Clearance Of Immune Complexes Research Articles

Binding of Free and Immune Complex-Associated Hepatitis C Virus to Erythrocytes Is Mediated by the Complement System.

Erythrocytes bind circulating immune complexes (ICs) and facilitate IC clearance from the circulation. Chronic hepatitis C virus (HCV) infection is associated with IC-related disorders. In this study, we investigated the kinetics and mechanism of HCV and HCV-IC binding to and dissociation from erythrocytes. Cell culture-produced HCV was mixed with erythrocytes from healthy blood donors, and erythrocyte-associated virus particles were quantified. Purified complement proteins, complement-depleted serum, and complement receptor antibodies were used to investigate complement-mediated HCV-erythrocyte binding. Purified HCV-specific immunoglobulin G (IgG) from a chronic HCV-infected patient was used to study complement-mediated HCV-IC/erythrocyte binding. Binding of HCV to erythrocytes increased 200- to 1,000-fold after adding complement active human serum in the absence of antibody. Opsonization of free HCV occurred within 10 minutes, and peak binding to erythrocytes was observed at 20-30 minutes. Complement protein C1 was required for binding, whereas C2, C3, and C4 significantly enhanced binding. Complement receptor 1 (CR1, CD35) antibodies blocked the binding of HCV to erythrocytes isolated from chronically infected HCV patients and healthy blood donors. HCV-ICs significantly enhanced complement-mediated binding to erythrocytes compared to unbound HCV. Dissociation of complement-opsonized HCV from erythrocytes depended on the presence of Factor I. HCV released by Factor I bound preferentially to CD19+ B cells compared to other leukocytes. Conclusion: These results demonstrate that complement mediates the binding of free and IC-associated HCV to CR1 on erythrocytes and provide a mechanistic rationale for investigating the differential phenotypic expression of HCV-IC-related disease.

Collectin-11 (CL-11) Is a Major Sentinel at Epithelial Surfaces and Key Pattern Recognition Molecule in Complement-Mediated Ischaemic Injury.

The complement system is a dynamic subset of the innate immune system, playing roles in host defense, clearance of immune complexes and cell debris, and priming the adaptive immune response. Over the last 40 years our understanding of the complement system has evolved from identifying its presence and recognizing its role in the blood to now focusing on understanding the role of local complement synthesis in health and disease. In particular, the local synthesis of complement was found to have an involvement in mediating ischaemic injury, including following transplantation. Recent work on elucidating the triggers of local complement synthesis and activation in renal tissue have led to the finding that Collectin-11 (CL-11) engages with L-fucose at the site of ischaemic stress, namely at the surface of the proximal tubular epithelial cells. What remains unknown is the precise structure of the damage-associated ligand that participates in CL-11 binding and subsequent complement activation. In this article, we will discuss our hypothesis regarding the role of CL-11 as an integral tissue-based pattern recognition molecule which we postulate has a significant contributory role in complement-mediated ischaemic injury.

Complement in the Initiation and Evolution of Rheumatoid Arthritis.

The complement system is a major component of the immune system and plays a central role in many protective immune processes, including circulating immune complex processing and clearance, recognition of foreign antigens, modulation of humoral and cellular immunity, removal of apoptotic and dead cells, and engagement of injury resolving and tissue regeneration processes. In stark contrast to these beneficial roles, however, inadequately controlled complement activation underlies the pathogenesis of human inflammatory and autoimmune diseases, including rheumatoid arthritis (RA) where the cartilage, bone, and synovium are targeted. Recent studies of this disease have demonstrated that the autoimmune response evolves over time in an asymptomatic preclinical phase that is associated with mucosal inflammation. Notably, experimental models of this disease have demonstrated that each of the three major complement activation pathways plays an important role in recognition of injured joint tissue, although the lectin and amplification pathways exhibit particularly impactful roles in the initiation and amplification of damage. Herein, we review the complement system and focus on its multi-factorial role in human patients with RA and experimental murine models. This understanding will be important to the successful integration of the emerging complement therapeutics pipeline into clinical care for patients with RA.

Essential Roles for Mannose-Binding Lectin-Associated Serine Protease-1/3 in the Development of Lupus-Like Glomerulonephritis in MRL/lpr Mice.

The complement system, composed of the three activation pathways, has both protective and pathogenic roles in the development of systemic lupus erythematosus (or lupus), a prototypic autoimmune disease. The classical pathway contributes to the clearance of immune complexes (ICs) and apoptotic cells, whereas the alternative pathway (AP) exacerbates renal inflammation. The role of the lectin pathway (LP) in lupus has remained largely unknown. Mannose-binding lectin (MBL)-associated serine proteases (MASPs), which are associated with humoral pattern recognition molecules (MBL or ficolins), are the enzymatic constituents of the LP and AP. MASP-1 encoded by the Masp1 gene significantly contributes to the activation of the LP. After the binding of MBL/ficolins to pathogens or self-altered cells, MASP-1 autoactivates first, then activates MASP-2, and both participate in the formation of the LP C3 convertase C4b2a, whereas, MASP-3, the splice variant of the Masp1 gene, is required for the activation of the zymogen of factor D (FD), and finally participates in the formation of the AP C3 convertase C3bBb. To investigate the roles of MASP-1 and MASP-3 in lupus, we generated Masp1 gene knockout lupus-prone MRL/lpr mice (Masp1/3−/− MRL/lpr mice), lacking both MASP-1 and MASP-3, and analyzed their renal disease. As expected, sera from Masp1/3−/− MRL/lpr mice had no or markedly reduced activation of the LP and AP with zymogen forms of complement FD. Compared to their wild-type littermates, the Masp1/3−/− MRL/lpr mice had maintained serum C3 levels, little-to-no albuminuria, as well as significantly reduced glomerular C3 deposition levels and glomerular pathological score. On the other hand, there were no significant differences in the levels of serum anti-dsDNA antibody, circulating ICs, glomerular IgG and MBL/ficolins deposition, renal interstitial pathological score, urea nitrogen, and mortality between the wild-type and Masp1/3−/− MRL/lpr mice. Our data indicate that MASP-1/3 plays essential roles in the development of lupus-like glomerulonephritis in MRL/lpr mice, most likely via activation of the LP and/or AP.

Lupus nephritis: the roles of C1q and C3 in preventing antibody mediated injury

Abstract Lupus nephritis (LN) is a common and serious complication of systemic lupus erythematosus (SLE). While defective clearance of apoptotic cells (AC) and immune complexes (IC) is implicated in LN pathogenesis, the precise way in which different complement components impact kidney protection and injury is unknown. To address this, we created C57BL/6 mice with defective clearance of AC (Mfge8 deficiency) and anti-chromatin antibodies (sle1 interval) that were also deficient in either C1q [C1q Triple mutant (C1qTM)] or C3 (C3TM). Both C1q and C3 TM mice spontaneously developed anti-DNA antibodies and glomerulonephritis associated with glomerular IgG deposits after the age of 6 months. To dissociate the effects of complement on B cells versus effects on the kidney, we examined the effects of antibody mediated kidney injury (nephrotoxic nephritis, NTN) in mice deficient in the clearance of AC with complement deficiency [double knockout (DKO) (Mfge8 C1q or Mfge8 C3) mice]. In NTN, 50% of C1q DKO and 25% of C3 DKO, but no Mfge8 KO, died after NTN induction and the surviving C1q DKO mice developed severe proteinuria. Surprisingly, both spontaneous and NTN-induced nephritis in C1q TM or C1q DKO had strong glomerular C3 and C3d staining, while strong staining for the membrane attack complex (MAC) was observed in C3 TM or C3 DKO mice. These findings indicate that: 1) C1q and C3 independently protect against kidney injury separate from their effects on B cell function 2) In the presence of excess AC and low C1q, antibody mediated kidney injury is associated with C3 activation, presumably by the lectin or alternative pathway and 3) In the presence of excess AC and low C3, antibodies can cause MAC activation by pathways that remain to be determined.

Complement Activation in Inflammatory Skin Diseases.

The complement system is a fundamental part of the innate immune system, playing a crucial role in host defense against various pathogens, such as bacteria, viruses, and fungi. Activation of complement results in production of several molecules mediating chemotaxis, opsonization, and mast cell degranulation, which can contribute to the elimination of pathogenic organisms and inflammation. Furthermore, the complement system also has regulating properties in inflammatory and immune responses. Complement activity in diseases is rather complex and may involve both aberrant expression of complement and genetic deficiencies of complement components or regulators. The skin represents an active immune organ with complex interactions between cellular components and various mediators. Complement involvement has been associated with several skin diseases, such as psoriasis, lupus erythematosus, cutaneous vasculitis, urticaria, and bullous dermatoses. Several triggers including auto-antibodies and micro-organisms can activate complement, while on the other hand complement deficiencies can contribute to impaired immune complex clearance, leading to disease. This review provides an overview of the role of complement in inflammatory skin diseases and discusses complement factors as potential new targets for therapeutic intervention.

TLR7/8 activation in neutrophils impairs immune complex phagocytosis through shedding of FcgRIIA.

Neutrophils play a crucial role in host defense. However, neutrophil activation is also linked to autoimmune diseases such as systemic lupus erythematosus (SLE), where nucleic acid-containing immune complexes (IC) drive inflammation. The role of Toll-like receptor (TLR) signaling in processing of SLE ICs and downstream inflammatory neutrophil effector functions is not known. We observed that TLR7/8 activation leads to a furin-dependent proteolytic cleavage of the N-terminal part of FcgRIIA, shifting neutrophils away from phagocytosis of ICs toward the programmed form of necrosis, NETosis. TLR7/8-activated neutrophils promoted cleavage of FcgRIIA on plasmacytoid dendritic cells and monocytes, resulting in impaired overall clearance of ICs and increased complement C5a generation. Importantly, ex vivo derived activated neutrophils from SLE patients demonstrated a similar cleavage of FcgRIIA that was correlated with markers of disease activity, as well as complement activation. Therapeutic approaches aimed at blocking TLR7/8 activation would be predicted to increase phagocytosis of circulating ICs, while disarming their inflammatory potential.

Rheumatoid factors do not predict cardiovascular disease and mortality in the general population in the Busselton Health Survey

BackgroundRheumatoid Factors (RF) are antibodies directed against the Fc portion of IgG and are involved in clearance of immune complexes. While RF can develop in a wide range of conditions, higher RF levels indicate a greater risk for a severe disease course in Rheumatoid Arthritis (RA) patients including cardiovascular complications and premature death. We investigated whether RF also constitute a risk factor for these outcomes in the general population.MethodsWe included 2,323 participants (46% male, mean age 50 years) free of CVD at baseline in 1972. RF positivity was defined as a score of ≥2 by latex agglutination (scale 0–5). All outcomes during 42-year follow-up were obtained from state-wide registries. The predictive value of RF for coronary heart disease, all cardiovascular disease and all-cause mortality was estimated by adjusted hazard ratios (HR) from Cox regression models.ResultsAfter adjustment for standard risk factors, RF positivity was not predictive of future CHD (HR 1.05, p = 0.61), CVD (HR 1,04, p = 0.63) or mortality (HR 1.03, p = 0.70) in the full CVD-free cohort. In an interaction model, RF in 41 out of 355 participants with an RA history was not predictive of CHD (HR 0.92, p = 0.77) or CVD events (HR 1.15, p = 0.51), but there was a borderline significant association with overall mortality (HR 1.41, CI 0.97–2.04, p = 0.07).ConclusionsRF detected by Latex agglutination do not independently predict future CHD, CVD or death in the general population. However, the presence of RF in the context of a history of RA is associated with a moderate, borderline significant increase in the long term adjusted risk for all-cause mortality.

Autoantibodies against complement components in systemic lupus erythematosus - role in the pathogenesis and clinical manifestations.

Many complement structures and a number of additional factors, i.e. autoantibodies, receptors, hormones and cytokines, are implicated in the complex pathogenesis of systemic lupus erythematosus. Genetic defects in the complement as well as functional deficiency due to antibodies against its components lead to different pathological conditions, usually clinically presented. Among them hypocomplementemic urticarial vasculitis, different types of glomerulonephritis as dense deposit disease, IgA nephropathy, atypical haemolytic uremic syndrome and lupus nephritis are very common. These antibodies cause conformational changes leading to pathological activation or inhibition of complement with organ damage and/or limited capacity of the immune system to clear immune complexes and apoptotic debris. Finally, we summarize the role of complement antibodies in the pathogenesis of systemic lupus erythematosus and discuss the mechanism of some related clinical conditions such as infections, thyroiditis, thrombosis, acquired von Willebrand disease, etc.

Targeted Fcγ Receptor (FcγR)-mediated Clearance by a Biparatopic Bispecific Antibody

Soluble ligands have commonly been targeted by antibody therapeutics for cancers and other diseases. Although monoclonal antibodies targeting such ligands can block their interactions with their cognate receptors, they can also significantly increase the half-life of their ligands by FcRn-mediated antibody recycling, thereby evading ligand renal clearance and requiring increasingly high antibody doses to neutralize the increasing pool of target. To overcome this issue, we generated a bispecific/biparatopic antibody (BiSAb) that targets two different epitopes on IL-6 to block IL-6-mediated signaling. The BiSAb formed large immune complexes with IL-6 that can bind Fcγ receptors on phagocytic cells and are rapidly internalized. In addition, rapid clearance of the BiSAb·IL-6 complex was observed in mice while the parental antibodies prolonged the serum half-life of IL-6. Intravital imaging of the liver in mice confirmed that the rapid clearance of these large immune complexes was associated with Fcγ receptor-dependent binding to Kupffer cells in the liver. The approach described here provides a general strategy for therapeutic antibodies with the ability to not only neutralize but also actively drive clearance of their soluble antigens.

Mannose-binding lectin (MBL) codon 54 (rs1800450) polymorphism predisposes towards medium vessel vasculitis in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multiple etiological factors. Mannose-binding lectin (MBL) plays a key role in innate immunity by activating antibody-independent lectin complement pathway, opsonisation, phagocytosis, and immune complex (IC) clearance. Genetic polymorphisms in the promoter and coding regions of MBL gene affect the circulatory levels and biological activity of MBL. Defects in MBL can lead to defective opsonisation and, hence, hamper clearance of apoptotic debris, the persistence of which can drive autoantibody formation in lupus. The exon1 variants at codon 52, 54, and 57 have been reported to augment the risk of SLE in different ethnic populations. Three hundred South Indian Tamil patients with SLE and 460 age-, sex-, and ethnicity-matched controls were genotyped for three polymorphisms at codon 52, 54, and 57 in exon1 of MBL gene by Taqman real-time PCR. The three polymorphisms in exon1 of MBL were observed not to confer risk of developing SLE. However, MBL codon 54 rs1800450 polymorphism was associated with the development of medium vessel vasculitis and gangrene (OR-2.29, CI 95% 1.08-4.83, p=0.02), whereas, the ancestral allele G conferred protection (OR-0.44, CI 95% 0.21-0.93, p=0.02). Genetic variants in the exon1 of MBL gene per se are not risk factors for SLE in South Indian Tamils. However, the association of codon 54 (rs1800450) with medium vessel vasculitis suggests that it may be a genetic modifier of clinical phenotype in SLE.

Anti-C1q Antibody is Associated with Renal and Cutaneous Manifestations in Asian Indian Patients with Systemic Lupus Erythematosus.

C1q play an important role in clearance of immune complexes and apoptotic cell debris. Impaired clearance leads to exposure of C1 native antigen and development of anti-C1q antibody formation. Anti-C1q antibody is well studied in Systemic Lupus Erythematosus (SLE). Significance of anti-C1q Ab in Indian SLE patients and their clinical manifestations is not clear. The aim of this study was to investigate associations between anti-C1q antibody and clinical as well as serological markers of SLE. Retrospective study of SLE patients fulfilling either American College of Rheumatology (ACR) 1990 or Systemic Lupus International Collaborating Clinics (SLICC) 2012 classification criteria were recruited from inpatients and outpatients services of the Clinical immunology and Rheumatology Department, Christian Medical College at Vellore, India between March 2013 and January 2015. Anti-C1q antibody was assayed by ELISA (Demeditec Diagnostics GmbH, Germany). Logistic regression analysis was performed to find the association of anti-C1q antibodies with serological and clinical parameters in SLE including Lupus Nephritis (LN). Sixty nine patients (54.76%) out of 126 SLE patients had LN. Anti-C1q levels were higher in patients with LN as compared to those without (p<0.05). Anti-C1q antibody was also significantly associated with positive C1q immunofluorescence staining in renal biopsy specimens (p<0.05). Overall, renal Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) {OR 1.35 (1.08-1.69)}, low C4 {OR 3.11 (1.04-9.26)} and mucocutaneous manifestation {OR 4.72 (1.38-16.05)} were independently associated with anti-C1q levels in serum. Renal SLEDAI, low C4 and mucocutaneous manifestations were independently associated with raised anti C1q antibody in SLE patients.

Human C1q Induces Apoptosis in an Ovarian Cancer Cell Line via Tumor Necrosis Factor Pathway.

Complement protein C1q is the first recognition subcomponent of the complement classical pathway that plays a vital role in the clearance of immune complexes, pathogens, and apoptotic cells. C1q also has a homeostatic role involving immune and non-immune cells; these functions not necessarily involve complement activation. Recently, C1q has been shown to be expressed locally in the microenvironment of a range of human malignant tumors, where it can promote cancer cell adhesion, migration, and proliferation, without involving complement activation. C1q has been shown to be present in the ascitic fluid formed during ovarian cancers. In this study, we have examined the effects of human C1q and its globular domain on an ovarian cancer cell line, SKOV3. We show that C1q and the recombinant globular head modules induce apoptosis in SKOV3 cells in a time-dependent manner. C1q expression was not detectable in the SKOV3 cells. Exogenous treatment with C1q and globular head modules at the concentration of 10 µg/ml induced apoptosis in approximately 55% cells, as revealed by immunofluorescence microscopy and FACS. The qPCR and caspase analysis suggested that C1q and globular head modules activated tumor necrosis factor (TNF)-α and upregulated Fas. The genes of mammalian target of rapamycin (mTOR), RICTOR, and RAPTOR survival pathways, which are often overexpressed in majority of the cancers, were significantly downregulated within few hours of the treatment of SKOV3 cells with C1q and globular head modules. In conclusion, C1q, via its globular domain, induced apoptosis in an ovarian cancer cell line SKOV3 via TNF-α induced apoptosis pathway involving upregulation of Bax and Fas. This study highlights a potentially protective role of C1q in certain cancers.

Complement receptor 1 gene polymorphisms are associated with cardiovascular risk

Background and aimsInflammation plays a key role in atherosclerosis. The complement system is involved in atherogenesis, and the complement receptor 1 (CR1) plays a role facilitating the clearance of immune complexes from the circulation. Limited evidence suggests that CR1 may be involved in cardiovascular disease. We investigated the relationship between CR1 gene polymorphisms and cardiovascular risk. MethodsSingle nucleotide polymorphisms (SNPs) within the CR1 region (n = 73) on chromosome 1 were assessed in 5244 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and followed for a mean of 3.2 years. Logistic regression, adjusted for gender, age, country and use of pravastatin, was used to assess the association between the SNPs and cardiovascular disease. ResultsAll 73 SNPs within the genomic region of the CR1 gene on chromosome 1 were extracted. In this region, strong LD was present leading to the occurrence of two haploblocks. Twelve of the 73 investigated CR1 SNPs were significantly associated with the risk of fatal or nonfatal myocardial infarction (all p < 0.05). Moreover, most of the associated SNPs were also associated with levels of serum C-reactive protein (CRP). The global p-value for the tail strength method to control for multiple testing was 0.0489, implying that the null hypothesis of no associated SNPs can be rejected. ConclusionsThese data indicate that genetic variation within the CR1 gene is associated with inflammation and the risk of incident coronary artery disease.

CD16b: Primary Structure of Human Neutrophil Antigen Epitopes and Their Functional Consequences

Neutrophil specific Fcg receptor IIIb (CD16b) is a glycosylphosphatidylinositol-anchored low-affinity glycoprotein that plays a significant role in phagocytosis and the clearance of immune complexes. CD16b has numerous polymorphic variants; the most relevant variants are associated with human neutrophil antigens (HNA) -1a, -1b, and -1c. HNA-1a and HNA-1b differ in four amino acids (aa) (positions 36, 65, 82 and 106). One additional aa mutation on HNA-1b at position 78 results in HNA-1c.Immunization against CD16b variants can lead to the production of alloantibodies (aabs) responsible for neonatal alloimmune neutropenia (NIN), autoimmune neutropenia of infancy (AIN) and transfusion-related acute lung injury (TRALI). The exact contribution of five aa mutations for the formation of HNA-1a, -1b and -1c and function of CD16b is currently unknown.In this study, permutation of each polymorphic aa from wild-type CD16b cDNA constructs was performed and stably expressed on HEK293 cells. In total, 3 cell lines expressing wild-type (HNA-1a, -1b and -1c) and 18 cell lines expressing mutant variants were produced; 14 derived from HNA-1a or HNA-1b (panel 1) and 4 derived from HNA-1c (panel 2). When panel 1 was tested with well-defined aabs by antigen capture assay, 4 cell lines reacted with anti-HNA-1a only, 4 with anti-HNA-1b only, 4 with both aabs, and 4 did not react with both aabs. These results indicate that aa36 and aa65 are responsible for the formation of the HNA-1a and HPA-1b epitope(s), respectively. Analysis of panel 2 showed that 2/4 mutant variants reacted with anti-HNA-1c exclusively, suggesting that the HNA-1c epitope is formed by Ala78Asp irrespective of the other polymorphic aa.To analyze the binding affinity of CD16b variants, adhesion assay onto immobilized IgG was performed. In comparison to HNA-1a, HNA-1b cells bound slightly weaker to IgG (p<0.002). In contrast, HNA-1c cells interacted significantly stronger with IgG in comparison to both, HNA-1a and -1b cells (p<0.0001). Similar results were obtained with HNA-1a, -1b and -1c recombinant proteins by direct protein-binding analysis (solid phase ELISA and Surface Plasmon Resonance). Interestingly, all mutant variants carrying HNA-1c bound also stronger to IgG than HNA-1a and -1b transfected cells. Similar results were observed with HNA-1c phenotyped neutrophils.In conclusion, although HNA-1a and HNA-1b differ in four aa positions, only two (aa36, aa65) are necessary for the complete formation of the respective epitopes. In contrast, the HNA-1c epitope is created by only one aa mutation (Ala78Asp). Furthermore, our results show that HNA-1c exhibits higher affinity to IgG compared to HNA-1a and HNA-1b forms. Accordingly, the Ala78Asp mutation is not only responsible for epitope formation, but is also involved in the regulation of CD16 affinity. Characterization of HNA-1 epitopes by tailored recombinant tools will help us to improve our diagnostic work-up in patients with suspected NIN, AIN and TRALI and our understanding on the role of CD16 polymorphism in other diseases such as, immune complex-mediated disorders. DisclosuresNo relevant conflicts of interest to declare.

New insights into the immunopathogenesis of systemic lupus erythematosus.

The aetiology of systemic lupus erythematosus (SLE) is multifactorial, and includes contributions from the environment, stochastic factors, and genetic susceptibility. Great gains have been made in understanding SLE through the use of genetic variant identification, mouse models, gene expression studies, and epigenetic analyses. Collectively, these studies support the concept that defective clearance of immune complexes and biological waste (such as apoptotic cells), neutrophil extracellular traps, nucleic acid sensing, lymphocyte signalling, and interferon production pathways are all central to loss of tolerance and tissue damage. Increased understanding of the pathogenesis of SLE is driving a renewed interest in targeted therapy, and researchers are now on the verge of developing targeted immunotherapy directed at treating either specific organ system involvement or specific subsets of patients with SLE. Accordingly, this Review places these insights within the context of our current understanding of the pathogenesis of SLE and highlights pathways that are ripe for therapeutic targeting.

CR1 exon variants are associated with lowered CR1 expression and increased susceptibility to SLE in a Plasmodium falciparum endemic population

BackgroundComplement receptor 1 (CR1) plays an important role in immune complex clearance by opsonisation and possibly protects subjects from development of autoantibodies. Lower CR1 expression has been associated with susceptibility...

Systemic Lupus Erythematosus and Deficiencies of Early Components of the Complement Classical Pathway

The complement system plays an important role in the innate and acquired immune response against pathogens. It consists of more than 30 proteins found in soluble form or attached to cell membranes. Most complement proteins circulate in inactive forms and can be sequentially activated by the classical, alternative, or lectin pathways. Biological functions, such as opsonization, removal of apoptotic cells, adjuvant function, activation of B lymphocytes, degranulation of mast cells and basophils, and solubilization and clearance of immune complex and cell lysis, are dependent on complement activation. Although the activation of the complement system is important to avoid infections, it also can contribute to the inflammatory response triggered by immune complex deposition in tissues in autoimmune diseases. Paradoxically, the deficiency of early complement proteins from the classical pathway (CP) is strongly associated with development of systemic lupus erythematous (SLE) – mainly C1q deficiency (93%) and C4 deficiency (75%). The aim of this review is to focus on the deficiencies of early components of the CP (C1q, C1r, C1s, C4, and C2) proteins in SLE patients.

Clearance Deficiency and Cell Death Pathways: A Model for the Pathogenesis of SLE.

Alterations of cell death pathways, including apoptosis and the neutrophil specific kind of death called NETosis, can represent a potential source of autoantigens. Defects in the clearance of apoptotic cells may be responsible for the initiation of systemic autoimmunity in several chronic inflammatory diseases, including systemic lupus erythematosus (SLE). Autoantigens are released mainly from secondary necrotic cells because of a defective clearance of apoptotic cells or an inefficient degradation of DNA-containing neutrophil extracellular traps (NETs). These modified autoantigens are presented by follicular dendritic cells to autoreactive B cells in germinal centers of secondary lymphoid organs. This results in the loss of self-tolerance and production of autoantibodies, a unifying feature of SLE. Immune complexes (IC) are formed from autoantibodies bound to uncleared cellular debris in blood or tissues. Clearance of IC by blood phagocytes, macrophages, and dendritic cells leads to proinflammatory cytokine secretion. In particular, plasmacytoid dendritic cells produce high amounts of interferon-α upon IC uptake, thereby contributing to the interferon signature of patients with SLE. The clearance of antinuclear IC via Fc-gamma receptors is considered a central event in amplifying inflammatory immune responses in SLE. Along with this, the accumulation of cell remnants represents an initiating event of the etiology, while the subsequent generation of autoantibodies against nuclear antigens (including NETs) results in the perpetuation of inflammation and tissue damage in patients with SLE. Here, we discuss the implications of defective clearance of apoptotic cells and NETs in the development of clinical manifestations in SLE.

Genetic Variants That Are Associated with Neuropsychiatric Systemic Lupus Erythematosus.

While genetic risks have been implicated in systemic lupus erythematosus (SLE), the involvement of various genotypes in neuropsychiatric SLE (NPSLE) remains uncertain. The present metaanalysis aimed to combine data from different studies and evaluate the association between each genotype and the risk of developing NPSLE. Studies were searched and retrieved from online databases (PubMed, EMBASE, BIOSIS, and ScienceDirect). Case-control studies were chosen if they reported genotype frequencies of the γ Fc region (FCγR) receptors II-A, III-A, and III-B; tumor necrosis factor-α (TNF-α); mannan-binding lectin (MBL); integrin alpha M (ITGAM); interleukin (IL) 1, IL-1β, and IL-6; IL-10 promoter; and vitamin D genes. The OR were used to assess the strength of this association between patients with NPSLE and SLE. A total of 33 studies were considered in this metaanalysis. The results suggest that these genotypes demonstrated a significant association with NPSLE: the homozygous FCγR IIIa 158 FF genotype (OR 1.89, p = 0.03 for FF vs VV + FV), heterozygous FCγR IIIb NA1/2 genotype (OR 2.14, p = 0.03 for NA1/2 vs NA1/1; OR 1.81, p = 0.04 for NA1/2 vs NA1/1 + NA2/2), and homozygous ITGAM rs1143679 HH genotype (OR 3.39, p = 0.04 for HH vs RH; OR 3.11, p = 0.048 for HH vs RR + RH). Polymorphisms of the TNF-α, MBL2, IL-1, IL-1β, IL-6, IL-10 promoter, and vitamin D receptor genes did not show a statistically significant association with the risk of developing NPSLE (p > 0.05). This metaanalysis indicates that polymorphisms in the pathways of immune complex clearance, such as the FcγRIIIa, FcγRIIIb, and ITGAM genotypes, are potential susceptibility genes for NPSLE.