UMLS:C0002878 - FACTA Search

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Query: UMLS:C0002878 (hemolytic anemia)
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Interleukin-2-deficient mice (IL-2-/-) crossed to a BALB/c genetic background develop a lymphoproliferative syndrome with severe hemolytic anemia and die within 5 weeks of age. The presence of autoantibodies of various specificities and inflammatory lesions in several organs are indicative of a generalized auto-immune disease. No alterations of the immune system were observed in 6-day-old animals, but 10-day-old mice already showed an increased proliferation and polyclonal activation of lymphocytes. The treatment of IL-2-/- mice with anti-gp39(CD40L) antibody prevented the disease and indicated that the appearance of activated CD4- T cells (CD44high, CD69-) represents the first alteration of the immune system in IL-2-/- mice. Collectively, our results suggest that an essential role of IL-2 in vivo, which is not compensated by other cytokines, is the maintenance of self tolerance.
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PMID:Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. 748 43

A selective CD3 gamma defect, involving point mutations in both the paternal and the maternal genes, has been analyzed. The CD3 gamma defect affected two brothers of a four sibs family; one of them died at the age of 3 of a viral pneumonia with concomitant autoimmune features (Haemolytic anaemia and gut epithelial cell autoantibodies), whereas the other is still alive at the age of 10 with relatively mild infection episodes. In this work, the effects of the absence of the CD3 gamma chain in the structure and signal transduction of the T-cell receptor (TCR)/CD3 complex and in the selection and function of T lymphocytes were studied. The absence of CD3 gamma did not prevent the expression of certain amounts of TCR/CD3 complexes on the surface of T lymphocytes. This suggests the existence of at least two TCR/CD3 isoforms in T cells, either with or without CD3 gamma. A persistent low proportion of CD8+ T cells, not functional in vitro (they were unable to proliferate) and probably in vivo (associated to a lethal viral pneumonia), was observed. In contrast, the proportion of CD4+ T cells was not altered, and they were functional both in vitro (they showed a normal proliferation and a low, but detectable, increase of cytosolic Ca2+ in response to anti-TCR/CD3 stimuli, although the production of IL-2 was impaired) and in vitro (they normally helped B cells). These results show that the absence of CD3 gamma affects the selection and function of cytotoxic, but apparently not helper, T lymphocytes, although the possibility that the CD4+ T cells represent a specific subpopulation can not be ruled out. They also suggest that the interactions of the TCR/CD3 complex with its co-receptors during thymic selection and antigen recognition in the periphery may be asymmetrical, with CD8 interacting through CD3 gamma and, probably, CD4 through the homologous CD3 delta.
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PMID:T lymphocyte signalling defects and immunodeficiency due to the lack of CD3 gamma. 790 75

B cell deficient animals obtained by various strategies of gene targeting were used to study the B cell development and examine the role of different immune compartments in the immune response to microbes. Study of muMT, JHD, lambda 5T and JHT models of B cell deficiency, was essential in order to understand the role of pre-B cell receptor in B cell development, allelic exclusion and variable gene rearrangement regulation. In the immune response to influenza virus, a protective role of T cells in a total absence of B cell compartment, was revealed by studying the JHD -/- model. Further, it was established that a T cell compartment is sufficient to mediate the recovery from influenza infection. Examination of immune response in muMT and JHD models of definitive B cell deficiency to various blood stage Plasmodia species, showed that whereas B cells are not required for recovery from infection with P. chabaudi adami, P. vinckei petteri and P. chabaudi chabaudi (CB), B cell compartment is important in the later stages of infection with P. chabaudi chabaudi (AS). Studies carried out in muMT model suggested a possible role for T gamma delta subpopulation in the immune response to blood stage malaria parasite. B cell deficiency models are valuable for understanding the normal and pathological immune response. Studies carried out in muMT model indicated that T cell responses are not significantly affected in the absence of B cells. These data can neither rule out a role for B cells in T cell priming, nor in triggering an effective T cell help for humoral response. Study of double homozygous mice deficient for B cells and FAS or IL-2 gene, pinpointed the role of B cells in pathogenesis of lupus-like nephritis and vasculitis from lpr mouse and in hemolytic anemia from IL-2 -/- mouse model, respectively.
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PMID:Immunoglobulin deficient mice generated by gene targeting as models for studying the immune response. 888 29

Interleukin-2-deficient mice (IL-2(-/-)) manifest severe immune system abnormalities characterized by an uncontrolled activation and proliferation of lymphocytes. A systemic autoimmune syndrome results, and hemolytic anemia leads to early death especially in mice derived from a BALB/c genotype. Remarkably, IL-2 treatment prevents both the activation of the immune system and the development of autoimmune disease. Moreover, adoptive transfer of lymphocytes from IL-2-treated IL-2(-/-) animals confers protection to IL-2(-/-) mice, suggesting that IL-2 induces a postnatal differentiation/maturation of regulatory cells necessary for self- and non-self-discrimination.
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PMID:Interleukin-2 is indispensable for development of immunological self-tolerance. 893 6

Il-2 has been described as a key cytokine regulating the growth, differentiation and function of lymphocytes. To better understand its in vivo function Il-2 deficient mouse mutants were generated on a mixed (129/Ola x C57BL6) genetic background which predominantly develop an ulcerative colitis-like disease (10). To further elucidate the complex disease syndrome of Il-2-/-mice and to study the possible contribution of genetic factors in its pathogenesis we have bred the IL-2-/-mice to various genetic backgrounds. The resulting phenotypes were analyzed clinically and morphologically and the status of their immune system was assessed. Il-2-/-mice backcrossed to BALB/c genetic background develop a generalized autoimmune disease, which becomes manifest as hemolytic anemia, follicular hyperplasia of lymphoid organs, inflammatory changes of pancreas, liver, heart, lungs and thoracal blood vessels but not of the colon (11). The mutants all die within 5 weeks of age. The changes of the immune system are dominated by an uncontrolled polyclonal activation and proliferation of T and B cells, associated with an increased production of autoantibodies. Treatment of Il-2-/-Balb/c mice with anti-gp39 (CD40L) antibody inhibited activation of B cells and CD8+ T cells, however, it did not affect the activation of CD4+ T cells. In such treated mice amelioration of hemolytic anemia but not of inflammatory lesions in most of the affected organs could be recognized. The primary immunologic change of Il-2-/-mice is obviously an uncontrolled proliferation of CD4+ T cells. It suggests that the in vivo function of IL-2 which is not compensated by other cytokines is the maintenance of self tolerance.
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PMID:[Generalized autoimmune diseases in BALB/c mice with a genetically dependent interleukin-2 deficiency]. 906 30

We report a case of granular lymphocyte proliferative disorder accompanied with hemolytic anemia and neutropenia. Phenotypes of the cells were T cell receptor gammadelta+ CD3+ CD4- CD8+ CD16+ CD56- CD57-. Southern blot analysis of T cell receptor beta and gamma chains demonstrated rearranged bands in both. Chromosomal analysis after IL-2 stimulation showed deletion of chromosome 6. Sorted gammadelta+ T cells showed an increase in Fas ligand expression compared with the levels in sorted alphabeta+ T cells. The expression of Fas ligand on these gammadelta+ T cells increased after IL-2 stimulation. The patient's anemia improved along with a decrease in granular lymphocyte count and disappearance of the abnormal karyotype without treatment. The expression of Fas ligand may be involved in spontaneous regression of granular lymphocyte proliferation with hemolytic anemia.
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PMID:Abnormal proliferation of CD4- CD8+ gammadelta+ T cells with chromosome 6 anomaly: role of Fas ligand expression in spontaneous regression of the cells. 1020 5

The immunopathogenic mechanisms underlying idiopathic autoimmune haemolytic anaemia (AIHA) are still unknown, although regulatory cytokines are thought to play an important role. We investigated cytokine production by mitogen-stimulated whole blood cultures from 21 patients with AIHA and from 22 age- and sex-matched controls. In parallel experiments, we studied the effect of mitogen and cytokine stimulation on anti-red blood cell (RBC) IgG antibody production, assessed as both binding on autologous RBCs and secretion in culture supernatants. To quantify anti-RBC antibody, we set up a sensitive and quantitative solid phase competitive immunoassay. The results showed that in AIHA patients production of interleukin (IL)-4, IL-6 and IL-13 was significantly increased, whereas that of interferon (IFN)-gamma was reduced. Multivariate analysis showed that IFN-gamma was the only independent factor significantly associated with the reduced T-helper-1-like cytokine profile. Patients with active haemolysis showed further reduction of IFN-gamma and IL-2 production and increased secretion of transforming growth factor (TGF)-beta. In AIHA patients, mitogen stimulation, as well as IL-6, significantly increased autologous anti-RBC-binding relative to unstimulated cultures. Mitogen stimulation and addition of IL-4, IL-6, IL-10, IL-13 and TGF-beta significantly increased both autologous anti-RBC binding and antibody secretion in AIHA patients compared with controls. The results suggest that a reduced T-helper-1- and a predominant T-helper-2-like profile and elevated TGF-beta levels might play a role in the immunopathogenesis of AIHA. Furthermore, our competitive anti-RBC antibody was able to detect anti-RBC antibody production in some direct antiglobulin test (DAT)-negative AIHA patients.
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PMID:In vitro quantification of anti-red blood cell antibody production in idiopathic autoimmune haemolytic anaemia: effect of mitogen and cytokine stimulation. 1112 84

Common variable immunodeficiency (CVI) is a primary immunodeficiency characterized by deficient antibody production. The cause of this immunodeficiency is unknown; several in vitro studies have revealed a significant number of alterations that could explain the hypogammaglobulinemia present in this syndrome. Among those described are primary B cell alterations, numerical and functional T cell abnormalities, and defects in the interaction between accessory cells. The alteration typical of CVI is the failure of B lymphocytes to differentiate from antibody-producing cells, resulting in deficient immunoglobulin secretion. Among the T cell abnormalities described are a diminished proliferative response to mitogens and antigens, alterations in the level of production of several cytokines, especially reduction in the production of IL-2, diminished antigen-specific T cells and increase basal apoptosis after stimulation. Antigen presenting cells, monocytes and dendritic cells can also present alterations and contribute to deficient antigen response. The clinical manifestations of these patients is variable; most present recurrent bacterial infections due to encapsulated bacteria, especially sinusitis, otitis, bronchitis, and pneumonias. A few patients can present mycobacterial or fungal infection and occasionally Pneumocystis carinii. Viral infection is uncommon in these patients although some suffer recurrent herpes zoster infection. Clinical features of septicemia and central nervous system infections are less frequent. The incidence of digestive tract infections in these patients is high. The most common cause of diarrhea is Giardia lamblia; Salmonella, Shigella and Campylobacter are also common pathogens. Autoimmune disease is also more prevalent in these patients than in the general population. The most frequently associated diseases are hemolytic anemia, idiopathic thrombocytopenic purpura and autoimmune neutropenia. Cancer is also frequently associated with CVI, the most common forms being lymphoproliferative syndromes, especially non-Hodgkin's lymphoma. Granulomas are a unusual manifestation in some patients with CVI; their localization varies but the most commonly affected organs are the spleen and lungs. Some authors have compared these granulomas with those characterizing sarcoidosis, especially when appearing in the lung. Diagnosis of CVI is usually by exclusion of other diseases, such as cystic fibrosis, immotile cilia syndrome or allergic processes. CVI should be suspected in all patients with recurrent bacterial infections especially those localized in the respiratory tract. Other primary immunodeficiencies which present clinical findings similar to CVI and which should be ruled out are selective IgG subclass deficiency, IgA deficiency and selective deficiency in the response to polysaccharide antigens with normal immunoglobulin levels. The serum hypogammaglobulinemia present in all patients with CVI provides the diagnostic key. The age at which clinical manifestations appear, the absence of familial antecedents and the presence of circulating B lymphocytes form the basis of the differential diagnosis between X-linked agammaglobulinemia and autosomal recessive forms. The treatment of choice of patients with CVI is treatment with human gamma-globulin. Currently, the most common route of administration is intravenous; these molecules have a half-life of approximately 21 days and a high degree of safety concerning the possible transmission of viral infections. Adverse reactions are generally few and clinically unimportant. The most frequently used doses oscillate between 200 and 400 mg/kg body weight every 2-4 weeks. Both the dose and its frequency should be personalized for each patient. Early diagnosis of patients with CVI, application of treatment with appropriate antibiotics for infections and treatment with gamma-globulins prevent long-term complications of this disease and dramatically improve the quality of life and life expectancy of these patients.
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PMID:[Common variable immunodeficiency. Review]. 1143 84

The levels of interleukin-13 (IL-13) in patients with systemic lupus erythematosus (SLE) were examined and related to other Th1-/Th2- related cytokines, clinical manifestations and other markers. Serum levels of IL-13 and other cytokines, soluble markers were measured by enzyme-linked immunosorbent assay (ELISA). Patients with active SLE had a significantly increased level of IL-13. Most patients with high levels of IL-13 had higher levels of IL-6, and some patients had high levels of gammaIFN. These patients were divided into two groups according to the patterns of these increased cytokines; one with a high level of only Th2 related cytokines (IL-13 or IL-6) and another with high levels of both Th2 related and Th1 related cytokines (gammaIFN or IL-2). The latter patients had high levels of soluble CD8 and CD23, and some of them had hemolytic anemia or pulmonary involvement, while most of the former patients had nephropathy. Thus, in SLE, the levels of IL-13 were increased, and the heterogeneity of increased Th2- and Th1-related cytokines was related to that of activation markers and clinical manifestations.
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PMID:The increased interleukin-13 in patients with systemic lupus erythematosus: relations to other Th1-, Th2-related cytokines and clinical findings. 1168 89

Anti-double strand DNA antibodies (anti-dsDNA) involve in lupus nephritis. However, their role in tissue damage mechanism remains unclear. In this study, a 45-kDa cognate antigen of anti-dsDNA monoclonal antibodies 9D7 was identified by two-dimensional gel electrophoresis and determined to be human phosphoglycerate kinase 1 (PGK-1) by MALDI-TOF analysis. The binding of 9D7 to PGK-1 was not affected by DNase I but was inhibited by thymus dsDNA. Human SLE sera with high anti-dsDNA titers had a high affinity with PGK. In activated Jurkat T cells, 9D7 decreased the PGK-1 mRNA production and IL-2 promoter activity. Reduction in IL-2 gene expression and protein production were observed in the 9D7-treated cells. Because PGK-1 deficiency may cause mental tardy and hemolytic anemia, interaction between anti-dsDNA and PGK-1 may be important in lupus pathogenesis. Moreover, reduction in IL-2 production by anti-dsDNA suggests their role in increasing infection rate and decreasing proper generation of activation-induced cell death.
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PMID:Monoclonal anti-double-stranded DNA antibodies cross-react with phosphoglycerate kinase 1 and inhibit the expression and production of IL-2 in activated Jurkat T cell line. 1685 29

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