Causes of alternative pathway dysregulation in dense deposit disease.
OBJECTIVE
This study was designed to investigate the causes of alternative pathway dysregulation in a cohort of patients with dense deposit disease (DDD).


METHODS
Thirty-two patients with biopsy-proven DDD underwent screening for C3 nephritic factors (C3Nefs), factor H autoantibodies (FHAAs), factor B autoantibodies (FBAAs), and genetic variants in CFH. C3Nefs were detected by: ELISA, C3 convertase surface assay (C3CSA), C3CSA with properdin (C3CSAP), two-dimensional immunoelectrophoresis (2DIEP), and immunofixation electrophoresis (IFE). FHAAs and FBAAs were detected by ELISA, and CFH variants were identified by Sanger sequencing.


RESULTS
Twenty-five patients (78%) were positive for C3Nefs. Three C3Nef-positive patients were also positive for FBAAs and one of these patients additionally carried two novel missense variants in CFH. Of the seven C3Nef-negative patients, one patient was positive for FHAAs and two patients carried CFH variants that may be causally related to their DDD phenotype. C3CASP was the most sensitive C3Nef-detection assay. C3CASP and IFE are complementary because C3CSAP measures the stabilizing properties of C3Nefs, whereas IFE measures their expected consequence-breakdown of C3b.


CONCLUSIONS
A test panel that includes C3CSAP, IFE, FHAAs, FBAAs, and genetic testing for CFH variants will identify a probable cause for alternative pathway dysregulation in approximately 90% of DDD patients. Dysregulation is most frequently due to C3Nefs, although some patients test positive for FHAAs, FBAAs, and CFH mutations. Defining the pathophysiology of DDD should facilitate the development of mechanism-directed therapies.
Department of Otolaryngology-Head & Neck Surgery, Caver College of Medicine, University of Iowa, 5270 CBRB Building, Iowa City, IA 52242, USA.
Yuzhou
Y
Zhang
Nicole C
NC
Meyer
Kai
K
Wang
Carla
C
Nishimura
Kathy
K
Frees
Michael
M
Jones
Louis M
LM
Katz
Sanjeev
S
Sethi
Richard J H
RJ
Smith
D000293:Adolescent; D000328:Adult; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D002648:Child; D003178:Complement C3 Nephritic Factor / Q000032:analysis; D050577:Complement C3-C5 Convertases / Q000276:immunology; D011415:Complement Factor B / Q000276:immunology; D017242:Complement Factor H / Q000235:genetics / Q000276:immunology; D003170:Complement Pathway, Alternative; D004252:DNA Mutational Analysis; D004797:Enzyme-Linked Immunosorbent Assay; D004912:Erythrocytes / Q000276:immunology; D005260:Female; D005838:Genotype; D015432:Glomerulonephritis, Membranoproliferative / Q000097:blood / Q000175:diagnosis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007123:Immunoelectrophoresis, Two-Dimensional; D007484:Iowa; D053208:Kaplan-Meier Estimate; D007668:Kidney / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010641:Phenotype; D011379:Prognosis; D011414:Properdin / Q000276:immunology; D012756:Sheep; D013997:Time Factors; D055815:Young Adult
D001323:Autoantibodies; D015415:Biomarkers; C493495:CFH protein, human; D003178:Complement C3 Nephritic Factor; D011414:Properdin; D017242:Complement Factor H; D050577:Complement C3-C5 Convertases; D011415:Complement Factor B