Antiphospholipid antibodies (aPLs) comprise a diverse family of autoantibodies targeted against proteins with the affinity toward negatively charged phospholipids or protein-phospholipid complexes. Their clinical significance, including prothrombotic potential of anti-cardiolipin antibodies (aCLs), anti-β2-glycoprotein I antibodies (aβ2-GPIs), and lupus anti-coagulant (LA), is well-established. However, the ontogeny of these pathogenic aPLs remains less clear. While transient appearance of aPLs could be induced by various environmental factors, in genetically predisposed individuals these factors may eventually lead to the development of the antiphospholipid syndrome (APS). Since the first description of APS, it has been found that a wide variety of microbial and viral agents influence aPLs production and contribute to clinical manifestations of APS. Many theories attempted to explain the pathogenic potential of different environmental factors as well as a phenomenon termed molecular mimicry between β2-GPI molecule and infection-relevant structures. In this review, we summarize and critically assess the pathogenic and non-pathogenic formation of aPLs and its contribution to the development of APS.

Background Although it is widely accepted that catecholamines and estrogens influence immunity and have consequences for health, their effect on innate immunity (e.g. monocytes and neutrophils) is still not fully investigated. Materials and methods Our study aimed to analyze the production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, monocyte chemoattractant protein (MCP)-1 and IL-8 by whole blood cells following short-term exposure to epinephrine (Epi) and 17β-estradiol (E2) in the presence or absence of lipopolysaccharide (LPS). We also evaluated the in vitro effect of these hormones on expression of β2 integrin (CD11b/CD18) and L-selectin (CD62L) by circulating neutrophils and monocytes in the blood of healthy subjects. Results Epi has shown a potential to modulate the production of pro-inflammatory mediators. Its exposure resulted in significantly increased production of IL-8 in a dose-dependent manner. On the contrary, a dose-dependent suppression of LPS-induced production of IL-1β, IL-8, and MCP-1 by Epi was observed. In neutrophils, a modest rise in CD11b expression was observed after Epi exposure. Simultaneously, Epi suppressed LPS-induced expression of CD11b and CD18. In monocytes, Epi suppressed LPS-induced expression of C11b. E2 inhibited LPS-induced TNF-α production and caused a significant decrease in CD62L expression in both cell populations. No significant changes were observed after double exposure of cells with Epi and E2. Conclusions Thus, our results show that Epi and E2 differentially modulate the innate immune response and have a dual effect on cytokine modulation. The findings suggest that the observed immunoregulatory role of Epi and E2 may influence the outcome in endotoxin responses and can be critical in the regulation of inflammatory responses.

The main purpose of this study was to investigate the profile of inflammatory response in patients with acute salmonellosis caused by two serotypes of Salmonella enterica, S. Enteritidis and S. Typhimurium, as well as in convalescent patients with previous acute disease caused by S. Enteritidis. Patients with acute disease showed significantly elevated levels of IL-1β, IL-17, IL-10, and calprotectin compared to healthy control subjects. In convalescent patients, these markers were also significantly elevated, with the exception of IL-1β. Multivariate statistical analyses with the use of these variables produced models with a good predictive accuracy resulting in excellent separation of the diseased and healthy cohorts studied. Overall, the results suggest that the profile of inflammatory response in this disease is determined, to a significant degree, by the serotype of Salmonella, and the profile of certain cytokines and calprotectin remains abnormal for a number of months following the acute disease stage.

BackgroundAutoinflammatory disorders, such as Familial Mediterranean fever (FMF), characterized by abnormally increased inflammation, and mediated predominantly by the cells of innate immune system. FMF characterized by the episodes of self-resolving severe inflammation, with fever and serositis. The major cell type found in FMF inflammatory exudates are neutrophils. It is not known whether bacterial lipopolysaccharide (LPS) could influence neutrophil activation in FMF. We examined in vitro effect of LPS (10 ng/ml) exposure on expression of 13 selected genes in FMF and control neutrophils using quantitative real-time RT-PCR. ResultsLPS exposure induced basal expression of TLR4 (4.4-fold increase, p < 0.05), IL-1β (9-fold, p < 0.01), IL-8 (13-fold, p=0.06), TNFAIP6 (11-fold, p < 0.05) genes in FMF neutrophils, and of TLR4 (17.6-fold, p < 0.001), IL-1β (25-fold, p < 0.001), IL-8 (36-fold, p < 0.001), TNFAIP6 (61-fold, p < 0.001) in healthy neutrophils. ConclusionsOur findings indicate that gene expression in LPS-exposed FMF and control neutrophils is characterized by a number of shared alterations. In spite of pre-activated state of FMF neutrophils, LPS exposure further enhanced expression of the investigated genes. The ability of FMF neutrophils to enhance LPS-induced inflammatory reaction was however attenuated compared to healthy neutrophils. In conclusion, our data indicate that FMF neutrophils may display features of LPS tolerance, and this speculation should be explored further.

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by thrombosis and recurrent fetal loss, with the persistent presence of antiphospholipid antibodies (aPLs). aPLs exert their pathogenic effect via the overproduction of tissue factor and activation of complement and several cell types, including endothelial cells, platelets and notably monocytes. As a result, a hypercoagulable state develops leading to APS-associated obstetric complications and fetal loss. Despite being far from optimal, treatment of APS usually includes heparin and low dose aspirin. Recently, plasma exchange (PE) therapy was successfully used in patients with APS with obstetric complications who did not respond to the standard treatment. Therefore, the present study investigated the mechanism underlying PE action, and aimed to determine whether PE affects the functional activity of APS monocytes by examining the expression of 11 mRNA transcripts encoding cytokines, signaling molecules and transcription factors. Monocytes were collected prior to and following the PE treatment from women with APS who experienced recurrent pregnancy losses, as well as from healthy volunteers. Compared with control cells, APS monocytes showed deregulated expression of interleukin (IL)-1β, IL-6, IL-23, chemokine (C-C motif) ligand 2 (CCL2), C-X-C motif chemokine 10 (CXCL10), toll-like receptor 2, and signal transducer and activator of transcription 3. PE treatment resulted in increased IL-1β, IL-6, IL-23, CCL2, P2X7 and tumor necrosis factor-α mRNA transcripts in APS monocytes, restoring the mRNA expression levels to within normal ranges. Furthermore, PE therapy counterbalanced the expression levels of CCL2 and CXCL10, the levels of which are indicative of T helper cell 1/2 balance. The results of the present study indicate that the altered transcriptional profile in APS monocytes was restored by the immunomodulatory effect of plasmapheresis.

Background: β2-Glycoprotein I (β2GPI) represents the major antigenic target for antiphospholipid antibodies (aPL), with domain 1 (D1) being identified as a risk factor for thrombosis and pregnancy complications in APS. We aimed to analyse the ability of aPL, and particularly anti-D1 β2GPI, to stimulate prothrombotic and proinflammatory activity of immune cells in vitro. Methods: Peripheral blood mononuclear cells (PBMCs) from 11 healthy individuals were incubated with: (1) "anti-D1(+)"-pooled plasma derived from patients suspected of having APS contained anticardiolipin antibodies (aCL), lupus anticoagulant (LA), anti-β2GPI and anti-D1 β2GPI; (2) "anti-D1(−)"-pooled plasma from patients suspected of having APS contained aCL, LA, anti-β2GPI, and negative for anti-D1 β2GPI; (3) "seronegative"-negative for aPL. Results: The presence of anti-D1(+) and anti-D1(−) plasma resulted in increased HLA-DR and CD11b on monocytes. While only anti-D1(+) plasma markedly increased the percentage and median fluorescence intensity (MFI) of CD142 (tissue factor, TF) on monocytes in comparison with those cultured with anti-D1(−) and seronegative plasma. Anti-D1(+) plasma resulted in increased percentage and MFI of activation marker CD69 on NK and T cytotoxic cells. Expression of IgG receptor FcγRIII(CD16) on monocytes and NK cells was down-regulated by the anti-D1(+) plasma. Conclusions: Taking together, our study shows the ability of patient-derived aPL to induce immune cell activation and TF expression on monocytes. For the first time, we demonstrated the influence of anti-D1 β2GPI on the activation status of monocytes, NK and cytotoxic T cells. Our findings further support a crucial role of D1 epitope in the promotion of thrombosis and obstetrical complications in APS.

Antiphospholipid syndrome (APS) is an acquired autoimmune disorder characterized by recurrent thrombosis and pregnancy morbidity in association with the presence of antiphospholipid antibodies. Growing evidence supports the involvement of monocytes in APS pathogenesis. Inflammatory activation of monocytes promotes thrombus formation and other APS complications. However, mechanisms underlying their activation are poorly investigated. We aimed to determine transcriptional activity of monocytes after exposing them to low concentrations of lipopolysaccharide (LPS) and LPS + adenosine triphosphate (ATP) using comparative qRT-PCR. The results showed that LPS significantly increased transcriptional levels of TLR2, IL-23, CCL2, CXCL10, IL-1β, and IL-6 in APS cells, while, in cells from healthy donors, LPS resulted in IL-6 and STAT3 elevated mRNAs. Double stimulation of the cells resulted in decreased mRNA levels of NLRP3 in monocytes isolated from healthy donors and CCL2, IL-1β in APS cells. By contrast, TLR2 mRNAs were elevated in both investigated groups after culture of the cells with LPS + ATP. Thus, the findings indicate increased sensitivity of APS cells to LPS that may contribute to thrombus formation and enhance development or progression of autoimmune processes. Low concentrations of ATP diminish LPS-induced inflammatory state of APS monocytes which might be a potential mechanism which regulates inflammatory state of the cells.

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