Serum biomarkers in Acute Respiratory Distress Syndrome an ailing prognosticator

The use of biomarkers in medicine lies in their ability to detect disease and support diagnostic and therapeutic decisions. New research and novel understanding of the molecular basis of the disease reveals an abundance of exciting new biomarkers who present a promise for use in the everyday clinical practice. The past fifteen years have seen the emergence of numerous clinical applications of several new molecules as biologic markers in the research field relevant to acute respiratory distress syndrome (translational research). The scope of this review is to summarize the current state of knowledge about serum biomarkers in acute lung injury and acute respiratory distress syndrome and their potential value as prognostic tools and present some of the future perspectives and challenges

A study of the genetic basis of C4A protein deficiency. Detection of C4A gene deletion by long-range PCR and its associated haplotypes.

Objective: Study the frequency of C4A gene deletions as the genetic basis of C4A protein deficiency (C4AQ0) and its associated haplotypes in Icelandic SLE families. Materials and methods: Nine multiplex SLE families were genotyped for C4A gene deletions using LR-PCR and MHC haplotypes were defined. Results: Of SLE patients, first- and second-degree relatives, 53,8%, 47,9% and 28,6% had C4AQ0, respectively. A C4A gene deletion is the genetic basis for C4AQ0 in 64,3% of SLE patients, 60,0% of first-degree and 50,0% of second-degree relatives. All individuals carrying haplotype B8-C4AQ0-C4B1-DR3 had a deletion and the deletion was also found on haplotypes B8-C4AQ0-C4B1-DR7 and B7-C4AQ0-C4B1-DR3. Conclusion: The study shows that a C4A gene deletion is the most common genetic basis for C4AQ0. It accounts for 2/3 of C4AQ0 and is found on different MHC haplotypes. 1/3 of C4AQ0 is due to other yet undefined genetic changes. The results thus demonstrate a heterogeneous genetic background for C4AQ0, giving further support for the hypothesis that C4AQ0 may be an independent risk factor for SLE

The quantitative role of alternative pathway amplification in classical pathway induced terminal complement activation

Complement activation with formation of biologically potent mediators like C5a and the terminal C5b-9 complex (TCC) contributes essentially to development of inflammation and tissue damage in a number of autoimmune and inflammatory conditions. A particular role for complement in the ischaemia/reperfusion injury of the heart, skeletal muscle, central nervous system, intestine and kidney has been suggested from animal studies. Previous experiments in C3 and C4 knockout mice suggested an important role of the classical or lectin pathway in initiation of complement activation during intestinal ischaemia/reperfusion injury while later use of factor D knockout mice showed the alternative pathway to be critically involved. We hypothesized that alternative pathway amplification might play a more critical role in classical pathway-induced C5 activation than previously recognized and used pathway-selective inhibitory mAbs to further elucidate the role of the alternative pathway. Here we demonstrate that selective blockade of the alternative pathway by neutralizing factor D in human serum diluted 1 : 2 with mAb 166–32 inhibited more than 80% of C5a and TCC formation induced by solid phase IgM and solid- and fluid-phase human aggregated IgG via the classical pathway. The findings emphasize the influence of alternative pathway amplification on the effect of initial classical pathway activation and the therapeutic potential of inhibiting the alternative pathway in clinical conditions with excessive and uncontrolled complement activation

Enhancement of lectin pathway haemolysis by immunoglobulins

We recently reported that indicator sheep erythrocytes (E) coated with mannan and sensitized with mannan-binding lectin (MBL) (E-M-MBL) are lysed by human serum in the absence of calcium via the lectin pathway of complement activation by a process which requires alternative pathway amplification and is associated with increased binding of and control by complement regulatory proteins C4 bp and factor H. In the present study, we investigated the effect of immunoglobulin (Ig) on this haemolysis. Co-sensitization of indicator E with anti-E haemolysin led to threefold enhancement of lectin pathway haemolysis in the absence of calcium, associated with increased binding of C3 and C5. Lysis was enhanced approximately twofold when E-M-MBL were chemically or immunologically coated with IgM or IgA, and fourfold when coated with IgG, prior to lysis in human serum-Mg-ethyleneglycol tetraacetic acid. The presence of haemolysin did not reduce the binding or inhibitory activity of C4 bp, and the enhancing activity of haemolysin was retained in serum depleted of C4 bp. By contrast, binding of factor H was greatly reduced in the presence of haemolysin, which had no enhancing effect in serum depleted of factor H. These experiments demonstrate the ability of IgG, IgM and IgA to enhance lectin pathway cytolysis, and that this enhancement occurs by neutralization of the inhibitory activity of factor H. Immunoglobulin enhancement of lectin pathway cytolysis represents another interaction between the innate and adaptive systems of immunity