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Biomedical subjects

J F Emile

Publications and source records attributed to J F Emile.

At least 19 recordsLinked to original sources
PubMed1998

Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency.

In humans, interferon gamma (IFN-gamma) receptor deficiency leads to a predisposition to mycobacterial infections and impairs the formation of mature granulomas. Interleukin-12 (IL-12) receptor deficiency was found in otherwise healthy individuals with mycobacterial infections. Mature granulomas were seen, surrounded by T cells and centered with epithelioid and multinucleated giant cells, yet reduced IFN-gamma concentrations were found to be secreted by activated natural killer and T cells. Thus, IL-12-dependent IFN-gamma secretion in humans seems essential in the control of mycobacterial infections, despite the formation of mature granulomas due to IL-12-independent IFN-gamma secretion.

Animals↗
PubMed1998

Langerhans cells in Langerhans cell granulomatosis are not actively proliferating cells.

Pulmonary Langerhans cell granulomatosis (LCG), also called histiocytosis X, is a disorder of unknown etiology characterized by the presence of destructive granulomas containing numerous Langerhans cells (LCs). The process may be localized or multifocal, and it remains unclear whether the same pathogenic mechanism is involved in all forms of the disease. It is often assumed that the massive accumulation of LCs at the sites of the lesions results from the abnormal proliferation of these cells, although it has been suggested that LCG in adults, at least in the lung, could be a reactive disorder initiated by activated LCs. Little is known, however, concerning the mechanisms responsible for the accumulation of large numbers of LCs in the course of the disease, and the relative contribution of recruitment and local proliferation of these cells remains to be established. To investigate this question, the proportion of replicating LCs was evaluated in biopsied granulomas from patients with localized or diffuse form of LCG by means of several histopathological techniques currently used in assessment of cell proliferation. The findings demonstrate that, except for proliferating cell nuclear antigen (PCNA), all parameters measured are low in all forms of the disease. They are similar to those of renewing epithelial cells and clearly less than those of neoplastic cells. These data strongly suggest that LCs in LCG granulomas are not a rapidly dividing cell population and that local LC replication makes only a minimal contribution to granuloma maintenance. Caution appears to be necessary in the use of PCNA as a marker of growth fraction.

Adenocarcinoma↗
PubMed1997

Partial interferon-gamma receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guérin infection and a sibling with clinical tuberculosis.

Complete interferon-gamma receptor 1 (IFNgammaR1) deficiency has been identified previously as a cause of fatal bacillus Calmette-Guérin (BCG) infection with lepromatoid granulomas, and of disseminated nontuberculous mycobacterial (NTM) infection in children who had not been inoculated with BCG. We report here a kindred with partial IFNgammaR1 deficiency: one child afflicted by disseminated BCG infection with tuberculoid granulomas, and a sibling, who had not been inoculated previously with BCG, with clinical tuberculosis. Both responded to antimicrobials and are currently well without prophylactic therapy. Impaired response to IFN-gamma was documented in B cells by signal transducer and activator of transcription 1 nuclear translocation, in fibroblasts by cell surface HLA class II induction, and in monocytes by cell surface CD64 induction and TNF-alpha secretion. Whereas cells from healthy children responded to even low IFN-gamma concentrations (10 IU/ml), and cells from a child with complete IFNgammaR1 deficiency did not respond to even high IFN-gamma concentrations (10,000 IU/ml), cells from the two siblings did not respond to low or intermediate concentrations, yet responded to high IFN-gamma concentrations. A homozygous missense IFNgR1 mutation was identified, and its pathogenic role was ascertained by molecular complementation. Thus, whereas complete IFNgammaR1 deficiency in previously identified kindreds caused fatal lepromatoid BCG infection and disseminated NTM infection, partial IFNgammaR1 deficiency in this kindred caused curable tuberculoid BCG infection and clinical tuberculosis.

Adolescent↗
PubMed1997

Correlation of granuloma structure with clinical outcome defines two types of idiopathic disseminated BCG infection.

Bacillus Calmette Guérin (BCG) is an attenuated strain of Mycobacterium bovis that is currently used as a live vaccine for human tuberculosis. Disseminated BCG infection may rarely occur following vaccination of children. In half of the cases, regarded as idiopathic, no well-defined immunodeficiency condition can account for the infection. However, the high rates of parental consanguinity and familial forms and the associated opportunistic infections with Salmonella suggest that these idiopathic BCG infections result from one or several new type(s) of inherited immune disorder(s). As an approach to the description and understanding of this newly described condition, the associated lesions were examined. Samples from 14 patients collected from a French national retrospective study were analysed. Pathological data from 22 cases reported in the world literature were also reviewed. Two types of granuloma were found. The first type (type I, tuberculoid) consisted of well-circumscribed and well-differentiated granulomas, with epithelioid and multinucleated giant cells containing very few acid-fast rods, surrounded by lymphocytes and fibrosis and occasionally with central caseous necrosis. The second type (type II, lepromatous-like) consisted of ill-defined and poorly differentiated granulomas, with few if any giant cells and lymphocytes but widespread macrophages loaded with acid-fast bacilli. Most children displayed a single type of granuloma. One half displayed type 1 lesions and the other half displayed type II lesions. There was a strong correlation between the type of granuloma and the clinical outcome. Tuberculoid lesions were associated with survival, whilst lepromatous-like lesions correlated with death. Correlation of granuloma structure with clinical outcome defines two types of idiopathic disseminated BCG infection. The phenotypic heterogeneity of the course of BCG infection reflects distinct pathogenic mechanisms and probably results from a genotypic heterogeneity of the underlying inherited immune disorder.

BCG Vaccine↗
PubMed1997

Lack of expression of E-cadherin is associated with dissemination of Langerhans' cell histiocytosis and poor outcome.

Langerhans' cell histiocytosis (LCH) often occurs in children as a cutaneous disease. The course of the disease is characterized by either spontaneous resolution or multivisceral dissemination with poor prognosis. The pathogenesis of LCH is not known. Since E-cadherin mediates homophilic adhesion of normal Langerhans' cells to keratinocytes and is also a ligand of the alpha E beta 7 intraepithelial lymphocyte integrin, this study was undertaken to investigate whether its expression on LCH cells correlates with the clinical behaviour of the disease. Clinical records of 14 children with LCH, all of whom had cutaneous involvement, were retrospectively analysed. The expression of E-cadherin was studied by in situ immunohistochemistry on 22 frozen biopsy samples with two specific monoclonal antibodies. LCH cells of the seven children with only skin involvement were positive for E-cadherin. By contrast, LCH cells of the seven children who further developed extensive LCH disclosed a negative or low expression of E-cadherin. This study shows that dissemination and poor prognosis are associated with lack of E-cadherin expression on LCH cells. Aggressive clinical evolution of LCH may therefore be related to the loss of functions mediated by E-cadherin.

Biomarkers↗
PubMed1997

Epidermal Langerhans' cells in children with primary T-cell immune deficiencies.

Dendritic cells are the major antigen-presenting cells, especially for naive T lymphocytes; it is conceivable therefore that their absence or dysfunction may induce an immune deficiency (ID). Few data are available, however, concerning dendritic cells in human primary ID. Langerhans' cells (LC) are intraepidermal dendritic cells which express specific markers and may therefore be studied by immunohistochemistry on paraffin-embedded skin samples. Skin samples of nine children with primary ID were studied and compared with five age-matched controls. LC were present within the epidermis of two children with X-linked severe combined ID, a condition related to the lack of the common gamma-chain of interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15 receptors. LC were also present in skin samples of a child with Omenn syndrome and in three children with combined ID. By contrast, no LC were detected in the skin samples of two children with alymphocytosis and of a child with reticular dysgenesis, a condition characterized by the absence of peripheral blood leukocytes.

Antigens, CD1↗
PubMed1997

Sensitivity of Epstein-Barr virus-induced B cell tumor to apoptosis mediated by anti-CD95/Apo-1/fas antibody.

Epstein-Barr virus (EBV) can induce uncontrolled B lymphocyte proliferation leading to fatal lymphoma in immunocompromised patients. The sensitivity to apoptosis of B lymphoid cell lines (LCL) derived from EBV-induced lymphoproliferative disorders was investigated. In vitro and in vivo, these B LCL strongly express CD95/Apo-1/fas antigen and undergo apoptosis upon stimulation with anti-Apo-1 monoclonal antibody. When inoculated into severe-combined immunodeficient (scid) mice, human B cells lines developed into rapidly growing tumors. Administration of an agonistic anti-Apo-1 antibody significantly delayed tumor progression. Relapses were frequent, but were not caused by selection of resistant B cells, since B cells from relapsing tumors underwent apoptosis on re-exposure. Induction of apoptosis by an anti-C95/Apo-1/fas-specific antibody could be applied for therapy of EBV-induced B cell tumors and contribute to our understanding of the mechanisms of T cell-mediated elimination of EBV lymphomas in immunodeficient patients.

Animals↗
PubMed1997

Cysteine protease CPP32, but not Ich1-L, is expressed in germinal center B cells and their neoplastic counterparts.

Ich-1/Nedd2 and CPP32/YAMA are cysteine proteases related to interleukin 1-beta-converting enzyme (ICE), which act as apoptosis effectors. Both molecules are expressed in T- and B-cell lines. The authors investigated their in vivo cellular distribution in normal and neoplastic human lymphoid tissues. Sixty-eight representative non-Hodgkin's lymphomas (NHL) and Hodgkin's disease (HD) samples, normal lymphoid organs, and nonlymphoid tumors were analyzed by immunohistochemistry (IHC). CPP32 expression in benign tissues was restricted to germinal center B cells, plasma cells, and a few interfollicular immunoblasts. All follicular NHLs and most diffuse large cell NHLs were CPP32 positive. Among T-cell NHLs, CPP32 expression was mainly observed in anaplastic large cell NHLs, whereas the other subtypes were less frequently positive. In contrast, lymphoid organs displayed only weak Ich1-L expression, located in sinusal histiocytes and thymic epithelial cells. Lymphomas were Ich1-L negative, except for T-cell-rich B-cell NHLs, and about half of the HD samples, in which Reed-Sternberg cells (RSC) were usually Ich1-L positive/CPP32 negative. Extralymphoid Ich1-L reactivity was found in particular organs like the kidney and various tumors. Western blot analysis confirmed the specificity of immunostaining. Neither CPP32 nor Ich1-L expression were correlated with intratumoral DNA fragmentation, as determined by the TUNEL assay. Altogether, these results indicate that CPP32 is preferentially expressed in germinal centers and thus could be involved in B-cell maturation. The differential expression of CPP32 and Ich1-L suggests that cysteine proteases differ in substrate specificities and carry out functions unrelated to apoptosis.

Apoptosis↗
PubMed1997

Detection of donor-derived Langerhans cells in MHC class II immunodeficient patients after allogeneic bone marrow transplantation.

T-cell dependent immune response is initiated by dendritic cells, which are the only leucocytes able to prime naive CD4-positive T cells. Langerhans cells (LC) are dendritic cells characterized by their localization within the epidermis, their dendritic shape, and their expression of specific markers such as major histocompatibility complex (MHC) class II molecules, CD1a and S100 protein. We retrospectively studied the phenotype of LC in the skin of eight children with MHC class II deficiency (bare lymphocyte syndrome) after allogeneic bone marrow transplantation (BMT). The presence of donor-derived MHC class II positive LC within the epidermis was studied by immunohistochemistry on skin biopsies performed for the determination of graft-versus-host disease. MHC class II positive LC were undetectable in the epidermis of a child who did not engraft and of three children 13-18 d after HLA-mismatched BMT, despite engraftment. However, donor-derived MHC class II positive LC were detected in four children 9-43 d after HLA-identical BMT. Our results demonstrate that LC can differentiate or expand very quickly, as early as within 9 d after BMT.

Biopsy↗
PubMed1997

Fatal disseminated Mycobacterium smegmatis infection in a child with inherited interferon gamma receptor deficiency.

Mycobacterium smegmatis is a common environmental mycobacterium that was first identified in 1884, yet is a rare pathogen in humans. The few M. smegmatis infections reported to date have been localized and have occurred in association with a primary lesion in otherwise immunocompetent individuals. To our knowledge, no case of disseminated M. smegmatis infection has ever been reported, even in patients with severe immune deficiencies. We report a case of disseminated mycobacterial infection that was diagnosed in a 3-year-old girl. The pathogen was not identified as M. smegmatis until the patient was 6 years old. Her condition gradually worsened, and she died when she was 8 years old despite appropriate antimycobacterial therapy. No other opportunistic infections were documented. Immunological investigations revealed an inherited interferon gamma receptor 1 deficiency. This report identifies M. smegmatis as a new opportunistic agent that may be responsible for disseminated disease in immunocompromised individuals.

Bacteremia↗
PubMed1997

[Congenital asplenia. A childhood immune deficit often detected too late].

We report a case of fatal pneumococcal sepsis in a previously healthy 22 month old child. At postmorten examination the patient was found to have an atrophic spleen. When other malformations are not associated, congenital asplenia is generally diagnosed after death related to pneumococcal infection.

Fatal Outcome↗
PubMed1996

Clinical, immunological, and pathological consequences of Fas-deficient conditions.

BACKGROUND: The surface molecule named Fas/CD95, which is expressed on activated lymphocytes, can trigger cell death following interaction with its ligand (Fas L). This Fas-Fas-L interaction is thought to be a major regulatory mechanism for controlling the life span of peripheral lymphocytes, and therefore autoimmunity. METHODS: We assessed clinical, immunological and pathological features in three children who inherited mutations of the Fas-encoding gene. One infant had a genomic homozygous deletion, while two siblings had a heterozygous mutation in the fas gene. FINDINGS: The patient with a complete lack of Fas protein expression had prenatal onset of massive lymphoproliferation, which involved the spleen, the liver, and the intrathoracic and abdominal lymph nodes. Lymphoproliferation mainly involved T cells negative for the CD4 and CD8 receptors. These cells, which had a high mitotic index, were essentially found in the T cell zones of lymphoid organs. Active cell division was indicated by a rapid rise in the lymphocyte count following a chemotherapy-induced reduction in the lymphocyte burden. Despite the total Fas protein deficiency, limited autoimmunity was found in this child at age 1 year. A lymphoproliferative syndrome with similar characteristics--but less intense than in the patient with complete Fas deficiency--also occurred from a young age in the siblings with a fas gene mutation on one allele only. One sibling developed neutropoenia, autoimmune haemolytic anaemia, and severe recurrent thrombocytopoenia. INTERPRETATION: Fas-deficiency causes a non-malignant syndrome characterised by the accumulation of dividing lymphocytes. Severity of disease is probably related to the degree of functional Fas deficiency. Heterozygous fas gene mutations, like homozygous deletions, can also be expressed in various cells and tissues and may predispose towards autoimmune disorders. Fas deficiency should be considered in children with enlarged peripheral lymphoid organs and hyperimmunoglobulinaemia, and sometimes the occurrence of autoimmune manifestations towards blood cells.

Anemia, Hemolytic↗
PubMed1996

CD5-CD56+ T-cell receptor silent peripheral T-cell lymphomas are natural killer cell lymphomas.

Non-Hodgkin's lymphomas are divided into B- and T-cell neoplasms. The existence and the clinical relevance of lymphomas derived from the third lymphocyte lineage, ie, natural killer (NK) cells are still controversial. NK cells are lymphocytes that mediate cytotoxicity without prior sensitization. NK cells also have phenotypic and genotypic characteristics: they express the NK-related antigen CD56, T-cell markers such as CD2 and CD7, but do not express CD5 and T-cell receptor (TCR) proteins, and their TCR locus is not rearranged. Therefore, if NK cell lymphomas exist, they should express some T-cell markers, but not alpha beta or gamma delta TCR proteins. Such lymphomas are actually called TCR silent peripheral T cell lymphomas (PTCL). To detect and characterize NK cell lymphomas, we investigated the immunophenotype and immunogenotype of 35 patients with TCR silent PTCL. The first group included 16 patients with a lymphoma of CD5-CD56+ phenotype, which is identical to normal NK cells. These patients had either a nasal/nasopharyngeal lymphoma (11 cases) or a lymphoma with predominant non-nasal/non-nodal initial involvement (five cases). Eight of the nine cases for which immunogenotypic data were available lacked clonal rearrangement of the TCR gamma genes. Thus, these tumors are likely to be NK cell lymphomas. The second group of 15 cases had a CD5+ phenotype (14 were CD56-, and 1 was CD56+) and clonal rearrangement of TCR gamma genes, indicating that they were true PTCL with unproductive TCR rearrangement. The four remaining cases were CD5- CD56- lymphomas and disclosed either a clonal (two cases) or no clonal (two cases) rearrangements of the TCR gamma genes. Altogether these findings show that CD5-CD56+ so-called "TCR silent PTCL" bear the immunophenotype and immunogenotype of normal NK cells and display peculiar clinical features distinct from true PTCL.

Adolescent↗
PubMed1996

Digestive tract involvement in Langerhans cell histiocytosis. The French Langerhans Cell Histiocytosis Study Group.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disease with a wide clinical spectrum. Although little is known of gastrointestinal involvement in LCH, it may be a major clinical problem. We investigated clinical, pathologic, and immunohistochemical features of digestive tract LCH involvement in children. PATIENTS: Selection criteria consisted of the presence of LCH with digestive symptoms, and histologic confirmation of gastrointestinal involvement. Seven children (2%) met the criteria among 348 cases of LCH in a French national retrospective survey from 1983 to 1993. Two children whose LCH was diagnosed in 1994 were also selected. RESULTS: Nine children with LCH and digestive tract involvement were studied. Clinical features at presentation included skin (9/9) and mucosal (4/9) involvement, failure to thrive (5/9), diarrhea (7/9), bloody stools (4/7), vomiting (4/9), and hypoalbuminemia (8/9). Five of the nine children died; factors associated with a poor prognosis included young age, organ dysfunction (stage 4), and need for parenteral nutrition. Unlike control biopsy specimens, LCH cells of children with digestive tract involvement disclosed expression of the mucosal homing receptor integrin alpha 4 beta 7 on frozen skin and digestive tract biopsy specimens. CONCLUSION: Cutaneous, mucosal, and digestive tract involvement in LCH is a clinicopathologic entity. The prognosis and treatment of LCH depend on the extent of the disease; therefore the treatment of these disseminated forms should not be delayed. Thus children with cutaneous LCH and digestive symptoms should undergo digestive tract biopsies. Studies of homing receptors may contribute to our understanding of the mechanisms of dissemination in LCH.

Biopsy↗