The Autoimmune Disease DEAP-Hemolytic Uremic Syndrome

Abstract

DEAP-HUS (deficiency of CFHR plasma proteins and factor H [FH] autoantibody positive hemolytic uremic syndrome [HUS]) is a new form of HUS characterized by a deletion of genes coding for FH-related proteins and the presence of autoantibodies directed to FH. These disease-associated autoantibodies inhibit FH (CFH) surface binding functions, which results in a defective regulation of the alternative pathway and damage of endothelial cells. Here we describe two representative patients with DEAP-HUS who both developed end-stage renal failure with the background of homozygous deletion of CFHR1 and CFHR3 genes and the presence of FH autoantibodies. Based on the retrospective diagnosis of DEAP-HUS 2 to 12 months after the initial clinical presentation, subsequent immunosuppressive therapy was initiated. The autoantibody titers decreased, and the complement status of the patients improved, as indicated by increased C3 levels. Thus early diagnosis of DEAP-HUS and immunosuppressive treatments are important factors to treat this particular type of HUS.

Causes of Alternative Pathway Dysregulation in Dense Deposit Disease

“…In the Tedecsco et al report Only one patient in our study was positive for FHAAs. These antibodies have been reported in other DDD patients and in aHUS (42,43). The different phenotypes reflect antibody specificity for either the amino-or carboxy-terminal SCRs of FH, respectively.…”

The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy

“…In addition to results from next-generation sequencing, 2 recipients with TMA had homozygous deletion of CFHR3/CFHR1 detected by multiple ligationdependent probe amplification that was not seen in recipients without TMA. 26 Both of the patients with homozygous deletion of CFHR3/ CFHR1 had severe multivisceral TMA and died. No known pathogenic variants were seen in recipients without TMA.…”

Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy

“…21 Patients with aHUS lacking CFHR1, but not those lacking CFHR3, present with CFH antibodies, suggesting that the generation of these antibodies is associated with CFHR1 deficiency. 15,16,22,24 Although CFH autoantibodies are reported in approximately 10% of patients with aHUS, they are not specific for aHUS and have been identified in 9% to 16% of patients with rheumatoid arthritis, 7% of patients with systemic lupus erythematosus, 9% of patients with a history of thrombosis and antiphospholipid antibodies, and 4% of adult volunteers in a large European study. 25 The same study reported that in patients with clinical disease, CFH autoantibody titers varied among individual patients throughout time and were usually detected during periods of more severe disease.…”

“…15,16 The role of complement in TMA occurring after stem cell transplantation has not been defined. We present our clinical observations suggesting the complement alternative pathway is involved in the pathogenesis of HSCT-associated TMA.…”