PubMed Health⌕ Search

Biomedical subjects

Yehuda Shoenfeld

Publications and source records attributed to Yehuda Shoenfeld.

At least 163 records · Page 9Linked to original sources
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↗
PubMed2003

[Anti-cyclic citrullinated peptide antibodies as a diagnostic test for rheumatoid arthritis].

Early diagnosis of rheumatoid arthritis (RA) is important since aggressive therapy should begin at an early stage. Diagnosis is made on a clinical basis, supported by the determination of rheumatoid factor (RF). However, RF is also positive in healthy subjects, as well as in other autoimmune and infectious diseases. Two other diagnostic markers with a high specificity for RA, antiperinuclear factor (APF) and antikeratin antibodies (AKA), are not in general use because of technical difficulties. APF and AKA are antifilaggrin antibodies (AFA) that bind to determinants rich in the unusual amino acid citrulline, generated by posttranscriptional modification of arginine residues by the enzyme peptidylarginine deiminase (PAD). Enzymatic determination of recombinant filaggrin fragments produces linear peptides, which are recognized by RA-specific autoantibodies. After substitution of serine by cysteine, a cyclic peptide is formed. The conformational change mimics the original structure of the filaggrin and enhances the affinity of the antibodies. Recently, an anti-cyclic citrullinated peptide (anti-CCP) ELISA was developed. The sensitivity of this test is usually 51%-68%, with a specificity of about 96%-98% (significantly higher than that of RF). Together with RF, anti-CCP increases the ability to diagnose patients with early RA. The test might help to predict which patients will develop persistent disease with evidence of radiologic lesions. Implementation of the highly specific anti-CCP test in conjunction with RF would enable reliable early diagnosis in some cases and allow the initiation of aggressive therapy with disease modifying anti-rheumatic drugs (DMARDs).

Antibodies↗
PubMed2003

[Why viral (SARS, Ebola and AIDS) epidemics now?].

In the last three decades we have seen several viral (and bacterial; i.e. TB) epidemics which took place at an era where we would have expected the eradication of many infectious diseases. There are many hypotheses to explain this paradox; 1) Is it the hygiene theory, namely extensive use of wide spread and too potent antibiotics which eliminate protective infecting agent? And hence the beneficial effect of probiotics? Is it the widespread use of vaccine? Is it a mistake or a terror acts of leakage of viral mutant from research or other laboratories? Be it as it may, the globalization and the employment of long distance flights make the spread easy to extreme points in the globe (Shanghai-Toronto). The new epidemiology? Immunology fields will have to deal with these novel aspects to combat and to prevent more events.

AIDS Vaccines↗
PubMed2002

Intravenous gamma globulin inhibits the production of matrix metalloproteinase-9 in macrophages.

BACKGROUND: Degradation of the extracellular matrix (ECM) is essential for progression and metastasis of cancer cells. The ECM-degrading enzymes, matrix metalloproteinases (MMPs), are produced mainly by intratumor monocytes/macrophages. MMPs, particularly MMP-9, are reported to be of crucial significance for both growth and tumor invasiveness. Inhibition of the expression of MMP-9 may prevent tumor development. High-dose intravenous gamma globulins (IVIG) effectively inhibit metastatic spread of tumors in mice and humans and a variety of mechanisms have been suggested to explain this effect. METHODS: We studied the effect of purified IVIG on MMP-9 secretion and mRNA expression by in vitro differentiated human monocytic cells (cell lines and peripheral blood monocytes). Zymography was employed to measure gelatinase secretion and Northern blot analysis was used to detect mRNA expression. Involvement of F(ab)(2) and Fc components in IVIG activity was also evaluated. RESULTS: IVIG dose dependently and significantly reduced the amount of secreted MMP-9 and its mRNA expression. F(ab)(2), but not Fc fragments, led to suppressed MMP-9 activity. However, competitive experiments demonstrated that Fc, but not F(ab)(2) fragments, reversed the IVIG-induced inhibitory effects. CONCLUSIONS: These results suggest that the whole IgG molecule may be needed for pertinent IVIG-induced MMP-9 down-regulation. This study points to an additional new mechanism whereby IVIG may play a beneficial role in the prevention of tumor spread in humans.

Blotting, Northern↗
PubMed2002

Oral tolerance with heat shock protein 65 attenuates Mycobacterium tuberculosis-induced and high-fat-diet-driven atherosclerotic lesions.

OBJECTIVE: The goal of this study was to explore the efficacy of oral tolerance with heat shock protein (HSP) 65 in two apparently non-overlapping models of murine atherosclerosis. BACKGROUND: Atherosclerosis is considered to be a chronic inflammatory process. Autoimmune mechanisms have been shown to influence atherogenesis in experimental animal models. Heat shock protein 65 is a candidate antigen thought to drive a proatherogenic immune-mediated response. Mucosal tolerance is a therapeutic means of accomplishing immune unresponsiveness toward a given antigen by feeding it before active induction of the disorder. METHODS: Low-density lipoprotein receptor deficient mice were fed with different doses of HSP65 every other day for 10 days. Feeding with either bovine serum albumin (BSA) or phosphate buffered saline (PBS) served as control. One day after the last feeding, mice were challenged either by immunization with heat killed Mycobacterium tuberculosis or by a high fat diet. RESULTS: Lymphocyte reactivity from mice fed with HSP65 and immunized either against HSP65 or M. tuberculosis was significantly reduced in comparison with BSA-fed mice. Moreover, co-incubation of splenocytes-from mice with tolerance induced with HSP65 but not BSA-with HSP65-reactive lymphocytes resulted in the suppression of HSP65 reactivity by the latter cells. Interleukin-4 production by HSP65-fed and immunized mice was increased upon priming with respective protein. Early atherosclerosis was attenuated in HSP65-fed mice, compared with either BSA- or PBS-fed mice, regardless of the method employed to induce fatty streaks (M. tuberculosis immunization or high-fat diet). CONCLUSIONS: Oral tolerance induced with HSP65 could prove to be a novel means of suppressing atherogenesis.

Administration, Oral↗
PubMed2002

Induction of oral tolerance in experimental antiphospholipid syndrome by feeding with polyclonal immunoglobulins.

Intravenous immunoglobulins (IVIG) contain a wide spectrum of anti-idiotypes associated with autoimmune diseases. Since part of these anti-idiotypes may bear an internal image of the eliciting antigen, IVIG might be suitable for induction of oral tolerance. In the current study we attempted to induce tolerance in an experimental model of anti-phospholipid syndrome (APS) by oral administration of IVIG. Naive mice were fed with IVIG, or anti-beta 2GPI-specific anti-idiotypic IVIG(alpha Id). Significantly diminished humoral response was noted in mice IVIG/ IVIG-F(ab')(2)or IVIG(alpha Id)-tolerized mice, accompanied by a significant attenuation of clinical manifestations. The maximal effect was achieved in the mice tolerized before disease induction. Abrogation of T lymphocyte proliferation to beta 2GPI was detected in the mice fed with IVIG prior to beta 2GPI immunization, mediated by TGFbeta and IL-10 secretion. The tolerance induced by IVIG-feeding was nonspecific and could be adoptively transferred to syngeneic mice by CD8alpha (+) cells. These CD8alpha (+) T cells, were found to secrete high levels of TGFbeta and IL-10. In summary, IVIG-induced oral tolerance has a nonspecific immunomodulatory effect in experimental APS, mediated by TGFbeta and IL-10-secreting CD8alpha (+) cells. Our results point to a possible application of IVIG in the induction of oral tolerance against various autoimmune diseases.

Administration, Oral↗
PubMed2002

Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients.

OBJECTIVE: To analyze the clinical and immunologic manifestations of antiphospholipid syndrome (APS) in a large cohort of patients and to define patterns of disease expression. METHODS: The clinical and serologic features of APS (Sapporo preliminary criteria) in 1,000 patients from 13 European countries were analyzed using a computerized database. RESULTS: The cohort consisted of 820 female patients (82.0%) and 180 male patients (18.0%) with a mean +/- SD age of 42 +/- 14 years at study entry. "Primary" APS was present in 53.1% of the patients; APS was associated with systemic lupus erythematosus (SLE) in 36.2%, with lupus-like syndrome in 5.0%, and with other diseases in 5.9%. A variety of thrombotic manifestations affecting the majority of organs were recorded. A catastrophic APS occurred in 0.8% of the patients. Patients with APS associated with SLE had more episodes of arthritis and livedo reticularis, and more frequently exhibited thrombocytopenia and leukopenia. Female patients had a higher frequency of arthritis, livedo reticularis, and migraine. Male patients had a higher frequency of myocardial infarction, epilepsy, and arterial thrombosis in the lower legs and feet. In 28 patients (2.8%), disease onset occurred before age 15; these patients had more episodes of chorea and jugular vein thrombosis than the remaining patients. In 127 patients (12.7%), disease onset occurred after age 50; most of these patients were men. These patients had a higher frequency of stroke and angina pectoris, but a lower frequency of livedo reticularis, than the remaining patients. CONCLUSION: APS may affect any organ of the body and display a broad spectrum of manifestations. An association with SLE, the patient's sex, and the patient's age at disease onset can modify the disease expression and define specific subsets of APS.

Adolescent↗
PubMed2002

Induction of biologically active antineutrophil cytoplasmic antibodies by immunization with human apoptotic polymorphonuclear leukocytes.

Translocation of intracellular components to the cell surface during the priming or apoptosis of polymorphonuclear leukocytes (PMN) is an important mechanism for interaction of antineutrophil cytoplasmic antibodies (ANCA) with these antigens. To test the capacity of apoptotic PMN to trigger production of ANCA, six groups of mice were immunized with either live or apoptotic lymphocytes, or with live, apoptotic, formalin-fixed, or lysed PMN. Mice immunized with both live and apoptotic neutrophils developed high titers of antibodies which gave a granular cytoplasmic immunofluorescent pattern. These antibodies were specific for lactoferrin and myeloperoxidase. Following a second intravenous infusion of apoptotic PMNs, mice developed anti-PR3 antibodies. Vasculitis lesions were not found in mice which developed ANCA. The ANCA-containing IgG fraction induced superoxide production by human PMNs. These results support the hypothesis that neutrophil-specific antigens presented on the cell membranes of apoptotic PMN may induce ANCA in the proper conditions.

Animals↗