Genetic studies into inherited and sporadic hemolytic uremic syndrome

Warwicker, Paul; Goodship, Timothy H.J.; Donne, Rosie; Pirson, Yves; Nicholls, Anthony; Ward, Roy; Turnpenny, Peter D.; Goodship, Judith A.

doi:10.1111/j.1523-1755.1998.00824.x

Cited by 462 publications

(273 citation statements)

References 25 publications

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“…However, uncontrolled activation results in collateral damage to surrounding host tissues. Organ damage from alternative complement dysregulation occurs in several renal diseases including atypical hemolytic uremic syndrome (aHUS) (233)(234)(235)(236)(237)(238)(239) and membranoproliferative glomerulonephritis type II (MPGNII) (240,241). In aHUS, widespread blood clot formation and reactive endothelial cell proliferation in small blood vessels can lead to acute renal failure.…”

Section: Association Of Amd With Other Diseasesmentioning

confidence: 99%

Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts

et al. 2006

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Today, the average life expectancy in developed nations is over 80 years and climbing. And yet, the quality of life during those additional years is often significantly diminished by the effects of age-related, degenerative diseases, including age-related macular degeneration (AMD), the leading cause of blindness in the elderly worldwide. AMD is characterized by a progressive loss of central vision attributable to degenerative and neovascular changes in the macula, a highly specialized region of the ocular retina responsible for fine visual acuity. Estimates gathered from the most recent World Health Organization (WHO) global eye disease survey conservatively indicate that 14 million persons are blind or severely visually impaired because of AMD. The disease has a tremendous impact on the physical and mental health of the geriatric population and their families and is becoming a major public health burden.Currently, there is neither a cure nor a means to prevent AMD. Palliative treatment options for the less prevalent, late-stage 'wet' form of the disease include anti-neovascular agents, photodynamic therapy and thermal laser. There are no current therapies for the more common 'dry' AMD, except for the use of antioxidants that delay progression in 20%-25% of eyes. New discoveries, however, are beginning to provide a much clearer picture of the relevant cellular events, genetic factors, and biochemical processes associated with early AMD. Recently, compelling evidence has emerged that the innate immune system and, more specifically, uncontrolled regulation of the complement alternative pathway plays a central role in the pathobiology of AMD. The complement Factor H gene-which encodes the major inhibitor of the complement alternative pathway-is the first gene identified in multiple independent studies that confers a significant genetic risk for the development of AMD. The emergence of this new paradigm of AMD pathogenesis should hasten the development of novel diagnostic and therapeutic approaches for this disease that will dramatically improve the quality of our prolonged lifespan.

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Section: Association Of Amd With Other Diseasesmentioning

confidence: 99%

Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts

et al. 2006

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“…Host cell recognition by CFH is mediated by domains 19-20 (10-12). The importance of CFH in controlling AP activation on host structures is exemplified by the often lethal atypical hemolytic uremic syndrome and dense deposit disease caused by malfunction of the domains 19-20 or 1-4 of CFH, respectively (13)(14)(15)(16). In addition, polymorphism Y402H in domain 7 of CFH is associated with age-related macular degeneration (AMD), the most common cause of visual loss in industrialized countries (17)(18)(19)(20).…”

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confidence: 99%

Acquisition of Complement Factor H Is Important for Pathogenesis ofStreptococcus pyogenesInfections: Evidence from Bacterial In Vitro Survival and Human Genetic Association

Haapasalo

Vuopio

Syrjänen

et al. 2012

The Journal of Immunology

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Streptococcus pyogenes (or group A streptococcus [GAS]) is a major human pathogen causing infections, such as tonsillitis, erysipelas, and sepsis. Several GAS strains bind host complement regulator factor H (CFH) via its domain 7 and, thereby, evade complement attack and C3b-mediated opsonophagocytosis. Importance of CFH binding for survival of GAS has been poorly studied because removal of CFH from plasma or blood causes vigorous complement activation, and specific inhibitors of the interaction have not been available. In this study, we found that activation of human complement by different GAS strains (n = 38) correlated negatively with binding of CFH via its domains 5–7. The importance of acquisition of host CFH for survival of GAS in vitro was studied next by blocking the binding with recombinant CFH5–7 lacking the regulatory domains 1–4. Using this fragment in full human blood resulted in death or radically reduced multiplication of all of the studied CFH-binding GAS strains. To study the importance of CFH binding in vivo (i.e., for pathogenesis of streptococcal infections), we used our recent finding that GAS binding to CFH is diminished in vitro by polymorphism 402H, which is also associated with age-related macular degeneration. We showed that allele 402H is suggested to be associated with protection from erysipelas (n = 278) and streptococcal tonsillitis (n = 209) compared with controls (n = 455) (p < 0.05). Taken together, the bacterial in vitro survival data and human genetic association revealed that binding of CFH is important for pathogenesis of GAS infections and suggested that inhibition of CFH binding can be a novel therapeutic approach in GAS infections.

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“…A typical hemolytic uremic syndrome (aHUS) 3 is inherited either as an autosomal dominant or autosomal recessive trait and the recessive form has been firmly associated with mutations clustering at the C-terminal end of complement factor H (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). aHUS is characterized by hemolytic anemia, thrombocytopenia, and acute renal failure.…”

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confidence: 99%

Critical Role of the C-Terminal Domains of Factor H in Regulating Complement Activation at Cell Surfaces

Ferreira

Herbert

Hocking

et al. 2006

The Journal of Immunology

133

109

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The plasma protein factor H primarily controls the activation of the alternative pathway of complement. The C-terminal of factor H is known to be involved in protection of host cells from complement attack. In the present study, we show that domains 19–20 alone are capable of discriminating between host-like and complement-activating cells. Furthermore, although factor H possesses three binding sites for C3b, binding to cell-bound C3b can be almost completely inhibited by the single site located in domains 19–20. All of the regulatory activities of factor H are expressed by the N-terminal four domains, but these activities toward cell-bound C3b are inhibited by isolated recombinant domains 19–20 (rH 19–20). Direct competition with the N-terminal site is unlikely to explain this because regulation of fluid phase C3b is unaffected by domains 19–20. Finally, we show that addition of isolated rH 19–20 to normal human serum leads to aggressive complement-mediated lysis of normally nonactivating sheep erythrocytes and moderate lysis of human erythrocytes, which possess membrane-bound regulators of complement. Taken together, the results highlight the importance of the cell surface protective functions exhibited by factor H compared with other complement regulatory proteins. The results may also explain why atypical hemolytic uremic syndrome patients with mutations affecting domains 19–20 can maintain complement homeostasis in plasma while their complement system attacks erythrocytes, platelets, endothelial cells, and kidney tissue.

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Genetic studies into inherited and sporadic hemolytic uremic syndrome

Cited by 462 publications

References 25 publications

Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts

Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts

Acquisition of Complement Factor H Is Important for Pathogenesis ofStreptococcus pyogenesInfections: Evidence from Bacterial In Vitro Survival and Human Genetic Association

Critical Role of the C-Terminal Domains of Factor H in Regulating Complement Activation at Cell Surfaces

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