Therapeutic Lessons to be Learned From the Role of Complement Regulators as Double-Edged Sword in Health and Disease

Mourik, Anouk G van; Jongerius, Ilse

doi:10.3389/fimmu.2020.578069

Cited by 12 publications

(10 citation statements)

References 245 publications

(364 reference statements)

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“… 11 , 20 , 21 This knowledge is highly relevant when developing disease‐specific complement‐targeting drugs. 6 The two complement therapeutics currently available in the clinic block C3 and C5 22 , 23 and thus do not target a specific activation pathway. However, complement therapeutics targeting specific complement activation pathways are emerging, such as the recently approved anti‐C1s sutimlimab, 24 for which a better understanding of the role of the AP in different diseases and contexts will be important.…”

Section: Introductionmentioning

confidence: 99%

“…However, complement therapeutics targeting specific complement activation pathways are emerging, such as the recently approved anti‐C1s sutimlimab, 24 for which a better understanding of the role of the AP in different diseases and contexts will be important. 6 , 11 , 25 , 26 …”

Section: Introductionmentioning

confidence: 99%

“…For other, mainly antibody‐driven diseases such as AIHA and rheumatoid arthritis (RA), CP activation is key, but the role of the LP and AP in disease development and progression is often unclear 11,20,21 . This knowledge is highly relevant when developing disease‐specific complement‐targeting drugs 6 . The two complement therapeutics currently available in the clinic block C3 and C5 22,23 and thus do not target a specific activation pathway.…”

Section: Introductionmentioning

confidence: 99%

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The contribution of the alternative pathway in complement activation on cell surfaces depends on the strength of classical pathway initiation

et al. 2023

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Objectives The complement system is an important component of innate immunity. The alternative pathway (AP) amplification loop is considered an essential feed forward mechanism for complement activation. However, the role of the AP in classical pathway (CP) activation has only been studied in ELISA settings. Here, we investigated its contribution on physiologically relevant surfaces of human cells and bacterial pathogens and in antibody‐mediated complement activation, including in autoimmune haemolytic anaemia (AIHA) setting with autoantibodies against red blood cells (RBCs). Methods We evaluated the contribution of the AP to complement responses initiated through the CP on human RBCs by serum of AIHA patients and recombinant antibodies. Moreover, we studied complement activation on Neisseria meningitidis and Escherichia coli. The effect of the AP was examined using either AP‐depleted sera or antibodies against factor B and factor D. Results We show that the amplification loop is redundant when efficient CP activation takes place. This is independent of the presence of membrane‐bound complement regulators. The role of the AP may become significant when insufficient CP complement activation occurs, but this depends on antibody levels and (sub)class. Our data indicate that therapeutic intervention in the amplification loop will most likely not be effective to treat antibody‐mediated diseases. Conclusion The AP can be bypassed through efficient CP activation. The AP amplification loop has a role in complement activation during conditions of modest activation via the CP, when it can allow for efficient complement‐mediated killing.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The contribution of the alternative pathway in complement activation on cell surfaces depends on the strength of classical pathway initiation

et al. 2023

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“…In health, the complement system is tightly regulated to prevent unwanted activation, inflammation and tissue damage. It has long been known that complement dysregulation contributes to various inflammatory and autoimmune diseases ( 4 – 6 ). A number of membrane-bound and fluid phase regulators ensure that the complement system is well-controlled (reviewed in ( 7 )).…”

Section: Introduction: the Factor H Protein Familymentioning

confidence: 99%

A Family Affair: Addressing the Challenges of Factor H and the Related Proteins

et al. 2021

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Inflammation is a common denominator of diseases. The complement system, an intrinsic part of the innate immune system, is a key driver of inflammation in numerous disorders. Recently, a family of proteins has been suggested to be of vital importance in conditions characterized by complement dysregulation: the human Factor H (FH) family. This group of proteins consists of FH, Factor H-like protein 1 and five Factor H-related proteins. The FH family has been linked to infectious, vascular, eye, kidney and autoimmune diseases. In contrast to FH, the functions of the other highly homologous proteins are largely unknown and, hence, their role in the different disease-specific pathogenic mechanisms remains elusive. In this perspective review, we address the major challenges ahead in this emerging area, including 1) the controversies about the functional roles of the FH protein family, 2) the discrepancies in quantification of the FH protein family, 3) the unmet needs for validated tools and 4) limitations of animal models. Next, we also discuss the opportunities that exist for the immunology community. A strong multidisciplinary approach is required to solve these obstacles and is only possible through interdisciplinary collaboration between biologists, chemists, geneticists and physicians. We position this review in light of our own perspective, as principal investigators of the SciFiMed Consortium, a consortium aiming to create a comprehensive analytical system for the quantitative and functional assessment of the entire FH protein family.

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“…Clearly, new options of treatment are required. In experimental models, the use of mini-FH (containing domains 1-4 and [19][20] offer promising results in the regulation of the alternative pathway (6). However, so far this has not been tested in FH-deficient patients.…”

Section: Introductionmentioning

confidence: 99%

A rare association between factor H deficiency and lupus: Case report and experimental treatment with curcumin

et al. 2022

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Factor H (FH) is one of the most important regulatory proteins of the alternative pathway of the complement system. FH deficiency is a rare condition that causes unregulated C3 consumption, leading to an increased susceptibility to infections and glomerulopathies. Our previous studies have demonstrated a FH deficient patient carrying a c.452G > A, p.R127H FH mutation which leads to a misfolded protein and its retention in the endoplasmic reticulum. In his cultured fibroblasts, FH-delayed secretion was partially rescued when treated with curcumin, and once secreted, exhibited normal regulatory function. Here, we report a childhood-onset systemic lupus erythematosus (cSLE) in this FH deficient patient and the results of experimental treatment with curcumin aiming to rescue FH secretion and regulatory activity.

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Therapeutic Lessons to be Learned From the Role of Complement Regulators as Double-Edged Sword in Health and Disease

Cited by 12 publications

References 245 publications

The contribution of the alternative pathway in complement activation on cell surfaces depends on the strength of classical pathway initiation

The contribution of the alternative pathway in complement activation on cell surfaces depends on the strength of classical pathway initiation

A Family Affair: Addressing the Challenges of Factor H and the Related Proteins

A rare association between factor H deficiency and lupus: Case report and experimental treatment with curcumin

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