By Clarice Tse
Immunoglobulin A nephropathy (IgAN), also known as Berger’s disease, is the most common glomerulonephritis worldwide and a vital cause of renal failure, especially in southeast asian countries. Characterised by the deposition of galactose-deficient Immunoglobulin A1 (IgA1) on the kidney glomerulus, IgAN was found to be in association with a life expectancy reduction of 6-10 years.1,2 Over 40% of patients develop end stage renal disease (ESRD) within 20 years after diagnostic biopsy while 20% of patients preserve their renal function.3 The cause of the huge variance in clinical outcomes among IgAN patients is still a mystery due to our incomplete understanding of IgAN pathogenesis and the correlation between the spectrum of disease severity and IgA deposition. Therefore, identifying the suitability of immunosuppression therapy for patients, and developing novel therapeutic strategies remains challenging. Recent research attempted to unravel the complicated IgAN pathogenic mechanism, with findings that suggest complement proteins as a potential target for therapeutic treatments of IgAN.
Immunoglobulin A (IgA) is an antibody produced in two major forms: the dimeric mucosal secretory IgA (sIgA) and monomeric serum IgA. There are also two subclasses, namely IgA1 and IgA2 which structurally differ at the hinge region.4 Monomeric IgA can also be joined together at the Fc region by the J chain polypeptide to form polymeric IgA (pIgA). The functions of IgA include downregulating pro-inflammatory responses, neutralizing intracellular pathogens, preventing the invasion of pathogens and commensal bacteria across the mucosal epithelial layer while simultaneously regulating homeostasis and symbiotic relationship with commensal bacteria.4 These widely known non-inflammatory functions of IgA caused scientists to perceive IgA as a neutralising body with a weak ability to activate the complement system. This is a major activator of inflammation that labels the membrane of pathogens for destruction and directs the killing of targeted cells. Even so, the systemic and renal complement activation in IgAN patients is well documented, indicating that IgA in patients might be involved in complement activation.
There are three pathways of complement activation, of which alternative pathway (AP) generally activates spontaneously through the hydrolysis of a component called C3. This exposes a thioester domain binding site for activated factor B to bind on, leading to the formation of C3(H2O)Bb convertase which cleaves C3 into its activated form, C3b, which then binds onto neighbouring surfaces covalently. Factor B in its activated form, Bb, associates with C3b in the presence of properdin and factor D to form alternative pathway, C3 convertase- C3bBb, which then cleaves even more C3 into its activated form, thus creating an amplification of C3 activity. As any C3 from any complement initiating pathway can be recruited into the alternative pathway amplification loop and be cleaved into C3bBb, alternative pathway is responsible for 80% of complement activation.5
Components of complement activation have been widely detected in IgAN renal biopsies with over 90% of patients having complement component C3 co-depositing with IgA on the kidney mesangium. Moreover, 75 to 100% of patients halved co-deposition of the complement activation positive regulator, properdin, which stabilises the complement alternative pathway C3 convertase (C3bBb). 6 The alternative pathway negative regulator, factor H (FH), which plays a role in the cleavage of C3b, was also found to be co-deposited on 30%-90% of patients and several studies of IgAN patients discovered the elevation of FH plasma levels.3 Moreover, higher levels of the cleavage fragments of C3, such as iC3b and C3d, were detected in the circulation of patients.7 The elevated levels of C3 breakdown products were associated with severity of the histologic renal lesions in one study and IgAN progression in another.8,9 Furthermore, immunostaining showed evidence of C3 breakdown products co-depositing with IgA on the glomerular mesangial and capillary areas in patients and this was shown to be greater in progressive IgAN samples than healthy samples.10 Together, these results suggest the contribution of alternative pathway activity in the histologic injury and disease severity of IgAN patients.
Recent genetic, serologic and histologic analysis of FH, Factor H Related 1 (FHR1) and Factor H Related 5 (FHR5) levels highlight the significance of alternative pathway dysregulation to IgAN, supporting the theory that a defect in alternative pathway contributes to the pathogenesis of IgAN. Here, FH acts a substrate to Factor I which inactivates C3b through cleavage of it into proteolytic fragments and also enhances the dissociation of the alternative pathway C3 convertase. Meanwhile, Factor H Related proteins (FHR) were found to be antagonists of FH by being structurally similar to FH, allowing it to bind to C3, but not the ability to inactivate it. Therefore, the FHR family can competitively attenuate FH dependent complement regulation through this process, termed as FH deregulation.3
Genetic studies have identified alternative pathway genetic variants that confer protection from IgAN. An allele in the FH gene locus has been discovered to associate with protection from IgAN by tagging the deletion polymorphism of the FHR1 and FHR3, reducing the risk of developing IgAN by 26% and lowering mesangial deposition of C3. This variant may contribute to the differences in complement activity and disease severity in patients. It is also suggested that the protective effects of delCFHR3-R1 could be due to reduced competition between FHR and FH binding in the same ligands, allowing for more FH to bind, deregulating C3 activity and subsequently downregulating the alternative pathway.11 Serologic and histologic studies further confirmed the association of FHR1 and FHR 5 with IgAN severity, progression and renal injury. For instance, FHR1 plasma levels were significantly higher in patients with IgAN than in control patients. The relative abundance of FHR1 and FH in the circulation correlated with disease severity, showing that the ratio of alternative pathway activator and regulator may determine the degree of impairment of FH-dependent complement regulation and capacity of complement deactivation of FH. Immunostaining of patient biopsies pf the mesangium showed FHR5 to co-deposit with C3b cleavage products C3b, iC3b, C3d and C3c and IgA thus correlating with disease progression and histologic injury severity.3 This evidence suggests that FHR proteins and FH levels have the ability to influence disease progression, renal injury and severity in IgAN. Moreoever, FHR proteins and FH specifically interact with alternative pathway C3b, further supporting the theory that the FH and FHR alternative pathway activation is altered in IgAN patients.
Due to the possible association and mechanisms of complement activation in IgAN, treatments of IgAN targeting complement activity were proposed. An example of a therapy under clinical trial is Iptacopan (LNP023), a highly potent, reversible and selective oral molecule that inhibits factor B, a serine protease involved in the amplification loop of alternative pathway. In a Phase II trial conducted in patients with IgAN by Norvartis, it was reported that Iptacopan lowered proteinuria and demonstrated the ability to stabilize kidney function after 90 days. This new data further supports the potential use of Iptacopan to offer targeted therapy to slow down the progression of dialysis in IgAN patients. Another therapy that targets the alternative pathway is APL-2, a Compstatin derivative that binds to C3 and prevents the cleavage to C3a and C3b by C3 convertase. A phase II study is currently being conducted to evaluate the safety and efficacy of APL-2 in IgAN patients.12
Despite the increasing evidence showing that the alternative pathway participates in the mechanism contributes to IgAN progression and renal injury in patients, the details as to why and how such complement activity is altered in patients is not well elucidated. Study findings mainly demonstrate correlation between complement activity and IgAN through elevated components or proteolytic fragment levels, and immunostains that indicate co-deposition and so the actual mechanism of altered activation is yet to be determined. Previous research suggested the ability of IgA to trigger alternative pathway activity, yet, the exact way is not known, thus further research is required to confirm this. Creating a model to mimic the disease pathogenesis to test for the presence and the degree of AP activity could be a possible direction of research in the future. It is hoped that the mechanism of AP activation in IgAN can be discovered as promising results from clinical trials will encouraging the development and proposals of new drugs and therapies that target AP complement activity.
- Jennette J. The Immunohistology of IgA Nephropathy. American Journal of Kidney Diseases. 1988;12(5):348-352.
- Hastings M, Bursac Z, Julian B, Villa Baca E, Featherston J, Woodford S et al. Life Expectancy for Patients From the Southeastern United States With IgA Nephropathy. Kidney International Reports. 2018;3(1):99-104.
- Maillard N, Wyatt R, Julian B, Kiryluk K, Gharavi A, Fremeaux-Bacchi V et al. Current Understanding of the Role of Complement in IgA Nephropathy. Journal of the American Society of Nephrology. 2015;26(7):1503-1512.
- Woof J, Kerr M. The function of immunoglobulin A in immunity. The Journal of Pathology. 2005;208(2):270-282.
- Medjeral-Thomas N, O’Shaughnessy M. Complement in IgA Nephropathy: The Role of Complement in the Pathogenesis, Diagnosis, and Future Management of IgA Nephropathy. Advances in Chronic Kidney Disease. 2020;27(2):111-119.
- Evans D, Williams D, Peters D, Sissons J, Boulton-Jones J, Ogg C et al. Glomerular Deposition of Properdin in Henoch-Schonlein Syndrome and Idiopathic Focal Nephritis. BMJ. 1973;3(5875):326-328.
- SØLLING J. CIRCULATING IMMUNE COMPLEXES AND COMPLEMENT BREAKDOWN PRODUCT C3d IN GLOMERULONEPHRITIS AND KIDNEY TRANSPLANTATION. Acta Pathologica Microbiologica Scandinavica Series C: Immunology. 2009;92C(1-6):213-220.
- Wyatt R, Kanayama Y, Julian B, Negoro N, Sugimoto S, Hudson E et al. Complement activation in IgA nephropathy. Kidney International. 1987;31(4):1019-1023.
- Zwirner J, Burg M, Schulze M, Brunkhorst R, Götze O, Koch K et al. Activated complement C3: A potentially novel predictor of progressive IgA nephropathy. Kidney International. 1997;51(4):1257-1264.
- Medjeral-Thomas N, Troldborg A, Constantinou N, Lomax-Browne H, Hansen A, Willicombe M et al. Progressive IgA Nephropathy Is Associated With Low Circulating Mannan-Binding Lectin–Associated Serine Protease-3 (MASP-3) and Increased Glomerular Factor H–Related Protein-5 (FHR5) Deposition. Kidney International Reports. 2018;3(2):426-438.
- Gharavi A, Kiryluk K, Choi M, Li Y, Hou P, Xie J et al. Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nature Genetics. 2011;43(4):321-327.
- Tortajada A, Gutierrez E, Pickering M, Praga Terente M, Medjeral-Thomas N. The role of complement in IgA nephropathy. Molecular Immunology. 2019;114:123-132.