UNASSIGNED: IgA nephropathy\'s (IgAN\'s) MEST-C classification relationship with complement activation is still not fully understood because of limited and conflicting evidence. Our study aimed to delineate this relationship through a systematic review.
UNASSIGNED: We adhered to the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines and conducted a systematic review, utilizing databases like MEDLINE (PubMed), Embase, Scopus, and Cochrane from January 2016 (year of updated MEST-C classification) to January 2023. We specifically selected studies that employed established methods to evaluate complement activation and the MEST-C classification.
UNASSIGNED: A total of 34 studies with 10,082 patients were included. Among these, 7 studies focused on the pediatric population (500 patients), and 22 studies involved 8128 patients from Asian populations. C4d, C3, C5b9, MBL, C4, and factor H-related protein 5 (FHR5) were the most frequently studied complement proteins in relation to the MEST-C classification. Complement activation assessment was primarily conducted using immunofluorescence and immunohistochemistry on kidney biopsy specimens. All complement proteins investigated showed associations with the C1-2 class. Notably, FB, FH, MASP1/3, MASP2, C5a, and C5b9 from the alternative, lectin, and terminal pathways were uniquely present in the C1-2 class. Whereas C3, FHR5, C4, and C4d were associated with all the MEST-C classes.
UNASSIGNED: We found evidence supporting the involvement of alternative and lectin complement pathways across all MEST-C classes. All examined complement factors were associated with the C1-2 class, emphasizing the critical role of complement activation, possibly at the endothelial surface. These findings may guide the development of personalized treatment strategies targeting complement pathways in relation to the MEST-C lesions.

As the most primitive vertebrates, lampreys are significant in understanding the early origin and evolution of the vertebrate innate and adaptive immune systems. The complement system is a biological response system with complex and precise regulatory mechanisms and plays an important role in innate and adaptive immunity. It consists of more than 30 distinct components, including intrinsic components, regulatory factors, and complement receptors. Complement system is the humoral backbone of the innate immune defense and complement-like factors have also been found in cyclostomes. Our knowledge as such in lamprey has dramatically increased in the recent years. The searching for complement components in the reissner lamprey Lethenteron reissneri genome database, together with published data, has unveiled the existence of all the orthologues of mammalian complement components identified thus far, including the complement regulatory proteins and complement receptors, in lamprey. This review, summarizes the key themes and recent updates on the complement system of agnathans and discusses the individual complement components of lampreys, and critically compare their functions to that of mammalian complement components. Interestingly, the adaptive immune system of agnathans differs from that of gnathostomes. Lamprey complement components also display some distinctive features, such as lampreys are characterized by the variable lymphocyte receptors (VLRs)-based alternative adaptive immunity. This review may serve as important literature for deducing the evolution of the immune system from invertebrates to vertebrates.

Primary membranous nephropathy (MN) is an important cause of nephrotic syndrome and chronic kidney disease (CKD) in the adult population. Although the discovery of different autoantibodies against glomerular/podocytic antigens have highlighted the role of B cells in the pathogenesis of MN, suboptimal response or even resistance to B cell-directed therapies occurs, suggesting that other pathophysiological mechanisms are involved in mediating podocyte injury. The complement system plays an important role in the innate immune response to infection, and dysregulation of the complement system has been observed in various kidney diseases. There is compelling evidence of complement cascade activation in primary MN, with the mannose-binding lectin (MBL) and alternative pathways particularly implicated. With appropriate validation, assays of complements and associated activation products could hold promise as adjunctive tools for non-invasive disease monitoring and prognostication. While there is growing interest to target the complement system in MN, there is concern regarding the risk of infection due to encapsulated organisms and high treatment costs, highlighting the need for clinical trials to identify patients most likely to benefit from complement-directed therapies.

BACKGROUND: To describe the optical coherence tomography angiograhy (OCTA) of drusenoid pigment epithelial detachments (PEDs) in a woman affected by Complement 3 (C3) glomerulopathy, which represents a spectrum of glomerular diseases characterized on fluorescent microscopy by C3 accumulation with absent, or scanty, immunoglobulin deposits. It is due to acquired or genetically defective alternative pathway control and is generally associated with drusen-like deposits in Bruch\'s membrane, as well as choriocapillaris. These retinal lesions can be associated with choroidal neovascularization and central serous chorioretinopathy (CSCR). OCTA is useful to detect neovascularization without injecting a contrast product, particularly in these patients who may have renal insufficiency.
METHODS: A 28-year-old woman affected by C3 glomerulpathy was diagnosed with asymptomatic multiple bilateral PEDs during a routine ophthalmologic consultation. To better characterize the lesions, multimodal imaging was performed and included: optic coherence tomography (OCT), en-face OCT, OCTA, fluorescence and indocyanine angiography. The OCTA clearly identified vascular network rarefaction with decreased choriocapillary vascularization. It confirmed that PEDs associated with C3 glomerulonephritis are not vascularized, but rather of serous type.
CONCLUSIONS: Patients affected by C3 glomerulopathy can develop neovascular membranes as retinal complications of pigment epithelial detachments. Optical coherence angiography may be indicated to identify this complication, without injecting any contrast product that could produce further kidney damage.

Age-related macular degeneration (AMD) is a progressive retinal disease and the major cause of irreversible vision loss in the elderly. Numerous studies have found both common and rare genetic variants in the complement pathway to play a role in the pathogenesis of AMD. In this review we provide an overview of rare variants identified in AMD patients, and summarize the functional consequences of rare genetic variation in complement genes on the complement system. Finally, we discuss the relevance of this work in light of ongoing clinical trials that study the effectiveness of complement inhibitors against AMD.

Age-related macular degeneration (AMD) is a major cause of visual impairment in the western world. It is characterized by the presence of lipoproteinaceous deposits (drusen) in the inner layers of the retina. Immunohistochemistry studies identified deposition of complement proteins in the drusen as well as in the choroid. In the last decade, genetic studies have linked both common and rare variants in genes of the complement system to increased risk of development of AMD. Here, we review the variants described to date and discuss the functional implications of dysregulation of the alternative pathway of complement in AMD.

BACKGROUND: The architecture of the complement system has evolved during the last 600 - 700 million years to become an amazingly efficient and highly versatile alerting and cell killing device. Under physiological conditions, this system acts as a well-regulated cascade, protecting the organism against pathogens and participating during the initial defensive steps of humoral and cellular response. The unregulated activation of this system may cause or even aggravate diseases; therefore, its modulation is currently considered of high importance.
METHODS: This review is a critical examination on patent literature published between 2008 and 2013. An insight is provided about the discovery and development of novel therapeutic agents. These include macromolecules, polysaccharides and proteins, specific antibodies, and hybrid or chimeric products. Peptides and low molecular weight organic compounds (natural products, their derivatives and fully synthetic molecules) are covered as well.
CONCLUSIONS: The search of specific inhibitors of the complement cascade has become one of the Holy Grails of Medicinal Chemistry for the last 30 - 40 years, with very few cases of success. Some highly specific macromolecules are currently available as modulators of the complement. However, there is still a marked need to find new, more specific, efficient and convenient alternatives, especially suited for chronic administration, including novel inexpensive small molecule inhibitors. Analogously, despite the initial success with specific monoclonal antibodies, a vast territory is awaiting to be explored and conquered, regarding the regulation of complement activation by antibody-mediated blockage of specific polypeptides or receptor sites.