Multifaceted Tissue-Protective Functions of Polyvalent Immunoglobulin Preparations in Severe Infections-Interactions with Neutrophils, Complement, and Coagulation Pathways

Abstract

Severe infections induce immune defense mechanisms and initial tissue damage, which produce an inflammatory neutrophil response. Upon dysregulation of these responses, inflammation, further tissue damage, and systemic spread of the pathogen may occur. Subsequent vascular inflammation and activation of coagulation processes may cause microvascular obstruction at sites distal to the primary site of infection. Low immunoglobulin (Ig) M and IgG levels have been detected in patients with severe infections like sCAP and sepsis, associated with increased severity and mortality. Based on Ig's modes of action, supplementation with polyvalent intravenous Ig preparations (standard IVIg or IgM/IgA-enriched Ig preparations) has long been discussed as a treatment option for severe infections. A prerequisite seems to be the timely administration of Ig preparations before excessive tissue damage has occurred and coagulopathy has developed. This review focuses on nonclinical and clinical studies that evaluated tissue-protective activities resulting from interactions of Igs with neutrophils, complement, and the coagulation system. The data indicate that coagulopathy, organ failure, and even death of patients can possibly be prevented by the timely combined interactions of (natural) IgM, IgA, and IgG with neutrophils and complement.

Keywords: bacterial infection; coagulation; human polyvalent immunoglobulins; neutrophils; sCAP; sepsis; tissue damage.

Figure 1

Immune responses in bacterial infections during Ig deficiency and Ig supplementation. (A) In the absence of sufficient amounts of Igs, tissue damage (release of DAMPs) can be caused by either bacteria or through secretion of bacterial exotoxins and release of endotoxins (i.e., PAMPs), for instance, after antibiotic treatment. DAMPs and PAMPs both lead to an inflammatory response followed by recruitment of neutrophils. Due to stimulation with toxins, PAMPS, and cytokines, neutrophils secrete ROS and proteases. Overstimulation might result in NETosis, causing secondary tissue damage. The cytokine storm and damaged tissues further fuel persistent inflammation. Persistent pro- and anti-inflammatory responses and overstimulation (proliferation) of T-cells may lead to pathological T-cell responses (e.g., apoptotic depletion, decreased proliferation, and T helper 2 cell polarization and unresponsiveness (T-cell anergy)). (B) In the presence of sufficient amounts of Igs, bacteria and their toxins as well as dead bacteria and disintegrated bacterial particles (i.e., PAMPs) and damaged tissue cells and particles (i.e., DAMPs) are opsonized with antibodies. In the presence of immune IgM, natural IgM, and IgG, additional complement opsonization facilitates fast clearance of bacteria, their PAMPs, and DAMPs via local phagocytosis by neutrophils and/or via transport on the RBCs to phagocytes in the liver. This prevents overstimulation of neutrophils, persistent inflammation, tissue damage, and immune suppression. C1q: complement factor C1q; C3b: complement factor C3b; CR: complement receptor; DAMPs: damage-associated molecular patterns; FcR: Fc receptor; IC: immune complexes; Ig(s): immunoglobulin(s); IL: interleukin; MHC-II: major histocompatibility complex II; NET: neutrophil extracellular trap; PAMPs: pathogen-associated molecular patterns; RBCs: red blood cells; ROS: reactive oxygen species; Tc: cytotoxic T-cell; TCR: T-cell receptor; TLR: toll-like receptor; TNF-a: tumor necrosis factor alpha.

Figure 2

Neutrophil and Ig actions at the epithelial/endothelial barrier of alveoli leading from lung infection to sepsis or from systemic infection to ARDS. (A) In the case of lung infection, bacteria (P) enter the lung alveoli (green area), where they are phagocytosed by alveolar macrophages. Due to infection-related damage of alveolar epithelium (1, green lining) and activation of macrophages, cytokines and chemokines (colored circles) are secreted. Neutrophils and platelets translocate from the vasculature (red lining) through the interstitium (gray area) into the alveoli. Neutrophils support phagocytosis, which is enhanced in the presence of polyvalent Igs (high IgM/IgG) and when bacteria are complement-opsonized (via CP). In the absence of Igs, particularly IgM (low IgM/IgG), complement is activated by the AP causing release of C5a (anaphylatoxin). Overactivation of neutrophils by bacteria (TLR stimulation), platelets, and C5a, leads to NETosis, which further damages the alveoli (2, green lining). Tissue damage facilitates translocation of bacteria into the blood stream (green arrows) causing sepsis. (B) When bacteria disseminate into the vasculature, they are phagocytosed by monocytes. Phagocytosis is enhanced in the presence of IgG, IgA, and IgM, and after additional complement deposition. If, however, bacterial load is too high, they cannot be sufficiently cleared and may damage endothelial cells (3, red lining). Platelets are activated and plug the damaged vessel wall. In addition, activated endothelial cells express adhesion molecules such as ICAM-1. Secretion of cytokines and chemokines attract and activate neutrophils that attach to the endothelium, e.g., via integrin LFA-1 to ligand ICAM-1. Activated platelets express P-selectin and engage with the P-selectin receptor (via the ligand PSGL-1) on neutrophils. In the absence of sufficient Ig levels (low IgM/IgG), neutrophils are overactivated by binding of PSGL-1 and C5a to their respective receptors and via TLR stimulation inducing NETosis of the attached neutrophils. C5a is generated via the AP and can induce NETs. This leads to activation of coagulation processes and ultimately to immunothrombosis, DIC, and to further vascular damage (4), thus facilitating translocation of bacteria into the interstitium and lung alveoli, causing ARDS (red arrows at the red and green lining). AP: alternative pathway; ARDS: acute respiratory distress syndrome; C: complement; C3b: complement factor C3b (anaphylatoxin); C5a: complement factor C5a (anaphylatoxin); CP: classical pathway; CR1: complement receptor 1; DIC: disseminated intravascular coagulation; FcR: Fc receptor; ICAM-1: intercellular adhesion molecule 1; Ig: immunoglobulin; LFA-1: lymphocyte function-associated antigen 1; MΦ: macrophage; NET: neutrophil extracellular trap; P: bacteria; PSGL-1: P-selectin glycoprotein ligand 1; ROS: reactive oxygen species; TLR: Toll-like receptor.