ES03.01 
The body as fortress: innate immune surveillance

In the front line of defence against the pervasiveness of infection are the elements of the innate immune system, which provide a sophisticated and interconnected defence surveillance system. Innate immunity can be likened to an ancient fortress supported by well-trained troops who have a well-defined battle plan, enabling them to deal with any breaches of the walls efficiently and quickly. Innate immunity is under-studied and poorly appreciated. However, in the first days after entry of a pathogen into the body, our entire protective response is dependent upon the various elements of our innate immune repertoire. Over hundreds of millions of years of evolution, nature has ensured that we have retained the elements and systems of our innate immune defences. The importance of innate immunity is often only revealed when our adaptive immune system is immature or compromised. In spite of its place as our initial defence against infection, attention is only now turning to therapeutic strategies that might enhance or supplement innate immunity. The immune system of the fetus is uniquely designed to allow the mother's immune system to present the major barrier and response to infection. Birth involves a transition from a normally sterile environment to an encounter with a range of commensal and pathogenic organisms. The neonatal immune system is immature in numerous ways, and consequently, maternal colonizing or commensal organisms frequently establish infection rather than colonization. For example, neonatal epithelia are both structurally and functionally weak barriers to infection. All the types of cells responsible for immune responses are present at birth (in some cases in higher numbers than later in life) but various aspects of their function are immature. The reserves of the bone marrow to produce more immune cells quickly are very limited, and recruitment of immune cells to sites of infection is markedly reduced. The fetus produces mostly IgM, in relatively low titres and generally with low affinity for pathogens, and the neonate cannot mount a prompt IgG response to infection. Much of the protection of the neonate is conferred by active transport of maternal IgG across the placenta. However, whether or not there is a protective titre of antibody to a particular pathogen depends on whether the mother has encountered it and how recently. Not only are newborns at high risk of infection, but infections that breach epithelial boundaries are much less likely to be locally contained (bloodstream and central nervous system infection is more likely) and infections that involve the bloodstream are more likely to invade the central nervous system (meningitis, brain abscess) or other ‘metastatic’ sites (e.g. bones, joints) than in older patients. These risks are intensified in the 10–15% of babies who are born prematurely. Deficiencies in the adaptive immune system predispose to infection risks of varying severity. The most profound of these is impairment of cell-mediated immunity resulting from human immunodeficiency virus infection or immunosuppressive therapy. CD4 lymphopenia in acquired immune deficiency syndrome (AIDS) patients predisposes to opportunistic infections and reactivation of parasitic, viral, fungal and bacterial pathogens. Immunosuppressive drugs such as glucocorticosteroids, cyclosporin A and fludarabine exert the same influence on CD4 cells, exposing organ transplant and chronic lymphocytic leukaemia patients to the same infection risks as AIDS patients. Immunoglobulin deficiency from common variable immunodeficiency or multiple myeloma increases the risk of sinopulmonary infection. Neutrophil numbers and function are crucial to defence against severe bacterial and fungal infection. Patients suffering prolonged neutropenia as a result of treatment with cytotoxic chemotherapy are at high risk of Gram-negative bacterial septicaemia, invasive candidiasis and invasive aspergillosis. This particularly applies to allogeneic bone-marrow transplant patients requiring myeloablative conditioning regimens. Impaired neutrophil function as found in the rare, chronic granulomatous disease predisposes to severe staphylococcal and Aspergillus infections. In its broadest sense, the innate immune system includes all the defences that do not require prior experience of a pathogen to prevent or control infection. Janeway and Medzhitov [1] elegantly summarized the key differences between the innate and adaptive immune systems. One is that the adaptive immune system has evolved to recognize an almost infinite variety of molecular structures, especially peptides and polysaccharides. Some of the innate defence mechanisms do not rely on molecular recognition to inhibit, kill or remove pathogens. Examples include hydrochloric acid produced by the stomach and lactic and fatty acids secreted by the skin. In both cases, the low-pH environment is hostile to a variety of microorganisms. Similarly, mucus non-specifically entraps microorganisms, holding them in contact with secreted inhibitors and preventing their adhesion to epithelia. In contrast, numerous other innate defences require recognition of pathogen-associated molecular patterns (PAMPs), groups of molecules that are found on a wide variety of microorganisms, but because of the evolutionary necessity to clearly distinguish self from non-self, are rarely expressed at high density on the cells or surfaces of higher organisms. Examples of PAMPs include lipopolysaccharide (LPS), peptidoglycans, mannans and double-stranded RNA. Importantly, the soluble and receptor motifs for recognition of PAMPs are encoded in the germline and are unchanging. Another key difference between the adaptive and innate immune systems is the rapidity of action. Most innate defences are constitutively expressed and peptide or protein transcription, translation, modification and secretion are not required for first-line response. Some, however, such as C-reactive protein (CRP) and mannose-binding lectin (MBL) are also acute-phase reactants, locally or systemically inducible in response to infection or inflammation. In contrast, the adaptive immune system is based on receptors (immunoglobulins and immunoglobulin-like receptors) on cells that are capable of endless rearrangement at the genetic level and clonal expansion on demand. This process takes a finite time and the adaptive response to infection is slower than the innate response. Although innate defences stand alone against organisms that evade adaptive immunity, vertebrates have evolved a complex system of interactions between the innate and adaptive immune systems. Innate immune system fluid-phase molecules can attract or activate cells of the adaptive immune system. Cells intrinsic to the adaptive immune system express homologues of innate immune receptors (for example Toll receptors and the C-type lectin DEC-205), in order to enhance rapid recognition and to amplify the response to pathogens by production of cytokines and costimulatory molecules. The complement system represents a major interface between the two systems, not only through its treble mechanisms for activation but also because complement stimulates antibody responses via complement receptors on B cells. Thus the boundaries of innate and adaptive immunity are quite indistinct and are only now becoming the subject of systematic research. The armoury of the innate immune system is made up of three broad defence categories. These are: barriers; fluid phase molecules; cells and their receptors. The metaphor of the body as fortress is no stronger than when these barriers are considered. None of the innate immune barriers relies on molecular recognition to inhibit, kill or remove pathogens. Continuous physical barriers include the skin, the epithelia of the gastrointestinal tract, and the airways. Mechanically active elements of innate protection against infection can be significant features, such as the cilia of the respiratory system, active microvilli, which are a feature of some areas of the gastrointestinal tract, and peristalsis in the gut. Often superimposed on the physical barriers are chemical barriers, such as high- or low-pH environments, digestive enzymes, mucus, lactic and fatty acids, HCl, and chemicals secreted by commensal organisms. The alternative and lectin pathways of complement activation belong to the primordial innate immune system, dating back as far as 900 million years. Complement component C3 is in high concentration in blood and tissues. The C3 molecule undergoes continuous auto-activation, degrading to C3b. C3b is a very reactive molecular species, binding to amino and hydroxyl groups commonly represented on bacteria. However, C3b needs to be very close to an organism because it will be neutralized by a water molecule if it does not attach to its target within 60 µs. Bound to a surface, C3b participates in the continued progression of the complement cascade, with final formation of the membrane attack complex and lysis of the targeted infectious cell. The lectin pathway of complement is initiated by binding of MBL and its closely allied MBL-associated serine protease 2 (MASP2) to pathogen-associated mannan groups. It can also be initiated by similar activation of MASP2 associated with ficolin L and H binding to microbial GlcNAC and GalNAC sugars, respectively. Activated MASP2 directly initiates the complement cascade via C4. The MBL pathway of complement activation is being recognized as a critical component of the innate immune system. MBL is a oligomeric, liver-derived plasma molecule that binds to pathogens and activates complement independently of antibody. MBL binds to repeating mannose and N-acetylglucosamine sugar motifs characteristically displayed in high density on bacteria, fungi, viruses and protozoa, but not on mammalian cells. Following pathogen binding, MBL undergoes a conformational change, associated serine proteases such as MASP-2 are activated, and the complement cascade is initiated via the lectin pathway. The primary structural unit of MBL is a 96-kDa molecule consisting of three identical 32-kDa peptide Gly–X–Y repeating units, each with its own C-terminal carbohydrate recognition domain, associated to form a collagenous triple helix. MBL, in plasma and in some inflamed tissues, functions as a direct opsonin, flagging pathogens for binding to phagocytic collectin receptors that may include C1q receptor or calreticulin. By activating complement, MBL amplifies its opsonization capacity with the added potential for direct lysis of pathogens. Together with other molecular elements of the innate, non-clonal, immune system, MBL also promotes the initiation of the adaptive immune response by regulating the expression of costimulatory activity on antigen-presenting cells and by signalling lymphocytes via effector cytokines. A wide spectrum of MBL oligomers is found in the circulation, from single structural units, through dimers, trimers, tetramers and pentamers, to very high- order oligomers. The overall complement activation ability of MBL is highly dependent on the molecular arrangement and relative abundance of higher order oligomers in plasma. The gene for human MBL, MBL2, lies on chromosome 10q11·2 – q21. Exon 1 can contain one of three single nucleotide substitutions in codons 52 (Arg→Cys, allele D), 54 (Gly→Asp, allele B) and 57 (Gly→Glu, allele C). These mutations either disrupt the Gly–X–Y repeating motif of exon 1, or disrupt the N-terminal disulphide bonds, impairing the assembly or stability of the basic MBL structural unit. Functional, higher order oligomers are fewer and circulating levels of complement-fixing MBL are reduced. The promoter and 5′ untranslated regions of the MBL2 gene are polymorphic. Promoter-region variants influence circulating MBL levels. The promoter variants are in absolute linkage disequilibrium with coding variants. Our contemporary understanding of exactly what constitutes an adequate level of MBL is still evolving. Levels of circulating MBL, as assessed by different assays and reported as adult population means, medians and/or ranges, have been reported in Japanese, white, African and Inuit population studies. Coding mutations of the MBL structural gene are present in up to ∼40% of unselected white populations, and result in profound reductions in levels of circulating, functional MBL. Superimposed on these gene effects on MBL levels are those of the more common MBL ‘low’ promoter gene variants. This is reflected in a wide range for assay results as illustrated for a normal blood donor and full term infant populations (Fig. 1). In addition to genetic control of an individual's MBL levels, modest peaks and troughs of MBL can be measured in some individuals in response to infection or inflammation, with kinetics reflecting an acute-phase response. Range of MBL levels determined in a mannan-binding assay for cord plasma from 250 normal-term neonates and plasma from 236 healthy blood donors. Many reports in the scientific literature substantiate an association between increased incidence and/or severity of different types of infection and low levels of MBL. Some study results have been reproduced and confirmed by other groups, while some associations are the subject of more intense scrutiny. Clearly, more prospective controlled studies are needed to realize any immutable disease links. A number of recent publications call for rapid progress towards clinical trial of MBL. One candidate MBL replacement therapeutic is a recombinant MBL (rMBL) developed by NatImmune in Denmark. This recombinant MBL has the same molecular weight as native MBL and has replicated in vitro the C4-activation capability of native MBL. If such a product is proven efficacious in vivo and it can be manufactured reliably in sufficient quantities, it may become generally available as a valuable therapeutic agent. Human plasma-derived MBL can be reliably purified from existing side fractions of manufacturing processes developed for other needed plasma proteins. To achieve safe and sufficient blood supplies, large quantities of cellular products and blood donor plasma must be collected and tested by national, regional and local blood services around the world; significant value could be added to these collections if a plasma-derived MBL could be reliably and safely produced from presently unused manufactured side fractions. Circulating in oligomeric form in plasma, two ficolins, L-ficolin and H-ficolin, are associated with MASPs, and like MBL, can activate complement through the lectin pathway. These ficolins have a collagenous domain but their carbohydrate-recognition specificity (GlcNAC and GalNAC, respectively) is embedded within a fibrinogen-like domain. The function of L- and H-ficiolin overlap that of MBL, but their distinct pattern-recognition character broadens the range of pathogens that can be targeted for immune-system recognition and destruction through lectin activation of complement. Absolute ficolin deficiency states have not yet been described, although low levels in chemotherapy patients compared with healthy controls have been observed recently. These members of the collectin family, first identified in pulmonary surfactant and secreted by alveolar type 2 pneumocytes are also oligomeric proteins composed of α-helical carbohydrate recognition domains attached to triple helical collagen-like regions. SP-A mostly assembles into octadecamers, whereas SP-D consists predominantly of dodecamers or cross-linked aggregates of dodecamers. SP-A is more the more abundant of the two proteins in the alveoli, where most is bound to surfactant phospholipids, whereas a higher proportion of SP-D is found in soluble form. Although they were at first thought to be specific to the alveolus and small bronchioles, SP-A is expressed at all levels of the respiratory tract, and in other sites including the large intestine, synovium, peritoneal cavity and middle ear. SP-D is also found in the stomach, small and large intestine, and peritoneum. Like MBL, SP-A and SP-D bind carbohydrate PAMPs, although there are subtle differences in sugar selectivities between these different collectins. Both SP-A and SP-D also bind glycolipids and some lipids, including bacterial LPS, and SP-A can interact with CD14, suggesting a role for SP-A in presenting LPS to effector cells. SP-A and SP-D opsonize a variety of pathogens. This helps prevent host infection by inhibition of microbial virulence and adherence, enhancement of phagocytosis and killing, chemotaxis, stimulation of the respiratory burst of alveolar macrophages, and modulation of cytokine production. Truncated or whole recombinant forms of surfactant proteins may have potential in the prevention of inflammatory and infectious diseases of the lung. CRP is an acute-phase reactant that was first found in the serum of patients with pneumococcal infection. 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