Anti-complement factor I antibody associated atypical hemolytic uremic syndrome – A new insight for future perspective!

Govindarajan, Srinivasavaradan; Rawat, Amit; Ramachandran, Raja; Hans, Rekha; Sharawat, Indar Kumar; Tiewsoh, Karalanglin

doi:10.1016/j.imbio.2020.152000

Cited by 8 publications

(3 citation statements)

References 10 publications

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“…This novel nding also suggests propensity for autoantibody generation in Indian children with aHUS, who have an unexplained high prevalence of autoantibodies to FH in almost one-half of the cohort [12]. In this regard, the detection of anti-FI antibodies in 11 of 31 Indian children with aHUS supports the above hypothesis [29]. In the present study, the level of anti-FH titers in patients with both anti-FB and anti-FH antibodies was almost twice higher than patients without anti-FB antibodies, suggesting more severe disease in the former.…”

Section: Discussionsupporting

confidence: 66%

“…We speculate that anti-FB antibodies might contribute to the pathogenesis of aHUS and C3 glomerulopathy by activating C3 convertase, with dysregulation of the alternative complement pathway. Upon activation of the alternative pathway, C3(H 2 O)-bound FB is cleaved by factor D, to release an enzymatically active fragment Bb [29]. The Bb fragment has two domains: the von Willebrand (vW) type A domain that interacts with C3b to form the C3 convertase complex, and a serine protease (SP) domain that further cleaves C3 to C3b, forming a self-ampli cation loop [25].…”

Section: Discussionmentioning

confidence: 99%

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Anti-factor B antibodies in atypical hemolytic uremic syndrome

Khandelwal,

Nambiar,

Saini

et al. 2024

Pediatr Nephrol

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BackgroundThe etiology of atypical hemolytic uremic syndrome (aHUS) is unknown in 30-40% patients. Anti-factor B (FB) antibodies are reported in C3 glomerulopathy (C3G) and immune-complex membranoproliferative glomerulonephritis (IC-MPGN), though not in aHUS. MethodsWe screened patients < 18-year-old from cohorts of aHUS and C3G/idiopathic IC-MPGN. Anti-FB IgG antibodies were measured by ELISA and con rmed by Western blot. Normative levels were based on antibody levels in 103 healthy blood donors. ResultsThe prevalence of anti-FB antibodies was 9.7% (95% CI 6.1-14.5%; n = 21) in 216 patients with aHUS, including 11.5% (95% CI 6.4-18.5%; n = 14) in anti-FH associated aHUS and 11.8% (95% CI 4.4-23.9%; n = 6) in patients without a de nitive genetic or autoimmune etiology. Patients with signi cant genetic variants did not show anti-FB antibodies. In patients with concomitant anti-FB and anti-FH antibodies, median anti-FH titers were higher (11312 AU/ml vs. 4920 AU/ml; P = 0.044). Anti-FB antibody titer correlated with disease severity (hemoglobin and platelets; P < 0.05), declined following plasma exchange and increased during relapse. While 4/64 patients with C3G (6.3%) and 1/17 with IC-MPGN showed anti-FB antibodies, titers were higher in aHUS (544.8 AU/ml vs.1028.8; P = 0.003). ConclusionAnti-FB antibodies are present in 6-10% patients with aHUS and C3G/IC-MPGN, with higher titers in the former. The diagnostic and therapeutic implication of anti-FB antibodies in aHUS needs con rmation and further studies. The study shows propensity for autoantibody generation and co-existence of multiple risk-factors for aHUS in Indian children.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Anti-factor B antibodies in atypical hemolytic uremic syndrome

Khandelwal,

Nambiar,

Saini

et al. 2024

Pediatr Nephrol

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“…Genetic testing of affected individuals revealed that all individuals with CFI autoantibodies have two copies of CFHR1 and CFHR3 genes, suggesting that CFI autoantibodies affect the development of CFH since low CFH levels were observed in all three patients. Govindarajan et al reported CFI autoantibodies identified in 31% of a sample pediatric aHUS population in India [ 47 ]. Age notably affected which antibodies were the most common, where aHUS patients under 2 years old mainly had CFI autoantibodies and children over 2 years old had anti-CFH antibodies.…”

Section: Selected Mutations and Anti-complement Factor Antibodiesmentioning

confidence: 99%

Pediatric Atypical Hemolytic Uremic Syndrome Advances

Raina

Vijayvargiya

Khooblall

et al. 2021

Cells

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Atypical hemolytic uremic syndrome (aHUS) is a rare disorder characterized by dysregulation of the alternate pathway. The diagnosis of aHUS is one of exclusion, which complicates its early detection and corresponding intervention to mitigate its high rate of mortality and associated morbidity. Heterozygous mutations in complement regulatory proteins linked to aHUS are not always phenotypically active, and may require a particular trigger for the disease to manifest. This list of triggers continues to expand as more data is aggregated, particularly centered around COVID-19 and pediatric vaccinations. Novel genetic mutations continue to be identified though advancements in technology as well as greater access to cohorts of interest, as in diacylglycerol kinase epsilon (DGKE). DGKE mutations associated with aHUS are the first non-complement regulatory proteins associated with the disease, drastically changing the established framework. Additional markers that are less understood, but continue to be acknowledged, include the unique autoantibodies to complement factor H and complement factor I which are pathogenic drivers in aHUS. Interventional therapeutics have undergone the most advancements, as pharmacokinetic and pharmacodynamic properties are modified as needed in addition to their as biosimilar counterparts. As data continues to be gathered in this field, future advancements will optimally decrease the mortality and morbidity of this disease in children.

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