Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome
ABSTRACT Hemolytic uremic syndrome (HUS) is characterized by the triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The non-Shiga toxin-associated HUS (atypical HUS [aHUS]) has been shown to be a disease of complement dysregulation. Mutations in the plasma complement regulators factor H and factor I and the widely expressed membrane cofactor protein (MCP; CD46) have been described recently. This study looked for MCP mutations in a panel of 120 patients with aHUS. In this cohort, approximately 10% of patients with aHUS (11 patients; nine pedigrees) have mutations in MCP. The onset typically was in early childhood. Unlike patients with factor I or factor H mutations, most of the patients do not develop end-stage renal failure after aHUS. The majority of patients have a mutation that causes reduced MCP surface expression. A small proportion expressed normal levels of a dysfunctional protein. As in other studies, incomplete penetrance is shown, suggesting that MCP is a predisposing factor rather than a direct causal factor. The low level of recurrence of aHUS in transplantation in patients with MCP mutations is confirmed, and the first MCP null individuals are described. This study confirms the association between MCP deficiency and aHUS and further establishes that a deficiency in complement regulation, specifically cofactor activity, predisposes to severe thrombotic microangiopathy in the renal vasculature.
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- "IFN-g production by murine CD4 + T cells is accompanied by specific metabolic changes (Chang et al., 2013), which led us to interrogate whether CD46 regulates human Th1 cell responses via modulation of key metabolic pathways. We used T cells from three patients with absent or severely reduced CD46 expression (CD46-1, CD46-2, and CD46-3 [Couzi et al., 2008; Fremeaux-Bacchi et al., 2006; and Figure S1B, legend]), T cells from healthy donors (HDs) in which CD46 protein expression was reduced by siRNA technique , and Jurkat T cell lines overexpressing specific CD46 isoforms . Whole-exome sequencing of DNA samples from patients CD46-2 (sibling of CD46-1) and CD46-3 confirmed the expected mutations in CD46 but did not identify additional mutations in candidate genes mediating T cell function or genes known to cause monogenic immune defects (Table S1 and S2). "
ABSTRACT: The discovery of new vaccines against infectious diseases and cancer requires the development of novel adjuvants with well-defined activities. The TLR4 agonist adjuvant GLA-SE elicits robust Th1 responses to a variety of vaccine Ags and is in clinical development for both infectious diseases and cancer. We demonstrate that immunization with a recombinant protein Ag and GLA-SE also induces granzyme A expression in CD4 T cells and produces cytolytic cells that can be detected in vivo. Surprisingly, these in vivo CTLs were CD4 T cells, not CD8 T cells, and this cytolytic activity was not dependent on granzyme A/B or perforin. Unlike previously reported CD4 CTLs, the transcription factors Tbet and Eomes were not necessary for their development. CTL activity was also independent of the Fas ligand-Fas, TRAIL-DR5, and canonical death pathways, indicating a novel mechanism of CTL activity. Rather, the in vivo CD4 CTL activity induced by vaccination required T cell expression of CD154 (CD40L) and target cell expression of CD40. Thus, vaccination with a TLR4 agonist adjuvant induces CD4 CTLs, which kill through a previously unknown CD154-dependent mechanism. Copyright © 2015 by The American Association of Immunologists, Inc.The Journal of Immunology 08/2015; DOI:10.4049/jimmunol.1501118 · 5.36 Impact Factor
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- "Mutation screening of CFH, CFI, CD46, C3 and CFB revealed a heterozygous CD46 splice site mutation (IVS2+2T>G). This change has previously been identified in a patient with aHUS and demonstrated to result in abnormal splicing [6, 7]. FACS analysis of granulocytes from the patient demonstrated that cell surface expression of CD46 was reduced by 50% (Figure 1). "
ABSTRACT: We present a case of haemolytic uraemic syndrome (HUS) triggered by Shigella flexneri. Of the Shigella species, only S. dysenteriae type 1 is said to produce Shiga toxin and consequently cause HUS. Investigation of the complement system in this patient revealed a CD46 mutation. In individuals with mutations in complement genes incomplete penetrance of atypical HUS (aHUS) is seen, suggesting that a trigger, such as infection, is required for disease to manifest. In an era of complement modulatory therapy for aHUS it is important to be alert to unusual presentations of diarrhoeal-associated disease.CKJ: Clinical Kidney Journal 06/2014; 7(3):286-288. DOI:10.1093/ckj/sfu032
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- "This suggests that aHUS results from a Transplantation Reviews xxx (2013) xxx–xxx complex interplay between genetics and environmental factors. Lossof-function mutations in genes encoding Complement Factor H (CFH)  , Complement Factor I (CFI)  , Membrane Cofactor Protein (MCP)    or thrombomodulin (THBD)   have been found in 20–30%, 2–12%, 10–15% and 0–5% of aHUS patients, respectively. Gain-of-function mutations in genes that encode Complement Factor B (CFB)  and complement Component 3 (C3)   have been identified in 1–2% and 10% of aHUS patients, respectively. "
ABSTRACT: Atypical hemolytic and uremic syndrome (aHUS) is associated with a high rate of recurrence and poor outcomes after kidney transplantation. Fortunately, recent advances in the understanding of the pathogenesis of aHUS have permitted an individualized risk assessment of post-transplant recurrence. Acquired or inherited dysregulation of the alternative complement pathway, thought to be the driving force of the disease, is identified in most aHUS patients. Notably, depending on the mutations involved, the risk of recurrence greatly varies, highlighting the importance of undertaking etiological investigations prior to kidney transplantation. In those with moderate to high risk of recurrence, the use of a prophylactic therapy, consisting in either plasmapheresis or eculizumab therapies, represents a major stride forward in the prevention of aHUS recurrence after kidney transplantation. In those who experience aHUS recurrence, a growing number of observations suggest that eculizumab therapy outperforms curative plasma therapy. The optimal duration of both prophylactic and curative therapies remains an important, yet unaddressed, issue. In this respect, the kidney transplant recipients, continuously exposed to endothelial-insulting factors, referred here as to triggers, might have a sustained high risk of recurrence. A global therapeutic approach should thus attempt to reduce exposure to these triggers.Transplantation reviews (Orlando, Fla.) 08/2013; 27(4). DOI:10.1016/j.trre.2013.07.003 · 2.68 Impact Factor