Search PubMed⌕ Search

Biomedical subjects

Y Shoenfeld

Publications and source records attributed to Y Shoenfeld.

At least 361 records · Page 20Linked to original sources
PubMed1997

Animal models for antiphospholipid syndrome in pregnancy.

Experimental models for antipospholipid syndrome (APS) have been established recently in lupus-prone mice and induced in naive mice. The induction of APS is performed by passive infusion or active immunization of antiphospholipid antibodies (aPL) or the cofactor beta 2GP-1. High levels of diverse aPL develop in the animals in conjunction with clinical manifestations similar to the human disease, entailing low fecundity rate, fetal resorptions, thrombocytopenia, prolonged activated partial thromboplastin time, and neurological and behavioral impairments. The pathogenicity of aPL was confirmed in an in vivo thrombosis model. Immunomodulation of APS manifestations and treatment regimens in the experimental models are discussed.

Animals↗
PubMed1997

Pathogenicity of human anti-platelet factor 4 (PF4)/heparin in vivo: generation of mouse anti-PF4/heparin and induction of thrombocytopenia by heparin.

Heparin-induced thrombocytopenia/thrombosis (HIT) is a severe thrombotic disorder that occurs in approximately 1% of patients treated with heparin. Affected patients commonly develop antibodies that recognize PF4/heparin complexes that may form on the surface of activated platelets and on the endothelium. However, it has not been established that anti-PF4/heparin antibodies are responsible for the clinical manifestations of HIT. To address this issue, we employed a recently developed model of active immunity to study the effect of IgG anti-PF4/heparin antibody in vivo. In previous studies we have shown that it is possible to induce autoimmune diseases such as systemic lupus erythematosus (SLE), anti-phospholipid syndrome (APS) or vasculitis in naive mice by active immunization with anti-DNA, anti-cardiolipin and anti-neutrophil cytoplasmic antibodies, respectively. Immunized animals develop anti-idiotypic antibodies (Ab2) and, after 2-4 months, anti-anti-idiotypic antibodies (Ab3). Ab3s generated in this manner often simulate the binding activity of Ab1 and their expression correlates with the development of specific clinical manifestations typical of the respective human disease. Based on this experience, naive BALB/c mice were immunized with IgG anti-PF4/heparin antibodies isolated from two patients with HIT. The actively immunized mice developed mouse anti-PF4/heparin antibody (Ab3). Administration of unfractionated heparin, but not low molecular weight heparin (LMWH), to the actively immunized animals induced thrombocytopenia by day 4 of drug exposure. There was no evidence of thrombosis. The results of this study support the importance of anti-PF4/heparin antibodies in the pathogenesis of HIT. Further, this model may help to elucidate the factors responsible for thrombosis as well as providing means to assess new treatment options for patients with this disorder.

Animals↗
PubMed1997

Oxidized low-density lipoprotein (Ox-LDL) but not LDL aggravates the manifestations of experimental antiphospholipid syndrome (APS).

Ox-LDL is thought to play a major role in atherogenesis. The mechanisms mediating the deleterious influences of Ox-LDL include foam cell formation and cell cytotoxicity. The production of anti-Ox-LDL antibodies results in the formation of immune complexes which are taken up at enhanced rate by macrophages, leading to foam cell formation. APS is characterized by repeated venous and arterial thromboembolic phenomena, recurrent fetal loss and thrombocytopenia, associated with the presence of antibodies to negatively charged phospholipids (aPL) (i.e. cardiolipin, phosphatidylserine). Phospholipids bear structural resemblance to LDL, and several studies have indeed proved that aPL display cross-reactivity with anti-Ox-LDL antibodies. In this study we assessed the capacity of oxidized and native forms of LDL to aggravate the clinical picture of experimentally induced APS in naive mice. Mice were actively immunized intradermally with anticardiolipin antibodies and developed a clinical picture resembling APS in humans. Subsequently, the mice were infused with either Ox-LDL, native LDL or PBS, and similar regimens were applied to controls. APS mice infused with Ox-LDL were found to exhibit a significantly more severe form of the disease in comparison with native LDL- and PBS-infused mice, expressed by lower platelet counts (261,000/mm3, 535,000/mm3 and 455,000/mm3, respectively), longer activated partial thromboplastin time (aPTT) (99 +/- 12 s, 63 +/- 8 s and 74 +/- 8 s, respectively) and higher fetal resorption rates (72.7%, 34.4% and 32.6%, respectively). The results of this study show that Ox-LDL, compared with native LDL, aggravates the clinical manifestations of experimental APS and suggest that cross-reactivity of Ox-LDL with phospholipids may provide a pathogenic explanation for this effect.

Animals↗
PubMed1997

Smoking and immunity: an additional player in the mosaic of autoimmunity.

Autoimmune diseases are associated with a variety of predisposing factors. However, the relative contribution of each remains to be established. The purpose of the paper is to focus on cigarette smoking, a common Western habit, as a possible environmental factor for the emergence of autoimmunity. This association is described in view of several recent studies documenting increased susceptibility to autoimmune diseases among smokers.

Animals↗
PubMed1997

Immunologic characterization and functional properties of murine antibodies raised against deleted mutants of human beta 2-glycoprotein I.

beta 2-Glycoprotein I (beta 2GPI) is a 50 kDa molecule proposed as a principal target of 'autoimmune' antiphospholipid antibodies (aPL). We have used deleted mutants (DM) representing different domains of beta 2GPI (I-IV, IV-V and V) for immunization of naive mice and studied the characteristics of the respective murine IgG preparations in comparison with affinity-purified IgG from two patients with primary antiphospholipid syndrome. Immunization with beta 2GPI and with the DM produced anti-beta 2GPI antibodies, part of which reacted with negatively charged phospholipids (PL), whereas reactivity with cardiolipin was evident only in the IgG from mice immunized with beta 2GPI. These results are consistent with the presumption that aPL are induced following the in vivo association of beta 2GPI (used for immunization) with resident negatively charged PL. Accordingly, DM which either lack the PL binding site or aPL attachment locus did not elicit, upon immunization, antibodies reactive with PL. Further, murine anti-beta 2GPI IgG and human 'autoimmune' aPL were similar, albeit not identical, in terms of DM requirement for PL binding and charge dependency. Murine antibodies and human aPL, regardless of their binding characteristics, were found to bind significantly to platelets upon their activation with thrombin and to promote platelet activation. The results of the current study emphasize the dissimilarities between human 'autoimmune' aPL and murine anti-beta 2GPI. Thus, anti-beta 2GPI antibodies to different DM as well as human aPL are capable of binding and activating human platelets provided beta 2GPI is present.

Animals↗
PubMed1997

Infections and Wegener's granulomatosis--a cause and effect relationship?

The association of infections and autoimmune disease has been noted by various authors. Several mechanisms have been proposed to explain this, with no current consensus. Wegener's granulomatosis (WG) is an autoimmune disease involving predominantly the pulmonary and renal systems, and is associated with a distinct autoantibody-the anti neutrophil cytoplasmic antibody (ANCA). Although no solid evidence implicates infections in the emergence of WG, direct and circumstantial data suggest this relation. We review this evidence and discuss possible underlying mechanisms. We emphasize the relationship between infections and ANCA, and their role in the maintenance of the 'on-going' inflammatory response.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1997

New methods of treatment in an experimental murine model of systemic lupus erythematosus induced by idiotypic manipulation.

In this article we have presented our experiences and those of others with various experimental and novel treatments in an experimental model of murine SLE, induced by immunisation with pathogenic anti-DNA antibody (fig 4). Many of the treatments (summarised in the table) were highly effective in ameliorating clinical, serological, and histological manifestations of the disease. According to our results, it seems that hormonal treatments--such as testosterone metabolites, anti-oestrogens, or bromocriptine--as well as immunomodulation with IVIG or anti-CD4 antibodies, hold the most promising potential for application in lupus patients. We believe, therefore, that these types of treatment should receive high priority in human trials. It should be emphasised, however, that the timing of treatment may be critical, since several treatments were effective when used before or during the induction of the disease. This limitation may pose difficulty for human application, since the aetiology of SLE is still obscure and is probably multifactorial38; therefore it is not yet possible to identify patients at risk of developing SLE. Nevertheless, those treatments which proved to be effective might be used early in the course of the disease in lupus patients and hence influence the outcome of the disease, or may even induce partial or complete remission.

Animals↗
PubMed1997

'Autoantibody dominance' pattern following idiotypic manipulation of naive mice by immunization with anti-U1RNP antibodies.

OBJECTIVE: To study the immune response and clinical findings in mice immunized with different epitope-specific anti-U1RNP antibodies purified from the sera of mixed connective tissue disease (MCTD) patients with various clinical manifestations. METHODS: BALB/c mice were immunized with anti-U1RNP-IgG preparations from 3 patients with MCTD. Group 1 was immunized with U1 70 kD A-positive IgG, group 2 with U1 70 kD-negative, U1A, U1C, B-B'-positive IgG and group 3 with U1 70 kD, U1A, U1C-positive IgG. The induced autoantibody response in the mice was studied by ELISA and immunoblots and the clinical findings of MCTD in humans were assessed. RESULTS: Immunoblot assays showed that mice immunized with different human anti-U1RNP antibodies developed predominantly autoantibodies directed against U1 68-70 kD epitope. This 'autoantibody dominance' pattern was not associated with clinical findings. CONCLUSIONS: The restricted murine autoimmune response may provide clues to the diversified autoantibody production in autoimmune diseases and explain in part the changing patterns of clinical findings in individuals with MCTD.

Animals↗
PubMed1997

Successful treatment of early secondary myelofibrosis in SLE with IVIG.

Myelofibrosis has been reported as a rare cause of pancytopenia in patients with autoimmune diseases. We describe a 54y old female patient who was admitted with severe anemia subsequently found to be due to marrow fibrosis. During the course of her hospitalization, relying both on her clinical symptoms as well as the results of a wide range of laboratory tests and diagnostic procedures, the diagnosis of systemic lupus erythematosus was established. The patient was treated with high dose steroids, but improvement of her clinical symptoms as well as normalization of her peripheral blood count were achieved only after high dose intravenous therapy with gamma globulin (IVIG) was instituted. Along with the improvement in the peripheral blood parameters normalization of the bone marrow architecture was recorded on a repeated bone marrow biopsy. IVIG therapy should be considered in extreme cases of bone marrow suppression in SLE.

Biopsy↗
PubMed1997

Prevalence of 13 autoantibodies and of the 16/6 and related pathogenic idiotypes in 465 patients with systemic lupus erythematosus and their relationship with disease activity.

With a cross sectional study of 465 consecutive systemic lupus erythematosus (SLE) patients tested for 13 autoantibodies (Aab) and two idiotypes we determined the prevalence of Aab according to disease activity, both general and at particular organ systems. Seventy seven percent of SLE sera had at least one Aab and 56% had it at high titres. Pathogenic idiotypes had a prevalence of less than 10% and 166 sera had Aab to 5 or more antigens and 9 sera had Aab against all 13 antigens tested. Patients with active disease had increased prevalence of Aab to DNP, ssDNA, ENA, mitochondria and histones when considered at 5 s.d. above the mean of normal controls. The higher positivity of Aab in patients with active disease was confirmed in logistic regression analysis adjusted by age, disease duration, and intensity of treatment. A trend was observed of increased prevalence and titres of Aab from inactive disease without treatment, to inactive disease but still being treated, to active disease. Only 22% of patients with active disease had no Aab and the higher the number of Aab the higher the frequency of active disease. Patients with active arthritis, and to a lesser degree those with active mucocutaneous involvement, had higher prevalence and titres of most autoantibodies than patients with disease activity at other organ systems. Active renal disease associated only with anti-dsDNA, whereas active CNS disease associated with anti-mitochondrial Aab. Our findings support the vision of SLE as an immune dysregulation leading to polyclonal B cell activation with resulting production of multiple Aab. Their profiles seem influenced by genetical, hormonal and environmental factors and, in turn, they contribute to the clinical picture in each patient. Disease activity influences the presence of some, but not all, Aab and some of them may remain present in some patients, even in remission.

Adult↗
PubMed1997

Primary antiphospholipid syndrome emerging following thymectomy for myasthenia gravis: additional evidence for the kaleidoscope of autoimmunity.

The etiology of autoimmune diseases is multifactorial. In many of them the stimulation by a specific autoantigen is claimed to be responsible for the initiation of the disease. Alternatively, an autoimmune state may be induced by a pure dysregulation of the immune system. Such is the case in which severe systemic lupus erythematosus (SLE) is induced in young patients with myasthenia gravis following thymectomy. We have referred to this set of events as the 'kaleidoscope of autoimmunity'. Herewith, we would like to present another example of the kaleidoscope phenomenon, namely: the emergence of a full blown clinical presentation of the primary antiphospholipid syndrome (APS-recurrent thromboembolic phenomena, repeated fetal loss with high titers of anti-cardiolipid antibodies) in a 32 y old female with myasthenia gravis, two years following thymectomy. Thymectomy in myasthenic patients may be associated with the emergence of new autoimmune conditions such as SLE and APS, pointing to the importance of immune dysregulation in the induction of these autoimmune diseases.

Abortion, Habitual↗
PubMed1997

IgG subclasses of human autoantibodies.

IgG comprises of four subclasses which differ from each other with respect to their biological properties. Fc gamma receptor shedding as well as a variety of T cell cytokines are influential in the distribution of these subclasses, but the route the antigen is introduced into the body is also important. With regard to nonorgan-specific autoimmune conditions, such as rheumatoid arthritis and systemic lupus erythematosus, IgG1 and IgG3 autoantibodies predominate, whereas IgG4 antibodies are regularly encountered in organ-specific autoimmune diseases. This suggests that the target organ may be continuously stimulating the immune system.

Autoantibodies↗
PubMed1997

The emerging concept of pathogenic natural autoantibodies.

Natural autoantibodies (NAA) are self-reacting antibodies found in the serum. NAA do not require antigenic or mitogenic stimuli for their synthesis. These low affinity antibodies are found in the sera of normal healthy subjects and animals and are thought to constitute part of the innate immunity by providing a first line of defense against foreign invading pathogens. In this paper we summarize the recently accumulated data which points to the pathogenic potential of NAA, challenging the paradigm of nonharmful antibodies.

Animals↗