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Are you struggling with the complexities of Periodontal Ehlers-Danlos Syndrome (pEDS) and seeking innovative therapeutic strategies? The intricate interplay of genetic mutations and the dysregulated complement system presents significant challenges. At Creative Biolabs, our comprehensive understanding of complement biology and cutting-edge research tools empower you to investigate and target the complement pathway in pEDS. We provide advanced platforms for complement protein analysis, inhibitor screening, and preclinical model development, helping you accelerate the discovery of effective complement-based therapeutics for pEDS.
pEDS Immunopathology Features
Named after two physicians at the turn of the 20th century, Ehlers-Danlos syndrome (EDS) is a group of heritable connective tissue disorder characterized by skin hyperextensibility, fragile and stretchy skin, unusual scars, easy bruising and generalized joint hypermobility. These could occur as early as at birth. EDS affects approximately 1 in 5,000 people all over the world. The prognosis depends on the specific type. In the majority of patients with classic EDS, the disease is caused by the mutation in one or more a dozen different genes. The specific gene determines the type of EDS. Thus, according to different mutations, EDS can be classified into 13 types as of 2017, with a significant overlap in features.
Periodontal Ehlers-Danlos syndrome (pEDS) is one subtype of EDS, which is transmitted in an autosomal dominant pattern and characterized by severe and intractable periodontitis of early childhood or adolescence, lack of attached gingiva, protibial plaques. In the teens, early-onset periodontitis leads to the inflammatory destruction of dental attachment and premature loss of teeth.
Features of pEDS
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Periodontitis
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Lack of attached gingiva
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Protibial plaques
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Pretibial hyperpigmentation
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Acrogeria
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Skin and gum fragility
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Dystrophic scarring
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Distal joint hypermobility
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Bruising out of proportion to trauma
Cause of pEDS
It is shown that pEDS is caused by mono-allelic missense or in-frame insertion/deletion alterations in C1R or C1S, the genes that encode the complement subunits C1r and C1s. These two proteins are sub-components of the C1 complex derived from the classical pathway of the complement system. Recognizing the antigen-antibody complex by the C1 complex initiates the classical pathway.
Diagnosis of pEDS
Genetic test: Genomic sequence analysis of C1r and C1s genes. Since it is discovered by scientists that pEDS is caused by the mutations of C1r and C1s genes derived from the complement system. Sequencing these two genes is an efficient way for the pEDS diagnosis.
Treatment of pEDS
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Mechanical debridement
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Adjunctive antibiotic therapy
Complement Activation Pathways in pEDS
Pathogenic mutations in the C1R and C1S genes, responsible for encoding the C1r and C1s subunits of the complement component C1 complex, are the basis for pEDS, with the C1 complex serving as the initiating component of the Classical Pathway in the complement system. The following details elucidate the pathogenesis of pEDS concerning the complement pathways:
Table 1 pEDS related complement activation pathways.
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Complement Activation Pathways
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pEDS Pathogenesis
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Classical Pathway
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C1 Complex Dysfunction: mutations in the C1R and C1S genes, which encode the essential serine proteases C1r and C1s for the activation of the Classical Pathway, directly cause pEDS, with these proteins being part of the C1 complex, where C1q recognizes and binds to immune or pathogen surfaces to initiate the pathway.
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Aberrant C1r and C1s Activity: In pEDS patients, mutations in C1R and C1S often result in C1r and/or C1s enzymes becoming constitutively active, thus activating independently of normal triggers like antigen-antibody complexes.
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Uncontrolled Complement Activation: Persistent activation of C1r and C1s in pEDS leads to unchecked activation of downstream Classical Pathway components, notably C4 and C2, causing excessive production of C3 convertase (C4b2a).
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Excessive Inflammation and Tissue Degradation: Overactivation of the Classical Pathway triggers overproduction of inflammatory mediators and the MAC, along with direct degradation of collagen I by activated C1s protease, contributing to periodontal destruction in pEDS.
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Periodontal Destruction: The severe and rapid degradation of periodontal structures, including gums, periodontal ligament, and alveolar bone—resulting in premature tooth loss—is due to chronic inflammation and direct collagen degradation caused by hyperactive C1s.
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Alternative Pathway
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Although the primary genetic defect in pEDS affects the Classical Pathway, its dysregulation induces chronic inflammation and tissue damage that may indirectly impact the Alternative Pathway.
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Tissue damage and release of DAMPs can activate the Alternative Pathway, amplifying the inflammatory response in the periodontium further.
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Lectin Pathway
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Not directly impacted by the C1R and C1S mutations causing pEDS.
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The inflammation within the periodontium caused by the hyperactive Classical Pathway might indirectly affect the Lectin Pathway, as molecules released from tissue damage could activate MBL, thereby enhancing inflammation.
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Complement Molecular Mechanisms in pEDS
The molecular mechanisms of complement-mediated pathogenesis in pEDS are centered around the dysregulation of the Classical Pathway due to mutations in the C1R and C1S genes. These mutations lead to a cascade of molecular events:
Table 2 Molecular mechanisms of complement-mediated.
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Key Complement Components
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Functions
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C1R and C1S
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Heterozygous mutations in C1R and C1S result in the production of abnormal C1r and/or C1s subunits of the C1 complex.
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These mutations often lead to constitutive activation of the C1r and C1s serine proteases.
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Specific mechanisms of constitutive activation can include intracellular auto-activation and exposure of cleavage sites.
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C3 convertase
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The persistently active C1r and C1s within the C1 complex lead to the unrestrained cleavage of their natural substrates, C4 and C2. This leads to an overproduction of C3 convertase within the Classical Pathway.
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C3a and C5a,
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The elevated activity of C3 convertase results in excessive production of the potent anaphylatoxins C3a and C5a, which bind to receptors on immune and endothelial cells, thereby increasing vascular permeability, and attracting more inflammatory cells to periodontal tissues.
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With the rich research experiences in drug discovery and complement therapeutic field, Creative Biolabs' experts are confident in providing high-quality biotherapeutics development services based on the Complement Therapeutics platform. We offer turn-key or ala carte services customized to our client’s needs.
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