Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study describes an approach to the development and use of anti-idiotypic antibodies as a possible immunization strategy to prevent retroviral infection. The rationale for using anti-idiotypes (anti-Ids) to try to elicit an antigenic-specific immune response is examined, and the production and characterization of polyclonal and monoclonal anti-Ids are described. Several techniques were used to determine antigenic mimicry and anti-Id subtypes. The potential use of anti-Ids in feline leukemia virus (FeLV) receptor studies and vaccine trials in vivo were investigated. Results from these studies suggest that the anti-Id strategy is feasible for the FeLV model. Polyclonal Ab2 reagents were developed that blocked virus-receptor binding and thus inhibited viral infection in vitro and induced humoral immune responses in 6- to 8-week old kittens characterized by production of Ab3 with the ability to bind the original FeLV envelope protein gp70 as assessed by Western blot analysis.
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PMID:Anti-idiotypic antibodies to feline leukemia virus: an approach for retroviral immunization strategies. 164 60

S-Antigen (S-Ag) is a well characterized 45,000 m.w. photoreceptor cell protein. When injected into susceptible animal species, including primates, it induces an experimental autoimmune uveitis, a predominantly T cell-mediated autoimmune disease of the retina and uveal tract of the eye, and of the pineal gland. In this study we found an amino acid sequence homology between a uveitopathogenic site of S-Ag, several viral proteins and one additional nonviral protein. An experimental autoimmune uveitis and pinealitis was induced in Lewis rats with these different synthetic peptides, corresponding to the amino sequence of hepatitis B virus DNA polymerase, gag-pol polyprotein of Baboon endogenous virus and gag-pol polyprotein of AKV murine leukemia virus and potato proteinase inhibitor IIa, which contain three or more consecutive amino acids identical to peptide M in S-Ag. Lymph node cells from rats immunized with either peptide M or the different synthetic peptides showed a significant degree of cross-reaction. Mononuclear cells from monkeys (Macaca fascicularis) immunized with peptide M also showed significant proliferation when incubated with either peptide M or synthetic peptides as measured by in vitro lymphocyte mitogenesis assay using [3H]TdR. Based on our findings we conclude that a viral infection may sensitize the mononuclear cells that can cross-react with self proteins by a mechanism termed molecular mimicry. Tissue injury from the resultant autoantigenic event can take place in the absence of the infectious virus that initiated the immune response.
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PMID:Molecular mimicry between a uveitopathogenic site of S-antigen and viral peptides. Induction of experimental autoimmune uveitis in Lewis rats. 168 49

Retinal S-antigen (S-Ag) is capable of inducing experimental autoimmune uveitis (EAU) in laboratory animals. EAU may serve as an animal model for studying human uveitis. As a first step we have determined the nucleotide sequence of an S-Ag gene and its cDNAs. The amino acid sequences were deduced from the cDNAs of various animals and human. Four uveitopathogenic sites in bovine S-Ag were characterized. One of the sites (peptide M) has sequence homology with non-self proteins from baker's yeast, potato, E. coli, hepatitis B virus, moloney murine leukemia virus, Moloney murine sarcoma virus, AKR murine leukemia virus and baboon endogenous virus. Mononuclear cells from animals immunized with peptide M showed significant proliferation when incubated with synthetic peptides corresponding to the amino acid sequences of the above-mentioned foreign proteins. In addition, all the peptides induced EAU in Lewis rats with a dose of 10-2000 micrograms. Moreover, native histone H3 from baker's yeast histone H3 induced EAU in Lewis rats. Thus, we found several examples of antigenic mimicry between self and non-self proteins. These findings establish a base to study further the mechanism of autoimmune inflammation.
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PMID:S-antigen: from gene to autoimmune uveitis. 219 11

A molecular analysis was carried out in 63 sequentially diagnosed childhood acute lymphoblastic leukemia (ALL) patients and 1011 controls to investigate the homozygosity rate for HLA-DR53. HLA-DR53 is associated with acute myeloblastic leukemia at the protein level, and our previous study has shown its association with early-onset chronic myeloid leukemia only in homozygous form at the DNA level. In the present study, the homozygosity rates for DR53 were 17.5 and 13.6% in patients and controls, respectively. Ten of the 11 homozygous patients were boys. In the common ALL group (n = 40), all seven DR53 homozygous patients were boys, and among 19 girls this genotype was not observed (P = 0.006). For males, homozygosity for DR53 revealed a relative risk (RR) of 3.29 (P = 0.008) for common ALL. Five of the 11 relapsed patients were homozygous for DR53. Heterozygous frequencies for HLA-DR53 were not different between patients and controls. Homozygosity for DR53 was associated with a very high relapse rate (45.5 vs 7.7%, P = 0.002, RR = 9.1). These results extended our findings in chronic myeloid leukemia and showed the recessive nature and the male predominance of the interactive HLA influence on the development of childhood leukemia. Molecular mimicry of an HLA-DR53 epitope by oncogenic (retro)viruses or putative susceptibility genes in linkage disequilibrium with HLA-DR53 may be responsible for this association.
Leukemia 1995 May
PMID:Nature of HLA-associated predisposition to childhood acute lymphoblastic leukemia. 776 51

Autoantibodies directed against peptide-defined epitopes of T-cell receptors occur in the serum of healthy humans with the levels and isotypic expression dependent upon physiological changes (aging, pregnancy) or upon the development of autoimmune disease. We carried out investigations of autoantibodies against Tcr peptide-defined epitopes in retroviral infections of humans (HIV-1) and mice (LP-BM5 strain of murine leukemia virus) to determine whether infection with these agents disrupted the regulation of the production of these antibodies. Retroviral infection in humans resulted in increased levels of autoantibody production against putative immunoregulatory regions of the Tcr beta chain (V beta CDR1 and Fr3), a result reflecting a disruption of regulation. In addition, antigenic mimicry was observed with a cross-reaction shared between the common portion of the V3 neutralizing loop of the HIV-1 gp120 molecule and the joining segment of T-cell receptors (J beta). Infection of mice with the defective retrovirus resulted in the induction of antibodies directed particularly against V beta CDR1 peptide-defined determinants. Analysis of the virally induced response to a set of 8 CDR1 peptide epitopes indicated a selectivity to the process. It was possible to partially reverse aberrant cytokine changes correlated with the onset of murine MAIDS by administration of T-cell receptor peptides in saline. These results show that retroviral infection in humans and mice has a profound dysfunctional effect on the regulation of autoantibodies to T-cell receptors. The function of these autoantibodies in the immunopathogenesis of acquired immunodeficiency remains to be determined.
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PMID:Autoantibodies against peptide-defined epitopes of T-cell receptors in retrovirally infected humans and mice. 864 4

Adenoviruses have mechanisms that allow persistence in lymphoid cells and immunoevasion. They downregulate major histocompatibility complex (MHC) class I antigen expression and may trigger an autoimmune reaction against MHC class II antigens through mimicry. Adenoviral persistence could be facilitated by human leukocyte antigens A2 and DR53, thereby allowing a preleukemic clone to escape immune surveillance and progress to leukemia.
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PMID:The implications for childhood leukemia of infection with adenovirus. 882 May 68

Molecular mimicry is defined as similar structures shared by products of dissimilar genes. This review article discusses a possible role of molecular mimicry in the production of autoantibodies. Antibodies reactive with products of bacterial and viral genes sometime cross-react with normal cellular proteins. Sera from patients with systemic autoimmune diseases show crossreactivity with some bacterial and/or viral gene products at a significant frequency. Identification of the structures of antigenic epitopes recognized by disease-associated autoantibodies by expression cloning of autoantigen molecules and gene fragment expression revealed the amino acid residues that are shared by autoantibody-defined epitopes and microbial proteins. The presence of amino acid sequences shared between microbial proteins and autoantigens and the detection of antibodies in patients' sera that bind to the crossreactive epitopes suggest that immune responses to bacterial and viral infections may initiate the production of autoantibodies. Receptor-mediated phagocytosis of autoantigen molecules by crossreactive B cells and subsequent antigen presentation to helper T cells may facilitate the production of autoantibodies reactive with separate epitopes, if the autoantigen complex contains multiple B-cell epitopes and a shared T helper cell epitope. Analyses of the fine specificity of T helper cell epitopes on Friend murine leukemia virus env gene products revealed unexpected heterogeneity and redundancy of T cell responses even to a single epitope. This heterogeneity in T cell responses might play a role in the activation of self-reactive T helper cells through molecular mimicry.
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PMID:[Molecular mimicry and mechanisms of autoantibody production]. 920 Sep 20

Autoantibodies to alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors may contribute to chronic hyperexcitability syndromes and neurodegeneration, but their origin is unclear. We examined LP-BM5 murine leukemia virus-infected mice, which manifest excitotoxic brain lesions and hypergammaglobulinemia, for the presence of AMPA-receptor Ab's. Endogenous IgG accumulated upon neurons in the neocortex and caudate/putamen of infected mice and interacted with native and recombinant AMPA-receptor subunits with the following relative abundance: GluR3 > or = GluR1 > GluR2 = GluR4, as determined by immunoprecipitation. In a radioligand assay, IgG preparations from infected mice specifically inhibited [(3)H]AMPA binding to receptors in brain homogenates, an activity that was lost after preadsorbing the IgG preparation to immobilized LP-BM5 virus. These IgGs also evoked currents when applied to hippocampal pyramidal neurons or to damaged cerebellar granule neurons. These currents could be blocked using any of several AMPA receptor antagonists. Thus, anti-AMPA-receptor Ab's can be produced as the result of a virus infection, in part through molecular mimicry. These Ab's may alter neuronal signaling and contribute to the neurodegeneration observed in these mice, actions that may be curtailed by the use of AMPA-receptor antagonists.
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PMID:LP-BM5 virus-infected mice produce activating autoantibodies to the AMPA receptor. 1125 73

Hairy cell leukemia (HCL) is a chronic mature B-cell leukemia characterized by malignant B cells that have typical hairy protrusions. To characterize possible HCL-associated tumor antigens, we generated an HCL-specific and HLA class II (DPw4)-restricted proliferative CD4+ T-cell clone. To identify the target antigen of these T cells, we constructed a synthetic peptide library dedicated to bind HLA DPw4, and identified a mimicry epitope recognized by the T-cell clone. With this epitope, the recognition motif of the T-cell clone was deduced and a peptide of human synaptojanin 2 (Syn 2) was identified that stimulated the HCL-reactive T-cell clone. Both Northern and Western blot analyses showed that Syn 2 expression was increased in HCL samples compared to other B cells. Besides, the Syn 2-expressing cell line AML193, with the introduced restrictive HLA-DPw4 molecules, was recognized by the HCL-specific T-cell clone. These results indicate that Syn 2 is a target of autoreactive HCL-specific T cells. Since Syn 2 is a phosphatidylinositol 4,5-biphosphatase involved in cell growth and rearrangement of actin filaments, the increased Syn 2 expression may correlate with the disease etiology or the characteristic morphologic alterations caused by the disease.
Leukemia 2003 Dec
PMID:Synaptojanin 2 is recognized by HLA class II-restricted hairy cell leukemia-specific T cells. 1456 16

The Philadelphia chromosome-negative chronic myeloproliferative disorders (CMPD), polycythemia vera (PV), essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (IMF), have overlapping clinical features but exhibit different natural histories and different therapeutic requirements. Phenotypic mimicry amongst these disorders and between them and nonclonal hematopoietic disorders, lack of clonal diagnostic markers, lack of understanding of their molecular basis and paucity of controlled, prospective therapeutic trials have made the diagnosis and management of PV, ET and IMF difficult. In Section I, Dr. Jerry Spivak introduces current clinical controversies involving the CMPD, in particular the diagnostic challenges. Two new molecular assays may prove useful in the diagnosis and classification of CMPD. In 2000, the overexpression in PV granulocytes of the mRNA for the neutrophil antigen NBI/CD177, a member of the uPAR/Ly6/CD59 family of plasma membrane proteins, was documented. Overexpression of PRV-1 mRNA appeared to be specific for PV since it was not observed in secondary erythrocytosis. At this time, it appears that overexpression of granulocyte PRV-1 in the presence of an elevated red cell mass supports a diagnosis of PV; absence of PRV-1 expression, however, should not be grounds for excluding PV as a diagnostic possibility. Impaired expression of Mpl, the receptor for thrombopoietin, in platelets and megakaryocytes has been first described in PV, but it has also been observed in some patients with ET and IMF. The biologic basis appears to be either alternative splicing of Mpl mRNA or a single nucleotide polymorphism, both of which involve Mpl exon 2 and both of which lead to impaired posttranslational glycosylation and a dominant negative effect on normal Mpl expression. To date, no Mpl DNA structural abnormality or mutation has been identified in PV, ET or IMF. In Section II, Dr. Tiziano Barbui reviews the best clinical evidence for treatment strategy design in PV and ET. Current recommendations for cytoreductive therapy in PV are still largely similar to those at the end of the PVSG era. Phlebotomy to reduce the red cell mass and keep it at a safe level (hematocrit < 45%) remains the cornerstone of treatment. Venesection is an effective and safe therapy and previous concerns about potential side effects, including severe iron deficiency and an increased tendency to thrombosis or myelofibrosis, were erroneous. Many patients require no other therapy for many years. For others, however, poor compliance to phlebotomy or progressive myeloproliferation, as indicated by increasing splenomegaly or very high leukocyte or platelet counts, may call for the introduction of cytoreductive drugs. In ET, the therapeutic trade-off between reducing thrombotic events and increasing the risk of leukemia with the use of cytoreductive drugs should be approached by patient risk stratification. Thrombotic deaths seem very rare in low-risk ET subjects and there are no data indicating that fatalities can be prevented by starting cytoreductive drugs early. Therefore, withholding chemotherapy might be justifiable in young, asymptomatic ET patients with a platelet count below 1500000/mm(3) and with no additional risk factors for thrombosis. If cardiovascular risk factors together with ET are identified (smoking, obesity, hypertension, hyperlipidemia) it is wise to consider platelet-lowering agents on an individual basis. In Section III, Dr. Gianni Tognoni discusses the role of aspirin therapy in PV based on the recently completed European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) Study, a multi-country, multicenter project aimed at describing the natural history of PV as well as the efficacy of low-dose aspirin. Aspirin treatment lowered the risk of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke (relative risk 0.41 [95% CI 0.15-1.15], P =.0912). Total and cardiovascular mortality were also reduced by 46% and 59%, respectively. Major bleedings were slightly increased nonsignificnsignificantly by aspirin (relative risk 1.62, 95% CI 0.27-9.71). In Section IV, Dr. Giovanni Barosi reviews our current understanding of the pathophysiology of IMF and, in particular, the contributions of anomalous megakaryocyte proliferation, neoangiogenesis and abnormal CD34(+) stem cell trafficking to disease pathogenesis. The role of newer therapies, such as low-conditioning stem cell transplantation and thalidomide, is discussed in the context of a general treatment strategy for IMF. The results of a Phase II trial of low-dose thalidomide as a single agent in 63 patients with myelofibrosis with meloid metaplasia (MMM) using a dose-escalation design and an overall low dose of the drug (The European Collaboration on MMM) will be presented. Considering only patients who completed 4 weeks of treatment, 31% had a response: this was mostly due to a beneficial effect of thalidomide on patients with transfusion dependent anemia, 39% of whom abolished transfusions, patients with moderate to severe thrombocytopenia, 28% of whom increased their platelet count by more than 50 x 10(9)/L, and patients with the largest splenomegalies, 42% of whom reduced spleen size of more than 2 cm.
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PMID:Chronic myeloproliferative disorders. 1463 83


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