Measuring IgA Anti-ß2-Glycoprotein I and IgG/IgA Anti-Domain I Antibodies Adds Value to Current Serological Assays for the Antiphospholipid Syndrome.

INTRODUCTION: Currently available clinical assays to detect antiphospholipid antibodies (aPL) test for IgG and IgM antibodies to cardiolipin (aCL) and ß2-glycoprotein I (aß2GPI). It has been suggested that testing for IgA aPL and for antibodies to Domain I (DI), which carries the key antigenic epitopes of ß2GPI, could add value to these current tests. We performed an observational, multicenter cohort study to evaluate the utility of IgG, IgM and IgA assays to each of CL, ß2GPI and DI in APS. METHODS: Serum from 230 patients with APS (n = 111), SLE but not APS (n = 119), and 200 healthy controls were tested for IgG, IgM and IgA aCL, aß2GPI and aDI activity. Patients with APS were further classified into thrombotic or obstetric APS. Logistic regression and receiver operator characteristic analyses were employed to compare results from the nine different assays. RESULTS: All assays displayed good specificity for APS; IgG aCL and IgG aß2GPI assays however, had the highest sensitivity. Testing positive for IgA aß2GPI resulted in a higher hazard ratio for APS compared to IgM aß2GPI. Positive IgG, IgM or IgA aDI were all associated with APS, and in subjects positive for aCL and/or aß2GPI, the presence of aDI raised the hazard ratio for APS by 3-5 fold. IgG aCL, aß2GPI, aDI and IgA aDI were associated with thrombotic but not obstetric complications in patients with APS. CONCLUSION: Measuring IgG aDI and IgA aß2GPI and aDI may be useful in the management of patients with APS, particularly thrombotic APS.

Effect of activin A on tumor necrosis factor-alpha/intercellular adhesion molecule-1 pathway in endometrial stromal cells.

UNLABELLED: OBJECTIVE[S]: Activin A and inhibin A are growth factors expressed by human endometrium involved in the control of endometrial functions. In the present study we investigated the effects of activin A and inhibin A in modulating the tumor necrosis factor (TNF)-alpha/intercellular adhesion molecule (ICAM)-1 system in cultured human endometrial stromal cells. STUDY DESIGN: Endometrial samples were obtained from 34 reproductive age women undergoing laparoscopy for benign ovarian cysts or infertility. Endometrial stromal cells were cultured and soluble ICAM-1 and TNF-alpha were measured in cell-free supernatants following treatment with or without activin A or inhibin A. Cell surface ICAM-1 was assayed by flow cytometry by staining endometrial cells with specific monoclonal antibodies. RESULTS: Activin A and inhibin A did not influence either the expression of cell surface ICAM-1 or soluble ICAM-1 shedding by cultured endometrial cells. On the other hand, TNF-alpha secretion significantly increased in presence of activin A but not of inhibin A. CONCLUSIONS: Since TNF-alpha modulates several endometrial processes such as menstruation, proliferation, apoptosis, implantation and decidualization, an effect of activin A in the physiological control of endometrium is further supported by the present data.

In vivo effects of maternal immunosuppression during pregnancy on the immune function of newborn infants.

When used in pregnancy, immunosuppressants can cross the placental barrier and enter foetal circulation, possibly affecting the immune system of the foetus. This study evaluated the immune function in eight children born by mothers with connective tissue diseases who received immunosuppressants (cyclosporine A or dexamethasone) during pregnancy and in six babies from mothers with similar diseases, but who did not receive any treatment. Judging by the cytokine production of interleukin-2 and interferon-gamma in peripheral blood mononuclear cells stimulated by phorbol-myristate-acetate (PMA) and ionomycin, immunosuppressive drugs given for rheumatic disorders during pregnancy do not induce significant immunosuppression in babies.

Association of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) shares genetic and cytokine profiles with other autoinflammatory diseases.

The association of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) has recently been described and suggested to be a new entity within the spectrum of autoinflammatory syndromes, which are characterized by recurrent episodes of sterile inflammation, without circulating autoantibodies and autoreactive T-cells. We conducted an observational study on 5 patients with PASH syndrome, analyzing their clinical features, genetic profile of 10 genes already known to be involved in autoinflammatory diseases (AIDs), and cytokine expression pattern both in lesional skin and serum. In tissue skin samples, the expressions of interleukin (IL)-1ß and its receptors I and II were significantly higher in PASH (P = 0.028, 0.047, and 0.050, respectively) than in controls. In PASH patients, chemokines such as IL-8 (P = 0.004), C-X-C motif ligand (CXCL) 1/2/3 (P = 0.028), CXCL 16 (P = 0.008), and regulated on activation, normal T cell expressed and secreted (RANTES) (P = 0.005) were overexpressed. Fas/Fas ligand and cluster of differentiation (CD)40/CD40 ligand systems were also overexpressed (P = 0.016 for Fas, P = 0.006 for Fas ligand, P = 0.005 for CD40, and P = 0.004 for CD40 ligand), contributing to tissue damage and inflammation. In peripheral blood, serum levels of the main proinflammatory cytokines, that is, IL-1ß, tumor necrosis factor-α, and IL-17, were within the normal range, suggesting that in PASH syndrome, the inflammatory process is mainly localized into the skin. Four out of our 5 PASH patients presented genetic alterations typical of well-known AIDs, including inflammatory bowel diseases, and the only patient lacking genetic changes had clinically evident Crohn disease. In conclusion, overexpression of cytokines/chemokines and molecules amplifying the inflammatory network, along with the genetic changes, supports the view that PASH syndrome is autoinflammatory in origin.

Posttransplant ischemia-reperfusion injury in transplanted heart is prevented by a minibody to the fifth component of complement.

BACKGROUND: Complement activation has been implicated in the development of posttransplant ischemia-reperfusion (I/R) which is responsible for the delayed function of 20% to 30% of grafts. C5a and the terminal complement complex (TCC) are the complement activation products mainly involved in tissue injury caused by I/R. METHODS: To control activation of the terminal step of the complement activation pathways, we used a neutralizing minibody to C5 containing a human single-chain fragment variable (scFv) linked to the hinge region, CH2, and CH3 domains of rat IgG1. RESULTS: The minibody acts on C5 inhibiting the release of C5a and the assembly of TCC and depletes circulating C5 in Sprague-Dawley rats with a therapeutic activity of 4 hr. Administration of the minibody to rats 30 min before heart allotransplantation prevented tissue deposition of TCC, apoptosis, and necrosis of the graft and increase in the levels of serum creatine phosphokinase and tumor necrosis factor-alpha observed in control transplanted rats. CONCLUSIONS: These data suggest that an anti-C5 therapy is effective in preventing graft injury caused by I/R. A minibody containing the human scFv linked to the hinge region and the CH2 and CH3 domains of human IgG1 is ready for use in clinical transplantation.