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Yehuda Shoenfeld

Publications and source records attributed to Yehuda Shoenfeld.

At least 19 recordsLinked to original sources
PubMed2003

Essential pathogenic role of endogenous IL-18 in murine diabetes induced by multiple low doses of streptozotocin. Prevention of hyperglycemia and insulitis by a recombinant IL-18-binding protein: Fc construct.

IL-18 is a cytokine structurally and functionally related to IL-1 that, in synergy with IL-12, stimulates the synthesis of IFN-gamma from T lymphocytes and natural killer cells. Because IFN-gamma plays a key pathogenic role in the development of murine immunoinflammatory diabetes induced by multiple low doses of streptozotocin (STZ) we investigated the effect of negating the actions of endogenous IL-18 in this model by administering recombinant IL-18-binding protein:Fc (IL-18 bp:Fc). C57BL/6 mice were injected once daily with 40 mg/kg STZ for 5 consecutive days, day 0 being the first day of STZ challenge. Relative to control animals treated in parallel with either PBS or human IgG, mice treated from day -3 to day 7 with daily doses of 150 microg of IL-18 bp:Fc exhibited lower incidence of diabetes and milder insulitis. In contrast, mice that were treated with IL-18 bp:Fc from day 7 to day 14 exhibited clinical and histological signs of STZ-induced diabetes similar to those of control mice treated with IgG. The protective effect of IL-18 bp:Fc was accompanied by modified ex vivo immune responses, in that spleen cells and peritoneal macrophages contained fewer IFN-gamma secreting cells and released lower amounts of nitrite (an index of nitric oxide production) and IL-1beta. We conclude that intact IL-18 function is essential for the full diabetogenic effect of low dose STZ in C57BL/6 mice.

Animals↗
PubMed2003

Antiphospholipid syndrome: pathogenic mechanisms.

Despite the strong association between antiphospholipid antibodies (aPL) and thrombosis, the pathogenic role of aPL in the development of thrombosis has not been fully elucidated. Proposed pathophysiological mechanisms may be categorized into two types. First, aPL may act in vivo by disrupting the kinetics of the normal procoagulant and anticoagulant reactions occurring on cell membranes. Second, aPL may stimulate certain cells thereby altering the expression and secretion of various molecules. In this article, we review the mechanisms by which aPL may develop thrombotic events.

Animals↗
PubMed2003

Immunization of naïve mice with mouse laminin-1 affected pregnancy outcome in a mouse model.

PROBLEM: Laminins have important roles during placental and embryonic development. The aim of our study was to determine if active immunization of mice with laminin-1 could elicit an autoimmune response, and induce features of reproductive failure. METHOD OF STUDY: BALB/c mice were immunized with mouse laminin-1. Autoantibodies to laminin-1 were measured by enzyme-linked immunosorbent assay. Pregnant mice were killed on day 14 of pregnancy and examined for pregnancy outcome. RESULTS: Mice immunized with laminin-1 developed elevated levels of anti-laminin-1 auto-antibodies contrary to the control group. A higher fetal resorption rate was found in the laminin-1 immunized group (23.8%) compared with that of the control group (12.2%), and was even higher in the subgroup of those animals with very high levels of anti-laminin-1 (P < 0.01). Laminin-1 immunized mice also had lower fetal and placental weights. CONCLUSIONS: Active immunization with laminin-1 followed by elevated circulating anti-laminin-1 antibodies results in reproductive failure manifested by a higher fetal resorption rate.

Animals↗
PubMed2003

Inhibition of ras by farnesylthiosalicylate significantly reduces the levels of autoantibodies in two animal models of the antiphospholipid syndrome.

BACKGROUND: Stimulation and proliferation of lymphocytes require activation of Ras. S-farnesylthiosalicylic acid (FTS) is a synthetic substance that detaches Ras from the inner cell membrane and induces its rapid degradation. Antiphospholipid antibodies (aPL) are a heterogeneous group of antibodies detected in patients with antiphospholipid syndrome (APS), which is associated with thrombosis, pregnancy losses, and thrombocytopenia. OBJECTIVE: To examine the effect of FTS treatment on aPL levels in a genetic autoimmune model (the MRL/lpr mice) and in an induced model of APS. METHODS: Female Balb/C mice immunized once with beta2-glycoprotein I (beta2-GPI) in complete Freund's adjuvant (CFA) and female MRL/lpr mice were treated intraperitoneally with either FTS (5 mg/Kg/day) or saline 3-5 times a week. aPL and anti-beta2-GPI antibodies were measured by ELISA. RESULTS: FTS treatment 3 times a week resulted in significant decreases of aPL and anti-beta2-GPI antibodies in both animal models. In contrast, more frequent treatment (5 times a week) had no significant effect on autantibody levels in both animal models. We further compared 2 protocols in the induced APS model, one for alternate day treatment and the other for daily treatment on the first 3 days each week, and found a decrease in autoantibody levels only in the alternate day protocol. CONCLUSIONS: Inhibition of Ras activation by FTS is effective in decreasing autoantibody levels in models of APS. The differential modulation of immune function by alternate day compared to daily treatment may provide better understanding of the role of Ras activation in this system.

Animals↗
PubMed2003

Antiphospholipid antibodies: are they pro-atherogenic or an epiphenomenon of atherosclerosis?

Antiphospholipid antibodies are the hallmark of the antiphospholipid syndrome which is characterized by thrombosis. There are currently data supporting an association between these autoantibodies and atherosclerosis as well. Human studies suggest that anti-cardiolipin and anti-beta2-glycoprotein-I antibodies are elevated in patients having coronary artery disease compared with controls. Anti-cardiolipin antibodies are also associated with typical chest pain, significant coronary artery stenosis on angiography and prediction of myocardial infarction. Laboratory studies and murine models support the pro-atherogenic role of these autoantibodies, as they are involved in uptake of oxidized LDL into macrophages, and immunization of mice with them results in enhanced atherosclerosis. There is some evidence that high anti-beta2-glycoprotein-I antibodies can present a risk factor for atherosclerosis, but more epidemiological data are required in order to confirm whether the pro-atherogenic properties of anti-phospholipid antibodies signifies an independent risk factor for atherosclerosis and its complications.

Animals↗
PubMed2003

Atherogenic autoantigen: oxidized LDL complexes with beta2-glycoprotein I.

Beta2-Glycoprotein I (beta2-GPI) is a major antigen for antiphospholipid antibodies present in patients with antiphospholipid syndrome (APS). In 1997, we demonstrated that beta2-GPI specifically binds to Cu2+-oxidized low-density lipoprotein (oxLDL) and that the beta2-GPI-oxLDL complex is subsequently targeted by anti-beta2-GPI antibodies in vitro. Then ligands for beta2-GPI were purified from oxLDL and characterized as omega-carboxylated 7-ketocholesteryl esters, such as 7-ketocholesteryl-9-carboxynonanoate (oxLig-1) and 7-ketocholesteryl-12-carboxy (keto) dodecanoate (oxLig-2). These ligands mediate to form oxLDL-beta2-GPI complexes, and the complexes are taken up avidly by macrophages via anti-beta2-GPI autoantibody-mediated phagocytosis. We recently demonstrated that appearance of autoantibodies against a complex of beta2-GPI and oxLig-1 are highly associated with a history of arterial thrombosis. Serum oxLDL-beta2-GPI complex and their IgG immune complexes are also risk factors arterial thrombosis in APS patients. There is increasing circumstantial evidence of autoimmune mechanism involving beta2-GPI and oxLDL in the atherogenesis in APS.

Animals↗
PubMed2003

Anti-idiotypes to oxidized LDL antibodies in intravenous immunoglobulin preparations--possible immunomodulation of atherosclerosis.

OBJECTIVE: The aim of this study was to examine whether intravenous immunoglobulin (IVIg) preparations contain anti-oxLDL and anti-anti-oxLDL antibodies. BACKGROUND: Oxidized low-density lipoprotein (oxLDL) is one of the major players in atherogenesis. IVIg can reduce atherosclerosis in experimental animal models. METHODS: Six commercial IVIg preparations were tested for the presence of anti-oxLDL antibodies by EIA. Inhibition studies were performed with the different IVIg preparations and IgGs purified from a pool of sera from patients with high anti-oxLDL antibody levels. Absorption assays were carried out to evaluate the presence of anti-idiotypes against anti-oxLDL antibodies in IVIg preparations. RESULTS: IVIg preparations tested had various degrees of reactivity towards oxLDL. Absorption experiments suggested that the reactivity was specific because it could be effectively absorbed by oxLDL and not by an irrelevant antigen PPD. The reactivity was smaller than that observed with the IgG from the pool with high anti-oxLDL antibody levels. Inhibition studies with IVIg demonstrated 20-45% inhibition of anti-oxLDL binding to oxLDL, compared to 76% inhibition by the pool with high anti-oxLDL levels. To investigate the presence of anti-idiotypes against anti-oxLDL antibodies within IVIg, F(ab')2 fragments of IVIg IgG were used to absorb IgG F(ab')2 fragments from the pool of sera with high anti-oxLDL levels. The decreased binding to oxLDL of the absorbed supernatants shows that IgG F(ab')2 fragments of the IVIg preparations had high inhibitory capacities ranging from 65 to 90%. CONCLUSIONS: IVIg preparations contain both anti-oxLDL and anti-anti-oxLDL activity. This finding may explain the immunomodulating effect of IVIg in atherosclerosis.

Adjuvants, Immunologic↗
PubMed2003

Titers of antibody to common pathogens: relation to food-based interventions in rural Kenyan schoolchildren.

BACKGROUND: Undernutrition is widely perceived to affect the development of an effective immune system. OBJECTIVE: We used a mini-analysis system to quantitate antibody titers and evaluate the sera of 200 Kenyan schoolchildren for antibodies to Helicobacter pylori [isotypes of immunoglobulins A (IgA), G (IgG), and M (IgM)], hepatitis A virus, rotavirus, tetanus toxoid (IgG), and a panel of recombinant malarial antigens (MSP1(19), MSP2, Ag512, MSP4, and MSP5). DESIGN: Children participated in a school-based feeding intervention with meat, milk, or nonanimal-source foods or in a nonintervention control group. Microvolumes (200 mL) of sera were analyzed at baseline and after 1 y. RESULTS: Nearly all children had elevated titers of antibody to H. pylori, hepatitis A virus, rotavirus, and malaria at the outset, despite a high prevalence of apparent biochemical micronutrient deficiencies and stunting, but many had titers of tetanus toxoid IgG antibodies below the protective concentration. Children with low hemoglobin had a greater proportion of elevated H. pylori IgM antibody titers at baseline, which suggests that current infection with H. pylori may be associated with anemia. Compared with the control subjects, only the group eating meat had a significant increase in H. pylori IgM antibodies during the intervention (P = 0.019). No other group comparisons with the control subjects were statistically significant. The additional finding that the sera of some children showed inadequate tetanus-protective antibodies, despite immunization, suggests that the vaccination program was suboptimal. CONCLUSIONS: A large battery of immune assays can be performed on microvolumes of sera. Furthermore, despite evidence of malnutrition, children do develop significant antibody-mediated responses to common pathogens.

Adolescent↗
PubMed2003

An association of IgG anti-laminin-1 autoantibodies with endometriosis in infertile patients.

BACKGROUND: Laminin-1, a multifunctional glycoprotein of the basement membrane, is thought to be important in embryogenesis, embryonic implantation, and placentation. We recently showed that serum IgG anti-laminin-1 autoantibodies (auto-Abs) are associated with recurrent first-trimester miscarriages. The present study assessed the clinical significance of anti-laminin-1 Abs with infertility, accompanied with or without endometriosis. METHODS: Sixty-eight infertile patients who underwent laparoscopy or laparotomy and 39 healthy non-pregnant women were tested for IgG anti-laminin-1 Abs. The association between the Abs and endometriosis was analysed. The presence of laminin-1 mRNA was detected in endometriotic lesions. RESULTS: Twenty infertile patients were positive for anti-laminin-1 Abs. The Ab levels in those patients were significantly higher than those in healthy non-pregnant women (P = 0.0005). The presence of the Abs was significantly associated with endometriosis in those patients (P = 0.0096). The Abs recognized a particular domain, i.e., the laminin-alpha1 chain G domain. mRNA encoding laminin-alpha1, -beta1, and -gamma1 chains was expressed in 90% of endometriotic lesions. CONCLUSIONS: IgG anti-laminin-1 Abs were significantly associated with endometriosis in infertile patients. The Abs might be clinically important in the development of autoimmune-mediated reproductive failures and the assessment of the Abs may provide a novel non-invasive diagnosis of endometriosis.

Adult↗
PubMed2003

The pathogenic role of anti-thyroglobulin antibody on pregnancy: evidence from an active immunization model in mice.

BACKGROUND: The presence of antibodies to thyroglobulin (Tg) is associated with fetal loss even in the absence of thyroid dysfunction. The aim of this study was to examine whether active immunization with Tg could elicit anti-Tg autoantibodies and reproductive failure without interfering with thyroid function. METHODS: BALB/c mice that were immunized with human Tg in complete Freund's adjuvant (CFA) or injected with only CFA were studied for the development of antibodies to Tg, T4, dsDNA, ssDNA and cardiolipin. Total T4, free T4 and thyroid-stimulating hormone (TSH) levels were also assessed before and during pregnancy. Percentages of resorbed fetuses (the equivalent to human missed abortion) were compared and autoantibody presence on the placentae and fetuses was examined. RESULTS: Following immunization, high levels of anti-Tg were observed in mice immunized with Tg, compared with mice injected with CFA [0.83 +/- 0.23 versus 0.012 +/- 0.016 respectively; mean +/- SD optical density (OD) at 405 nm; P < 0.001]. The specificity of binding to Tg was confirmed by competition assay. Although total T4 levels were increased in comparison with control mice, this was associated with the presence of antibodies to T4. Indeed, free T4 levels and TSH were similar to control mice. Mice were killed after 14 days of pregnancy. The thyroid function and the histology of the thyroid glands were normal. Increased fetal wastage was found among the Tg-immunized mice compared with the CFA-injected mice (P = 0.04), with lower fetal and placental weights (fetal weights: 194 +/- 4 mg versus 240 +/- 6 mg; placental weights: 105 +/- 2 mg versus 130 +/- 3; P < 0.001 for both). Antibodies to Tg were demonstrated only on the placentae of Tg-immunized mice. CONCLUSION: Immunization with Tg results in the production of Tg antibodies and fetal resorption. These effects occur in the absence of thyroid dysfunction.

Animals↗
PubMed2003

Novel Approaches to Therapy for SLE.

Systemic lupus erythematosus (SLE) is an autoimmune disease manifested by multi-organ involvement and elevated titers of anti-DNA antibodies. Current therapies for SLE are broadspectrum, and include steroids and immunosuppressive cytotoxic agents that are counterbalanced by the toxicity and side effects of the medications. One of the goals is to target therapies by altering specific known mechanisms of inflammation and autoimmunity. Although the inciting antigen is still unknown in SLE, it may be possible to alter the regulation of the immune response by targeted molecular therapy. Methods under investigation, which may be beneficial, are manipulation of second-signal stimulation of the immune response (anti-CD40L), manipulation of cytokines (monoclonal anti-IL-10), inducing tolerance by administration of blocking peptides (LJP394), and the manipulation of idiotypes (IVIg). In this article, we also discuss modalities that are steroid-sparing (MTX), and selective immunosuppression (stem-cell restoration and MMF). We review the ongoing literature from 2000-2002, utilizing the MEDLINE search. Controlled trials, open trials, and trials in phase I and II have been included, and anecdotal reports were excluded. The major advances have been with mycophenolate mofetil (MMF) and LJP 394.

Autoimmunity↗
PubMed2003

Osteonecrosis in patients with SLE.

Osteonecrosis is a clinical entity characterized by death of bone marrow and trabecular bone as a result of disruption of blood supply to the bone (1,2). Other aspects of this condition include avascular necrosis, aseptic necrosis, and osseous ischemic necrosis of bones. Osteonecrosis is classified into two main forms; post-traumatic and nontraumatic. The post-traumatic form of osteonecrosis usually develops as a result of traumatic displacement of bone fragments, which leads to impaired blood supply and ischemia to the affected bone. Osteonecrosis of the femoral head is common following fracture of the femoral neck. A variety of systemic diseases and clinical conditions are associated with nontraumatic osteonecrosis. These include autoimmune rheumatic diseases, alcoholism, pregnancy, Gaucher's disease, thrombophilia, corticosteroid therapy, Sickle-cell anemia, pancreatitis, inflammatory bowel diseases, and use of cytotoxic drugs and others. Idiopathic forms of osteonecrosis have also been reported (2-4). Among the rheumatic diseases, osteonecrosis is strongly associated with systemic lupus erythematosus (SLE) (5). However, osteonecrosis has been diagnosed in patients with primary antiphospholipid syndrome (APS) (6), rheumatoid arthritis (7), and systemic vasculitis (8). This article reviews the causes, clinical and epidemiological features, diagnosis, and treatment options for osteonecrosis among patients with SLE.

Humans↗
PubMed2003

SLE and infections.

Infections are common in systemic lupus erythematosus (SLE), and remain a source of mortality. The types of infections (such as pneumonia, urinary tract infection, cellulitis, and sepsis) in SLE patients are similar to the general population and include the same pathogens (Gram-positive and Gram-negative). SLE patients may also develop opportunistic infections, especially when treated with immunosuppressive agents. As a high-risk population, identification and treatment of chronic infections such as tuberculosis, hepatitis B, or human immunodeficiency virus (HIV), are important prior to the institution of immunosuppression to prevent reactivation or exacerbation of the infection. A common caveat is to distinguish between a lupus flare and an acute infection; judicious use of corticosteroids and cytotoxic drugs is critical in limiting infectious complications. The risk factors associated with susceptibility to disease include severe flares, active renal disease, treatment with moderate or high doses of corticosteroids and/or immunosuppressive agents, and others. Genetic factors (complement deficiencies, mannose-binding lectin, Fcgamma III, granulocyte macrophage colony-stimulating factor [GM-CSF], osteopontin) may predispose certain SLE patients to develop infections. Parameters including C-reactive protein (CRP) and adhesion molecules may help to differentiate an infectious disease from an exacerbation of the disease. Finally, the mechanism of molecular mimicry by specific microbial agents may play a role in the induction of SLE.

Bacterial Infections↗
PubMed2003

Systemic lupus erythematosus and parvovirus B-19: casual coincidence or causative culprit?

Systemic lupus erythmatosus (SLE) is a multi-system autoimmune disease characterized by auto-reactive cells and auto-antibodies, which can potentially affect all organ systems. Typical organ systems that are affected include the heart, lungs, skin, kidneys, and central nervous system. Its expression is believed to be dependent on various factors such as genetic predisposition, environmental agents, immune dysregulation, crossreactivity with auto-antigens, alterations in auto-antigens, or most likely, a combination of these. Parvovirus B19, a virus which commonly runs an asymptomatic or benign self-limiting course such as erythema infectiosum, transient aplastic crisis, flu-like symptoms, rash, arthalgia, and arthritis, has recently been associated with a number of rheumatic diseases, more specifically with SLE. Like SLE, it can present with multi- systemic symptoms resembling SLE both clinically and serologically. Similarities have been so striking that patients have been initially misdiagnosed with SLE, having fulfilled 3-5 of the criteria of the American College of Rheumatology, currently used for the diagnosis of SLE, only to discover later that they were infected by parvovirus B19. This paper will discuss parvovirus' link to SLE, its similarities and differences, and whether parvovirus can act as a trigger of, or simply mimic, SLE.

Diagnosis, Differential↗
PubMed2003

Atherosclerosis and antiphospholipid syndrome.

Atherosclerosis is an autoimmune/inflammatory disease associated with infectious, inflammatory, and autoimmune factors. Both humoral and cellular immune mechanisms have been proposed to participate in the onset and/or progression of atheromatous lesions. Heat-shock protein (hsp), oxidized low-density lipoprotein (LDL), and beta2-GPI have been reported to elicit humoral and cellular immune response in both experimental animals and humans. These autoantigens are expressed within atherosclerotic lesions. Immunization with the given autoantigens elicits an immune response that influences lesion progression. Atherosclerosis susceptibility can be transferred by autoantigen-sensitized lymphocytes from immunized animals. Patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) have a high risk for atherosclerotic cardiovascular events. The traditional risk factors fail to fully account for accelerated atherosclerosis in SLE and APS. Immunological alterations, such as antibodies to oxidized LDL, antiphospholipid antibodies (aPL), antibodies to beta-2 Glycoprotein (anti-beta2-GPL), anti-prothrombin antibodies, may play a role in premature atherosclerosis in SLE and APS. Paraoxonase (PON1) is an enzyme with antioxidant activity attached to the circulating high-density lipoprotein (HDL) in plasma. Its function is to prevent oxidation of LDL, thereby accounting for the antioxidant properties and the atherosclerotic protective effects of HDL. The relationship between PON1 and aPL has been recently suggested. IgG anti-HDL and IgG anti-beta2-GPI antibodies were associated with reduced PON1 activity in patients with SLE and primary APS. The determination of classic and new factors, together with specific autoantibody titers and the use of Doppler carotid ultrasound, are useful methods to detect early atherosclerosis in SLE and PAPS. Therapeutic strategies, including early control of disease and other risk factors, are essential to reduce morbidity and mortality.

Antibodies, Antiphospholipid↗