Genetic variation in complement regulators and susceptibility to age-related macular degeneration

Cipriani, Valentina; Matharu, Baljinder K; Khan, Jane C.; Shahid, Humma; Stanton, Chloe; Hayward, Caroline; Wright, Alan F.; Bunce, Catey; Clayton, David; Moore, Anthony T.; Yates, John R.

doi:10.1016/j.imbio.2011.09.002

Cited by 24 publications

(15 citation statements)

References 30 publications

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“…57 CD46 is also a clinically "attractive" molecule because single nucleotide polymorphisms in the CD46 gene are either causative or contribute to hemolytic uremic syndrome, age-related macular degeneration, and possibly pre-eclampsia. [58][59][60] On resting CD4 + T cells, CD46 presence sustains (via signals that have not yet been identified) the expression of the interleukin (IL)-7 receptor (CD127). Incoming IL-7R signals in circulating T cells maintain basic glucose transporter 1 (GLUT1) surface expression, which, in turn, allows for glucose-mediated protein kinase B (AKT) activation and anti-apoptotic B cell lymphoma (BCL-2) expression, all such events being required for normal T cell survival in the periphery.…”

Section: The Complosome In T Cell Homeostasismentioning

confidence: 99%

Complement and human T cell metabolism: Location, location, location

West

Kunz

Kemper

2020

Immunological Reviews

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Immunological Reviews. 2020;295:68-81. wileyonlinelibrary.com/journal/imr 1 | INTRODUC TI ON Our contemporary immune system has evolved under the constant pressure from a broad range of pathogens that manipulate the host to enhance their own propagation. As diverse as the pathogenic threats are, ranging from intra-and extracellular bacteria, viruses, fungi, and complex parasites, as elegant and effective are the defense mechanisms developed and employed by the host to combat this constant onslaught. Particularly, the detection systems that are functioning as the first lines of defense against such invaders are formidable. If a microbe has managed to penetrate the protective physical barriers, such as the skin, or lung, a range of innate immune sensors either circulating in the blood, lymph, and interstitial fluids or expressed in and on scavenger and sentinel cells, such as neutrophils and microphages, detect the conserved pathogen-associated molecular patterns (PAMPs). These sensor systems comprise several pattern recognition receptors (PRRs) and include the Toll-like receptors (TLRs), the NOD-like receptors (NLRs), the retinoic acid-inducible gene-I (RIG)-like system, several distinct inflammasomes, and the complement system-derived receptors. 1,2 Activation of PRRs by a pathogen is most often triggered in several sensor systems in parallel and then initiates the general inflammatory reaction as well as tailored immune cell activation specifically effective toward the identified pathogen. The ability of PRR systems to decisively discriminate between a real threat, that is non-self and dangerous self via recognizing so-called danger-associated molecular patterns (DAMPs), and self and harmless alterations of self is critical for our health. Thus, there are several checks and balances build into the PRR systems that prevent unwanted reactions against sensed AbstractThe complement system represents one of the evolutionary oldest arms of our immune system and is commonly recognized as a liver-derived and serum-active system critical for providing protection against invading pathogens. Recent unexpected findings, however, have defined novel and rather "uncommon" locations and activities of complement. Specifically, the discovery of an intracellularly active complement system-the complosome-and its key role in the regulation of cell metabolic pathways that underly normal human T cell responses have taught us that there is still much to be discovered about this system. Here, we summarize the current knowledge about the emerging functions of the complosome in T cell metabolism. We further place complosome activities among the non-canonical roles of other intracellular innate danger sensing systems and argue that a "location-centric" view of complement evolution could logically justify its close connection with the regulation of basic cell physiology. K E Y W O R D S CD46, complement, complosome, metabolism, T cells | 69 WEST ET al.innocuous antigens. However, PRRs not only take care to contain tissue injury during their...

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Section: The Complosome In T Cell Homeostasismentioning

confidence: 99%

Complement and human T cell metabolism: Location, location, location

West

Kunz

Kemper

2020

Immunological Reviews

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“…The role of the complement system in the pathogenesis of AMD has been studied and reviewed extensively over the past decade (Warwick et al, ; Bora et al, ; McHarg et al, ). Key facts supporting the role of the complement system in the pathogenesis of AMD include the following: (i) Several complement components have been detected in drusen and AMD lesions (Anderson et al, , ); (ii) higher plasma levels of C3a, C3d, Bb, and C5a have been observed in AMD patients (Scholl et al, ; Reynolds et al, ; Lechner et al, ); (iii) polymorphisms in a number of complement genes (CFH, CFB, C2, SERPING1, and C3) are genetic risk factors of AMD (Edwards, ; Cipriani et al, ); and (iv) inhibition of complement suppresses laser‐induced CNV in mice (Nozaki et al, ; Bora et al, ; Kim et al, ; Lipo et al, ). Mechanistically, CFH may inhibit CD47‐mediated resolution of subretinal inflammation and this inhibitory effect could be enhanced by the AMD associated CFH (H402) variant (Calippe et al, ).…”

Section: Targeting the Complement System In Retinal Degenerative Disementioning

confidence: 99%

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

et al. 2018

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This review highlights the role of three key immune pathways in the pathophysiology of major retinal degenerative diseases including diabetic retinopathy, age‐related macular degeneration, and rare retinal dystrophies. We first discuss the mechanisms how loss of retinal homeostasis evokes an unbalanced retinal immune reaction involving responses of local microglia and recruited macrophages, activity of the alternative complement system, and inflammasome assembly in the retinal pigment epithelium. Presenting these key mechanisms as complementary targets, we specifically emphasize the concept of immunomodulation as potential treatment strategy to prevent or delay vision loss. Promising molecules are ligands for phagocyte receptors, specific inhibitors of complement activation products, and inflammasome inhibitors. We comprehensively summarize the scientific evidence for this strategy from preclinical animal models, human ocular tissue analyses, and clinical trials evolving in the last few years.

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“…This finding suggests that RPE cells exposed to oxidative insult are permissive for complement activation on their surfaces. A recent case-control studies has reported an absence of an association between AMD and gene variants in CD46, CD55 and CD59 (Cipriani et al, 2012). …”

Section: Complement Components In Rpe-bruch’s Membrane–choroid Commentioning

confidence: 99%

Complement dysregulation in AMD: RPE-Bruch’s membrane-choroid

Sparrow¹,

Ueda²,

Zhou³

2012

Molecular Aspects of Medicine

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The question as to why the macula of the retina is prone to an aging disease (age-related macular degeneration) remains unanswered. This unmet challenge has implications since AMD accounts for approximately 54% of blindness in the USA (Swaroop, Chew, Bowes Rickman and Abecasis, 2009). While AMD has onset in the elder years, it likely develops over time. Genetic discovery to date has accounted for approximately 50% of the inheritable component of AMD. The polymorphism that has been most widely studied is the Y402H allele in the complement factor H gene. The implication of this genetic association is that in a subset of AMD cases, unregulated complement activation is permissive for AMD. Given that this gene variant results in an amino acid substitution, it is assumed that this change will have functional consequences although the precise mechanisms are still unknown. Genetic predisposition is not the only factor however, since in this complex disease there is substantial evidence that lifestyle factors such as diet and smoking contribute to risk. Here we provide an overview of current knowledge with respect to factors involved in AMD pathogenesis. Interwoven with these issues is a discussion of the significant role played by aging processes, some of which are unique to the retina and retinal pigment epithelium. One recurring theme is the potential for disease promotion by diverse types of oxidation products.

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Genetic variation in complement regulators and susceptibility to age-related macular degeneration

Cited by 24 publications

References 30 publications

Complement and human T cell metabolism: Location, location, location

Complement and human T cell metabolism: Location, location, location

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

Complement dysregulation in AMD: RPE-Bruch’s membrane-choroid

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