The role of properdin and Factor H in disease

Cortés, Claudio; Desler, Caroline; Mazzoli, A.B; Chen, Jin Y.; Ferreira, Viviana P.

doi:10.1016/bs.ai.2021.12.001

Cited by 4 publications

(5 citation statements)

References 351 publications

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“…Five rare variants (L3V, R127H, R166Q, C1077S, and N1176K) in the FH gene have been found to predispose to the occurrence of severe PE (52). Moreover, FH reduction can also be due to the presence of anti-FH autoantibodies, consumption of FH, or by the fact that FH is overwhelmed by a massive disease burden (53).…”

Section: Discussionmentioning

confidence: 99%

Protective role of complement factor H against the development of preeclampsia

Yasmin,

Agostinis,

Toffoli

et al. 2024

Front. Immunol.

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Pregnancy is an immunologically regulated, complex process. A tightly controlled complement system plays a crucial role in the successful establishment of pregnancy and parturition. Complement inhibitors at the feto-maternal interface are likely to prevent inappropriate complement activation to protect the fetus. In the present study, we aimed to understand the role of Factor H (FH), a negative regulator of complement activation, in normal pregnancy and in a model of pathological pregnancy, i.e. preeclampsia (PE). The distribution and expression of FH was investigated in placental tissues, various placental cells, and in the sera of healthy (CTRL) or PE pregnant women via immunohistochemistry, RT-qPCR, ELISA, and Western blot. Our results showed a differential expression of FH among the placental cell types, decidual stromal cells (DSCs), decidual endothelial cells (DECs), and extravillous trophoblasts (EVTs). Interestingly, FH was found to be considerably less expressed in the placental tissues of PE patients compared to normal placental tissue both at mRNA and protein levels. Similar results were obtained by measuring circulating FH levels in the sera of third trimester CTRL and PE mothers. Syncytiotrophoblast microvesicles, isolated from the placental tissues of PE and CTRL women, downregulated FH expression by DECs. The present study appears to suggest that FH is ubiquitously present in the normal placenta and plays a homeostatic role during pregnancy.

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Section: Discussionmentioning

confidence: 99%

Protective role of complement factor H against the development of preeclampsia

Yasmin,

Agostinis,

Toffoli

et al. 2024

Front. Immunol.

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“…As reviewed in details in, 65,66 packing interaction involving two TSR2 domains in this structure illustrates how the TSR-associated mannosylations may form hydrogen bonds with carbohydrate groups on host glycan or glycosylated proteins. 15 Interestingly, our structures also predict that empty C3b/convertase binding sites in the FP3 and FP4 oligomers point in a direction opposite to the occupied site(s) due to their rather flat structures (Figure 3G).…”

Section: Non -C Anonic Al Inter Ac Tion Partner Smentioning

confidence: 92%

“…In contrast to the convertase‐related functions, the role of FP as a C3b independent pattern recognition molecule is still up for debate. As reviewed in details in, 65,66 FP has been proposed to bind directly to pathogens, activated platelets and apoptotic/necrotic host cells and thereby recruit fluid phase C3b or the C3 tick‐over product C3(H 2 O) and support initiation of the alternative pathway amplification on the FP binding pattern. C3b independent recruitment of FP has been questioned, 67 but in a C3 knockout mouse FP was still deposited at injured glomeruli in vivo although the responsible FP binding pattern was not identified 68 .…”

Section: Non‐canonical Interaction Partnersmentioning

confidence: 99%

Structural studies offer a framework for understanding the role of properdin in the alternative pathway and beyond

Pedersen

Lorentzen

Andersen

2022

Immunological Reviews

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The complement cascade is activated when pattern recognition molecules recognize pathogens, dying host cells or immune complexes. The proteolytic cascades in complement can initiate through the classical pathway (CP) or the lectin pathway (LP) which leads to assembly of the CP/LP C3 convertase C4b2a. This proteolytic enzyme turns over complement C3 into the anaphylatoxin C3a and the opsonin C3b that may become covalently linked to the surface of the complement activator (Figure 1A). The downstream alternative pathway (AP) provides an amplification loop for the two other pathways. 1 The C3b initially deposited by the CP C3 convertase can associate with Factor B (FB) and form the AP proconvertase C3bB that upon cleavage by Factor D (FD) becomes the active AP C3 convertase C3bBb. 1 This initiates a positive feedback loop, which markedly amplifies the complement activation through the CP and LP. 2,3 FP is central in the AP amplification loop and binds directly to C3b, the C3bB proconvertase, and the C3bBb convertase (Figure 1A). The alternative pathway may also initiate in the

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“…In specific, gut microbiota that produce the endotoxin lipopolysaccharides (LPS) may contribute to amyloid deposition and neuroinflammation in Alzheimer’s ( 65 ). LPS interacts with the microbiota-gut-brain-immune interface via Toll-like receptor (TLR) 4 and the NF-κB pathway, stimulating an inflammatory cascade, triggering leaky gut, and leading to neuroinflammation ( 18 , 23 , 64 – 66 ).…”

Section: Neuroinflammationmentioning

confidence: 99%

The microbiota-gut-brain-immune interface in the pathogenesis of neuroinflammatory diseases: a narrative review of the emerging literature

Warren,

Nyavor,

Zarabian

et al. 2024

Front. Immunol.

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ImportanceResearch is beginning to elucidate the sophisticated mechanisms underlying the microbiota-gut-brain-immune interface, moving from primarily animal models to human studies. Findings support the dynamic relationships between the gut microbiota as an ecosystem (microbiome) within an ecosystem (host) and its intersection with the host immune and nervous systems. Adding this to the effects on epigenetic regulation of gene expression further complicates and strengthens the response. At the heart is inflammation, which manifests in a variety of pathologies including neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Multiple Sclerosis (MS).ObservationsGenerally, the research to date is limited and has focused on bacteria, likely due to the simplicity and cost-effectiveness of 16s rRNA sequencing, despite its lower resolution and inability to determine functional ability/alterations. However, this omits all other microbiota including fungi, viruses, and phages, which are emerging as key members of the human microbiome. Much of the research has been done in pre-clinical models and/or in small human studies in more developed parts of the world. The relationships observed are promising but cannot be considered reliable or generalizable at this time. Specifically, causal relationships cannot be determined currently. More research has been done in Alzheimer’s disease, followed by Parkinson’s disease, and then little in MS. The data for MS is encouraging despite this.Conclusions and relevanceWhile the research is still nascent, the microbiota-gut-brain-immune interface may be a missing link, which has hampered our progress on understanding, let alone preventing, managing, or putting into remission neurodegenerative diseases. Relationships must first be established in humans, as animal models have been shown to poorly translate to complex human physiology and environments, especially when investigating the human gut microbiome and its relationships where animal models are often overly simplistic. Only then can robust research be conducted in humans and using mechanistic model systems.

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The role of properdin and Factor H in disease

Cited by 4 publications

References 351 publications

Protective role of complement factor H against the development of preeclampsia

Protective role of complement factor H against the development of preeclampsia

Structural studies offer a framework for understanding the role of properdin in the alternative pathway and beyond

The microbiota-gut-brain-immune interface in the pathogenesis of neuroinflammatory diseases: a narrative review of the emerging literature

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