Anti C1q Antibodies and Phagocytosis of Apoptotic Cells

Anti C1q Antibodies and Phagocytosis of Apoptotic CellsThe equilibrate system is one of the study effector mechanisms of the innate resistive system and it plays an important role in immune defense. The biological functions of balance are opsonization and phagocytosis, stimulation of incitive reactions by anaphylatoxins and backup-mediated cytolysis of microbes, especially encapsulated bacteria. The complement system is formed by an enzymatic cascade composed of plasma proteins that, once stimulated, can achieve wonderful amplification and effectively fight the invading microorganisms (Abbas et al., 2009).Under certain conditions, a pathological immune reaction may develop against complement fixingss, which on one hand reflects an underlying autoimmune mathematical process and may soften to inflammation and tissue injury on the other (Potlukova and Kralikova, 2008).The first component of the unspotted pathway of complement energizing, C1q, plays a crucial role in the cl earance of immune complexes and apoptotic bodies from the organism. Autoantibodies against C1q (anti C1q) have been found in a way out of autoimmune and infectious diseases. They have been best described in patients with systemic lupus erythematosus, where they are thought to play a infectious role in lupus nephritis (LN). Their mellow negative predictive value for the occurrent of participating proliferative LN, as well as their possible ability to indicate a renal flare as soon as 6 months in advance, have rendered anti C1q antibodies a novel non-invasive tool in the detection of active LN (Potlukova and Kralikova, 2008).The Complement C1q and Its AntibodiesC1q is the first component of the classical pathway of complement activating. Together with the enzymatically active components C1r and C1s, C1q forms the C1 complex. Binding of C1 to immunoglobulins in the form of immune complexes leads to activation of protease function of C1r and C1s and further activation of the cl assical pathway of complement (Schumaker et al., 1986).C1q is a glycoprotein belonging to the collectin family with a molecular weight of about 410-462 kDa. It is a hexamer composed of globular heads attached to coll shape upn-like triple-helix tails (Fig. 8). The globular heads of C1q specifically attach to the constant unsounded (CH2) domain of immunoglobulin G motes or the CH3 domain of IgM. each heavy chain of the immunoglobulin molecule contains only one medical dressing site for C1q. Since C1q must link to at least two heavy chains in order to change its conformation and activate C1r and C1s, its activation ensues only after binding to immunoglobulins in the form of immune complexes ensnare to multivalent antigens (Schumaker et al., 1986).Most complement proteins are synthesized in the liver by hepatocytes. However, macrophages can synthesize early complement components of both the classical and alternate pathways and can provide suitable local tissue complement for ops onization without recruiting plasma complement (Colten et al., 1986). C1q is unusual, for a complement protein, that it is synthesized by tissue macrophages entirely not hepatocytes (Loos et al., 1989).In addition to being the first component of the classical pathway of complement activation, C1q has m either physiological roles. C1q can directly change apoptotic cells (AC) for phagocytosis. In vitro, C1q binds to surface blebs on AC but not figure host cells (Korb and Ahearn, 1997). C1q binds to calreticulin (CRT) in AC blebs and opsonizes AC for enhanced phagocytosis through C1q interaction with CD91. C1q can opsonize AC in like manner indirectly through complement activation (Lu et al., 2008). Consistent with this, the finding that C1q-deficient mice have been shown to have an accumulation of apoptotic bodies in the kidneys (Botto et al., 1998) and macrophages of C1q-deficient mice and humans have a decreased ability to clear apoptotic bodies in vitro (Botto, 1998 Taylor e t al., 2000).In this way, C1q promotes the clearance of autoantigens, preventing stimulation of the immune system and disruption of this process may lead to evolution of autoimmunity (Botto, 2001).C1q-opsonized AC besides regulates DC action of cytokines, but data from different studies are not entirely reconciled (Lu et al., 2008). Apparently, most studies report C1q inhibition of IL-12 production from DCs and that AC stimulated macrophages take more IL-10 and less IL-12. This suggests a tolerogenic property of C1q which is consistent to the development of autoimmunity at C1q deficiency (Botto et al., 1998).C1q has also miscellaneous roles in regulation of multiple macrophage activities, in DC differentiation, activation and antigen presentation and in granulocytes, mast cells and fibroblasts regulation (Lu et al., 2008).There are several autoantibodies to complement proteins that interfere with the physiological regulation of complement activation in vivo, and each of these h as been associated with the development of disseminated lupus erythematosus. These antibodies are C3 nephritic factor, anti-C1 inhibitor autoantibodies, and anti C1q antibodies. In each of these lessons, there is a chicken and egg dispute, since it could be argued that development of the anticomplement autoantibody is itself part of the SLE process. However, in the case of C3 nephritic factor, which stabilizes the C3bBbC3 convertase enzyme of the alternative pathway, 8 cases of SLE have been described )Sheeran et al., 1995 Walport et al., 1994). In each of these, the on coif of SLE occurred mevery years after the development of the main clinical phenotypes associated with the front of C3 nephritic factor, supporting the idea that the C3 nephritic factor was the egg alternatively than the chicken.History and epidemiology of anti C1q antibodiesBinding of monomeric IgG to C1q was first described in 1971, in sera from patients with SLE with hypocomplementemia (Agnello et al., 1971), and in 1978, precipitation of C1q by monomeric IgG was record in the hypocomplementemic urticarial vasculitis syndrome (HUVS) (Marder et al., 1978). In 1984, anti C1q antibodies were found in patients with SLE (Uwatoko et al., 1984). Since then, occurrence of anti C1q antibodies has been described with varying prevalence in patients with autoimmune and also some infectious diseases (Wisnieski and Jones, 1992).Anti C1q antibodies were mostly of the IgG subtype with IgG1 and IgG2 being the frequent subclasses (Siegert et al., 1990). The prevalence of anti C1q in the general population varies among 2% and 8% (Potlukova et al., 2008). As is the case with other autoantibodies, the occurrence of anti C1q increases with age (Ravelli et al., 1997 Siegert et al., 1993). The mere positivity for anti C1q antibodies in an otherwise healthy single does not appear to bear any pathological or predictive significance (Potlukova and Kralikova, 2008).Pathogenic role of anti C1q antibodiesAnti C 1q antibodies have high negative predictive value for active lupus nephritis (LN) suggesting a pathogenic role in SLE patients. In addition, the elimination of anti C1q antibodies from circulation by repeated plasmapheresis or C1q immunoabsorption brought alleviation of the patients symptoms (Berner et al., 2001 Grimbert, et al., 2001).The binding of anti C1q antibodies to C1q is mediated via pleasing fragments and in contrast to immune complexes, anti C1q antibodies do not bind to globular heads of the C1q molecule but to its collagen-like tail (Fig. 8). The binding is very watery in the liquid phase, but achieves high affinity in the case of a conformationally changed C1q in the bound state exposing new antigenic determinants. Thus, any possible pathogenic role of anti C1q antibodies probably remains control to local deposits of C1q in tissues (Potlukova and Kralikova, 2008).Another intriguing mechanism of the pathogenicity of anti C1q antibodies capacity be a switch from non- inflammatory identification of apoptotic bodies by C1q and its receptors to inflammatory recognition when C5a and other complement activation fragments are generated during enhanced complement activation due to anti C1q antibodies at sites where C1q is recognizing nuclear antigens (Holers, 2004).Fig. 8 A simplified scheme of the binding of anti C1q antibodies to the molecule of C1q.Anti C1q antibodies per se do not seem to activate complement however, their binding to C1q may overdo complement activation by increasing the amount of the bound IgG in a vicious circle manner. Furthermore, they might attenuate the physiological functions of C1q, including the capacity to activate the classical pathway of complement and to clear immune complexes and apoptotic bodies. Taken together, several different mechanisms seem to be involved in the pathogenicity of anti C1q antibodies (Potlukova and Kralikova, 2008).The presence of anti C1q antibodies in lupus is typically accompanied by a numbe r of clinical and serological features. The complement profile is mistakable to that seen in HUVS, with very low levels of C1q, C4, and C2, and, to a lesser extent, C3. Anti C1q antibodies feed to remain positive in SLE for protracted periods, and there is associated prolonged hypocomplementemia. This differs from anti-double-stranded DNA antibody levels, which tend to fluctuate in concentration, together with inverse changes in complement levels (Pickering et al., 2000). Anti C1q antibodies in infectious diseasesAnti C1q antibodies have also been found in some infectious diseases Prohaszka et al. (1999) have found an increase occurrence of anti C1q antibodies in patients infected with human immunodeficiency virus 13% of infected patients were positive when compared with 5% controls. Furthermore, the levels of anti C1q antibodies significantly decreased during a follow-up period of 65 months. Interestingly, sera with detectable anti C1q antibodies were more potential to neutrali ze HIV than sera without them in in-vitro experiments.Saadoun et al. (2006) have reported an increased prevalence of anti C1q antibodies in patients infected with hepatitis C virus (HCV), with 26% being positive. Contrary to expectations, the occurrence of anti C1q antibodies did not differ between HCV-infected patients with and without blend cryoglobulinemia indicating that immune complexes do not cross-react with the anti C1q assay and proving also the exuberant presence of immune complexes in the circulation does not seem to be sufficient to provoke generation of anti C1q. Further studies are needed to polish off their role and clinical relevance in other diseases.Measurement of anti C1q antibodiesIn the past, radioimmunoassay based on the binding of immune complexes to C1q fixed to a solid phase was mainly white plagued to determine the concentration of immune complexes (Hay et al., 1976). Later, the solid-phase C1q binding assay was modified into an enzyme-linked immunosorb ent assay (ELISA). For this purpose, either solely C1q or the collagen-like region of C1q was employed. However, the use of individually prepared ELISA kits with differently set cut-off limits for positivity led to a rather large disparity between the results of clinical studies. Nowadays, measurement of anti C1q antibodies in serum has become easier thank to commercially available and standardized ELISA kits using the whole C1q molecule as antigen (Potlukova and Kralikova, 2008).The main pitfall in the measurement of anti C1q antibodies consists in a possible binding of circulating immune complexes to the solid-phase bound whole C1q. However, it has been shown that the use of high ionic strength conditions in the incubation media inhibits any similar unwelcome binding and it renders the ELISA reliable for clinical use (Kohro-Kawata et al., 2002).