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Introduction Activation of the complement pathway by immune complexes is a key feature of systemic lupus erythematosus (SLE) and SLE glomerulonephritis, which translates into low levels of C3 and C4 during active disease. C3 glomerulonephritis (C3GN) is part of a broader group of rare renal diseases, the C3 glomerulopathies, characterized by prominent C3 accumulation in the glomeruli with minimal to no immunoglobulin (Ig) deposition secondary to dysregulation of the alternative pathway of the complement system. Distinguishing lupus nephritis from other complement-mediated kidney disorders, including C3GN, represents a diagnostic challenge with potential therapeutic implications. Methods We report an unusual case of a 55-year-old woman with SLE and previous biopsy-proven class IV lupus nephritis, subsequently diagnosed with C3GN. Furthermore, we review the available literature published from January 2010—March 2021 on the clinical features and management of C3GN in the setting of SLE. Results In addition to our case, very few reports exist in the literature regarding C3GN in association with SLE. The underlying pathogenic mechanism of C3GN consists of dysregulation of the alternative pathway of the complement system, either due to genetic variation in complement-related genes or to acquired autoantibodies targeting C3 or C5 convertases; the latter mechanism could explain the occurrence of C3GN in the setting of autoimmune diseases, although it was not definitively identified in our patient or others with SLE. Similar to some of the previous reports, after suboptimal renal response on mycophenolate mofetil and rituximab, our patient has been successfully treated with eculizumab, thus far with >50% improvement in proteinuria. Conclusions C3GN represents an additional mechanism of renal injury in SLE mediated by alternative complement pathway dysregulation. Although rare, patients with SLE and persistent proteinuria with very low C3 would benefit from expedited renal biopsy to evaluate for C3GN as well as genetic testing, since this entity could require a different therapeutic approach.

Some adjuvants may exert adverse effects upon injection or, on the other hand, may not trigger a full immunological reaction. The mechanisms underlying adjuvant adverse effects are under renewed scrutiny because of the enormous implications for vaccine development. In the search for new and safer adjuvants, several new adjuvants were developed by pharmaceutical companies utilizing new immunological and chemical innovations. The ability of the immune system to recognize molecules that are broadly shared by pathogens is, in part, due to the presence of special immune receptors called toll-like receptors (TLRs) that are expressed on leukocyte membranes. The very fact that TLR activation leads to adaptive immune responses to foreign entities explains why so many adjuvants used today in vaccinations are developed to mimic TLR ligands. Alongside their supportive role, adjuvants were found to inflict by themselves an illness of autoimmune nature, defined as ‘the adjuvant diseases’. The debatable question of silicone as an adjuvant and connective tissue diseases, as well as the Gulf War syndrome and macrophagic myofaciitis which followed multiple injections of aluminium-based vaccines, are presented here. Owing to the adverse effects exerted by adjuvants, there is no doubt that safer adjuvants need to be developed and incorporated into future vaccines. Other needs in light of new vaccine technologies are adjuvants suitable for use with mucosally delivered vaccines, DNA vaccines, cancer and autoimmunity vaccines. In particular, there is demand for safe and non-toxic adjuvants able to stimulate cellular (Th1) immunity. More adjuvants were approved to date besides alum for human vaccines, including MF59 in some viral vaccines, MPL, AS04, AS01B and AS02A against viral and parasitic infections, virosomes for HBV, HPV and HAV, and cholera toxin for cholera. Perhaps future adjuvants occupying other putative receptors will be employed to bypass the TLR signaling pathway completely in order to circumvent common side effects of adjuvant-activated TLRs such as local inflammation and the general malaise felt because of the costly whole-body immune response to antigen. Lupus (2009) 18, 1217—1225.

Antiphospholipid syndrome is characterized by thrombosis and pregnancy loss. Infections are generally associated with autoimmune diseases, but in the setting of antiphospholipid syndrome this link has been suggested as having a pathogenic role. In this study, 98 patients with antiphospholipid syndrome were screened for antibodies directed to several infectious agents. The main finding in this study is the significantly higher prevalence of IgM antibodies to toxoplasma and rubella. This novel finding suggests that these infections might be associated with antiphospholipid syndrome. As autoimmune diseases and, in particular, antiphospholipid syndrome are associated with infections, mainly the catastrophic type of the syndrome, this finding implies that a current infection with these agents, i.e. toxoplasma and rubella, might either be related to the pathogenesis of antiphospholipid syndrome or alternatively to its manifestations. Lupus (2009) 18, 1149—1153.

The antiphospholipid (Hughes) syndrome (APS) includes systemic and central nervous system (CNS) pathology associated with antibodies to a complex of phospholipids and beta2-glycoprotein I (beta2-GPI). Beta2-GPI immunized mice develop systemic manifestations of APS and we presently examined CNS manifestations in this APS model. Female BALB/c mice were immunized once with beta2-GPI in complete Freund's adjuvant (CFA) or with CFA alone (controls). A staircase test and a T-maze alternation test were performed to test behavior and cognition in independent groups of mice 6, 12 and 18 weeks following the immunization. The APS mice developed elevated levels of antibodies against negatively charged phospholipids and beta2-GPI. Neurological impairment was detected only 18 weeks after the induction of the APS and consisted of both cognitive (53 +/- 4 vs 71 +/- 3% correct choices in the T-maze alternation for APS vs control mice, P < 0.001) and behavioral changes (higher number of rears (18 +/- 2 vs 11 +/- 1, P < 0.006) and higher number of stairs climbed (12 +/- 2 vs 7 +/- 1, P < 0.02). This is the first report of cognitive deficits in this APS model and demonstrates the time course for the development of previously described behavioral changes. The mechanism involved in these CNS manifestations remains to be elucidated.

The potential of oral treatment with AVEMAR (AVEMAR), a new benzoquinone-containing fermentation product of wheat germ, on features of experimental systemic lupus erythematosus (SLE) in naive mice, induced by idiotypic manipulation, was studied. We assessed the effect of AVEMAR on the profile of autoantibody production and the response of Th1=Th2 related cytokines as well as the clinical picture of experimental SLE in the SLE-induced mice. When the product was given in the pre-immunization period, down-regulation of autoantibody production (anti-dsDNA, mouse 16=6 Id, and anti-histones) following treatment with AVEMAR was noted (eg anti-dsDNA decreased from 0.898 0.097 OD at 405 nm to 0.519 0.103 OD following treatment). This effect was sustained for at least 4 weeks after discontinuation of the therapy. Serological manifestations associated with a delay in Th2 response (IL-4 and IL-10) were recorded (eg IL-4 decreased from 91.7 8.11 to 59.55 7.78 ng =ml in splenocyte condition media). The mice showed normal ESR, WBC and less than 100 mg/dl of protein in the urine in comparison to > 300 mg/dl protein in the SLE non-treated mice. In conclusion, oral intake of AVEMAR can ameliorate the clinical manifestations of experimental SLE, via affecting the Th1=Th2 network inhibiting Th2 response.

Background Ferritin is an iron storage protein considered also as an acute phase reactant with high levels in various inflammatory conditions. Recently, a plausible role for ferritin in the pathogenesis of immune-mediated and especially autoimmune diseases has been suggested. However, the link between ferritin and the antiphospholipid syndrome (APS) has been rarely explored. Therefore, in the current study we evaluated ferritin levels and their correlation to clinical and serological manifestations in patients with APS. We further analyzed ferritin levels among patients with the catastrophic variant of APS (cAPS). Methods Ferritin levels were determined in serum samples of 176 APS patients and 98 matched healthy controls according to age and sex (LIAISON, DiaSorin, Italy). APS samples were further analyzed for antiphospholipid (anti-cardiolipin, anti- beta-2-glycoprotein, lupus anticoagulant) and anti-infectious antibodies (CMV, EBV, rubella, toxoplasma, HBV) (LIAISON, DiaSorin, Italy). Clinical, serological and demographic manifestations were recorded. An additional analysis of ferritin levels among 14 patients with cAPS was performed. Results Hyperferritinemia was present in 9% vs. 0% of APS patients and controls, respectively ( p Conclusions Herein, we found that hyperferritinemia correlates with the presence of APS, its clinical manifestations and specifically with the catastrophic variant of this disease. Hyperferritinemia was also linked with anti-CMV antibodies among patients with APS. These associations allude to a pathogenic role of ferritin in the pathogenesis of APS, and the plausible role of ferritin as a marker of ensuing cAPS, although further studies are needed to elucidate these associations.

During the last few years several murine models for APS have been described. These include spontaneous occurring disease, or APS induced by immunization with pathogenic autoantibodies. Employing those models, several treatment modalities, in different stages of the disease, were studied. Treatments which showed promising potential for application in patients with APS include immunomodulation with specific anti-idiotypic or anti-CD4 antibodies, treatment with IL-3, high-dose intravenous immunoglobulins, ciprofloxacin or bromocriptine, as well as antithrombotic and anticoagulant treatments using aspirin and/or low-molecular-weight heparin. Bone-marrow transplantation was also found to improve clinical and serological manfestations of the disease. These studies might promote the handling of controlled clinical trials assessing their efficacy in APS patients.

Vaccination of healthy individuals is the most effective approach to protect the public from infections and prevent the spread of many infectious diseases all over the globe. Licensed vaccines are mostly safe, but in rare cases they may be associated with humoral response to self-antigens due to molecular mimicry, epitope spread, bystander activation or polyclonal triggering. Moreover, the clinical picture of autoimmune conditions following post-vaccination is rarer. Nevertheless, anecdotal case reports on the flare of autoimmune response with clinical manifestations were reported. Herein, we discuss this topic in relation to post-vaccination-induced antiphospholipid antibodies following tetanus toxoid vaccine, HBV and influenza associated in rare cases with antiphospholipid syndrome clinical manifestations. We will discuss the possible mechanisms which pertain to ASIA (Shoenfeld syndrome).

Adjuvants may induce autoimmune diseases in susceptible individuals, a phenomenon recently defined as autoimmune/inflammatory syndrome induced by adjuvants (ASIA). Patients with both antiphospholipid antibodies (aPL) and the genetic coagulopathy factor V Leiden (FVL) are frequently found. We therefore evaluated whether adjuvant can induce aPL in heterozygous FVL mice. aPL were measured in naïve mice and at 1 and 5 months after immunization with either complete or incomplete Freund’s adjuvant (CFA, IFA) in FVL and control C57/B6 background mice. We defined antibody levels 3 SD above the mean of C57/B6 mice immunized with adjuvant as positive (specificity of 99%). For β2GPI-dependent aPL, 28.6% (6/21) of FVL mice 5 months after immunization with adjuvant (both IFA and CFA) were positive compared with 4.8% (1/22) of FVL mice 1 month after adjuvant and 0% of naïve FVL and C57/B6 mice (0/16, p 2GPI-independent aPL. We hypothesize that the FVL aPL association is not a coincidence, but that chronic coagulation defects combined with external inflammatory stimuli analogous to adjuvant may induce aPL and also antiphospholipid syndrome, thus supporting the notion of ASIA.

We evaluated the embryolethality and embryotoxicity of sera from patients suffering from autoimmune diseases during remission on post-implantation rat embryos cultured on these sera and determined the association between the patients’ clinical history, high blood levels of specific antibodies, medications, and oxidative stress parameters. One hundred and eighty, 10.5-day-old rat embryos were cultured in their yolk sacs in 33 sera of systemic lupus erythematosus (SLE)/antiphospholipid syndrome (APS) patients, and compared with 84 embryos cultured in rat sera and 88 embryos cultured in control human sera. The sera proved to be lethal and embryotoxic but not teratogenic resulting in smaller yolk sacs and embryos, lower protein level and lower developmental score. Significantly less embryos cultured in ‘toxic’ SLE/APS sera had peak 2 of low molecular weight antioxidants (LMWA) wave, implying a delayed maturation of the antioxidant defense. Lower peak 1 of LMWA correlated with a history of recurrent abortions. Embryonic levels of superoxide dismutase (SOD) and catalase (CAT) did not correlate with sera toxicity, patients’ clinical history or specific antibodies. We conclude that SLE/APS patients’ clinical remission did not prevent death or developmental delay accompanied by later appearance of peak 2 of LMWA in post-implantation rat embryo cultures. The normal levels of the antioxidant enzymes evaluated may indicate that sera toxicity is not related to oxidative stress. Lupus (2010) 19, 1623—1631.

Increased levels of serum prolactin have been reported in patients with various autoimmune diseases and have been associated with lupus disease activity. Currently, there is a lack of data regarding hyperprolactinaemia in patients with the antiphospholipid syndrome. Hence, this study was carried out in order to evaluate the prevalence and clinical significance of hyperprolactinaemia in antiphospholipid syndrome. A total of 172 European patients with antiphospholipid syndrome and 100 geographically and sex-matched healthy controls were included in the study; none had obvious causes of hyperprolactinaemia. All patients underwent clinical assessment for disease manifestations, in addition to laboratory assessment for serum prolactin, antiphospholipid antibodies and some other biomarkers of autoimmune diseases. The tests were performed utilizing the LIAISON® Analyzer (DiaSorin, Sallugia Italy). Hyperprolactinaemia was detected in 21/172 patients with antiphospholipid syndrome and 0/100 controls (p < 0.001). This significant difference was present in both genders and was obvious even after subgrouping the patients into primary and secondary antiphospholipid syndrome. When clinical features were compared, hyperprolactinaemia was associated with reproductive failure, including early and late pregnancy loss (p < 0.05), as well as intrauterine growth retardation (p < 0.05). Hyperprolactinaemia was negatively related to arthralgias, venous thrombosis, pulmonary microthrombosis, pulmonary hypertension in both primary antiphospholipid syndrome and antiphospholipid syndrome secondary to other diseases, and to neurological manifestations in primary antiphospholipid syndrome (p

Systemic lupus erythematosus is a multi-systemic autoimmune disease distinguished by the presence of various autoantibodies. Like most autoimmune diseases, systemic lupus erythematosus is believed to be induced by a combination of genetic, immunologic, and environmental factors, mainly infectious agents. Molecular mimicry between an infectious antigen and self-components is implicated as a pivotal mechanism by which autoimmune diseases such as systemic lupus erythematosus are triggered. Here we review the current evidence of molecular mimicry between different infectious agents and systemic lupus erythematosus.

The antiphospholipid syndrome (APS) is now recognized as a multi-system disease, the clinical expression of which may include various target-organs involvements. Despite the reported heterogeneity in clinical presentation of APS, the interrelations between various manifestations of the disease has not yet been studied. We evaluated the principle associations between a variety of clinical manifestations in APS patients, applying factor analysis. Two-hundred and forty-six APS patients were studied. The following disease manifestations were used for the factor analysis: recurrent fetal loss, intrauterine growth restriction (IUGR), venous and arterial thrombosis, cardiac valves thickening/dysfunction, valvular vegetations, stroke, epilepsy, migraine, arthritis, livedo reticularis, thrombocytopenia, leukopenia and autoimmune hemolytic anemia (AIHA). The results were further analysed in relation to sex and to primary APS versus APS associated with SLE. Five factors were derived, which accounted for 59.7% of the variance of the matrix. Factor 1 (which explained 18.5% of variance of the original matrix) represented the association between cardiac valves abnormalities, livedo reticularis and AIHA. Factor 2 (13.8% of variance) represented association between arthritis, thrombocytopenia and leukopenia. Factor 3 (10.3% of variance) represented an association between recurrent fetal loss and IUGR. Factor 4 (9.3% of variance) represented inverse correlation between arterial and venous thrombosis. Factor 5 (7.8% of variance) represented an association between epilepsy and migraine. Application of factor analysis revealed specific clusters of cardiac, cutaneous, hematological and neurological manifestations. Our result also point to a possible divergence of arterial and venous thrombotic tendency. Awareness of these patterns might give us a better understanding of the disease.

The heart lesions of rheumatic fever and the heart involvement in antiphospholipid syndrome (APS), have different clinical pictures. Yet, there are several common characteristics linking both diseases: 1) central nervous system (CNS) and heart involvement; 2) molecular mimicry between the a pathogen and the origin of the disease; 3) cross reacting antibodies between the pathogen and self molecules; 4) endothelial cell activation in the ‘crime-area’ i.e., the valves; 5) some of the patients with RF have circulating antiphospholipid antibodies, while APS may be associated with streptococcal infection; and 6) recently, a cross-reactivity between antibodies directed to the streptococcal M-protein and its synthetic derivative in rheumatic fever (RF) and antibodies derived from APS patients targeting the beta-2-glycoprotein-I (β2GPI) and a β2GPI related synthetic peptide. In the current paper, we summarize the possible links between the heart involvement in RF and APS.

Autoimmune factors are involved in some of the cases of reproductive failure. These factors entail several autoantibodies, especially in patients having systemic lupus erythematosus (SLE) or the antiphospholipid syndrome (APS). These autoantibodies include mainly antibodies directed to phospholipid such as cardiolipin, phosphatidylserine, phosphatidylethanolamine or phospholipids binding glycoproteins such as b2glycoprotein-I, annexin V, prothrombin and protein-Z. There are also some other autoantibodies directed to laminin-I, thromboplastin, mitochondrial antibodies of the M5 type, corpus luteum, prolactin, poly (ADP-ribose), thyroglobulin and more, which were also found in SLE or APS patients with reproductive failure. Moreover, the presence of additional autoantibodies directed to actin, enolase, cubilin and others, needs further investigation to support a firm association to reproductive failure in women. Future studies are likely to help to determine and expand the number of autoantibodies screened in these patients, as well as by the use of proteomics technology, to determine peptides resembling the epitope specificities associated with the specific clinical manifestations.

Some cases of reproductive failure with autoimmune background are characterized by the involvement of autoantibodies. This occurs mainly in patients having systemic lupus erythematosus or antiphospholipid syndrome. The autoantibodies associated with reproductive failure include: a) antibodies which directly bind phospholipid (e.g., cardiolipin, phosphatidylserine, phosphatidylethanolamine); b) antiphospholipid Abs which bind the phospholipid via phospholipid-binding glycoproteins such as b2glycoprotein-I, annexin V and prothrombin; c) autoantibodies directed to laminin-I, actin, thromboplastin, the corpus luteum, prolactin, poly (ADP-ribose), thyroglobulin and mitochondrial antibodies of the M5 type. This paper will focus on the association of antiphosphatidylserine autoantibodies and reproductive failure. Future studies are likely to help to identify peptides resembling the epitope specificities associated with the specific clinical manifestations.

Naked DNA encoding TNFalpha was introduced to BALB/c mice with experimental antiphospholipid syndrome (APS) induced by beta2GPI. Administration of naked DNA encoding TNFalpha resulted in the generation of immunological memory to its gene product, associated with elevated circulating anti-TNFalpha antibodies. Enriched IgG fraction of the mouse anti-TNFalpha was biologically active since it prevented endothelial cell activation by TNFalpha e.g., inhibition of monocyte adhesion to activated endothelial cells (HUVEC). Mice immunized with beta2GPI, vaccinated with TNFalpha DNA at an early stage of disease development, showed decreased titres of circulating anti-beta2GPI antibodies as compared to the group of mice vaccinated with a control naked DNA. The reduction of antiphospholipid antibody production was followed by amelioration of the foetal loss, increased platelet count to normal values as well as normalization of the prolonged aPTT. APS mice which were introduced to the TNFalpha DNA vector at a later stage of the disease development, showed less improvement in their clinical manifestations. The current study suggests a way in which a DNA vaccine can be employed for induction of a protective immunity in experimental APS.

Prolactin (PRL) is closely associated with autoimmune diseases in animal models and humans, and several disease-related autoantibodies were reported in increased titers in patients with hyperprolactinemia (HPRL). We studied the presence of anti-endothelial cell antibodies (AECA) and other autoantibodies in sera of female patients with HPRL. Sera from 25 HPRL patients and 10 healthy female controls were tested for AECA (against both macrovascular and microvascular endothelial cell antigens), anti-dsDNA, and anti-cardiolipin (anti-CL) using ELISA. Sera were considered positive for the autoantibody when the optical density (OD) value was more than 3 s.d. above the mean of the OD in normal controls. Sera from 13 patients were obtained repeatedly during dopaminergic anti-PRL treatment, to relate PRL level or anti-PRL treatment with the autoantibody levels. Elevated micro and/or macrovascular AECA were observed in sera from 19=25 patients (76%). Elevated titers of anti-CL Abs, all b2-GPI-dependent, and low levels of anti-dsDNA antibodies (Abs) were also observed in the HPRL patients. Inhibition studies showed that the affinity purified AECAs bound the endothelial cell (EC) antigens in a dose-dependent manner. Titers of AECA as well as anti-DNA and anti-CL autoantibodies did not correlate with PRL level nor with the use or duration of anti-PRL treatment. None of the HPRL patients presented clinical manifestations of autoimmune disease. We conclude that elevated levels of AECA as well as anti-DNA and anti-CL autoantibodies are frequent in hyperprolactinemia. Our results further support the association of PRL and autoimmunity, and may point to a relationship between AECA-associated diseases and HRPL. The presence of autoantibodies in patients with HPRL might portend an increased risk for future development of autoimmune disease.

Atherosclerosis is a process initiated by accumulation of macrophages in distinct areas of endothelial cell damage and uptake of large amounts of lipids. Recently, it has been shown that the immune system plays an active part in the progression of the atherosclerotic plaque although its precise role has not yet been elucidated.Anticardiolipin antibodies (aCL) are generally found in the sera of patients with the antiphospholipid syndrome (APS) and are associated with a prothrombotic state. Several authors have demonstrated that aCL can activate platelets and endothelial cells as well as increase oxidized low density lipoprotein (LDL) uptake by macrophages. In the present study we sought to assess the effect of immunization with aCL (Ab1, leading to the production of mouse aCL-Ab3) on the progression of atherosclerosis. Two groups of 8-weeks old female LDL-receptor knockout mice (n = 13 per group) were immunized with IgG purified from the serum of an APS patient or with normal human IgG, respectively. The aCL immunized mice developed high titres of 'self' aCL (detected using the standard aCL ELISA) as compared with the normal human IgG immunized mice, whereas no differences were noted between both study groups with respect to the serum lipid levels. The extent of fatty streak formation was significantly higher in the aCL immunized mice in comparison with the human IgG injected mice (mean aortic lesion size of 5308 ± 471 μm2vs 1027 ± 184 μm2, respectively, P < 0.01). The immunohistochemical analysis of the atherosclerotic plaques from both mouse groups did not display differences in cellular composition.The results of the study show that mouse aCL induced by immunization with human aCL from an APS patient enhance atherogenesis in LDL-RKO mice and imply that these antibodies may play a role in atherosclerosis development in patients with the APS.

Objective. The objective of this study was to assess the beneficial effects of an early adminis tration of low dose linomide, a new immunomodulator, in an animal model of experimental systemic lupus erythematosus (SLE).Methods. Experimental SLE was induced in naive BALB/c mice, by immunization with anti-DNA mAb (MIV-7). Control Mice immunized with irrelevant human IgM served as controls. The immunized mice were treated with linomide (0.1 mg/ml in the drinking water), four weeks prior to the first immunization, at an early stage of the disease induction (one month after boost injection), or at a later stage (3 months following boost immunization). The treatment duration was 3 months in all schedules. The follow-up studies continued for 8 weeks after discontinuation of the treatment.The presence in the serum of autoantibodies against ssDNA, dsDNA, histones, phospho lipids and an irrelevant autoantigen - pyruvate dehydrogenase, was determined by enzyme- linked immunosorbent assay (ELISA). The clinical parameters assessed included erythrocyte sedimentation rate, peripheral blood cell counts and proteinuria.Results. There was a 50-64% decrease in autoantibody levels in the sera of mice immunized with anti-DNA (MIV-7) mAb at the early stage of experimental SLE in mice which received linomide for a period of 3 months. No effect of linomide was noted in mice which received the drug during the later stages of experimental SLE when the disease was fully developed. Linomide had a preventive effect on the induction of experimental SLE in naive mice, when the treatment was initiated before the induction of the disease. This effect was abolished following cessation of the treatment.Conclusions. Linomide proved to be effective at the early stages of induction of the experi mental SLE. However, the autoantibody levels rose following discontinuation of the therapy.

Objective. To examine the potential immunologic mechanism and involvement of antiphos pholipid antibodies in the pathogenesis of heart valve lesions in patients with the antiphos pholipid syndrome (APS).Methods. Immunoperoxidase and immunofluorescence staining methods were used to evaluate 13 heart valve specimens derived from eight patients with the APS, either primary or secondary to systemic lupus erythematosus. Primary antibodies to human immuno globulins, complement components, serum albumin and a monoclonal anti-idiotypic anti body to human anticardiolipin antibodies (aCL) were employed. Various tissue specimens from a patient with the APS as well as deformed and normal valves from subjects without the APS were used as controls.Results. Linear subendothelial deposition consisting of immunoglobulins with complement components but not of a non-specific serum protein was found in deformed valves from patients with the APS. None of the control valves or tissues disclosed similar deposition. The same pattern and location of staining was obtained by the anti-idiotypic antibody to aCL. A significant amount of IgG immunoglobulins that bound to cardiolipin was eluted from a valve of a patient with secondary APS.Conclusion. Deposits of immunoglobulins including aCL, and of complement components, are common in affected valves of patients with primary and secondary APS. Such deposits may be involved in the pathogenesis of valvular lesions.

To study whether monoclonal anticardiolipin antibodies (aCL), derived from patients with antiphospholipid syndrome (APS). have similar pathogenic potential, we have employed an experimental model of antiphospholipid syndrome.Monoclonal aCL were produced by the combined method of EBV transformation and somatic cell hybridization of lymphocytes, derived from patients with APS. The monoclonal aCL were used to immunize mice at the footpads and the mice were followed for serological and clinical manifestations of APS.The monoclonal antibody EY2C9, was found to bind weakly to cardiolipin and other phospholipids (i.e. phosphatidyl-serine, phosphatidyl-ethanolamine and phosphatidyl-inositol). The antibody TM 1B9, although derived from a patient with SLE and with secondary APS, did not react with phospholipids. Immunization of naive BALB/c mice with EY2C9 was followed by production of sustained high titers of antiphospholipid antibodies associated with prolonged activated partial thromboplastin time (APTT) (46.8 ± 5.0 s vs. 22.4 ± 1.7 s, in the non-immunized mice). Mice immunized with TM 1 B9 had a more moderate titer of antiphospholipid antibodies and did not show prolonged APTT. The pregnant mice, that were immunized with EY2C9, had increased fetal resorption rate (the equivalent of fetal loss in the human) of 36.8 ± 10% (vs. 2 ± 4% in mice immunized with TM 1 B9).Our results confirm that monoclonal aCL, derived from a patient with APS, can have a pathogenic potential, dysregulating the idiotypic network and leading to the development of characteristic signs of APS. Moreover, our findings suggest that immunization with antibody, although non-reactive with what is thought to be the antigen, but derived from a patient with active disease, can still promote the development of related antibodies, probably because it has other characteristics of pathogenicity (i.e. idiotype).