Pathogenic role of antinuclear antibodies in lupus disease

The majority of anti-nuclear antibodies do not have a proven pathogenic role in systemic lupus erythematosus (SLE). The pathogenicity of native anti-DNA antibodies, suggested by clinical data, is difficult to confirm. It is linked to several factors: isotype and avidity of these antibodies, affinity for DNA, size of immune complexes. DNA, anti-DNA antibodies and cross-reactive anti-DNA idiotypes (16/6) have been isolated from human and NZB mouse glomeruli. Moreover, DNA has a particular affinity for the glomerular membrane due to its cross-reactivity with some constituents of this membrane. Anti-SSA (Ro) antibodies may play a role in some cases of nephropathy in SLE and participate in photosensitization. They are associated with neonatal lupus, with some cases of fetal death in black women and with the atrioventricular heart block. However, factors other than these antibodies are needed to induce such lesions. Anti-U1 RNP antibodies do not protect against kidney involvement in SLE; however, they can decrease suppressive function by penetrating into suppressor T cells. Anti-Sm antibodies may have particular immunoregulation properties. Some antinuclear antibodies may at least in part, be responsible for the lesions in SLE, in conjunction with other still-unknown factors.     

Pathogenic mechanisms mediating antiphospholipid syndrome

Antiphospholipid antibodies are the marker for antiphospholipid syndrome. There is evidence that these autoantibodies lead to both thrombotic diathesis and obstetrical manifestations. Besides the known interaction with soluble coagulation factors, in vitro and in vivo experimental models and studies in humans recently have shown the ability of antiphospholipid antibodies to modulate functions of cells involved in coagulation homeostasis. These findings support a new hypothesis to explain the paradox of the prolongation of coagulation assays in vitro and the association with thrombophilic diathesis in vivo. Obstetrical manifestations have been linked to a direct antibody effect on the trophoblast leading to defective placentation that is not necessarily associated with thrombotic phenomena. Phospholipid binding proteins such as beta 2 -glycoprotein I appear to behave as a bridge between circulating antiphospholipid antibodies and cellular targets.     

Pediatric antiphospholipid antibodies and antiphospholipid syndrome

Antiphospholipid syndrome (APS) can occur in children, like adults, with the same diverse spectrum of thrombotic sites but predominately with deep vein thrombosis and stroke. In contrast with adults, however, transient nonthrombogenic antiphospholipid (aPL) antibodies are seen more commonly, usually after childhood infections. In those with "true" aPL antibodies, recurrent thrombotic events seem less frequent than in adults, perhaps reflecting the less prothrombotic hemostatic state of childhood. Children with thrombotic events in APS present difficult management problems, as there is little evidence-based medicine. The duration and intensity of anticoagulation are unresolved management issues, but a target international normalized ratio of 2 to 3 is used by most. Multicenter randomized controlled trials would provide answers to some of these issues but are difficult to organize due to ethical issues and the rarity of the condition. A pediatric APS registry such as the Ped-APS Register is more easy to organize and can yield informative data.     

抗膜联蛋白A2抗体在抗磷脂综合征中的作用

目的 研究抗膜联蛋白A2抗体在抗磷脂综合征(APS)、系统性红斑狼疮(SLE)的血栓/病态妊娠中的可能作用.方法 先用分子克隆方法表达纯化出重组膜联蛋白A2,然后以重组膜联蛋白A2为抗原,采用酶联免疫吸附试验(ELISA)法分别检测了,101例APS患者,41例SLE合并血栓患者,124例无血栓的SLE患者及120名健康人的血清中IgG型抗膜联蛋白A2抗体水平.结果 APS组和SLE合并血栓组的IgC型抗膜联蛋白A2抗体阳性率分别为21.8%,26.8%,均品著高于单纯SLE组(6.5%)(P值均<0.0.).IgG型抗膜联蛋白A2抗体与血栓/病态妊娠有关联(P<0.01).IgG型抗膜联蛋白A2抗体对血栓/病态妊娠诊断的敏感性、特异性、预测值分别为0.232、0.935、0.805.结论 IgG型抗膜联蛋白A2抗体与APS和SLE患者的血栓/病态妊娠表现相关,将有助于一些潜在的APS患者的诊断.     

Acute cytomegalovirus infection and venous thrombosis: role of antiphospholipid antibodies

Cytomegalovirus (CMV)-induced thrombosis has been reported in immunocompromised patients, such as transplant recipients and patients with AIDS. Recent cases also describe thrombotic phenomena in immunocompetent patients with CMV infection. Various mechanisms may explain the role of CMV in thrombosis: this virus can damage endothelial cells, activate coagulation factors, and induce production of antiphospholipid (aPL) antibodies. We present a case report of a previously healthy white woman with a pulmonary embolism associated with CMV infection and the presence of aPL antibodies, and we discuss the role of the aPL antibodies associated with CMV infection in the pathogenesis of thrombosis.     

Origin of antiphospholipid antibodies

Our observations and those from others give further support to our hypothesis that "autoimmune aPL" may be generated by immunization with products from bacteria or viruses after incidental exposure or infection. We also were able to generate an APS-like syndrome in a strain of mice susceptible to autoimmunity, indicating that other factors such as genetic factors are likely to be involved in development of APS. Furthermore, not all aPL generated by immunization with bacterial or viral products were pathogenic. Based on the clinical experience and on the numerous reports indicating the presence of aPL in large number of infectious diseases, it may be expected that not all aPL produced during infection are pathogenic. We hypothesize that a limited number aPL induced by certain viral or bacterial products would be pathogenic in certain groups of predisposed individuals. Identification of those bacterial or viral agents may help to find strategies for the prevention of production of "pathogenic" aPL. Alternatively, free peptides may be used to induce tolerance against aPL production.     

Pathophysiology of antiphospholipid antibodies

The presence of antiphospholipid antibodies in plasma is a risk factor for thromboembolic complications. In vitro, however, the same antibodies can prolong dotting times in coagulation assays, a classic marker for a bleeding tendency. For years this contradiction has puzzled many scientists. Recently new insights into the interaction between antiphospholipid antibodies and their main target, the protein beta-2-glycoprotein I, have opened new avenues for the understanding of the pathology of this syndrome.     

A possible role for antiphospholipid antibodies in acquired cardiac valve deformity

We studied the frequency of antiphospholipid antibodies (aPL) in patients undergoing cardiac valve replacement, and present the results in the context of the pathology of the valve lesions. Forty-eight consecutive patients undergoing valve replacement were studied. Of the whole group, 15 (31%) had antibody levels greater than 2 SD above the mean for a control group of healthy persons and 11 (23%) had a level of greater than 3 SD. There was an increased frequency of elevated antibody levels in patients with valves showing fibrocalcific change and a significant association between aPL and valve thrombus. The possible role of these antibodies in the pathogenesis of the valve lesions is discussed.     

Lupoid sclerosis: a possible pathogenetic role for antiphospholipid antibodies.

The case of a 45-year-old woman is described who developed transverse myelitis over a one-year period. Serological tests suggested a lupus-like illness. Antibodies to cardiolipin of the IgM class were detected in high titres in her serum. These may have played a part in the pathogenesis of her disease.     

Managing antiphospholipid antibodies and antiphospholipid syndrome in children

Antiphospholipid antibodies (aPL) and antiphospholipid syndrome (APS) are increasingly being recognized in children. Transient non-pathogenic aPL are often seen after childhood infections, while thrombotic events seem rare in those with true aPL. We discuss the main scenarios faced when dealing with children with aPL--asymtomatic aPL, primary APS and secondary APS. Children with thrombotic events present difficult management problems, as there is little evidence-based medicine in this area. We discuss the manifestations and management of childhood aPL--asymptomatic aPL, primary and secondary APS elucidated with case histories. Insufficient safety data on anticoagulation and limited information on the effects of warfarin, use of aspirin, duration and intensity of anticoagulation are some of the unresolved issues in managing aPL and APS in children. Multicenter randomized controlled trials may provide answers to some of these issues.     

Update on antiphospholipid antibodies

The association of antibodies with an apparent specificity for anionic phospholipids with thrombosis, fetal loss, thrombocytopenia, and certain other clinical manifestations is now well-recognized as the antiphospholipid syndrome (APS). Recent advances in our understanding of the antibodies and antigens involved include discovery of the crystal structure of beta2-glycoprotein I, (beta2GPI), genetic studies of beta2GPI polymorphisms, and the development of anti-beta2GPI and antiprothrombin immunoassays as clinical laboratory tests. The identification of antigen-specific T cells in APS patients has stimulated interest in the role of the cellular immune response in the syndrome. Clinical research in APS will also benefit from the development of preliminary classification criteria.     

Clinical consequences of antiphospholipid antibodies

Antiphospholipid antibodies (aPL), notably the lupus anticoagulant and anticardiolipin antibodies, are the serological hallmarks of the antiphospholipid syndrome. Thrombosis and pregnancy complications are the most prominent clinical manifestations of this syndrome. This paper provides the clinician with guidelines for ordering and interpreting tests for aPL and discusses consequences for treatment if persistently positive tests are found.     

The adjunctive role of antiphospholipid antibodies in systemic lupus erythematosus cardiac involvement

OBJECTIVE: To evaluate the prevalence of cardiac alterations by trans thoracic echocardiography (TTE) and the possible role of aPLs in determining heart damage in SLE patients. PATIENTS AND METHODS: We investigated 34 consecutive Caucasian SLE patients and 34 age and sex- matched controls. All patients underwent TTE. Lupus anticoagulant (LA) was assayed. IgG and IgM antiphospholipid antibodies against cardiolipin (aCL), phosphatidylinositol (aPI), phosphatidylserine (aPS), phosphatidic acid (aPA), and anti-Beta2-glycoprotein I antibodies (aBeta2GPI) were determined by ELISA. RESULTS: Nineteen (56%) SLE patients showed at least one cardiac abnormality (P < 0.0001 - RR 19; OR 41.8; 95% CI 5.1-342). The predominant valve dysfunctions were represented by mitral (21%) and tricuspidal (18%) regurgitation. Aortic regurgitation was observed in 12% of patients, pericardial effusion and left atrial enlargement were identified in 15% and 12% of cases, respectively. Mitral valvular strands were detected in one patient. The prevalence of cardiac abnormalities correlated with disease duration. Echocardiographic alterations were more common in aPLs positive than in aPLs negative patients (P = 0.02 - RR 2.5; OR 6.1; 95% CI 1.2-30.1). Patients with IgG-aPA, -aPI and -aPS had a higher prevalence of left atrial enlargement (P < 0.05); IgG-aPA and -aPI were significantly associated with increased interventricular septum thickness (P < 0.05). CONCLUSION: Our findings confirm that the heart is one of the main target in SLE patients. The association between aPLs and cardiac impairment suggests an adjunctive role of these autoantibodies in determining heart damage. SLE vasculopathy is a multifactorial process leading to accelerated atherosclerosis. Heart involvement over the course of disease requires a comprehensive screening and management of traditional and new cardiovascular risk factors to prevent cardiac damage, which represents the primary cause of morbidity and mortality in SLE patients.     

The Michael Mason Prize: Pathogenic antiphospholipid antibodies, stressed out antigens and the deployment of decoys

The antiphospholipid syndrome is a common autoimmune cause of vascular thrombosis and recurrent miscarriages. aPLs that target the N-terminal domain [Domain I (DI)] of the phospholipid binding protein ?2-glycoprotein I (?2GPI) represent the key sub-population of aPLs that promote thrombosis. This review describes two research arms relating to the study of this autoantigen. The first arm describes recent novel biochemical and functional insights into the molecular structure of ?2GPI in vivo and how this may be altered in APS. These findings support the emerging hypothesis that redox modification of ?2GPI may be relevant to the pathogenesis of APS and the development of pathogenic anti-?2GPI antibodies. The second arm describes how a recombinant DI peptide engineered using a bacterial expression system was used to delineate the fine immunodominant epitopes on DI that pathogenic anti-?2GPI antibodies target. The epitope was found to be conformational and revolve around arginine (R) 39 within DI. Thus, whole recombinant DI was used in an in vivo mouse model as a novel decoy peptide inhibitor of anti-?2GPI antibodies. DI and a high binding mutant completely abrogated the pathogenic effects of aPL in this murine model, with loss of inhibition of pathogenicity observed upon mutating the residue R39 to serine. This proof-of-principle study supports the ongoing development of recombinant DI as a novel therapeutic inhibitory peptide for patients with APS.     

Pathogenic role and clinical relevance of antineutrophil cytoplasmic antibodies in vasculitides

Within the last year, a growing body of evidence for a distinct role of antineutrophil cytoplasmic antibodies (ANCA) in the pathogenesis of ANCA-associated vasculitides (AAV) has developed. An experimental model of myeloperoxidase (MPO)-ANCA-associated vasculitis provided direct and convincing in vivo evidence that MPO-ANCA are primary pathogenic factors in small-vessel vasculitis by augmenting of leukocyte-vessel wall interaction and leukocyte-mediated vascular injury. Determination of bacterial lipopolysaccharide (LPS) effects on disease severity in a mouse model of anti-MPO-induced glomerulonephritis showed that ANCA and other proinflammatory stimuli of infectious origin acted in synergism in the development of destructive inflammation.     

The significance of antiphospholipid antibodies

Antiphospholipid antibodies (APLA) present very heterogeneous groups of antibodies which can significantly influence processes on different levels of coagulation cascade depending on effects of phospholipid surfaces on blood coagulation. This usually leads to a particular level of thrombophylia. Clinical syndrome accompanying positive APLA, such as antiphospholipid syndrome, was defined by clinical and laboratory symptoms. This clinical syndrome can be a primary syndrome, if other disorders with ability to induce generation of antibodies can be excluded, or a secondary syndrome. The most often in cases of systemic tissue disease. APLA can be divided according to the presence of lupus anticoagulant and anticardiolipin antibodies. According to a definition lupus anticoagulants are antibodies able to inhibit and prolong in vitro one or more blood clotting processes dependent on phospholipid surfaces. Anticardiolipin antibodies are antibodies measured by ELISA method with cardiolipin used as an antibody. Findings show that some APLA are directed against proteins bound to phospholipid surfaces. Main cofactor proteins include beta 2-GPI and prothrombin. Because of their heterogeneous specificity, APLA are directed against negative phospholipids or proteins bound to phospholipid surfaces and have important pathophysiology role in development of antiphospholipid syndrome.