Bench-to-bedside review: Immunoglobulin therapy for sepsis - biological plausibility from a critical care perspective

  • Manu Shankar-Hari1, 2, 3Email author,

    Affiliated with

    • Jo Spencer2,

      Affiliated with

      • William A Sewell4,

        Affiliated with

        • Kathryn M Rowan3 and

          Affiliated with

          • Mervyn Singer5

            Affiliated with

            Critical Care201216:206

            DOI: 10.1186/cc10597

            Published: 16 March 2012

            Abstract

            Sepsis represents a dysregulated host response to infection, the extent of which determines the severity of organ dysfunction and subsequent outcome. All trialled immunomodulatory strategies to date have resulted in either outright failure or inconsistent degrees of success. Intravenous immunoglobulin (IVIg) therapy falls into the latter category with opinion still divided as to its utility. This article provides a narrative review of the biological rationale for using IVIg in sepsis. A literature search was conducted using the PubMed database (1966 to February 2011). The strategy included the following text terms and combinations of these: IVIg, intravenous immune globulin, intravenous immunoglobulin, immunoglobulin, immunoglobulin therapy, pentaglobin, sepsis, inflammation, immune modulation, apoptosis. Preclinical and extrapolated clinical data of IVIg therapy in sepsis suggests improved bacterial clearance, inhibitory effects upon upstream mediators of the host response (for example, the nuclear factor kappa B (NF-κB) transcription factor), scavenging of downstream inflammatory mediators (for example, cytokines), direct anti-inflammatory effects mediated via Fcγ receptors, and a potential ability to attenuate lymphocyte apoptosis and thus sepsis-related immunosuppression. Characterizing the trajectory of change in immunoglobulin levels during sepsis, understanding mechanisms contributing to these changes, and undertaking IVIg dose-finding studies should be performed prior to further large-scale interventional trials to enhance the likelihood of a successful outcome.

            Introduction

            Sepsis is an inflammatory condition arising from a dysregulated host response to infection [1]. It is clinically manifest in a highly heterogeneous manner ranging from relatively mild features of systemic inflammation through to severe sepsis and shock where organ function is significantly compromised. The extrapolated population incidence of severe sepsis from national epidemiological studies varies between 51 and 153 per 100,000 population and carries a hospital mortality of 20 to 52% [2]. Survival rates have improved yet the overall incidence and the total number of associated hospital deaths continue to rise, in part due to increased recognition but also due to increasingly aggressive healthcare interventions in an ageing population [3, 4]. Many factors influence outcomes from sepsis, ranging from patient-intrinsic factors, such as genetic polymorphisms and co-morbidities, through to environmental factors, such as critical care resource availability [5]. Sepsis thus remains a challenging and important condition to both diagnose and treat, especially as it carries a high risk of death, of short- and long-term morbidity, and a substantial healthcare burden [6].

            Well-established clinical and biochemical criteria are used to define sepsis and organ dysfunction [1], yet these fail to adequately differentiate the individual, multifaceted host response to infection and the complex interplay between neural, immune, hormonal, circulatory, coagulation, metabolic and bioenergetic systems [7, 8]. While modulating the early host response to infection to protect organ function is a well-worn concept [9], so is the recognition that such therapies do not address the multisystem interactions that characterize the septic process [10]. The many clinical therapeutic failures witnessed to date relate to an over-extrapolation of findings derived from laboratory models [11, 12], and an ongoing inability to accurately delineate the host response in clinical practice and thus determine the optimal timing, dosing and duration of an intervention [13].

            An effective intervention should reduce the burden of illness associated with sepsis. This may be achieved through boosting cellular protection, enhancing the resolution of inflammation, accelerating recovery processes or, if effected early enough, by primary targeting of 'upstream' mediators (such as signalosomes and inflammasomes) that trigger the excessive activation or suppression of 'downstream' mediators and multi-system pathways such as cytokines and the complement system. Particularly with regard to the latter strategy, it is unlikely that the patient with severe sepsis will present early enough for successful therapeutic administration of a drug modulating a single upstream pathway. Far greater utility is likely to be gained through a cocktail approach, or by using agents with multiple modes of action. Prime examples of multi-modal stand-alone agents for severe sepsis and septic shock are corticosteroids and polyvalent intravenous immunoglobulins (IVIg).

            After a brief review of relevant sepsis biology, this article will focus upon immunoglobulins and their receptors, the potential beneficial effects of IVIg therapy in modulating the host response to infection, and an overview of the possible reasons for the limited success to date of clinical trials.

            Overview of sepsis pathobiology

            Initiation of host response

            The initial host response to infection involves overlapping, interlinked phases of innate pathogen and damage recognition. Microbial infection results in release of (i) pathogen-associated molecular patterns (PAMPs), that is, conserved molecular structures expressed by the microbe species, and (ii) damage-associated molecular patterns (DAMPs), that is, extracellular matrix components and intracellular constituents (for example, mitochondria, DNA, S100 proteins) released due to local tissue damage or immune cell activation [14]. PAMPs and DAMPs are recognised as danger signals by pattern recognition receptors on the surface of immune, epithelial, endothelial and parenchymal cells. This early innate response aims to limit systemic dissemination of infection, allowing slower though immunologically more potent and focused adaptive immune pathways to develop [15].

            Host responses to 'danger signals'

            Infection and/or tissue damage can trigger a dysregulated and systemic inflammatory response through multi-point activation of genes transcribing for pro-inflammatory mediators and receptors. These act via inflammasomes and signalosomes - 'upstream' mediators of the host response [16, 17]. Inflammasomes are multimeric protein complexes generated in response to distress signals from PAMPs and DAMPs that act as primary initiators of the innate host response (for example, NLR-NOD proteins) [1719]. Signalosomes are molecular complexes that mediate phosphorylation and poly-ubiquitination of inhibitory kinase complexes (for example, IκB), thereby releasing activated transcription factors that enter the nucleus and increase transcription of target genes involved in the inflammatory response. These include genes encoding downstream mediators such as cytokines, chemokines, adhesion factors, nitric oxide synthase, tissue factor and cyclo-oxygenase pathways [17, 2022]. This complex 'downstream' response could be conceptualised as being generated and amplified from an inflammatory hub consisting of high mobility group B-1 protein (HMGB-1), complement factors, macrophage migration inhibitory factor, IL-17 and other mediators. Both upstream and downstream mediators and networks are interlinked, impairing cellular bioenergetic and metabolic function at multiple levels, and resulting in organ dysfunction [7, 2325] (Figure 1). These changes also affect innate immune cell function, thereby impairing bacterial clearance [26, 27].
            http://static-content.springer.com/image/art%3A10.1186%2Fcc10597/MediaObjects/13054_2012_9930_Fig1_HTML.jpg
            Figure 1

            Invading pathogens have pathogen-associated molecular patterns (PAMPs) and tissue injury generates damage-associated molecular patterns (DAMPs), which are recognised by pattern recognition receptors (PRRs). Interaction of PRRs with PAMPs/DAMPs initiates the cellular activation that characterises host response in sepsis syndromes. Inflammasomes and signalosomes generated from these initiator pathways provide the feedback amplifier loops perpetuating host response. This unregulated multi-system activation involves inflammatory pathways, cytokines, coagulation, inducible nitric oxide pathways, the autonomic nervous system and the immune system. This is manifested biologically as microvascular failure, mitochondrial dysfunction and apoptotic changes - surrogates of severity of organ dysfunction in sepsis. HMGB, High mobility group box protein; iNO, inducible nitric oxide; MIF, macrophage migration inhibitory factor.

            The host responses described above involve concomitant activation of pro- and anti-inflammatory pathways. The balance of the host response shifts towards predominantly anti-inflammatory pathways later on in critical illness. While this results in an overall immune anergy [28, 29], some immune cell types remain hyper-responsive, underlying the complexity of the condition.

            Emerging literature on viral reactivation following acute pro-inflammatory critical illnesses provides further evidence that immunosuppression is a key sequela in sepsis and critical illness. This is likely related to T-cell defects, leading onto macrophage dysfunction [30, 31]. Other causes for immune anergy include (but are not limited to) enhanced regulatory T-cell activity [32], activation of anti-inflammatory phenotypes in inflammatory cells [28, 33], and activation of apoptotic pathways [34]. At present, anergy is considered primarily due to lymphocyte and dendritic cell loss.

            Immunoglobulin physiology

            Immunoglobulins (Ig) are glycoprotein molecules produced by plasma cells. B lymphocytes that are activated and propagated in a T-cell-dependent manner are the precursors of high-affinity antibody-secreting plasma cells [35]. T-cell-independent pathways can also generate plasma cells, including those secreting naturally occurring antibodies.

            Each Ig molecule monomer consists of identical heavy (50 to 70 kDa) and light chain pairs (23 kDa) held together by electrostatic forces and disulphide bonds. Each heavy chain consists of amino acid sequence regions (three to four constant, one variable) that fold into globular regions called domains. Within each variable region of heavy chains and light chains there are three hypervariable or complementarity-determining regions that determine antibody specificity. The combined variable and constant regions of the heavy and light chains form the antigen-binding region on the Fab. Amino acid sequences in the remainder of the two constant regions of the heavy chains, the Fc, determine the immunoglobulin class and subclass, and therefore its functional capability.

            The large diversity of antigenic epitopes are recognised by the variable region of the Ig molecules. This is a function of the adaptive immune system. Binding of Ig results in many diverse antigens being signalled through a small number of Ig isotypes. Based on their heavy chain characteristic, Ig isotypes are classified into G, A, M, D and E [36, 37].

            Fcγ receptors

            Ig mediate their immunomodulatory and predominantly anti-inflammatory effects through Fcγ receptors (FcγRs). There are six human FcγRs encoded by genes on chromosome 1, FcγRI, FcγRIIA, FcγRIIB, FcγRIIC, FcγRIIIA and FcγRIIIB [38]. FcγRs bind to Ig and to the pentraxin family of immune mediators that includes C-reactive protein and serum amyloid P (SAP). Pentraxins activate the classical complement pathway and compete with Ig for FcγR binding, thereby activating immune cells. Pentraxin-opsonized pathogens are phagocytosed by immune cells via FcγR pathways [39].

            The distribution of receptors on immune cells and their affinity to IgG differs between FcγRs (Table 1) [38, 4043]. FcγRs can be either activating or inhibitory depending on their inclusion or association with either the activating (immunoreceptor tyrosine-based activating motif (ITAM)) or inhibitory (ITIM) motifs in their cytoplasmic domains. Bacterial infection increases FcγR expression on innate and adaptive immune cells. FcγRI is the only high-affinity receptor that can bind to circulating monomeric IgG, while all low-affinity receptors only interact with immune complexes for signal transduction [44, 45].
            Table 1

            Salient characteristics of Fcγ Receptors [38, 4043]

             

            Fcγ receptors

            Characteristics

            FcγRIA

            FcγRIIA

            FcγRIIC

            FcγRIIIA

            FcγRIIIB

            FcγRIIB

            Function

            Activatory

            Activatory

            Activatory

            Activatory

            Activatory

            Inhibitory

            Affi nity to IgG

            High

            Low

            Low

            Low

            Low

            Low

            IgG subtype affinity

            IgG1 >>> IgG3 = IgG4 = IgG2

            IgG1 = IgG3 >> IgG2 > IgG4

            IgG1 > IgG3 > IgG4 >> IgG2

            IgG1 >> IgG3 = IgG2 > IgG4

            IgG1 = IgG3 >> IgG2 = IgG4

            IgG1 > IgG3 > IgG4 >> IgG2

            Cell type receptor

            Monocytes, macrophages, neutrophils, eosinophils, dendritic cells

            Monocytes, macrophages, neutrophils, dendritic cells, platelets

            Natural killer cells

            Monocytes, macrophages natural killer cells, dendritic cells

            Neutrophils, eosinophils, basophils

            Monocytes, macrophage mast cells, B cells, plasma cells, neutrophils, basophils, dedritic cells

            Binding

            IgG

            Only to IgG immune complexes

                

            Signal transfer

            ITAM

            ITAM

            ITAM

            ITAM

            ITAM

            ITIM

            Other characteristics

             

            1. Immune response to streptococcal infection

              

            1.Glycosylphosphatidyl-inositol-linked receptor that has no cytoplasmic domain

            1. Regulates B-cell activation and plasma cell survival

              

            2. Low affi nity to IgG2 isoform - FcγRIIA-R131 homozygous state predisposes to infection

               

            2. Basal level inhibition to dendritic cell maturation

                  

            3. Polymorphisms important in malaria

            FcγR, Fcγ receptor; Ig, immunoglobulin; ITAM, immunoreceptor tyrosine-based activating motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; IVIg, polyvalent intravenous immunoglobulin.

            All FcγRs except FcγRIIB are stimulatory (that is, associated with the ITAM cytoplasmic domain) and therefore activate immune cells following IgG- or pentraxin-protein or immune complex binding. Aggregation of ITAMs results in phosphorylation of ITAM tyrosines and stimulates multiple downstream activation pathways [46]. By contrast, FcγRIIB is associated with the ITIM cytoplasmic domain with phosphorylation of tyrosines in ITIMs resulting in attenuation of activation pathway activity [46].

            The level of FcγRIIB-related activity compared to other FcγR activity (that is, those associated with ITAM domains) plays a key role in balancing the pro- and anti-inflammatory humoral pathways in sepsis [47, 48]. It is biologically plausible that Ig modulates innate and adaptive immune effector activity essential for bacterial clearance by altering the balance between ITAM and ITIM activity via FcγRs; this equilibrium may be potentially influenced favourably with IVIg therapy [40].

            Other receptors

            Another receptor involved in IgG pathways is the neonatal FcR (FcRn). This belongs to the family of major histocompatibility (MHC) class I molecules but is not involved in antigen presentation. Its primary roles are to maintain constant IgG and albumin concentrations and to prolong the half-life of IgG and albumin through endosome-to-cell surface recycling. FcRn-mediated pathways are important in maintaining the serum retention of native and infused IgG preparations [42]. Other receptors for Ig molecules include the tripartite motif-containing (TRIM) protein family, some members of which appear to be particularly important in the response to viral infections [49].

            Polyvalent intravenous immunoglobulins

            IVIg is a blood product prepared from a pool of more than 1,000 donors (frequently more than 10,000 donors), thus providing a broad spectrum of opsonic and neutralizing IgG antibodies against a variety of microbial antigens and multiple epitopes. Opsonic and neutralizing IgG antibody content varies with each product batch, primarily due to differences in the local pathogen ecology of donor exposure. IgG and complement proteins are the principal classes of opsonins contributing to bacterial clearance (amongst other opsonins such as C-reactive protein). Only one product, Pentaglobulin® (Biotest, Germany), is IgM-enriched. The principal manufacturing process in all current Ig preparations is cold ethanol fractionation with product-specific additional processes for manufacturing. The commonest processes for virus reduction include solvents/detergents, low pH (pH 4) incubation, nanofiltration and chromatography.

            The biological rationale for administering IVIg in sepsis

            The biological rationale for IVIg therapy in sepsis can be summarized into four main categories: (i) its role in pathogen recognition, clearance and toxin scavenging, (ii) scavenging and inhibition of 'upstream mediator' gene transcription, (iii) scavenging and inhibition of inflammatory 'downstream mediator' gene transcription, and (iv) non-apoptotic and anti-apoptotic immune cell effects.

            Role in pathogen recognition, clearance and toxin scavenging

            PAMPs are recognised by naturally occurring antibodies that can also act as innate immune receptors. IgG and the complement proteins are the principal opsonins for bacterial clearance. The classical pathway is activated by C1 complex interaction with Ig, acute phase proteins and various non-specific activators [50]. The C1q molecule within the C1 complex contains a multimeric globular ligand detection domain with the ability to bind IgG and IgM Fc regions, and hence detect a large spectrum of antigens. Binding of C1q to IgG1 or IgM leads to potent activation of the classical complement pathway, thereby generating C4b2a (recently renamed as C4b2b), the classical pathway C3 convertase [50, 51]. IgG combines with C3b and this opsonisation facilitates phagocytosis [52].

            Human neutrophils express multiple cell surface Fcγ receptors that bind IgG. These receptors are constitutive (for example, FcγRIIa (CD32), FcγRIIIb (CD16) [53]) or inducible (FcγR1 (CD64)). IgG binding to these receptors results in neutrophil activation via tyrosine kinase pathways. Activated neutrophils upregulate expression of adhesion, chemoattractant and phagocytic receptors that identify and phagocytose pathogens opsonised with complement proteins and IgG [5457]. Neutrophil activation and phagocytosis signals may be suboptimal in IgG-deficient patients with sepsis; this population may be an 'ideal' cohort for IVIg supplementation to augment early bacterial clearance. IVIg also contains anti-siglec-9 antibodies and their anti-idiotypes that reduce neutrophil loss in early sepsis [5860].

            Severe sepsis is associated with a decrease in circulating immunoglobulin levels [6164]. Three-quarters of patients admitted with community-acquired pneumonia and shock had hypogammaglobulinaemia, of whom three quarters had low levels of IgG. Hypogammaglobulinaemic patients had a significantly longer duration of shock and a higher incidence of severe lung injury [61]. Patients from the Score-Based Immunoglobulin G Therapy of patients with sepsis (SBITs) study demonstrated a wide distribution in IgG levels, although in this study low levels did not carry any prognostic significance [62, 63]. Furthermore, in a recent observational study of patients enrolled within day 1 or 2 of presentation with septic shock, 61% had IgG levels below the lower limit for age-matched reference values. This hypogammaglobulinaemia was transient and also had no prognostic significance [64].

            Role in scavenging toxins

            Superantigen exotoxins released by staphylococci and streptococci activate T cells [65, 66]. IVIg preparations contain inhibitory or neutralising IgG molecules against superantigens, and these inhibit superantigen-mediated T-cell and monocyte activation [67, 68]. In addition, IVIg preparations have also been shown to inhibit superantigen-induced cytokine production and lymphocyte proliferation, that is, independent of the presence of neutralising antibodies [69]. Of note, toxin neutralisation is profoundly influenced not only by the antigen-binding activity of the antibodies within IVIg, but also by the Fc region of the IgG molecules, so the balance of IgG isotypes within the anti-toxin response is also critical [70]. IVIg therapy has been shown to be beneficial in toxin-mediated bacterial diseases and shock syndromes [71, 72], although the results are inconsistent [73]. IVIg preparations, in particular IgM-enriched preparations, contain antibodies against lipopolysaccharides of Escherichia coli, Pseudomonas aeruginosa and Klebsiella spp. [74].

            Acquired hypogammaglobulinaemia may prevent optimal pathogen clearance and pathogen toxin scavenging, thereby perpetuating the sepsis response. As immunoglobulin levels in health vary significantly, interpretation of single-time point determinations of immunoglobulin concentration in the context of sepsis pathobiology is a key challenge. By relating the temporal profile of Ig concentrations to the trajectory and severity of sepsis, a high-risk sepsis cohort may be potentially identified for stratified IVIg intervention. However, the reasons underlying these temporal changes are currently unclear. Altered distribution due to endothelial dysfunction and capillary leak [17], an iatrogenic fluid resuscitation-related increase in extravascular volume with dilution of Ig [64, 75], decreased production and/or increased consumption may be implicated, as could alterations in FcRn activity resulting in impaired recycling [76]. All the above knowledge gaps need addressing, ideally prior to further clinical trials.

            Scavenging of 'upstream mediators' and inhibition of 'upstream mediator' gene transcription

            NF-κB dependent signalling (signalosome) is a key mechanism for generating downstream host response mediators in sepsis and other inflammatory diseases. Patients with hypogammaglobulinaemia [77], sepsis [17], and Kawasaki's disease [78] have NF-κB-mediated up-regulation of IL-1 and IL-1r activity. These components of the IL-1 system decrease following IVIg dosing of 0.4 g/kg, secondary to a reduction in IL-1-mediated peripheral blood mononuclear cell activation, and by induction of IL-1 receptor antagonist (IL-1ra) [77]. The presence of neutralising antibodies in IVIg preparations may also be contributory. IVIg inhibit TNF-alpha-induced NF-κB activation on neutrophils while IgG1 blocks FcγRIIIA receptors on peripheral blood mononuclear cells, further impairing their activation [79]. IVIg can also inhibit endothelial cell activation as demonstrated by a decrease in markers such as adhesion molecules, endothelins, pro-inflammatory cytokines (for example, IL-6) and inducible nitric oxide pathways [80, 81]. In addition, naturally occurring anti-idiotypic antibodies, auto-antibodies and immune proteins in IVIg preparations also contribute to its immunomodulatory properties [82].

            There is little direct evidence of IVIg effects on caspase signalling in sepsis. Caspases and calpain activation may contribute to myocardial dysfunction [83], pulmonary microvascular endothelial damage [84], and skeletal muscle and protein wasting in sepsis [85, 86]; thus, inhibition of these pathways may be potentially beneficial. In pemphigus, IVIg upregulated endogenous caspase and calpain inhibitors (FLIP and calpastatin, respectively) [87]. Extrapolating this evidence will help determine whether IVIg therapy in sepsis could potentially attenuate myocardial and pulmonary dysfunction.

            Scavenging of 'downstream mediators' and inhibition of 'downstream mediator' gene transcription

            Cytokine neutralisation is an important component of anti-inflammatory IVIg activity. Autoantibodies to cytokines such as IFN-α, -β and -γ, IL-1α, -2, -4, -6, -8, and -10, TNF-α and -β and soluble TNF receptors have all been reported in normal individuals. Thus, IVIg preparations are likely to contain such antibodies, which contribute to cytokine neutralisation [8890].

            HMGB-1 released into the circulation in sepsis syndromes is considered a key signalling molecule in the inflammatory hub concept of severe sepsis, activating cell-to-cell signalling, procoagulant activity and late phase responses [7]. In addition, HMGB-1 is considered to have prognostic significance [91] and is a possible therapeutic target in sepsis syndromes and other inflammatory disorders [92]. In septic rats, high-dose IgG pre-treatment reduced HMGB-1 activity [93]. As IgG and IgM HMGB-1 antibodies are found in the serum samples of healthy individuals, an IVIg preparation should be able to limit HMGB-1-related activation of inflammatory and coagulation pathways [94].

            IVIg also inhibit pro-inflammatory cytokine production by bacterial superantigens or lipopolysaccharidestimulated mononuclear cells while increasing the production of IL-1 receptor antagonist, an anti-inflammatory cytokine [77]. Cytokine-induced endothelial activation and expression of adhesion factors are key events in sepsis [17, 95]. IVIg inhibit endothelial cell proliferation and downregulate mRNA expression of adhesion molecules (for example, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule-1), chemokines (monocyte chemoattractant protein-1), growth factors (monocyte colony stimulating factor and granulocyte-macrophage colony stimulating factor), and pro-inflammatory cytokines (TNF-α, IL-1, and IL-6) [96]. In addition, IVIg attenuated IL-1α-dependent leukocyte adhesion to endothelium, activation and tissue injury [81]. The endothelial effects of IVIg are thus potentially useful in reducing the severity, or possibly preventing the onset, of new organ dysfunction in sepsis.

            Bacterial clearance is the primary innate immune function of the complement system. This occurs via detection of PAMPs followed by recruitment and activation of proteases. Complement pathway activation results in opsonisation of bacteria with C3b to facilitate phagocytosis, generation of membrane attack complex for bacterial cell lysis, and generation of pro-inflammatory chemokine anaphylotoxins such as C3a and C5a, which are central mediators of the inflammatory hub in sepsis [7, 50, 9799].

            Notwithstanding its desired effect on bacterial clearance, there are numerous systemic and cellular adverse effects of unregulated complement system activation. In patients with severe sepsis this may cause impaired neutrophil chemotaxis and phagocytic function secondary to down-regulation of C5a receptor type 1 (CD88) expression, leading to reduced bacterial clearance [27, 98, 100]. Complement activation can also impair cardiomyocyte function in sepsis. In an animal model this was prevented by C5a-blocking antibodies [101]. Further-more, C5a is a key perpetuator of coagulation cascade activation [102], accelerated lymphocyte apoptosis, immunoparesis and autonomic nervous system dysfunction [7, 50, 98].

            IVIg have complement-scavenging properties that attenuate these undesired effects of anaphylotoxins. Crucially, the anti-complement activity of IVIg does not affect bacterial clearance [103]. The Fab2 region of the Ig molecule interacts with and scavenges C3a and C5a, thereby reducing complement-mediated cytotoxicity [104]. Scavenging of C5a also reverses C5a-mediated up-regulation of FcγIIIa receptors and down-regulation of FcγIIb receptors. The resulting high ratio of inhibitory FcγIIb to FcγIIIa on immune activator cells such as monocytes and macrophages is responsible for IVIg-induced immunomodulation and contributes to its anti-inflammatory effects [105]. As deregulated excessive C5a activity is likely to be a key molecular mechanism in sepsis [7, 106], C5a scavenging by IVIg therapy should improve neutrophil [27] and myocardial function [101], as well as reducing coagulopathy [102], immune cell apoptosis [28, 107109] and autonomic nervous system dysfunction.

            Immune cell effects

            Non-apoptotic

            Dysregulation in the nitric oxide pathway, glucose metabolism and inflammatory networks contribute to impaired neutrophil function in severe sepsis [110]. As these represent downstream mediators scavenged by IVIg, IVIg therapy could restore neutrophil function and improve bacterial clearance.

            Dendritic cells act as intermediaries transducing the anti-inflammatory effects of IVIg. The DC-SIGN receptor (dendritic cell-specific ICAM3-grabbing non-integrin) acts as a major regulatory pathway [111]. IVIg can down-regulate class II MHC expression by dendritic cells, directly inhibiting the classical CD3-T cell receptor pathway of T-cell activation [112]. The resulting reduction in pro-inflammatory cytokine production and increasing anti-inflammatory cytokine production further contributes to the anti-inflammatory and immunomodulatory activity of IVIg [113]. IVIg also inhibited invariant natural killer T-cell activation mediated through FcγRIIIA receptor effects [114]. IgG can determine the CD1 expression profile of monocyte-derived dendritic cells as this is mediated, at least in part, by FCγIIA receptors. An Ig-rich milieu induced CD1d expression, whereas Ig depletion increased expression of CD1a, CD1b, and CD1c [115].

            A relative IgG deficiency in sepsis could potentially impair homeostatic T-cell regulation, with deleterious effects on host immune function [116118]. Proliferation of activated T cells is regulated by suppressive CD4+CD25(hi) natural regulatory T cells, a pathway enhanced by IgG. In patients with common variable immunodeficiency, low dose IVIg therapy directly activated B-cell proliferation independent of T-cell signalling. This effect could be beneficial in sepsis by preventing late-onset immune anergy, potentially through reducing B cell loss [119]. Thus, IVIg therapy in Ig-deficient patients may potentially facilitate these beneficial, lymphocyte-mediated immune responses orchestrated through dendritic cells.

            Anti-apoptotic

            Activation of the extrinsic death receptor pathway and intrinsic mitochondria-endoplasmic reticulum pathways primarily result in immune cell apoptosis during sepsis [34, 120]. Initiators of apoptosis include complement proteins (C5a, via C5aR over-expression in both immune and non-immune cells) [107], enhanced sialic acid-binding immunoglobulin-like lectin (Siglec)-9 expression (mediating neutrophil death) [121], Toll-like receptor pathways (dendritic cell depletion) [122], the FcγRIIb pathway (lymphocyte apoptosis) [47], and impaired mitochondrial function.

            Significant B and T cell apoptosis reported in a humanised (innate and adaptive immune system) mouse model of severe sepsis has been replicated in patients with severe sepsis [123]. Excessive apoptosis in sepsis has been shown in both circulating and lymphoid organ lymphocytes [124126]. In addition, lymphopenia has been associated with adverse outcomes in severe sepsis, although causality has yet to be shown [127].

            Apoptotic pathways thus contribute significantly to sepsis-induced immune 'anergy' via lymphocytes and dendritic cell loss. If IVIg can attenuate immune and non-immune cell apoptosis by inhibition of extrinsic pathway activity through its ability to target upstream and downstream mediators (for example, via NF-κB and C5a inhibition), this may prevent immune anergy and maintain the significant role lymphocytes play in bacterial clearance. It may also moderate the organ dysfunction, including immune anergy [120, 128, 129].

            The effects of IVIg on apoptotic pathways are inconsistent; some reports even suggest an increase in apoptosis [130, 131]. This inconsistency probably relates to IVIg preparation, composition, disease state and dose. Further studies are needed before any claims of potential benefit of IVIg therapy on immune cell apoptosis can be made.

            Influence of IVIg preparations on efficacy

            Manufacturing processes have changed significantly in the past two decades and will likely influence the pharmacodynamic and pharmacokinetic properties of the final preparations. Current processes aim to maintain the physiological balance of the four IgG subclasses, which is important for both bacterial clearance and immunomodulation in severe sepsis [132134]. The glycosylation status of IgG in IVIg preparations can profoundly influence its anti- and pro-inflammatory effects [135]. Studies of the degree and type of IgG glycosylation of commercial IVIg products demonstrate significant inter-product differences (S Khan, WA Sewell et al., submitted). IVIg preparations have variable pro- and anti-apoptotic properties depending on the pharmacological composition of the IVIg preparation as these have varying levels of stimulating and inhibiting antibodies to Fas and Siglec receptors [136, 137]. Which preparation is optimal may well be patient- and/or IVIg preparation-dependent. This area clearly needs further investigation.

            Clinical trials in sepsis syndromes

            To date, 17 randomised placebo-controlled clinical trials in adult critical care patients with severe sepsis have been published, evaluating the efficacy of standard polyclonal IVIg or IgM-enriched polyclonal IVIg [63, 71, 138152]. Meta-analyses on these trials [153159] published to date highlight several limitations: a) non-uniform selection of study subjects due to variation in disease definition (severe sepsis); b) the intervention itself (for example, relationship of timing of the intervention to illness trajectory, lack of use of biomarkers to stratify intervention and to target likely responders, no pharmacokinetic profiling of the intervention, and an inability to achieve a definition for the adequacy of dosing); and c) shortcomings in trial design (for example, single-centre underpowered studies with limited external validity, intervention bias from lack of blinding of the control arm) [62, 111, 137150]. The heterogeneity in sepsis definitions used for trial inclusion [9, 10, 13], and in interventions (dose, timing, placebo intervention) is highlighted in Table 2.
            Table 2

            Summary of inclusion criteria, IVIg preparation, dose and the control arm intervention in randomised clinical trials [63, 71, 138152]

            Study

            Sepsis criteria and definitions used in IVIg trials

            IVIg preparationa

            IVIg dosing regime

            Control

            Werdan et al. (2007) [63]

            1. At least 4 out of 9 components of sepsis criteria: temperature >38.5°C or <36°C; white blood cell count >12 × 109 l-1 or < 3.5 × 109 l-1; heart rate >100 minute-1; respiratory rate >28 minute-1 or fraction of inspired oxygen (FiO2) >0.21; mean arterial pressure <75 mmHg; cardiac index >4.5 l minute-1 m-2 or systemic vascular resistance <800 dyn s cm-5; platelet count <100 × 109 l-1; positive blood cultures; clinical evidence of sepsis (surgical or invasive procedure during the preceding 48 h or presence of an obvious septic focus).

            Polyglobin N (Bayer Biological Products, Germany)

            0.6 g kg-1 on day zero

            0.3 g. kg-1 on day one or two

            0.1% HAS

             

            2) Sepsis score 12 to 27

               
             

            3) APACHE II score 20 to 35

               

            Hentrich et al. (2006) [138]

            ACCP/SCCM criteria and a diagnosis of haematological malignancy; neutropenia

            Pentaglobin® (Biotest Pharma, Germany)

            1,300 ml over 72 h: 200 ml initially (0.5 ml minute-1) then 11 infusions 100 ml every 6 h

            HAS

            Rodriguez et al. (2005) [139]

            Severe sepsis/septic shock of intra-abdominal origin admitted to a critical care unit within 24 hours of onset of symptoms. Abdominal sepsis defined by the presence of SIRS and a surgically confirmed abdominal focus. Obtaining purulent material or detecting potential pathogens using Gram staining was mandatory. Appropriateness of the surgical procedure (successful eradication of focus), according to criteria of the attending surgical team and the intensivist, required for inclusion

            Pentaglobin® (Biotest Pharma, Germany)

            0.35 g kg-1 day-1

            5% HAS

            Darenberg et al. (2003) [71]

            Streptococcal Toxic Shock Syndrome consensus definition

            Endobulin SD (Baxter)

            Loading dose of 1 g kg-1 then 0.5 g kg-1 every 24 h for three doses

            1% HAS

            Tugrul et al. (2002) [140]

            Severe sepsis

            Pentaglobin® (Biotest Pharma, Germany)

            5 ml kg-1 day-1 over 6 h

            No treatment

            Karatzas et al. (2002) [141]

            Severe sepsis

            Pentaglobin® (Biotest Pharma, Germany)

            5 ml kg-1 day-1 over 6 h

            No Treatment

            Masaoka et al. (2000) [142]

            ACCP/SCCM criteria

            Suspected sepsis, as defined by heart rate >90 minute-1, respiratory rate >20 minute-1, in addition to positive C-reactive protein and sustained fever ≥38°C with

            Not specified

            5 g day-1 for three consecutive days

            No treatment

             

            a) specifi c infection: for example, respiratory tract infection such as pneumonia, urinary tract infection

               
             

            b) no tumour, transfusion, drug-induced fever

               
             

            c) blood culture negative

               
             

            Patients were randomised if they were 'non-responders'- did not have enough improvement of symptoms with administration of broad-spectrum antibiotics for more than three consecutive days (72 h)

               

            Dominioni et al. (1996) [143]

            Sepsis following surgery or trauma with a Sepsis Score ≥17

            Sandoglobulin (Sandoz Pharmaceutical Corp, Italy)

            0.4 g kg-1 on day zero

            0.4 g kg-1 24 h later

            0.2 g kg-1 5 days later

            5% HAS

            Schedel et al. (1991) [144]

            Detection of endotocaemia (>12.5 pg/ml endotoxin) and at least fi ve of the following criteria: clinical indications of septicaemia; fever ≥38.5°C; platelet count <100 × 109 l-1 or a 30% drop in last 24 h; shift to left in the blood count; granulocytopenia; pulmonary congestion; disseminated intravascular coagulation; systolic blood pressure <100 mmHg; heart rate >120 minute-1; urine output <500 ml day-1

            Pentaglobin® (Biotest Pharma. Germany)

            Loading dose 600 ml over 8 h then two further doses of 300 ml every 24 h

            No treatment

            Burns et al. (1991) [145]

            1. Platelet count <75 × 109 |-1

            Sandoglobulin (Sandoz Pharmaceutical Corp, Italy)

            0.4 g kg-1 day-1

            HAS

             

            2. Documentation of suspected infection with positive culture

               
             

            3. Suspected infection documented by one or more of the following: fever; leukocytosis; elevated band neutrophil count; infiltrate on X-ray of chest consistent with pneumonia; toxic granulations or Dohle bodies on peripheral smear; positive Gram stain of body fluid or exudates

               

            Wesoly et al. (1990) [146]

            Post-operative sepsis with a Sepsis Score ≥12

            Pentaglobin® (Biotest Pharma, Germany)

            0.25 g kg-1 day-1

            No treatment

            Grundmann et al. (1988) [147]

            Post-operative Gram-negative bacterial infection with positive endotoxin in plasma for two subsequent days and sepsis score >12

            Intraglobin F (Biotest Pharma, Germany)

            0.25 g kg-1 day-1

            No treatment

            De Simone et al. (1988) [148]

            Severe sepsis

            Sandoglobulin (Sandoz Pharmaceutical Corp, Italy)

            0.4 g kg-1 on day zero

            No treatment

               

            0.2 g kg-1 48 h later

             
               

            0.4 g kg-1 5 days later

             

            Lindquist et al. (1981) [149]

            Purulent meningitis irrespective of aetiology

            Pepsis treated human gamma globulin -Gammavenin

            0.15 g kg-1 over 1 h

            No treatment

             

            Suspected or verified bacterial pneumonia (day time admissions only)

               
             

            Sepsis secondary to 'septicaemia' based on Svanbom criteria

               

            Yakut et al. (1998) [150]

            Post-surgical sepsis with Sepsis Score >16

            Gamumine N% 10 (Miles Inc. Pharmaceutical Division, USA)

            0.4 g kg-1 on day 0

            20% HAS

               

            0.4 g kg-1 on day 1

             
               

            0.2 g kg-1 on days 2 to 7

             

            Behre et al. (1995) [151]

            ACCP/SCCM criteria and a diagnosis of haematological malignancy; neutropenia

            Pentaglobin® (Biotest Pharma, Germany)

            Loading dose 10 g then 5 g six hourly for 72 h

            5% HAS

            Spannbruker et al. (1987) [152]

            Septic shock

            Pentaglobin® (Biotest Pharma, Germany)

            0.15 g kg-1 day-1

            No treatment

            ACCP, American College of Chest Physicians; APACHE, Acute Physiology and Chronic Health Evaluation; HAS, Human Albumin solution; IVIg, polyvalent intravenous immunoglobulin; SCCM, Society of Critical Care Medicine; SIRS, systemic inflammatory response syndrome.

            No less than seven recent systematic reviews and meta-analyses have summarized these interventional trials yet have yielded conflicting results [153159]. IVIg therapy is reported by most meta-analyses to be associated with an overall survival benefit when compared with placebo or no intervention in adult patients with severe sepsis. Two meta-analyses [155, 158] separately estimated treatment effects for IVIg and IVIgAM and found a strong treatment effect for IgM-enriched IVIg (risk ratio (RR) = 0.66; 95% confidence interval (CI) 0.51 to 0.85.) and a borderline significant effect for IVIg (RR = 0.81; 95% CI 0.70 to 0.93) [158]. When analyses were restricted to studies at low risk of bias, neither IVIg nor IgM-enriched IVIg showed significant benefit at the 5% level (RR = 0.97; 95% CI 0.81 to 1.15; 5 trials, n = 945) [158]. Likewise, the metaanalyses restricted to 'high quality' trials report non-significant results with IVIg treatment [154, 156, 158]. The reasons for heterogeneity in treatment effects include dosage regimen, duration of therapy, trial quality, publication date and whether patients had septic shock or other forms of severe sepsis [153]. In seven studies (560 patients) that used either a total dose ≥1 g IVIg per kilogram body weight (RR = 0.61; 95% CI 0.40 to 0.94]), or provided IVIg therapy for ≥2 days (17 trials, n = 1,847, RR = 0.66; 95% CI 0.53 to 0.82) there was a strong association with survival benefit [153].

            It should also be stressed that IVIg therapy is not without side effects. Common complications reported include thromboembolic events, renal dysfunction, aseptic meningoencephalitis, and anaphylaxis or anaphylactoid reactions. IVIg are often dispensed as a 5% solution; the effects of inappropriate volume loading in critically ill patients could be detrimental. In addition, subclinical sepsis can be associated with IVIg infusion reactions in patients with antibody deficiency [160].

            Future research

            Observational research is necessary (i) to characterize changes in Ig concentrations during the septic process and (ii) to delineate mechanisms contributing to any impact on outcome parameters (for example, duration, progression and severity of organ dysfunction, new organ dysfunctions during critical care stay, and fatality).

            From the literature review presented, we feel the pleotropic effects of IVIg on the sepsis-induced host response are likely to be secondary to both suppression of synthesis and direct scavenging of upstream and downstream mediators of the host response, and complex yet unclarified immunomodulatory effects mediated via Fcγ receptors. These mechanisms require confirmation with well-conducted pharmacodynamic studies to provide the rationale for use of a specified dose and duration. Whether plasma Ig levels, or another variable, can be a useful theragnostic marker for identifying and optimally treating a septic cohort also requires delineation.

            Pharmacokinetic studies of IVIg in sepsis are yet to be performed, and this is an important omission. Data for dosage selection in current practice are principally derived from studies in volunteers and in patients with primary immune deficiencies and other indications for immunomodulation [161]. In severe sepsis, potential confounders include systemic inflammation with fluctuations in immune function, increased vascular permeability, massive trans-compartmental fluid shifts and endothelial dysfunction. Existing pharmacokinetic studies [161] also do not address Ig clearance nor the serum Ig concentration to which dosing was targeted for modelling dosing calculations in sepsis.

            Such observational studies will crucially underpin the design of an explanatory interventional trial by informing the hypothesis for justifying an IVIg intervention, that is, replacement of low Ig concentration to physiological levels versus immunomodulation. The dosing and frequency of IVIg administration may differ significantly depending on the underlying scientific rationale. A theragnostic marker(s) may identify a high-risk cohort and there may be a predefined value for an IgG cutoff. This explanatory trial should ideally precede any large, multicentre, interventional trial testing the efficacy of IVIg in a well-defined critically ill population with sepsis.

            Conclusion

            Severe sepsis results in persistent excessive stimulation of multiple pro-inflammatory cellular pathways leading to host tissue damage, amplification and dysregulation of the immune response through further stimulation of the pattern recognition receptors. This destructive and self-amplifying response to infection is accompanied by a fall in serum Ig concentrations through mechanisms as yet unknown. Ig have many beneficial effects, either as natural, innate Ig or by inducing specific antibody through the adaptive immune response. It is logical to predict that replacement of serum Ig through infusion of IVIg would restore important Ig functions as described above. The failure to date to show benefit may be a consequence of the di culty in providing meaningful data and the differences in preparations used. Stringently controlled studies are required, ideally against direct indicators of the patient's immune status.

            Abbreviations

            CI: 

            confidence interval

            DAMP: 

            damage-associated molecular pattern

            FcγR: 

            Fcγ receptor

            FcRn: 

            neonatal FcR

            HMGB: 

            High mobility group box protein

            ICAM: 

            intercellular adhesion molecule

            IFN: 

            interferon

            Ig: 

            immunoglobulin

            IL: 

            interleukin

            ITAM: 

            immunoreceptor tyrosine-based activating motif

            ITIM: 

            immunoreceptor tyrosine-based inhibitory motif

            IVIg: 

            polyvalent intravenous immunoglobulin

            MHC: 

            major histocompatibility

            NF-κB: 

            Nuclear factor kappa beta

            PAMP: 

            pathogen-associated molecular pattern

            RR: 

            risk ratio

            Siglec: 

            sialic acid-binding immunoglobulin-like lectin

            TNF: 

            tumour necrosis factor.

            Declarations

            Acknowledgements

            None of the authors received any funding with respect to this work.

            Authors’ Affiliations

            (1)
            Department of Critical Care Medicine, Guy’s and St Thomas’ NHS Foundation Trust
            (2)
            School Of Medicine, Kings College London, Strand
            (3)
            Intensive Care National Audit and Research Centre (ICNARC)
            (4)
            Scunthorpe General Hospital, Scunthorpe
            (5)
            Bloomsbury Institute of Intensive Care Medicine, University College London

            References

            1. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003, 31:1250–1256.PubMedView Article
            2. Linde-Zwirble WT, Angus DC: Severe sepsis epidemiology: sampling, selection, and society. Crit Care 2004, 8:222–226.PubMedView ArticlePubMed Central
            3. Harrison DA, Welch CA, Eddleston JM: The epidemiology of severe sepsis in England, Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high quality clinical database, the ICNARC Case Mix Programme Database. Crit Care 2006, 10:R42.PubMedView ArticlePubMed Central
            4. Martin GS, Mannino DM, Eaton S, Moss M: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003, 348:1546–1554.PubMedView Article
            5. Angus DC, Wax RS: Epidemiology of sepsis: an update. Crit Care Med 2001, 29:S109–116.PubMedView Article
            6. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR: Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001, 29:1303–1310.PubMedView Article
            7. Rittirsch D, Flierl MA, Ward PA: Harmful molecular mechanisms in sepsis. Nat Rev Immunol 2008, 8:776–787.PubMedView ArticlePubMed Central
            8. Abraham E, Singer M: Mechanisms of sepsis-induced organ dysfunction. Crit Care Med 2007, 35:2408–2416.PubMedView Article
            9. Bone RC: Why sepsis trials fail. JAMA 1996, 276:565–566.PubMedView Article
            10. Phillip Dellinger R, Parrillo JE: Mediator modulation therapy of severe sepsis and septic shock: does it work? Crit Care Med 2004, 32:282–286.PubMedView Article
            11. Rittirsch D, Hoesel LM, Ward PA: The disconnect between animal models of sepsis and human sepsis. J Leukoc Biol 2007, 81:137–143.PubMedView Article
            12. Dyson A, Singer M: Animal models of sepsis: why does preclinical efficacy fail to translate to the clinical setting? Crit Care Med 2009, 37:S30–37.PubMedView Article
            13. Dellinger RP, Vincent JL, Marshall J, Reinhart K: Important issues in the design and reporting of clinical trials in severe sepsis and acute lung injury. J Crit Care 2008, 23:493–499.PubMedView Article
            14. Bianchi ME: DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 2007, 81:1–5.PubMedView Article
            15. Oberholzer A, Oberholzer C, Moldawer LL: Sepsis syndromes: understanding the role of innate and acquired immunity. Shock 2001, 16:83–96.PubMedView Article
            16. Takeuchi O, Akira S: Pattern recognition receptors and inflammation. Cell 2010, 140:805–820.PubMedView Article
            17. Cinel I, Opal SM: Molecular biology of inflammation and sepsis: a primer. Crit Care Med 2009, 37:291–304.PubMedView Article
            18. Hoffman HM, Brydges SD: The genetic and molecular basis of inflammasome-mediated disease. J Biol Chem 2011, 286:10889–10896.PubMedView ArticlePubMed Central
            19. Latz E: The inflammasomes: mechanisms of activation and function. Curr Opin Immunol 2010, 22:28–33.PubMedView ArticlePubMed Central
            20. Orel L, Neumeier H, Hochrainer K, Binder BR, Schmid JA: Crosstalk between the NF-kappaB activating IKK-complex and the CSN signalosome. J Cell Mol Med 2010, 14:1555–1568.PubMedView ArticlePubMed Central
            21. Abraham E: Nuclear factor-kappaB and its role in sepsis-associated organ failure. J Infect Dis 2003, 187:S364–369.PubMedView Article
            22. Wei N, Serino G, Deng XW: The COP9 signalosome: more than a protease. Trends Biochem Sci 2008, 33:592–600.PubMedView Article
            23. Corda S, Laplace C, Vicaut E, Duranteau J: Rapid reactive oxygen species production by mitochondria in endothelial cells exposed to tumor necrosis factor-alpha is mediated by ceramide. Am J Respir Cell Mol Biol 2001, 24:762–768.PubMedView Article
            24. Samavati L, Lee I, Mathes I, Lottspeich F, Huttemann M: Tumor necrosis factor alpha inhibits oxidative phosphorylation through tyrosine phosphorylation at subunit I of cytochrome c oxidase. J Biol Chem 2008, 283:21134–21144.PubMedView ArticlePubMed Central
            25. Singer M: Mitochondrial function in sepsis: acute phase versus multiple organ failure. Crit Care Med 2007, 35:S441–448.PubMedView Article
            26. Conway Morris A, Kefala K, Wilkinson TS, Dhaliwal K, Farrell L, Walsh T, Mackenzie SJ, Reid H, Davidson DJ, Haslett C, Rossi AG, Sallenave JM, Simpson AJ: C5a mediates peripheral blood neutrophil dysfunction in critically ill patients. Am J Respir Crit Care Med 2009, 180:19–28.PubMedView Article
            27. Huang X, Venet F, Wang YL, Lepape A, Yuan Z, Chen Y, Swan R, Kherouf H, Monneret G, Chung CS, Ayala A: PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci USA 2009, 106:6303–6308.PubMedView ArticlePubMed Central
            28. Ward NS, Casserly B, Ayala A: The compensatory anti-inflamatory response syndrome (CARS) in critically ill patients. Clin Chest Med 2008, 29:617–625. viiiPubMedView ArticlePubMed Central
            29. Osuchowski MF, Welch K, Siddiqui J, Remick DG: Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. J Immunol 2006, 177:1967–1974.PubMedView Article
            30. Limaye AP, Kirby KA, Rubenfeld GD, Leisenring WM, Bulger EM, Neff MJ, Gibran NS, Huang ML, Santo Hayes TK, Corey L, Boeckh M: Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA 2008, 300:413–422.PubMedView ArticlePubMed Central
            31. Luyt C-E, Combes A, Deback C, Aubriot-Lorton M-H, Nieszkowska A, Trouillet J-L, Capron F, Agut H, Gibert C, Chastre J: Herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation. Am J Respir Crit Care Med 2007, 175:935–942.PubMedView Article
            32. Ni Choileain N, MacConmara M, Zang Y, Murphy TJ, Mannick JA, Lederer JA: Enhanced regulatory T cell activity is an element of the host response to injury. J Immunol 2006, 176:225–236.PubMedView Article
            33. Hotchkiss RS, Coopersmith CM, McDunn JE, Ferguson TA: The sepsis seesaw: tilting toward immunosuppression. Nat Med 2009, 15:496–497.PubMedView ArticlePubMed Central
            34. Hotchkiss RS, Nicholson DW: Apoptosis and caspases regulate death and inflammation in sepsis. Nat Rev Immunol 2006, 6:813–822.PubMedView Article
            35. Durandy A, Kaveri SV, Kuijpers TW, Basta M, Miescher S, Ravetch JV, Rieben R: Intravenous immunoglobulins - understanding properties and mechanisms. Clin Exp Immunol 2009, 158:2–13.PubMedView ArticlePubMed Central
            36. Späth PJ: Structure and function of immunoglobulins. Sepsis 1999, 3:197–218.View Article
            37. Kazatchkine MD, Kaveri SV: Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 2001, 345:747–755.PubMedView Article
            38. Smith KG, Clatworthy MR: FcgammaRIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nat Rev Immunol 2010, 10:328–343.PubMedView ArticlePubMed Central
            39. Lu J, Marnell LL, Marjon KD, Mold C, Du Clos TW, Sun PD: Structural recognition and functional activation of FcgammaR by innate pentraxins. Nature 2008, 456:989–992.PubMedView ArticlePubMed Central
            40. Espeli M, Niederer HA, Traherne JA, Trowsdale J, Smith KGC: Genetic variation, Fc [gamma] receptors, KIRs and infection: the evolution of autoimmunity. Curr Opin Immunol 2010, 22:715–722.PubMedView Article
            41. Aschermann S, Lux A, Baerenwaldt A, Biburger M, Nimmerjahn F: The other side of immunoglobulin G: suppressor of inflammation. Clin Exp Immunol 2010, 160:161–167.PubMedView ArticlePubMed Central
            42. Willcocks LC, Smith KG, Clatworthy MR: Low-affinity Fcgamma receptors, autoimmunity and infection. Expert Rev Mol Med 2009, 11:e24.PubMedView Article
            43. Nimmerjahn F, Ravetch JV: Antibody-mediated modulation of immune responses. Immunol Rev 2010, 236:265–275.PubMedView Article
            44. Chiamolera M, Launay P, Montenegro V, Rivero MC, Velasco IT, Monteiro RC: Enhanced expression of Fc alpha receptor I on blood phagocytes of patients with gram-negative bacteremia is associated with tyrosine phosphorylation of the FcR-gamma subunit. Shock 2001, 16:344–348.PubMedView Article
            45. Leino L, Sorvajarvi K, Katajisto J, Laine M, Lilius EM, Pelliniemi TT, Rajamaki A, Silvoniemi P, Nikoskelainen J: Febrile infection changes the expression of IgG Fc receptors and complement receptors in human neutrophils in vivo. Clin Exp Immunol 1997, 107:37–43.PubMedView ArticlePubMed Central
            46. Waterman PM, Cambier JC: The conundrum of inhibitory signaling by ITAM-containing immunoreceptors: potential molecular mechanisms. FEBS Lett 2010, 584:4878–4882.PubMedView ArticlePubMed Central
            47. Pinheiro-da-Silva F, Chiamolera M, Charles N, Kanamaru Y, Velasco IT, Benhamou M, Monteiro RC: B lymphocytes undergo apoptosis because of FcgammaRIIb stress response to infection: a novel mechanism of cell death in sepsis. Shock 2006, 25:61–65.PubMedView Article
            48. Nimmerjahn F, Ravetch JV: The antiinflammatory activity of IgG: the intravenous IgG paradox. J Exp Med 2007, 204:11–15.PubMedView ArticlePubMed Central
            49. McNab FW, Rajsbaum R, Stoye JP, O'Garra A: Tripartite-motif proteins and innate immune regulation. Curr Opin Immunol 2011, 23:46–56.PubMedView Article
            50. Sjoberg AP, Trouw LA, Blom AM: Complement activation and inhibition: a delicate balance. Trends Immunol 2009, 30:83–90.PubMedView Article
            51. Roumenina LT, Ruseva MM, Zlatarova A, Ghai R, Kolev M, Olova N, Gadjeva M, Agrawal A, Bottazzi B, Mantovani A, Reid KB, Kishore U, Kojouharova MS: Interaction of C1q with IgG1, C-reactive protein and pentraxin 3: mutational studies using recombinant globular head modules of human C1q A, B, and C chains. Biochemistry 2006, 45:4093–4104.PubMedView Article
            52. Frank MM, Basta M, Fries LF: The effects of intravenous immune globulin on complement-dependent immune damage of cells and tissues. Clin Immunol Immunopathol 1992, 62:S82–86.PubMedView Article
            53. Garcia-Garcia E, Nieto-Castaneda G, Ruiz-Saldana M, Mora N, Rosales C: FcgammaRIIA and FcgammaRIIIB mediate nuclear factor activation through separate signaling pathways in human neutrophils. J Immunol 2009, 182:4547–4556.PubMedView Article
            54. Seely AJ, Pascual JL, Christou NV: Science review: Cell membrane expression (connectivity) regulates neutrophil delivery, function and clearance. Crit Care 2003, 7:291–307.PubMedView ArticlePubMed Central
            55. Seely AJ, Naud JF, Campisi G, Giannias B, Liu S, DiCarlo A, Ferri LE, Pascual JL, Tchervenkov J, Christou NV: Alteration of chemoattractant receptor expression regulates human neutrophil chemotaxis in vivo. Ann Surg 2002, 235:550–559.PubMedView ArticlePubMed Central
            56. Ferri LE, Pascual J, Seely AJ, Chaudhury P, Christou NV: Soluble L-selectin attenuates tumor necrosis factor-alpha-mediated leukocyte adherence and vascular permeability: a protective role for elevated soluble L-selectin in sepsis. Crit Care Med 2002, 30:1842–1847.PubMedView Article
            57. Swartz DE, Seely AJ, Ferri L, Giannias B, Christou NV: Decreased systemic polymorphonuclear neutrophil (PMN) rolling without increased PMN adhesion in peritonitis at remote sites. Arch Surg 2000, 135:959–966.PubMedView Article
            58. Schaub A, von Gunten S, Vogel M, Wymann S, Ruegsegger M, Stadler BM, Spycher M, Simon HU, Miescher S: Dimeric IVIG contains natural anti-Siglec-9 autoantibodies and their anti-idiotypes. Allergy 2011, 66:1030–1037.PubMedView Article
            59. von Gunten S, Schaub A, Vogel M, Stadler BM, Miescher S, Simon HU: Immunologic and functional evidence for anti-Siglec-9 autoantibodies in intravenous immunoglobulin preparations. Blood 2006, 108:4255–4259.PubMedView Article
            60. von Gunten S, Simon HU: Natural anti-Siglec autoantibodies mediate potential immunoregulatory mechanisms: implications for the clinical use of intravenous immunoglobulins (IVIg). Autoimmun Rev 2008, 7:453–456.PubMedView Article
            61. Taccone FS, Stordeur P, De Backer D, Creteur J, Vincent JL: Gamma-globulin levels in patients with community-acquired septic shock. Shock 2009, 32:379–385.PubMedView Article
            62. Dietz S, Lautenschlaeger C, Mueller-Werdan U, Werdan K: Low levels of immunoglobulin G in patients with sepsis or septic shock: a signum mali ominis? Crit Care 2010, 14:P26.View ArticlePubMed Central
            63. Werdan K, Pilz G, Bujdoso O, Fraunberger P, Neeser G, Schmieder RE, Viell B, Marget W, Seewald M, Walger P, Stuttmann R, Speichermann N, Peckelsen C, Kurowski V, Osterhues HH, Verner L, Neumann R, Müller-Werdan U, Score-Based Immunoglobulin Therapy of Sepsis (SBITS) Study Group: Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study. Crit Care Med 2007, 35:2693–2701.PubMedView Article
            64. Venet F, Gebeile R, Bancel J, Guignant C, Poitevin-Later F, Malcus C, Lepape A, Monneret G: Assessment of plasmatic immunoglobulin G, A and M levels in septic shock patients. Int Immunopharmacol 2011, 11:2086–2090.PubMedView Article
            65. Krakauer T: Chemotherapeutics targeting immune activation by staphylococcal superantigens. Med Sci Monit 2005, 11:RA290–295.PubMed
            66. Bueno C, Criado G, McCormick JK, Madrenas J: T cell signalling induced by bacterial superantigens. Chem Immunol Allergy 2007, 93:161–180.PubMedView Article
            67. Darville T, Milligan LB, Laff oon KK: Intravenous immunoglobulin inhibits staphylococcal toxin-induced human mononuclear phagocyte tumor necrosis factor alpha production. Infect Immun 1997, 65:366–372.PubMedPubMed Central
            68. Takei S, Arora YK, Walker SM: Intravenous immunoglobulin contains specific antibodies inhibitory to activation of T cells by staphylococcal toxin superantigens [see comment]. J Clin Invest 1993, 91:602–607.PubMedView ArticlePubMed Central
            69. Kato K, Sakamoto T, Ito K: Gamma-globulin inhibits superantigen-induced lymphocyte proliferation and cytokine production. Allergol Int 2007, 56:439–444.PubMedView Article
            70. Abboud N, Chow SK, Saylor C, Janda A, Ravetch JV, Scharff MD, Casadevall A: A requirement for FcgammaR in antibody-mediated bacterial toxin neutralization. J Exp Med 2010, 207:2395–2405.PubMedView ArticlePubMed Central
            71. Darenberg J, Ihendyane N, Sjolin J, Aufwerber E, Haidl S, Follin P, Andersson J, Norrby-Teglund A: Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebocontrolled trial. Clin Infect Dis 2003, 37:333–340.PubMedView Article
            72. O'Horo J, Safdar N: The role of immunoglobulin for the treatment of Clostridium difficile infection: a systematic review. Int J Infect Dis 2009, 13:663–667.PubMedView Article
            73. Shah SS, Hall M, Srivastava R, Subramony A, Levin JE: Intravenous immunoglobulin in children with streptococcal toxic shock syndrome. Clin Infect Dis 2009, 49:1369–1376.PubMedView ArticlePubMed Central
            74. Trautmann M, Held TK, Susa M, Karajan MA, Wulf A, Cross AS, Marre R: Bacterial lipopolysaccharide (LPS)-specific antibodies in commercial human immunoglobulin preparations: superior antibody content of an IgM-enriched product. Clin Exp Immunol 1998, 111:81–90.PubMedView ArticlePubMed Central
            75. Rivers EP: Point: adherence to early goal-directed therapy: does it really matter? Yes. After a decade, the scientific proof speaks for itself. Chest 2010, 138:476–480.PubMedView Article
            76. Tesar DB, Bjorkman PJ: An intracellular traffic jam: Fc receptor-mediated transport of immunoglobulin G. Curr Opin Struct Biol 2010, 20:226–233.PubMedView ArticlePubMed Central
            77. Aukrust P, Muller F, Svenson M, Nordoy I, Bendtzen K, Froland SS: Administration of intravenous immunoglobulin (IVIG) in vivo - down regulatory effects on the IL-1 system. Clin Exp Immunol 1999, 115:136–143.PubMedView ArticlePubMed Central
            78. Ichiyama T, Yoshitomi T, Nishikawa M, Fujiwara M, Matsubara T, Hayashi T, Furukawa S: NF-kappaB activation in peripheral blood monocytes/macrophages and T cells during acute Kawasaki disease. Clin Immunol 2001, 99:373–377.PubMedView Article
            79. Ichiyama T, Ueno Y, Hasegawa M, Niimi A, Matsubara T, Furukawa S: Intravenous immunoglobulin inhibits NF-kappaB activation and affects Fcgamma receptor expression in monocytes/macrophages. Naunyn Schmiedebergs Arch Pharmacol 2004, 369:428–433.PubMedView Article
            80. Ichiyama T, Ueno Y, Isumi H, Niimi A, Matsubara T, Furukawa S: An immunoglobulin agent (IVIG) inhibits NF-kappaB activation in cultured endothelial cells of coronary arteries in vitro. Inflamm Res 2004, 53:253–256.PubMedView Article
            81. Macmillan HF, Rowter D, Lee T, Issekutz AC: Intravenous immunoglobulin G selectively inhibits IL-1alpha-induced neutrophil-endothelial cell adhesion. Autoimmunity 2010, 43:619–627.PubMedView Article
            82. Sewell WA, Jolles S: Immunomodulatory action of intravenous immunoglobulin. Immunology 2002, 107:387–393.PubMedView ArticlePubMed Central
            83. Li X, Li Y, Shan L, Shen E, Chen R, Peng T: Over-expression of calpastatin inhibits calpain activation and attenuates myocardial dysfunction during endotoxaemia. Cardiovasc Res 2009, 83:72–79.PubMedView Article
            84. Hu H, Li X, Li Y, Wang L, Mehta S, Feng Q, Chen R, Peng T: Calpain-1 induces apoptosis in pulmonary microvascular endothelial cells under septic conditions. Microvasc Res 2009, 78:33–39.PubMedView Article
            85. Fareed MU, Evenson AR, Wei W, Menconi M, Poylin V, Petkova V, Pignol B, Hasselgren PO: Treatment of rats with calpain inhibitors prevents sepsis induced muscle proteolysis independent of atrogin-1/MAFbx and MuRF1 expression. Am J Physiol Regul Integr Comp Physiol 2006, 290:R1589–1597.PubMedView Article
            86. Wei W, Fareed MU, Evenson A, Menconi MJ, Yang H, Petkova V, Hasselgren PO: Sepsis stimulates calpain activity in skeletal muscle by decreasing calpastatin activity but does not activate caspase-3. Am J Physiol Regul Integr Comp Physiol 2005, 288:R580–590.PubMedView Article
            87. Arredondo J, Chernyavsky AI, Karaouni A, Grando SA: Novel mechanisms of target cell death and survival and of therapeutic action of IVIg in Pemphigus. Am J Pathol 2005, 167:1531–1544.PubMedView ArticlePubMed Central
            88. Ross C, Svenson M, Nielsen H, Lundsgaard C, Hansen MB, Bendtzen K: Increased in vivo antibody activity against interferon alpha, interleukin-1alpha, and interleukin-6 after high-dose Ig therapy. Blood 1997, 90:2376–2380.PubMed
            89. Menezes MC, Benard G, Sato MN, Hong MA, Duarte AJ: In vitro inhibitory activity of tumor necrosis factor alpha and interleukin-2 of human immunoglobulin preparations. Int Arch Allergy Immunol 1997, 114:323–328.PubMedView Article
            90. Bendtzen K, Hansen MB, Ross C, Svenson M: Detection of autoantibodies to cytokines. Mol Biotechnol 2000, 14:251–261.PubMedView Article
            91. Ueno T, Ikeda T, Ikeda K, Taniuchi H, Suda S, Yeung MY, Matsuno N: HMGB-1 as a useful prognostic biomarker in sepsis-induced organ failure in patients undergoing PMX-DHP. J Surg Res 2011, 171:183–190.PubMedView Article
            92. Mantell LL, Parrish WR, Ulloa L: Hmgb-1 as a therapeutic target for infectious and inflammatory disorders. Shock 2006, 25:4–11.PubMedView Article
            93. Hagiwara S, Iwasaka H, Hasegawa A, Asai N, Noguchi T: High-dose intravenous immunoglobulin G improves systemic inflammation in a rat model of CLP-induced sepsis. Intensive Care Med 2008, 34:1812–1819.PubMedView Article
            94. Urbonaviciute V, Furnrohr BG, Weber C, Haslbeck M, Wilhelm S, Herrmann M, Voll RE: Factors masking HMGB1 in human serum and plasma. J Leukoc Biol 2007, 81:67–74.PubMedView Article
            95. Ait-Oufella H, Maury E, Lehoux S, Guidet B, Off enstadt G: The endothelium: physiological functions and role in microcirculatory failure during severe sepsis. Intensive Care Med 2010, 36:1286–1298.PubMedView Article
            96. Xu C, Poirier B, Duong Van Huyen JP, Lucchiari N, Michel O, Chevalier J, Kaveri S: Modulation of endothelial cell function by normal polyspecific human intravenous immunoglobulins: a possible mechanism of action in vascular diseases. Am J Pathol 1998, 153:1257–1266.PubMedView ArticlePubMed Central
            97. Rittirsch D, Flierl MA, Nadeau BA, Day DE, Huber-Lang M, Mackay CR, Zetoune FS, Gerard NP, Cianflone K, Köhl J, Gerard C, Sarma JV, Ward PA: Functional roles for C5a receptors in sepsis. Nat Med 2008, 14:551–557.PubMedView ArticlePubMed Central
            98. Liu B, Zhang J, Tan PY, Hsu D, Blom AM, Leong B, Sethi S, Ho B, Ding JL, Thiagarajan PS: A computational and experimental study of the regulatory mechanisms of the complement system. PLoS Comput Biol 2011, 7:e1001059.PubMedView ArticlePubMed Central
            99. Singer M, Jones AM: Bench-to-bedside review: The role of C1-esterase inhibitor in sepsis and other critical illnesses. Crit Care 2011, 15:203.PubMedView ArticlePubMed Central
            100. Thrane AS, Skehan JD, Thrane PS: A novel interpretation of immune redundancy and duality in reperfusion injury with important implications for intervention in ischaemic disease. Med Hypotheses 2007, 68:1363–1370.PubMedView Article
            101. Niederbichler AD, Hoesel LM, Westfall MV, Gao H, Ipaktchi KR, Sun L, Zetoune FS, Su GL, Arbabi S, Sarma JV, Wang SC, Hemmila MR, Ward PA: An essential role for complement C5a in the pathogenesis of septic cardiac dysfunction. J Exp Med 2006, 203:53–61.PubMedView ArticlePubMed Central
            102. Amara U, Flierl MA, Rittirsch D, Klos A, Chen H, Acker B, Brückner UB, Nilsson B, Gebhard F, Lambris JD, Huber-Lang M: Molecular intercommunication between the complement and coagulation systems. J Immunol 2010, 185:5628–5636.PubMedView ArticlePubMed Central
            103. Tanaka J, Nakae T, Onoe T, Horiuchi Y, Miyamoto H, Adan-Kubo J, Adachi H, Ono Y: Complement-mediated bacteriolysis after binding of specific antibodies to drug-resistant Pseudomonas aeruginosa: morphological changes observed by using a field emission scanning electron microscope. J Infect Chemother 2010, 16:383–387.PubMedView Article
            104. Basta M, Van Goor F, Luccioli S, Billings EM, Vortmeyer AO, Baranyi L, Szebeni J, Alving CR, Carroll MC, Berkower I, Stojilkovic SS, Metcalfe DD: F(ab)'2-mediated neutralization of C3a and C5a anaphylatoxins: a novel effector function of immunoglobulins. Nat Med 2003, 9:431–438.PubMedView Article
            105. Konrad S, Baumann U, Schmidt RE, Gessner JE: Intravenous immunoglobulin (IVIG)-mediated neutralisation of C5a: a direct mechanism of IVIG in the maintenance of a high Fc gammaRIIB to Fc gammaRIII expression ratio on macrophages. Br J Haematol 2006, 134:345–347.PubMedView Article
            106. Rittirsch D, Flierl MA, Ward PA: Harmful molecular mechanisms in sepsis. Nat Rev Immunol 2008, 8:776–787.PubMedView ArticlePubMed Central
            107. Ward PA: Sepsis, apoptosis and complement. Biochem Pharmacol 2008, 76:1383–1388.PubMedView ArticlePubMed Central
            108. Tha-In T, Metselaar HJ, Tilanus HW, Groothuismink ZM, Kuipers EJ, de Man RA, Kwekkeboom J: Intravenous immunoglobulins suppress T-cell priming by modulating the bidirectional interaction between dendritic cells and natural killer cells. Blood 2007, 110:3253–3262.PubMedView Article
            109. Parrino J, Hotchkiss RS, Bray M: Prevention of immune cell apoptosis as potential therapeutic strategy for severe infections. Emerg Infect Dis 2007, 13:191–198.PubMedView ArticlePubMed Central
            110. Turina M, Fry DE, Polk HC Jr: Acute hyperglycemia and the innate immune system: clinical, cellular, and molecular aspects. Crit Care Med 2005, 33:1624–1633.PubMedView Article
            111. Anthony RM, Wermeling F, Karlsson MC, Ravetch JV: Identification of a receptor required for the anti-inflammatory activity of IVIG. Proc Natl Acad Sci USA 2008, 105:19571–19578.PubMedView ArticlePubMed Central
            112. Crow AR, Brinc D, Lazarus AH: New insight into the mechanism of action of IVIg: the role of dendritic cells. J Thromb Haemost 2009, 7:245–248.PubMedView Article
            113. Tawfik DS, Cowan KR, Walsh AM, Hamilton WS, Goldman FD: Exogenous immunoglobulin downregulates T-cell receptor signaling and cytokine production. Pediatr Allergy Immunol 2012,23(1):88–95.PubMedView Article
            114. Araujo LM, Chauvineau A, Zhu R, Diem S, Bourgeois EA, Levescot A, Huerre M, Gombert JM, Bayry J, Daëron M, Bruhns P, Kaveri SV, Herbelin A: Cutting edge: intravenous Ig inhibits invariant NKT cell-mediated allergic airway inflammation through FcgammaRIIIA-dependent mechanisms. J Immunol 2011, 186:3289–3293.PubMedView Article
            115. Smed-Sorensen A, Moll M, Cheng TY, Lore K, Norlin AC, Perbeck L, Moody DB, Spetz AL, Sandberg JK: IgG regulates the CD1 expression profile and lipid antigen-presenting function in human dendritic cells via FcgammaRIIa. Blood 2008, 111:5037–5046.PubMedView ArticlePubMed Central
            116. MacMillan HF, Lee T, Issekutz AC: Intravenous immunoglobulin G-mediated inhibition of T-cell proliferation reflects an endogenous mechanism by which IgG modulates T-cell activation. Clin Immunol 2009, 132:222–233.PubMedView Article
            117. De Groot AS, Moise L, McMurry JA, Wambre E, Van Overtvelt L, Moingeon P, Scott DW, Martin W: Activation of natural regulatory T cells by IgG Fc-derived peptide "Tregitopes". Blood 2008, 112:3303–3311.PubMedView ArticlePubMed Central
            118. Kessel A, Ammuri H, Peri R, Pavlotzky ER, Blank M, Shoenfeld Y, Toubi E: Intravenous immunoglobulin therapy affects T regulatory cells by increasing their suppressive function. J Immunol 2007, 179:5571–5575.PubMedView Article
            119. Bayry J, Fournier EM, Maddur MS, Vani J, Wootla B, Sibéril S, Dimitrov JD, Lacroix-Desmazes S, Berdah M, Crabol Y, Oksenhendler E, Lévy Y, Mouthon L, Sautès-Fridman C, Hermine O, Kaveri SV: Intravenous immunoglobulin induces proliferation and immunoglobulin synthesis from B cells of patients with common variable immunodeficiency: A mechanism underlying the beneficial effect of IVIg in primary immunodeficiencies. J Autoimmun 2011, 36:9–15.PubMedView Article
            120. Wesche-Soldato DE, Swan RZ, Chung CS, Ayala A: The apoptotic pathway as a therapeutic target in sepsis. Curr Drug Targets 2007, 8:493–500.PubMedView ArticlePubMed Central
            121. von Gunten S, Yousefi S, Seitz M, Jakob SM, Schaffner T, Seger R, Takala J, Villiger PM, Simon HU: Siglec-9 transduces apoptotic and nonapoptotic death signals into neutrophils depending on the proinflamatory cytokine environment. Blood 2005, 106:1423–1431.PubMedView Article
            122. Pène F, Courtine E, Ouaaz F, Zuber B, Sauneuf B, Sirgo G, Rousseau C, Toubiana J, Balloy V, Chignard M, Mira JP, Chiche JD: Toll-like receptors 2 and 4 contribute to sepsis-induced depletion of spleen dendritic cells. Infect Immun 2009, 77:5651–5658.PubMedView ArticlePubMed Central
            123. Unsinger J, McDonough JS, Shultz LD, Ferguson TA, Hotchkiss RS: Sepsis induced human lymphocyte apoptosis and cytokine production in "humanized" mice. J Leukoc Biol 2009, 86:219–227.PubMedView ArticlePubMed Central
            124. Wang SD, Huang KJ, Lin YS, Lei HY: Sepsis-induced apoptosis of the thymocytes in mice. J Immunol 1994, 152:5014–5021.PubMed
            125. Schroeder S, Lindemann C, Decker D, Klaschik S, Hering R, Putensen C, Hoeft A, von Ruecker A, Stuber F: Increased susceptibility to apoptosis in circulating lymphocytes of critically ill patients. Langenbecks Arch Surg 2001, 386:42–46.PubMedView Article
            126. Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM, Buchman TG, Karl IE: Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999, 27:1230–1251.PubMedView Article
            127. Le Tulzo Y, Pangault C, Gacouin A, Guilloux V, Tribut O, Amiot L, Tattevin P, Thomas R, Fauchet R, Drenou B: Early circulating lymphocyte apoptosis in human septic shock is associated with poor outcome. Shock 2002, 18:487–494.PubMedView Article
            128. Wheeler D: Death to sepsis: targeting apoptosis pathways in sepsis. Crit Care 2009, 13:1010.PubMedView ArticlePubMed Central
            129. Savill J, Fadok V: Corpse clearance defines the meaning of cell death. Nature 2000, 407:784–788.PubMedView Article
            130. Nakatani K, Takeshita S, Tsujimoto H, Sekine I: Intravenous immunoglobulin (IVIG) preparations induce apoptosis in TNF-alpha-stimulated endothelial cells via a mitochondria-dependent pathway. Clin Exp Immunol 2002, 127:445–454.PubMedView ArticlePubMed Central
            131. Prasad NK, Papoff G, Zeuner A, Bonnin E, Kazatchkine MD, Ruberti G, Kaveri SV: Therapeutic preparations of normal polyspecific IgG (IVIg) induce apoptosis in human lymphocytes and monocytes: a novel mechanism of action of IVIg involving the Fas apoptotic pathway. J Immunol 1998, 161:3781–3790.PubMed
            132. Radosevich M, Burnouf T: Intravenous immunoglobulin G: trends in production methods, quality control and quality assurance. Vox Sang 2010, 98:12–28.PubMedView Article
            133. St-Amour I, Laroche A, Bazin R, Lemieux R: Activation of cryptic IgG reactive with BAFF, amyloid beta peptide and GM-CSF during the industrial fractionation of human plasma into therapeutic intravenous immunoglobulins. Clin Immunol 2009, 133:52–60.PubMedView Article
            134. Beck OE, Kaiser PE: Distribution of human IgG subclasses in commercial intravenous immunoglobulin preparations: a rate nephelometric method. Vox Sanguinis 1981, 41:79–84.PubMedView Article
            135. Ravetch J: In vivo veritas: the surprising roles of Fc receptors in immunity. Nat Immunol 2010, 11:183–185.PubMedView Article
            136. von Gunten S, Simon HU: Cell death modulation by intravenous immunoglobulin. J Clin Immunol 2010, 30:S24–30.PubMedView Article
            137. Reipert BM, Stellamor MT, Poell M, Ilas J, Sasgary M, Reipert S, Zimmermann K, Ehrlich H, Schwarz HP: Variation of anti-Fas antibodies in different lots of intravenous immunoglobulin. Vox Sanguinis 2008, 94:334–341.PubMedView Article
            138. Hentrich M, Fehnle K, Ostermann H, Kienast J, Cornely O, Salat C, Ubelacker R, Buchheidt D, Behre G, Hiddemann W, Schiel X: IgMA-enriched immunoglobulin in neutropenic patients with sepsis syndrome and septic shock: a randomized, controlled, multiple-center trial. Crit Care Med 2006, 34:1319–1325.PubMedView Article
            139. Rodriguez A, Rello J, Neira J, Maskin B, Ceraso D, Vasta L, Palizas F: Eff ects of high-dose of intravenous immunoglobulin and antibiotics on survival for severe sepsis undergoing surgery. Shock 2005, 23:298–304.PubMedView Article
            140. Tugrul S, Ozcan PE, Akinci O, Seyhun Y, Cagatay A, Cakar N, Esen F: The effects of IgM-enriched immunoglobulin preparations in patients with severe sepsis [ISRCTN28863830]. Crit Care 2002, 6:357–362.PubMedView ArticlePubMed Central
            141. Karatzas S, Boutzouka E, Venetsanou K, Myrianthefs P, Fildisis G, Baltopoulos G: The effects of IgM-enriched immunoglobulin preparations in patients with severe sepsis: another point of view. Crit Care 2002, 6:543–544. author reply 545PubMedView ArticlePubMed Central
            142. Masaoka T: [Combination therapy of antibiotics and intravenous immunoglobulin]. Nippon Rinsho 2001, 59:781–784.PubMed
            143. Dominioni L, Bianchi V, Imperatori A, Minoia G, Dionigi R: High-dose intravenous IgG for treatment of severe surgical infections. Digestive Surg 1996, 13:430–434.View Article
            144. Schedel I, Dreikhausen U, Nentwig B, Hockenschnieder M, Rauthmann D, Balikcioglu S, Coldewey R, Deicher H: Treatment of gram-negative septic shock with an immunoglobulin preparation: a prospective, randomized clinical trial. Crit Care Med 1991, 19:1104–1113.PubMedView Article
            145. Burns ER, Lee V, Rubinstein A: Treatment of septic thrombocytopenia with immune globulin. J Clin Immunol 1991, 11:363–368.PubMedView Article
            146. Wesoly C, Kipping N, Grundmann R: Immunoglobulin therapy of postoperative sepsis. Zeitschrift fur experimentelle Chirurgie, Transplantation, und kunstliche Organe: Organ der Sektion Experimentelle Chirurgie der Gesellschaft fur Chirurgie der DDR 1990, 23:213–216.
            147. Grundmann R, Hornung M: Immunoglobulin therapy in patients with endotoxemia and postoperative sepsis--a prospective randomized study. Prog Clin Biol Res 1988, 272:339–349.PubMed
            148. De Simone C, Delogu G, Corbetta G: Intravenous immunoglobulins in association with antibiotics: a therapeutictrial in septic intensive care unit patients. Crit Care Med 1988, 16:23–26.PubMedView Article
            149. Lindquist L, Lundbergh P, Maasing R: Pepsin-treated human gamma globulin in bacterial infections. A randomized study in patients with septicaemia and pneumonia. Vox Sang 1981, 40:329–337.PubMedView Article
            150. Yakut M, Cetiner S, Akin A, Tan A, Kaymakcioglu N, Simsek A, Sen D: Sepsisdeki hastalarda immunglobulin G (IgG) kullaniminin mortalite oranina etkisi. GATA Bulteni 1998, 40:76–81.
            151. Behre G, Ostermann H, Schedel I, Helmerking M, Schiel X, Rothenburger M, Geiger S, Dedroogh M, Bockelmann D, Wormann B, Kienast J, Hiddemann W, Abakumov MM: Endotoxin concentrations and therapy with polyclonal IgM-enriched immunoglobulins in neutropenic cancer patients with sepsis syndrome: pilot study and interim analysis of a randomized trial. Antiinfective Drugs Chemother 1995, 13:129–134.
            152. Spannbrucker N, Munch HG, Kunze R, Vogel F: Auswirkungen von immunglobulinsubstitution bei sepsis. Intensivmedizin 1987, 6:314.
            153. Turgeon AF, Hutton B, Fergusson DA, McIntyre L, Tinmouth AA, Cameron DW, Hebert PC: Meta-analysis: intravenous immunoglobulin in critically ill adult patients with sepsis. Ann Intern Med 2007, 146:193–203.PubMedView Article
            154. Laupland KB, Kirkpatrick AW, Delaney A: Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: a systematic review and meta-analysis. Crit Care Med 2007, 35:2686–2692.PubMedView Article
            155. Kreymann KG, de Heer G, Nierhaus A, Kluge S: Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock. Crit Care Med 2007, 35:2677–2685.PubMedView Article
            156. Pildal J, Gotzsche PC: Polyclonal immunoglobulin for treatment of bacterial sepsis: a systematic review. Clin Infect Dis 2004, 39:38–46.PubMedView Article
            157. Norrby-Teglund A, Haque KN, Hammarstrom L: Intravenous polyclonal IgMenriched immunoglobulin therapy in sepsis: a review of clinical efficacy in relation to microbiological aetiology and severity of sepsis. J Intern Med 2006, 260:509–516.PubMedView Article
            158. Alejandria MM, Lansang MA, Dans LF, Mantaring JB: Intravenous immunoglobulin for treating sepsis and septic shock. Cochrane Database Syst Rev 2002, (1):CD001090.
            159. Alejandria MM, Lansang MA, Dans LF, Mantaring JB: Intravenous immunoglobulin for treating sepsis and septic shock. Cochrane Database Syst Rev 2001, (2):CD001090.
            160. Khan S, Abuzakouk M, Dore PC, Sewell WA: Administering intravenous immunoglobulin during infection is associated with infusion reactions in selected patients. Ir J Med Sci 2011, 180:125–128.PubMedView Article
            161. Koleba T, Ensom MH: Pharmacokinetics of intravenous immunoglobulin: a systematic review. Pharmacotherapy 2006, 26:813–827.PubMedView Article

            Copyright

            © BioMed Central Ltd 2012