Lupus nephritis (LN) is one of the most severe complications of Systemic Lupus Erythematous (SLE), affecting a significant proportion of lupus patients, 50% of adults, and up to 60-70% of children within 5 years of diagnosis (1). The clinical presentation of LN is extremely variable, ranging from forms characterized by normal renal function with isolated urinary abnormalities or with nephrotic syndrome to others with acute renal dysfunction such as cases of nephritic syndromes or the rarer forms of rapidly progressive renal failure. Although it is intuitive that the more severe the clinical presentation, the worse the prognosis of the patient is, in many cases, there isn’t a correspondence between the severity of the clinical presentation and that of the histological lesions at kidney biopsy (2). Consequently, to assess the prognosis and decide the treatment, a kidney biopsy is mandatory at LN diagnosis. Based on the recent histological classification (3, 4), glomerular lesions can be classified into six classes, being class III and IV the most frequently diagnosed, and those associated with a worse prognosis if not adequately and timely treated. In addition to the histological class, an evaluation of the active inflammatory lesions, responsive to therapy, and the chronic irreversible lesions, the so-called activity and chronicity indexes, is recommended. LN commonly exhibits a fluctuating course characterized by periods of remission and exacerbation. There are two different types of renal flares; nephritic flares and proteinuric flares (5). Nephritic flares are defined by worsening renal function and active urinary sediment with or without an increase in proteinuria, while protenuric flares by an increase in proteinuria with stable renal function and with or without active urinary sediment. The rapid reduction of complement levels and/or a significant rise in anti-DNA antibody title can be the prodromal of a renal or extrarenal SLE reactivation, and these situations require a stricter monitoring of the patients. Reactivation of the urinary sediment with the reappearance of dysmorphic red blood cells or erythrocyte casts may be a warning of kidney reactivation, but, even in these cases, we do not recommend to increase immediately the therapy to avoid an increase in side effects, but only close observation. Despite significant improvement in renal prognosis, LN is still associated with a high rate of morbidity and mortality, leading to end-stage kidney disease (ESKD) in 5-10% of patients within 10 years of diagnosis (6, 7). The pathogenesis of LN is multifactorial although not completely understood. It involves dysregulation of the immune system, deposition of immune complexes, inflammation, and tissue damage. A main issue for the clinician involved in the management of LN is that LN course often exhibits periods of quiescence alternating with flares of activity. It is not always easy to detect the presence of a flare in patients with LN (2). Even in these cases, kidney biopsy remains the cornerstone for a correct diagnosis, prognosis and treatment of LN (8). Patients who experience multiple episodes of active nephritis, particularly those characterized by deteriorating kidney function, are at an increased risk of progressing to ESKD (9, 10). Repeating biopsy in patients with multiple flares can be difficult and poorly accepted by reluctant patients. On the other hand, rapid diagnosis and prompt treatment of renal flares are crucial in determining LN prognosis (11, 12). A noninvasive tool that could help monitor LN activity in the long term would be of utmost importance. In the last decades, there has been a growing interest in noninvasive immunological biomarkers capable of measuring disease activity, predicting flares and relapses, and influencing outcomes (13). In the realm of immunological biomarkers, anti-C1q antibodies (anti-C1qAb) have emerged as a compelling area of research interest, raising intriguing questions about their role in the pathogenesis and clinical course of LN (14–21).

In this narrative review, the intricate relationship between anti-C1qAb and SLE, with a focus on LN, will be reviewed and the potential significance of anti-C1qAb as diagnostic and prognostic biomarkers of disease activity will be outlined.

We conducted a comprehensive literature search from 1985 until December 2023, using the following terms: C1q, anti-C1q antibodies, autoimmune disease, systemic lupus erythematosus (SLE), lupus nephritis, flares, and immune biomarkers. Our search was performed in databases including PubMed, Medline, and Embase, as well as through the reference lists of retrieved articles. Additionally, we manually searched cited papers to identify additional studies relevant to the topic. The quality of the studies was assessed based on criteria including the number of participants included (more than 20) and the importance of the published findings.

Anti-C1q antibodies are autoantibodies directed against C1q, the first component of the complement system. Complement activation has long been known to have a role in the pathogenesis of SLE and LN (22, 23). The classical pathway of the complement system is activated when IgM and IgG immune complexes bind to the C1 complex. The C1 complex is composed of C1q and two serine proteases, C1r and C1s ( Figure 1 ). C1q is a large highly cationic glycoprotein with a molecular weight of around 410 kD and it is formed by six copies of three polypeptide chains (A, B and C) (24). After immune complex binding, the C1q conformation changes and subsequently activates C1r and C1s, with cleavage of C4 and C2, leading the formation of C3 convertase (C4b2a), then C5 convertase (C4b2a3b) and at the end the membrane attack complex with the involvement of C6-C9 (25–27) ( Figure 1 ). The primary physiological role of C1q is its involvement in the clearance of immune complexes and apoptotic bodies, acting as a bridging molecule. Disruption of these processes may contribute to the development of autoimmune diseases. In the presence of impaired clearance of apoptotic cells, C1q bound to the surface of apoptotic cells may become antigenic, similar to nuclear components that are typically concealed from the immune system. Prolonged exposure of novel epitopes to the immune system may eventually lead to an autoimmune response against C1q, resulting in the formation of anti-C1q antibodies (28, 29). Notably, individuals with genetic defects in C1q are at increased risk of developing SLE, and experimental studies in mice have demonstrated an accumulation of apoptotic bodies in their kidneys (30, 31). In rodents, infusion of anti-C1qA has been associated with the formation and deposition of immune complexes in glomeruli, as well as glomerulonephritis (32). However, whether anti-C1qAb can directly activate the complement pathway in humans remains debated (33, 34). Anti-C1qAb are found in various types of infections and autoimmune diseases, including hypocomplementemic urticarial vasculitis, SLE, rheumatoid vasculitis, and Sjogren’s syndrome, but also in 3-5% of healthy individuals. High titers of anti-C1q antibodies are particularly prevalent in patients with hypocomplementemic urticarial vasculitis syndrome, reaching 100% prevalence (35–37). Anti-C1q antibodies are typically detected using an ELISA test with a high salt concentration to prevent immune complex binding (35, 38). Although several assays are available for detecting anti-C1q antibodies, none has received universal approval from the Food and Drug Administration due to a lack of systematic studies comparing their performance (39), which remains the primary obstacle to incorporating anti-C1qAb into the criteria for clinical management of SLE. Most anti-C1q antibodies belong to the IgG isotype, with a predominance of the IgG1 and IgG2 subclasses. C1q consists of an N-terminal collagen-like region (CLR) and six globular head regions (GR), with epitopes predominantly located on the CLR (14). It is suggested that anti-C1qAb primarily bind to a neoepitope in the CLR of C1q, exposed upon activation of the C1 complex and removal of C1r and C1s. Recent research indicates that anti-C1q antibodies bind specifically to solid-phase C1q rather than fluid-phase C1q, potentially leading to the exposure of cryptic epitopes that enhance Fc-receptor-mediated effector functions and contribute to autoimmune disease (34).

The correlation between antibodies against specific C1q epitopes and SLE or LN remains debated due to conflicting data (40). A large explorative study suggests that antibodies to different C1q peptide epitopes correlate with distinct disease manifestations, with antibodies against the N-terminal C1q A-chain potentially distinguishing SLE patients from healthy controls (41). Moreover, the identification of peptide A08 as a major linear epitope of C1q in SLE, along with antibodies against epitope A08 demonstrating higher sensitivity and specificity compared to conventional anti-C1qAb, has been reported (42). These findings were corroborated by Pang et al., who demonstrated that anti-A08 IgG antibodies may better differentiate LN activity (40). Consequently, a protocol for quantifying anti-C1qAb using a more sensitive assay for their detection and specific for active LN has been recently published (43).

While hereditary C1q deficiency is uncommon among SLE patients, multiple lines of evidence underscore the significance of C1q in the inflammatory mechanisms associated with SLE. Firstly, SLE patients often display low levels of the complement pathway, including C1q. Moreover, C1q deposition is a distinctive histological finding in kidney biopsies of LN patients, and autoantibodies against C1q can be detected in the serum of patients with LN (44, 45). The presence of anti-C1q antibodies in the serum of individuals with SLE was initially identified in 1984, with a reported prevalence of 34-47% (36). In a subsequent study, anti-C1q antibodies were isolated from the glomerular basement membrane of proliferative forms of LN patients, suggesting deposition through binding to deposited C1q (46). Subsequent studies confirmed a prevalence of high anti-C1q antibodies in the serum of SLE patients ranging from 30 to 51% (16, 17, 20). Some authors reported a correlation between high levels of anti-C1q and active SLE (47). A recent Egyptian study of 70 patients with SLE confirmed that anti-C1q antibodies were present in 37% of patients with SLE and were associated with higher SLEDAI and proteinuria (48). In a large Chinese cohort of 260 SLE patients, a strong correlation with SLEDAI and anti-C1q antibodies was observed, particularly in patients with anti-A08 antibodies (40). Akhter et al., testing the sera of 47 SLE patients for the presence of anti-C1q, anti-chromatin, anti-dsDNA, anti-ribosomal P, MCP-1, VCAM, ICAM, and complement fractions, found that anti-C1q antibodies had the best association with parameters of SLE disease activity, particularly with the Physician’s Global Assessment and with modified SELENA-SLEDAI, and the highest association with proteinuria (49).

In the context of SLE, over the last two decades, studies on anti-C1q antibodies increasingly suggest that high titers of anti-C1q antibodies can predict the onset of LN. Based on these results, it was suggested that testing and monitoring anti-C1q antibody levels could be helpful as a non-invasive biomarker for kidney disease in SLE patients (28, 50).

Limited studies are available about the role of anti-C1qAb in children with SLE, and the results are controversial. Ravelli et al. studied 29 patients with SLE and found anti-C1qAb in 59% of patients but without correlation with clinical manifestations, including renal involvement (72). Instead, Kozyro et al., in a large prospective study on 112 children with different histological forms of glomerular diseases, demonstrated an association between high anti-C1qAb levels and active LN. Seven out of twelve LN patients had anti-C1qAb, and six of them had active renal disease at the time of the serum sampling compared to only one of the five anti-C1q-negative children (73). A Chinese study confirmed the potential diagnostic value of anti-C1qAb also for children with LN. In this study, both C1q and anti-C1qAb were tested in 90 SLE patients, of whom 43 had active and 47 inactive SLE. C1q levels were significantly lower, and anti-C1qAb were significantly higher in SLE patients compared to healthy children and children with other rheumatic diseases. The sensitivity and specificity of anti-C1qAb to identify SLE pediatric patients were 80% and 92.1%, respectively, compared to a sensitivity and specificity of 63.3% and 94.7%, respectively, for anti-dsDNA antibodies. Anti-C1q titers were positively correlated with SLEDAI. Ninety-three percent of SLE patients who had high anti-C1qAb levels also showed kidney damage. In conclusion, reduced C1q and increased anti-C1qAb significantly correlated with LN in children and may have diagnostic value for monitoring LN in children (74). More recently, in a retrospective study including 27 SLE pediatric patients (19 with a history of LN), anti-C1qAb were tested during active and inactive SLE and compared with Farr anti-dsDNA antibody titers. Thirty-one flares (of which 18 were renal flares) were diagnosed at the start of the study or during the 55.5 months of observation. A significantly better correlation was demonstrated between anti-C1qAb and SLEDAI than with anti-dsDNA antibody. Anti-C1q antibodies were positive and at high titers during active renal flares, showing a sensitivity of 94% and a specificity of 73%, compared to the same sensitivity but a lower specificity (19%) for anti-dsDNA antibody. However, the positivity of Anti-C1q at diagnosis did not predict renal or extra-renal flares (75). In a cohort of 192 Chinese children with biopsy-proven LN, anti-C1qAb were tested among several other clinical and immunological tests to identify the predictors of the presence of glomerular microthrombi at kidney biopsy. Anti-C1qAb were present in 67.5% of patients. In multivariate analysis, anti-C1qAb, together with hemoglobin and eGFR at kidney biopsy, were identified as independent risk factors for the presence of glomerular microthrombi. Moreover, the level of anti-C1qAb was directly correlated with the activity index at kidney biopsy and with class III and IV LN (76).

A rapid diagnosis of a renal flare remains a major challenge to preserve kidney function in the long-term in LN. Although there is no universally accepted test for the determination and quantification of anti-C1qAb, the wealth of data available points towards the usefulness of monitoring these antibodies in the management of patients with LN. The presence of these antibodies in SLE seems to be strongly associated with kidney involvement in its active phases and in proliferative histological forms with high activity index. These characteristics make anti-C1qAb a useful noninvasive biomarker to be used alone or associated with the classical serum SLE biomarkers such as anti-dsDNA Ab and C3 and C4 serum fractions, in identifying LN activity. Serial anti-C1qAb measurements during follow-up are needed to establish the role of these antibodies in predicting renal flares ( Figure 2 ). An effort of all the components of the scientific community (clinicians, laboratory physicians) would be desirable to develop and evaluate in clinical practice a reliable and reproducible test for the detection of anti-C1qAb. Moreover, due to the low incidence of SLE in the general population, controlled and multicenter trials are needed to establish the benefits of anti-C1qAb for prompt detection and management of lupus flares. Waiting for these data, we recommend looking for the presence of anti-C1qAb in all patients with SLE, at the diagnosis and at the appearance of signs of kidney damage, such as proteinuria, hematuria, or an increase in serum creatinine, anti-C1q should be monitored. In patients with LN, the titers of anti-C1qAb should monitored regularly during the follow-up. This may help the clinician in identifying/confirming the diagnosis of activity or remission of LN.

MC: Writing – original draft, Writing – review & editing. GM: Conceptualization, Writing – original draft, Writing – review & editing. EC: Writing – review & editing. MS: Writing – review & editing. FG: Writing – review & editing. CP: Supervision, Writing – review & editing.