parameter which correlated best with SLAM. It also correlated with sedimentation rate, C reactive protein, thrombopenia, anemia, creatinine level, anti-DNA antibodies and sR-IL2. The longitudinal study pointed out however that this finding is not consistent for each patient. CONCLUSION: A rise in sR-TNF related to systemic lupus activity but is of limited practical interest for individual patient follow-up.
C-Reactive Protein↗
[Humoral immunity].
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Antibody Formation↗
Autoantibodies in mice lacking terminal deoxynucleotidyl transferase: evidence for a role of N region addition in the polyreactivity and in the affinities of anti-DNA antibodies.
The generation of terminal deoxynucleotidyl transferase knockout mice (TdT0) has demonstrated that TdT is the only major activity involved in N region addition. This enzyme generates diversity by adding random nucleotides at the V-D-J junctions and by disrupting the formation of repetitive "homology-directed" junctions. Several studies have demonstrated that the Ig heavy chain third complementarity-determining region (H-CDR3) and the N region play a critical role: 1) in distinguishing between polyreactive and monospecific combining sites in natural and Ag-induced Abs; and 2) in the specificity and polyreactivity of natural autoantibodies (autoAbs) and in particular of anti-DNA Abs. To examine the impact of the lack of TdT on the natural autoAb repertoire in adult mice, we have stimulated TdT0 and TdT+ littermates with LPS. Serum studies demonstrate that TdT is not critical for the generation of B cells expressing autoAbs including anti-DNA Abs and rheumatoid factors. However, the generation of a large collection of hybridomas indicates that the frequencies of these cells are reduced in TdT0 mice mainly due to a lower incidence of polyreactivity; also, the lack of N region diversity seems to negatively affect the affinity of anti-DNA Abs. The physiologic relevance of these data is discussed.
Amino Acid Sequence↗