Complement dysregulation in glomerulonephritis

Kaartinen, Kati; Safa, Adrian; Kotha, Soumya; Ratti, Giorgio; Meri, Seppo

doi:10.1016/j.smim.2019.101331

Cited by 42 publications

(39 citation statements)

References 102 publications

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“…Complement dysregulation, and most commonly dysregulation of the alternative pathway, is known to cause or accentuate several different inflammatory glomerular diseases ( 59 ). In these diseases, glomerular injury leads to the appearance of hematuria and proteinuria and ultimately to the development of progressive chronic kidney disease.…”

Section: Dysregulation Of Complement Activation In Autoimmune Diseases Where the Alternative Complement Pathway Plays An Important Rolementioning

confidence: 99%

Complement Factor D as a Strategic Target for Regulating the Alternative Complement Pathway

Barratt

Weitz

2021

Front. Immunol.

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The complement system is central to first-line defense against invading pathogens. However, excessive complement activation and/or the loss of complement regulation contributes to the development of autoimmune diseases, systemic inflammation, and thrombosis. One of the three pathways of the complement system, the alternative complement pathway, plays a vital role in amplifying complement activation and pathway signaling. Complement factor D, a serine protease of this pathway that is required for the formation of C3 convertase, is the rate-limiting enzyme. In this review, we discuss the function of factor D within the alternative pathway and its implication in both healthy physiology and disease. Because the alternative pathway has a role in many diseases that are characterized by excessive or poorly mediated complement activation, this pathway is an enticing target for effective therapeutic intervention. Nonetheless, although the underlying disease mechanisms of many of these complement-driven diseases are quite well understood, some of the diseases have limited treatment options or no approved treatments at all. Therefore, in this review we explore factor D as a strategic target for advancing therapeutic control of pathological complement activation.

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Section: Dysregulation Of Complement Activation In Autoimmune Diseases Where the Alternative Complement Pathway Plays An Important Rolementioning

confidence: 99%

Complement Factor D as a Strategic Target for Regulating the Alternative Complement Pathway

Barratt

Weitz

2021

Front. Immunol.

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“…Complement dysregulation due to mutations in complement genes, autoantibodies against complement proteins or over-activation in response to certain viral infections leads to a long list of diseases. C3G, PNH and aHUS are examples where complement is the main driver of the disease (8, 13, 59). Although the development of drugs to regulate the complement response and restore homeostasis is of huge interest, C1 esterase inhibitor and blocking antibodies against C5 are the only available so far (29).…”

Section: Discussionmentioning

confidence: 99%

A synthetic protein as efficient multitarget regulator against complement over-activation

Molina

Müeller

Hoernstein

et al. 2021

Preprint

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The complement system constitutes the innate defense against pathogens. Its dysregulation leads to diseases and is a critical determinant in many viral infections, e.g. COVID-19. Factor H (FH) is the main regulator of the alternative pathway of complement activation and could be a therapy to restore homeostasis. However, recombinant FH is not available. Engineered FH versions may be alternative therapeutics. Here, we designed a synthetic protein, MFHR13, as a multitarget complement regulator. It combines the dimerization and C5-regulatory domains of human FH-related protein 1 (FHR1) with the C3-regulatory and cell surface recognition domains of human FH, including SCR13. In summary, the fusion protein MFHR13 comprises SCRs FHR11-2:FH1-4:FH13:FH19-20. It protects sheep erythrocytes from complement attack exhibiting 26 and 4-fold the regulatory activity of eculizumab and human FH, respectively. Furthermore, we demonstrate that MFHR13 and FHR1 bind to all proteins forming the membrane attack complex, which contributes to the mechanistic understanding of FHR1. We consider MFHR13 a promising candidate as therapeutic for complement-associated diseases.

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“…However, the rare observation of these variants in healthy individuals indicates that no single variant so far seems to be sufficient to induce renal disease per se at the heterozygous state. The variants may increase the predisposition to develop the glomerulopathy or they could exacerbate the course of the disease (Kaartinen et al, 2019 ). The disease itself is likely triggered by other factors.…”

Section: Discussionmentioning

confidence: 99%

Case Report: A Rare Truncating Variant of the CFHR5 Gene in IgA Nephropathy

et al. 2021

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IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Despite appropriate therapy, 20–40% of affected-patients evolve toward end-stage kidney disease (ESKD). Mesangial IgA deposits are the hallmark of IgAN, and complement deposition (C3) seems to differentiate latent IgA mesangial deposits from active IgAN. Atypical hemolytic uremic syndrome (aHUS), another disease in which complement plays an important role, is caused by inherited or acquired deregulation of the alternative pathway (AP) of complement. A subgroup of IgAN shows thrombotic microangiopathy (TMA) lesions in kidney biopsies, the histological characteristic of aHUS. Genetic variants of complement Factor H (CFH), known to be present in aHUS, have been associated with rapidly progressive forms of IgAN and a clinical pattern of aHUS. Genome-wide association studies (GWAS) have confirmed that the 1q32 region, encoding for CFH and its related proteins, is an IgAN susceptibility locus. A 30 year-old man was admitted for seizures and malignant hypertension. The kidney biopsy showed IgAN associated with features of TMA. Despite five plasma exchanges, the patient remained dialysis-dependent, and ESKD was diagnosed. Functional and genetic complement analysis were performed. A monoallelic protein-truncating, likely loss-of-function variant was identified in the CFHR5 gene. Eculizumab is the treatment of aHUS. As it has been successfully used in a few cases of rapidly progressive IgAN, it was decided to administer eculizumab over a period of 12 months in addition to the usual immunosuppression for renal transplantation. After a follow-up of 3 years, there was no clinical disease recurrence. Systematic biologic and genetic screening of complement in individuals with IgAN might be useful to better delineate the role of the AP of complement in renal disease progression, and this may have therapeutic implications.

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Complement dysregulation in glomerulonephritis

Cited by 42 publications

References 102 publications

Complement Factor D as a Strategic Target for Regulating the Alternative Complement Pathway

Complement Factor D as a Strategic Target for Regulating the Alternative Complement Pathway

A synthetic protein as efficient multitarget regulator against complement over-activation

Case Report: A Rare Truncating Variant of the CFHR5 Gene in IgA Nephropathy

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