In the past 20 years, our understanding of the workings of complement regulatory protein, CD46 (membrane cofactor protein), has grown as has the impressive list of pathogens interacting with this membrane-bound complement inhibitor. Referred to as a "pathogen magnet," CD46 serves as a receptor for seven human pathogens. Initially discovered as a widely expressed C3b- and C4b-binding protein, it was subsequently shown to be a cofactor for the serine protease factor I to inactivate by limited proteolysis these two opsonins and components of the convertases. The involvement of CD46 in reproductive processes continues to be an emerging story. It is a protector of placental tissue, but it may also play a more direct role in reproduction through its expression on the inner acrosomal membrane of spermatozoa. Cross-linking CD46 with antibodies or natural or pathogenic ligands induces rapid turnover and signaling events. In this regard, much attention is currently focused on generating human T lymphocyte regulatory cells by cross-linking CD46. Finally, highlighting its importance in protecting cells against excessive complement activation is the discovery that even a heterozygous deficiency of CD46 predisposes to hemolytic uremic syndrome.
"A growing body of evidence demonstrates the critical role of signals transduced by complement receptors expressed on CD4 + T cells, in addition to T cell receptor (TCR) activation, costimulation , and environmental presence of interleukin-12 (IL-12) (Murphy and Stockinger, 2010), in T helper 1 (Th1) cell-mediated immunity (Liu et al., 2005; Strainic et al., 2008). In particular, the C3 activation fragments C3a and C3b, generated by the T cell itself (Cardone et al., 2010; this study did not define the mechanism underlying autocrine C3 activation), are required for the induction of interferon-g (IFN-g) secretion via autocrine engagement of their respective receptors, the G protein-coupled receptor (GPCR) C3a receptor (C3aR) and the complement regulator CD46 (which binds C3b) (Le Friec et al., 2012; Liszewski et al., 2005). This observation is underpinned by the fact that CD46- deficient patients throughout life or C3-deficient patients in early childhood suffer from recurrent infections and have severely reduced T helper 1 (Th1) cell-mediated responses (Th2 cell responses are normal) (Ghannam et al., 2008; Le Friec et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: Complement is viewed as a critical serum-operative component of innate immunity, with processing of its key component, C3, into activation fragments C3a and C3b confined to the extracellular space. We report here that C3 activation also occurred intracellularly. We found that the T cell-expressed protease cathepsin L (CTSL) processed C3 into biologically active C3a and C3b. Resting T cells contained stores of endosomal and lysosomal C3 and CTSL and substantial amounts of CTSL-generated C3a. While "tonic" intracellular C3a generation was required for homeostatic T cell survival, shuttling of this intracellular C3-activation-system to the cell surface upon T cell stimulation induced autocrine proinflammatory cytokine production. Furthermore, T cells from patients with autoimmune arthritis demonstrated hyperactive intracellular complement activation and interferon-γ production and CTSL inhibition corrected this deregulated phenotype. Importantly, intracellular C3a was observed in all examined cell populations, suggesting that intracellular complement activation might be of broad physiological significance.
"Like CR1 it is involved in the uptake of microbes and particles coated with C3b (and to some extent iC3b) . CD46 is an important and widely distributed complement inhibitor with four extracellular domains . The two most membrane proximal domains (CCP3 and 4) have been shown to have the C3b binding sites . "
[Show abstract][Hide abstract] ABSTRACT: The complement system contains a great deal of biological "energy". This is demonstrated by the atypical hemolytic uremic syndrome (aHUS), which is a thrombotic microangiopathy (TMA) characterized by endothelial and blood cell damage and thrombotic vascular occlusions. Kidneys and often also other organs (brain, lungs and gastrointestinal tract) are affected. A principal pathophysiological feature in aHUS is a complement attack against endothelial cells and blood cells. This leads to platelet activation and aggregation, hemolysis, prothrombotic and inflammatory changes. The attacks can be triggered by infections, pregnancy, drugs or trauma. Complement-mediated aHUS is distinct from bacterial shiga-toxin (produced e.g. by E. coli O:157 or O:104 serotypes) induced "typical" HUS, thrombotic thrombocytopenic purpura (TTP) associated with ADAMTS13 (an adamalysin enzyme) dysfunction and from a recently described disease related to mutations in intracellular diacylglycerol kinase ε (DGKE). Mutations in proteins that regulate complement (factor H, factor I, MCP/CD46, thrombomodulin) or promote (C3, factor B) amplification of its alternative pathway or anti-factor H antibodies predispose to aHUS. The fundamental defect in aHUS is an excessive complement attack against cellular surfaces. This can be due to 1) an inability to regulate complement on self cell surfaces, 2) hyperactive C3 convertases or 3) complement activation and coagulation promoting changes on cell surfaces. The most common genetic cause is in factor H, where aHUS mutations disrupt its ability to recognize protective polyanions on surfaces where C3b has become attached. Most TMAs are thus characterized by misdirected complement activation affecting endothelial cell and platelet integrity.
European Journal of Internal Medicine 06/2013; 24(6). DOI:10.1016/j.ejim.2013.05.009 · 2.89 Impact Factor
"One cellular receptor for HHV-6A is CD46 , a complement inhibitor molecule that is expressed on all nucleated cells . Therefore, although HHV-6A/6B predominantly infects CD4+ T cells , , HHV-6A may have tropism for many different cell types, including immune cells like dendritic cells (DC). "
[Show abstract][Hide abstract] ABSTRACT: Human herpesvirus 6A (HHV-6A) is a common virus with a worldwide distribution that has been associated with multiple sclerosis. Whether HHV-6A can replicate in dendritic cells (DC) and how the infection might modulate the functional properties of the cell are currently not well known and need further investigations. Here, we show that a non-productive infection of HHV-6A in DC leads to the up-regulation of HLA-ABC, via autocrine IFN-α signaling, as well as the up-regulation of HLA-DR and CD86. However, HHV-6A exposure reduces IL-8 secretion by DC and their capacity to stimulate allogenic T cell proliferation. The ability to suppress DC functions important for activation of innate and adaptive immune responses might be one successful strategy by which HHV-6A avoids the induction of appropriate host defense mechanisms, and thus facilitating persistent infection.
PLoS ONE 03/2013; 8(3):e58122. DOI:10.1371/journal.pone.0058122 · 3.23 Impact Factor
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