Structure-function studies of the receptors for complement C1q

C1q is an essential component of the phylo-genetically ancient innate complement (C) system and is crucial to our natural ability to ward off infection and clear toxic cell debris (e.g. amyloid fibrils, apoptotic cells). Several candidate C1q receptors [C1q receptor for phagocytosis enhancement (C1qRp), complement receptor (CR) 1, calreticulin (CRT), binding protein for the globular head of C1q (gC1qbp)] have been described, and the aim of this review is to shed light on their structure-function relationships. One cell-surface molecule, C1qRp, has emerged as a defence collagen receptor for C1q, as well as mannose-binding lectin (MBL) and surfactant protein A. C1qRp (also known as the AA4 antigen in rodents) is the antigen recognized by a pro-adhesive monoclonal antibody called mNI-11 and antibodies against CD93, but recent results failed to confirm C1q binding activity. CR1 (CD35), a multifunctional receptor both in its ligand specificity and in its C regulation activities, is found on circulating monocytes and neutrophils, but the major site of expression is B-lymphocytes. As a receptor, CR1 binds to C1q, other C opsonins (C4b, C3b, iC3b) and MBL, and as such, has been involved in promoting phagocytosis. Several studies support a role for the cell surface receptor for the collagenous domains of C1q (cC1qR; also known as CRT). CRT belongs to the family of heat-shock proteins, the most abundant and ubiquitous soluble intracellular proteins. Though CRT does not have a transmembrane domain, it seems to mediate phagocytosis of the apoptotic cells through association with CD91. A 33 kDa protein interacts with the globular head of C1q and, logically, has been termed gC1qbp. This protein is located in mitochondria, suggesting that gC1 qbp is not a cell-surface receptor itself

Acute lung injury in preterm newborn infants: mechanisms and management

Respiratory morbidity and mortality remain common in preterm infants. The immature pretermlung is especially prone to injury. This process often starts in-utero due to maternal chorioamnionitis, priming the lung for further injury in response to post-natal ventilation, oxygen and nosocomial infection. Pulmonary inflammation has been strongly implicated in the pathway leading to lunginjury in this population of infants. Several therapeutic approaches have been attempted to prevent acutelunginjury or to limit its progress. The mechanisms of acutelunginjury in preterm infants; their clinical correlates and available therapeutic approaches are reviewed here

Divergent roles for C-type lectins expressed by cells of the innate immune system

In recent years there has been increasing interest in the diversity and function of carbohydrates present on a range of endogenous mammalian glycoproteins and pathogen surfaces. It is clear that carbohydrate structures are not merely structural components of the molecules which bear them but are, in many instances, a source of information to be decoded by biological systems including the immune system. Macrophages and other antigen presenting cells express a variety of pattern recognition molecules which allow discrimination between self and non-self ligands and are well known for their ability to recognise and internalise foreign antigens. The role of carbohydrates as molecular determinants of self/non-self has been recognised for many years and a family of proteins known as the C-type lectins are implicated as the main players in carbohydrate recognition within the immune system. More recently, C-type lectin receptors which bind ligands other than carbohydrates have been identified, and there are additional receptors which bind both carbohydrate and non-carbohydrate ligands. In this review article we seek to shed light on the varied roles of this family of receptors, particularly those receptors expressed by antigen presenting cells and those with known ligands. We also review more recent data on several members of this family

Ligand recognition by antigen-presenting cell C-type lectin receptors

It is now appreciated that the range of ligands interacting with C-type lectin type receptors on antigen presenting cells includes endogenous self-molecules as well as pathogens and pathogen-derived ligands. Interestingly, not all interactions between these receptors and pathogenic ligands have beneficial outcomes, and it appears that some pathogens have evolved immunoevasive or immunosuppressive activities through receptors such as DC-SIGN. In addition to this, recent data indicate that the well-characterised macrophage mannose receptor is not essential to host defence against fungal pathogens, as previously thought, but has an important role in regulating endogenous glycoprotein clearance. New studies have also demonstrated that different ligand binding and/or sensing receptors collaborate for full and effective immune responses

Off to a slow start: under-development of the complement system in term newborns is more substantial following premature birth

Complement represents a keystone to the innate immune system, with three activation pathways that utilise foreign microbial pattern recognition as well as activation by the host's specific antibodies. However, innate immunity is not synonymous with neonatal immunity. The complement system in healthy term (38–42 weeks gestation) newborns is under-developed and, with only a few exceptions (e.g. C7 and factor D), the circulating complement component concentrations are between 10 and 80% of adult levels. Complement activation is tightly regulated and the circulating regulator levels are also low relative to adults, sometimes at almost undetectable levels (e.g. C4b-binding protein). For premature newborns, these relative deficiencies are even more marked. Newborns are known to be more susceptible to infection, and the importance of complement, not only through its decreased ability to directly lyse bacteria with the common terminal pathway, but also its reduced ability to recruit (chemotaxis) innate and adaptive leukocytes to sites of microbial invasion and reduced ability to enhance phagocytosis (opsonisation) will be discussed. Complement also holds a key role in enhancing and directing refinement of the specific antibody response to pathogens (as an adjuvant) that likely plays a role in the well-known under-performance of the humoral immune response in newborns

Molecular and cellular properties of the rat AA4 antigen, a C-type lectin-like receptor with structural homology to thrombomodulin

The murine fetal stem cell marker AA4 has recently been cloned and is known to be the homolog of the human phagocytic C1q receptor involved in host defense. We herein report the molecular cloning and the cellular expression pattern of the rat AA4 antigen. Modular architecture analysis indicated that the rat AA4 is a member of C-type lectin-like family and, interestingly, displays similar domain composition and organization to thrombomodulin. Northern blot and reverse transcriptase-polymerase chain reaction analyses indicated that rat AA4 was encoded by a single transcript of 7 kilobases expressed constitutively in all tissues. In situhybridization showed that AA4 was expressed predominantly by pneumocytes and vascular endothelial cells. Using an affinity purified polyclonal antibody raised against a rat AA4-Fc fusion protein, AA4 was identified as a glycosylated protein of 100 kDa expressed by endothelial cells > platelets > NK cells and monocytes (ED1+ cells). The staining was associated to the cell surface and intracytoplasmic vesicles. Conversely, erythrocytes, T and B lymphocytes, neutrophils, and macrophages (ED2+ cells) were consistently negative for AA4. As expected, the macrophage cell line NR8383 expressed weak levels of AA4. Taken together, our results support the idea that AA4/C1qRp is involved in some cell-cell interactions

Human C1qRp is identical with CD93 and the mNI-11 antigen but does not bind C1q

It has been suggested that the human C1qRp is a receptor for the complement component C1q; however, there is no direct evidence for an interaction between C1q and C1qRp. In this study, we demonstrate that C1q does not show enhanced binding to C1qRp-transfected cells compared with control cells. Furthermore, a soluble recombinant C1qRp-Fc chimera failed to interact with immobilized C1q. The proposed role of C1qRp in the phagocytic response in vivo is also unsupported in that we demonstrate that this molecule is not expressed by macrophages in a variety of human tissues and the predominant site of expression is on endothelial cells. Studies on the rodent homolog of C1qRp, known as AA4, have suggested that this molecule may function as an intercellular adhesion molecule. Here we show that C1qRp is the Ag recognized by several previously described mAbs, mNI-11 and two anti-CD93 Abs (clones X2 and VIMD2b). Interestingly, mNI-11 (Fab') has been shown to promote monocyte-monocyte and monocyte-endothelial cell adhesive interactions. We produced a recombinant C1qRp-Fc chimera containing the C-type lectin-like domain of C1qRp and found specific binding to vascular endothelial cells in sections of inflamed human tonsil, indicating the presence of a C1qRp ligand at this site. This interaction was Ca(2+) independent and was not blocked by our anti-C1qRp mAb BIIG-4, but was blocked by the proadhesive mAb mNI-11. Collectively, these data indicate that C1qRp is not a receptor for C1q, and they support the emerging role of C1qRp (here renamed CD93) in functions relevant to intercellular adhesion

Complement components of the innate immune system in health and disease in the CNS

The innate immune system and notably the complement (C) system play important roles in host defense to recognise and kill deleterious invaders or toxic entities, but activation at inappropriate sites or to an excessive degree can cause severe tissue damage. C has been implicated as a factor in the exacerbation and propagation of tissue injury in numerous diseases including neurodegenerative disorders. In this article, we review the evidence indicating that brain cells can synthesise a full lytic C system and also express specific C inhibitors (to protect from C activation and C lysis) and C receptors (involved in cell activation, chemotaxis and phagocytosis). We also summarise the mechanisms involved in the antibody-independent activation of the classical pathway of C in Alzheimer's disease, Huntington's disease and Pick's disease. Although the primary role of C activation on a target cell is to induce cell lysis (particularly of neurons), we present evidence indicating that C (C3a, C5a, sublytic level of C5b-9) may also be involved in pro- as well as anti-inflammatory activities. Moreover, we discuss evidence suggesting that local C activation may contribute to tissue remodelling activities during repair in the CNS

The contribution of naturally occurring IgM antibodies, IgM cross-reactivity and complement dependency in murine humoral responses to pneumococcal capsular polysaccharides

Immunogenicity of 12 capsular polysaccharides (CPS) from Streptococcus pneumoniae did not correlate with pre-existing levels of natural IgM anti-CPS antibodies in mice. Immunization of mice with individual CPS, with the exception of type 14 (the only neutral CPS tested), increased serum IgM that also bound other CPS serotypes independent of structural similarity or commonly known contaminants. Surprisingly only IgM response to type 4 (which has a small immunodominant epitope) was dependent on either complement C3 or complement receptors CD35/CD21. IgG anti-CPS responseswere infrequently induced, but critically dependentoncomplement. Our resultshave clarifiedthe role ofcomplement in the induction of IgM and IgG anti-CPS antibody responses in mice and have implications for CPS vaccine development