Significance of Anticardiolipin Antibodies on Short and Long Term Allograft Survival and Function following Kidney Transplantation

The significance of anticardiolipin antibodies (ACAs) prior to renal transplantation is unclear. We studied a cohort of 337 patients who underwent renal transplantation from 1996 to 2001. Follow-up continued until allograft loss, patient death or 31 December 2002. The primary outcome was a composite endpoint of death-censored allograft loss or a 25% reduction in estimated glomerular filtration rate (GFR) from 1-month post-transplant. Secondary outcomes were allograft loss, a 25% reduction in GFR, acute rejection and creatinine at 1 year. IgG and IgM ACA titers were positive (> or =15) in 18.1% of recipients. There were no significant differences at baseline between recipients, except coumadin therapy in those with positive ACA titers (20% vs. 7.4%). Post-transplant, there was no increase in the primary outcome in ACA-positive patients, even after adjustment for anticoagulation with coumadin (HR = 1.42 [0.68, 2.96]). There was no difference in secondary outcomes between those with or without positive titers. Two of five patients with very high titers (>50) who were not anticoagulated had early graft loss. A positive ACA titer prior to kidney transplantation was not associated with inferior renal outcomes after transplantation, although more research is required to address the prognostic significance of very high ACA titers.     

Histones interact with anionic phospholipids with high avidity; its relevance for the binding of histone-antihistone immune complexes.

Antibodies recognizing anionic phospholipids have been described in systemic lupus erythematosus (SLE) and other autoimmune diseases. Recent studies have shown that some of these antibodies may recognize a cardiolipin-binding protein (apolipoprotein H) rather than phospholipids. A similar possibility is conceivable for other cardiolipin-binding proteins that are targets of autoantibodies. In this study we have addressed whether this might be the case for histones, a set of highly cationic and widely distributed proteins that react in a well known autoantibody system. Our results indicate that: (i) histones bind to anionic phospholipids (cardiolipin and phosphatidylserine) with high avidity, but not to zwitterionic phospholipids (phosphatidylcholine); (ii) monoclonal and polyclonal antihistone antibodies recognize histones bound to cardiolipin; (iii) the addition of histones to serum samples containing antihistone antibodies often enhances their anticardiolipin reactivity. In addition, we have found that antihistone-producing hybridomas derived from MRL-lpr mice may show anticardiolipin activity due to the presence of histones in the cell culture supernatants with the resultant formation of immune complexes. Taken together, the results suggest a potential role for histones in the anti-cardiolipin activity detected in sera containing antihistone antibodies. These histone-phospholipid interactions should be taken into account when evaluating the pathogenic effects of antihistone antibodies or other autoantibodies reacting with nuclear components (e.g. nucleosomes) containing histones.     

Pathogenesis of antiphospholipid syndrome: recent insights and emerging concepts

Introduction: Even though our understanding of the antiphospholipid syndrome (APS) has improved tremendously over the last decades, we are still not in a position to replace symptomatic anticoagulation by pathogenesis based causal treatments.

Areas covered: Recent years have provided further insights into pathogenetically relevant mechanisms. These include a differentiation of pathogenic subtypes of antiphospholipid antibodies (aPL), novel mechanisms modulating disease activity, for example, extracellular vesicles and microRNA, and novel players in pathogenesis, for example, neutrophils and neutrophil extracellular traps (NETs).

Expert commentary: It is evident that aPL induce a proinflammatory and procoagulant state and recent data suggest that different aPL species activate different signaling pathways which sometimes converge into a common cellular response. This implies that presence of more than one aPL species may disproportionally increase the risk for the major manifestations of APS, that is, thrombosis and fetal loss. Further delineation of the pathogenic mechanisms will hopefully provide clues to causal rather than symptomatic treatments of APS.     

Alveolar macrophages from subjects infected with HIV-1 express macrophage inflammatory protein-1 alpha (MIP-1 alpha): contribution to the CD8+ alveolitis.

A human monoclonal anticardiolipin autoantibody (ACA) of the IgA-k isotype, designated 185/12, is described. The antibody was prepared from peripheral B cells, obtained from a patient with a history of habitual abortion, by immortalization with Epstein-Barr virus (EBV). The antibody displays a strong binding activity to cardiolipin and phosphatidyl L-serine, but not to phosphatidylcholine, phosphatidylinositol, ssDNA and dsDNA. It binds to cardiolipin in a concentration-related and saturable manner (Kd = 3.0 x 10(-8) M). This reaction is dependent upon the presence of bovine serum, and is fully inhibited by cardiolipin vesicles. The 185/12 antibody exhibits different binding patterns to the solid-phase bound cardiolipin-serum complex and to its individual components (cardiolipin and bovine serum). The Bmax of 185/12 binding to the complex (0.968 OD units) is higher than the sum of the Bmax values calculated for each one of the complex components (0.352 + 0.179 = 0.531 OD units). Bovine serum as well as purified beta 2-glycoprotein I (beta 2-GPI) in suspension inhibit the binding of 185/12 to the complex. 185/12 binding capacity increases in direct relation to the rising concentration of beta 2-GPI. Collectively, these data may be interpreted to suggest that 185/12 antibody, which is an IgA isotype, exhibits characteristics usually attributed only to antiphospholipid autoantibodies (APA) of the IgG isotype, that are associated with the clinical spectrum of APA syndrome (APA-S). It is, therefore, possible that autoantibodies of the IgA isotype could play a pathogenic role, which may be different from that of the IgG isotype, in the development of autoimmune phenomena.     

Association between the occurrence of the anticardiolipin IgM and mite allergen-specific IgE antibodies in children with extrinsic type of atopic eczema/dermatitis syndrome

BACKGROUND: As the literature has only controversial data on the role of nonallergen-specific antibodies in atopic eczema dermatitis syndrome, the authors investigated the link between the occurrence of the antiphospholipid [anticardiolipin (ACL), anti-beta2-glycoprotein I] and allergen-specific immunoglobulin E (IgE) antibodies in 72 children with atopic eczema/dermatitis syndrome (AEDS). METHODS: The measurement of antiphospholipid antibodies was carried out by enzyme-linked immunosorbent assay (ELISA), serum total IgE by nephelometry, and allergen-specific IgE by immunoblotting assay. The statistical analysis was carried out by Fisher's exact test and odds ratio was calculated. RESULTS: Thirteen of 72 children with AEDS (mean age 8.3 years) had elevated serum levels of ACL, and eight anti-beta2-glycoprotein I antibodies. The presence of allergen-specific IgE against inhalant allergens and nutritive allergens was among eight of 13 and three of eight in the cases with elevated ACL. The ratio of patients with highly increased severity scoring of atopic dermatitis (SCORAD) index (>75) was significantly higher in the group with elevated (4/13) than in those with the normal ACL levels (2/59). There was a significant association between the appearance of mite (Dermatophagoides pteronyssinus, D. farinae)-specific IgE and ACL IgM antibodies (6/13). CONCLUSION: These findings show that there are significant linkage and association between the appearance of ACL IgM or the production of allergen-specific IgE against inhalant (mainly mite) allergens in children with atopic eczema/dermatitis syndrome.     

原发性肾病综合征患者抗心磷脂抗体的研究

检测６８例原发性肾病综合征和３０例正常人抗心磷脂抗体（Ａｃｌ抗体）。结果示：Ａｃｌ抗体阳性率分别为３２３５％和３３３％;阳性组的高凝状态及肾小球损伤比阴性组病人更为明显,且对治疗的敏感性也显著降低。提示Ａｃｌ抗体在原发性肾病综合征的发病及发展中可能有着重要的作用。     

抗心磷脂抗体与原因不明胎儿宫内生长迟缓的关系

用酶联免疫吸附法（ＥＬＩＳＡ）检测胎儿宫内生长迟缓（ＩＵＧＲ）孕妇血清抗心磷脂抗体（ＡＣＡ）,探讨ＩＵＧＲ与ＡＣＡ的相关性。结果显示：①ＩＵＧＲ组与正常妊娠组比较,ＡＣＡＩｇＭ和ＡＣＡＩｇＡ结合指数显著增高（Ｐ＜０．０５）。②ＩＵＧＲ组ＡＣＡＩｇＭ增高与其Ｃ３及Ｃ４下降呈负相关（ｒ＝－０．４１０８,－０．４０９２,Ｐ＜０．０５）。提示ＡＣＡ的产生参与了ＩＵＧＲ的发病过程,其检测有助于ＩＵＧＲ的早期诊治     

抗心磷脂抗体检测在青光眼中的初步应用

目的探讨抗心磷脂抗体（ＡＣＡ）与青光眼疾患的临床相关意义。方法对２６例青光眼患者及１１例非青光眼患者,采用抗心磷脂抗体酶免疫（ＥＬＩＳＡ）测定法,进行抗心磷脂抗体检测。结果青光眼组ＩｇＧＡＣＡ与ＩｇＭＡＣＡ值均比对照组高,有显著差异（Ｐ＜０．０５）;其中开角型青光眼ＩｇＧＡＣＡ与对照组之ＩｇＧＡＣＡ值比较无显著差异（Ｐ＞０．０５）;开角型青光眼ＩｇＭＡＣＡ与对照组之ＩｇＭＡＣＡ值比较有显著差异（Ｐ＜０．０５）。闭角型青光眼与对照组比较：ＩｇＧＡＣＡ与ＩｇＭ之ＡＣＡ值比较均有显著差异（Ｐ＜０．０５）。结论青光眼病人的抗心磷脂抗体较高,预测可能产生视网膜静脉阻塞,需进一步追踪随访     

Enhancement of human platelet activation by the combination of low concentrations of collagen and rabbit anticardiolipin antibodies

Low concentrations of collagen and anticardiolipin antibodies (ACLA), which were raised in rabbits by immunization with cardiolipin (CL), co-operatively activated human gel-filtrated platelets (GFP). GFP activated by adding ACLA 5 min prior to collagen (ACLA + Col) showed strong responses in cytosolic Ca2+ mobilization and cell aggregation; the responses decreased after 1 min, however, when collagen was added prior to ACLA (Col + ACLA). Col + ACLA was 30% less effective than the ACLA + Col in: (1) the phosphorylation of pleckstrin and myosin light chain; and (2) the secretion of alpha- and dense granules. Indomethacin inhibited Ca2+ mobilization, pleckstrin phosphorylation and cell aggregation in platelets stimulated by ACLA + Col. The thromboxane B2 level in platelets induced by ACLA + Col was similar to that stimulated by low concentrations of collagen alone. ACLA + Col increased the activities of phospholipase C (PLC) as determined by formation of phosphatidic acid (PA), whereas indomethacin and adenosine 2',5'-diphosphate, an antagonist of the ADP P2Y1 receptor, inhibited PA formation. These results suggest that ACLA, thromboxane A2 derived from the collagen pathway and secreted ADP co-operatively augment PLC activity and lead to platelet aggregation.     

Relationship of Interleukin-12 and Interleukin-13 imbalance with class-specific rheumatoid factors and anticardiolipin antibodies in systemic lupus erythematosus

 The aim of the study was to evaluate whether the imbalance between IL-12 and IL-13 serum levels, reflecting Th1/Th2 activity, is related to class-specific circulating rheumatoid factors (RF) and anticardiolipin (aCL) antibodies in SLE. Using ELISA we measured serum IL-12, IL-13, RF and aCL antibodies in 73 SLE patients and 20 healthy controls. The determination of IL-12/IL-13 ratio showed that IL-12 levels were above (group A), equal to (group B) or below (group C) IL-13 levels in 71.2%, 15.1% and 13.7% of SLE patients, respectively. IgM-RF levels were significantly higher in group C than in groups A (P < 0.002) and B (P < 0.019). Group C had also higher IgM-aCL levels than group A (P < 0.04). No relationship between IL-12/IL-13 ratio and clinical or other laboratory parameters was found. It was concluded that the increased levels of both IgM-RF and IgM-aCL in patients with prevalent Th2 activity suggest that the predominance of Th2 over Th1 could drive autoantibody production in SLE patients. Received: 15 July 2002 / Accepted: 23 September 2002