Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency

Józsi, Mihály; Licht, Christoph; Strobel, Stefanie; Zipfel, S.; Richter, Heiko; Heinen, Stefan; Zipfel, Peter F.; Skerka, Christine

doi:10.1182/blood-2007-09-109876

Cited by 330 publications

(323 citation statements)

References 26 publications

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“…Patients who have aHUS with combined mutations have been reported (4). Approximately 10% of children with aHUS have an acquired functional CFH deficiency caused by anti-CFH autoantibodies, frequently associated with absent CFHR1/ CFHR3 (11)(12)(13). In mutation carriers, aHUS penetrance is approximately 50%, suggesting that other genetic or environmental modifiers are needed for disease expression (3).…”

Section: H Emolytic Uremic Syndrome (Hus) Is a Clinical Triad Ofmentioning

confidence: 99%

Complement Inhibitor Eculizumab in Atypical Hemolytic Uremic Syndrome

Mache

Acham-Roschitz

Frémeaux‐Bacchi

et al. 2009

Clinical Journal of the American Society of Nephrology

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144

103

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Background and objectives: Atypical hemolytic uremic syndrome (aHUS) is associated with a congenital or acquired dysregulation of the complement alternative pathway that leads to continuous complement activation on host cells causing inflammation and damage. Eculizumab, a humanized mAb against complement protein C5, inhibits activation of the terminal complement pathway.Design, setting, participants, & measurements: We report an adolescent with relapsing unclassified aHUS. On admission, a high plasma creatinine level indicated a poor prognosis, and hemodialysis had to be started. Plasma exchanges were initially effective against the microangiopathic hemolytic activity and allowed a temporary improvement of renal function with termination of hemodialysis after 7 wk. Subsequently, plasma exchanges (three times per week) failed to prevent ongoing aHUS activity and progressive renal failure. After 12 wk, aHUS treatment was switched to eculizumab.Results: Eculizumab was effective in terminating the microangiopathic hemolytic process in two aHUS relapses; however, after normalization of complement activity, aHUS recurred and ultimately led to anuric end-stage renal failure.Conclusions: In this patient, complement inhibition by eculizumab temporarily terminated the microangiopathic hemolytic activity. Nevertheless, renal damage as a result of preceding and subsequent aHUS activity resulted in end-stage renal failure; therefore, therapeutic success may depend on early administration of eculizumab. The optimal duration of treatment may be variable and remains to be determined.

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Section: H Emolytic Uremic Syndrome (Hus) Is a Clinical Triad Ofmentioning

confidence: 99%

Complement Inhibitor Eculizumab in Atypical Hemolytic Uremic Syndrome

Mache

Acham-Roschitz

Frémeaux‐Bacchi

et al. 2009

Clinical Journal of the American Society of Nephrology

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144

103

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“…Bacteria (10 4 CFU) were incubated in 5% NHS diluted either in DGVB ϩϩ or 10% FH-depleted serum prepared as described previously (38) in a final volume of 100 l. At different time points, 10-l aliquots were removed and spread onto chocolate agar plates. After 18 h of incubation at 37°C, CFUs were determined.…”

Section: Serum Bactericidal Assaymentioning

confidence: 99%

Haemophilus influenzae Interacts with the Human Complement Inhibitor Factor H

Hallström

Zipfel

Blom

et al. 2008

The Journal of Immunology

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Pathogenic microbes acquire human complement inhibitors to circumvent the innate immune system. In this study, we identify two novel host-pathogen interactions, factor H (FH) and factor H-like protein 1 (FHL-1), the inhibitors of the alternative pathway that binds to Hib. A collection of clinical Haemophilus influenzae isolates was tested and the majority of encapsulated and unencapsulated bound FH. The isolate Hib 541 with a particularly high FH-binding was selected for detailed analysis. An increased survival in normal human serum was observed with Hib 541 as compared with the low FH-binding Hib 568. Interestingly, two binding domains were identified within FH; one binding site common to both FH and FHL-1 was located in the N-terminal short consensus repeat domains 6–7, whereas the other, specific for FH, was located in the C-terminal short consensus repeat domains 18–20. Importantly, both FH and FHL-1, when bound to the surface of Hib 541, retained cofactor activity as determined by analysis of C3b degradation. Two H. influenzae outer membrane proteins of ∼32 and 40 kDa were detected with radiolabeled FH in Far Western blot. Taken together, in addition to interactions with the classical, lectin, and terminal pathways, H. influenzae interferes with the alternative complement activation pathway by binding FH and FHL-1, and thereby reducing the complement-mediated bactericidal activity resulting in an increased survival. In contrast to incubation with active complement, H. influenzae had a reduced survival in FH-depleted human serum, thus demonstrating that FH mediates a protective role at the bacterial surface.

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“…7 We have also shown that NAHR in this region leads to deletions incorporating CFHR3/CFHR1 and CFHR1/CFHR4, which are associated with the presence of fH autoantibodies in aHUS. [8][9][10] We routinely use multiplex ligation-dependent probe amplification (MLPA) 11 to screen for genomic disorders in aHUS. In this study, we report the finding of a deletion in the C terminal region of CFH in a large aHUS family.…”

Section: Introductionmentioning

confidence: 99%

A novel hybrid CFH/CFHR3 gene generated by a microhomology-mediated deletion in familial atypical hemolytic uremic syndrome

Francis

McNicholas

Awan

et al. 2012

Blood

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Genomic disorders affecting the genes encoding factor H (fH) and the 5 factor H related proteins have been described in association with atypical hemolytic uremic syndrome. These include deletions of CFHR3, CFHR1, and CFHR4 in association with fH autoantibodies and the formation of a hybrid CFH/CFHR1 gene. These occur through nonallelic homologous recombination secondary to the presence of large segmental duplications (macrohomology) in this region. Using multiplex ligation-dependent probe amplification to screen for such genomic disorders, we have identified a large atypical hemolytic uremic syndrome family where a deletion has occurred through microhomologymediated end joining rather than nonallelic homologous recombination. In the 3 affected persons of this family, we have shown that the deletion results in formation of a CFH/CFHR3 gene. We have shown that the protein product of this is a 24 SCR protein that is secreted with normal fluid-phase activity but marked loss of complement regulation at cell surfaces despite increased heparin binding. In this study, we have therefore shown that microhomology in this area of chromosome 1 predisposes to disease associated genomic disorders and that the complement regulatory function of fH at the cell surface is critically dependent on the structural integrity of the whole molecule. (Blood. 2012;119(2):591-601)

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Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency

Abstract: Atypical hemolytic uremic syndrome (aHUS) is a severe renal disease that is associated with defective complement regulation caused by multiple factors. We previously described the deficiency of factor H-related proteins CFHR1 and CFHR3 as predisposing factor for aHUS.

Cited by 330 publications

References 26 publications

Complement Inhibitor Eculizumab in Atypical Hemolytic Uremic Syndrome

Complement Inhibitor Eculizumab in Atypical Hemolytic Uremic Syndrome

Haemophilus influenzae Interacts with the Human Complement Inhibitor Factor H

A novel hybrid CFH/CFHR3 gene generated by a microhomology-mediated deletion in familial atypical hemolytic uremic syndrome

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