Antibodies to α5 chain of collagen IV are pathogenic in Goodpasture's disease.
Autoantibody against glomerular basement membrane (GBM) plays a direct role in the initiation and development of Goodpasture's (GP) disease. The principal autoantigen is the non-collagenous domain 1 (NC1) of α3 chain of collagen IV, with two immunodominant epitopes, EA-α3 and EB-α3. We recently demonstrated that antibodies targeting α5NC1 are bound to kidneys in GP patients, suggesting their pathogenic relevance. In the present study, we sought to assess the pathogenicity of the α5 autoantibody with clinical and animal studies. Herein, we present a special case of GP disease with circulating autoantibody reactive exclusively to the α5NC1 domain. This autoantibody reacted with conformational epitopes within GBM collagen IV hexamer and produced a linear IgG staining on frozen sections of human kidney. The antibody binds to the two regions within α5NC1 domain, EA and EB, and inhibition ELISA indicates that they are targeted by distinct sub-populations of autoantibodies. Sequence analysis highlights five residues that determine specificity of antibody targeting EA and EB epitopes of α5NC1 over homologous regions in α3NC1. Furthermore, immunization with recombinant α5NC1 domain induced crescentic glomerulonephritis and alveolar hemorrhage in Wistar-Kyoto rats. Thus, patient data and animal studies together reveal the pathogenicity of α5 antibodies. Given previously documented cases of GP disease with antibodies selectively targeting α3NC1 domain, our data presents a conundrum of why α3-specific antibodies developing in majority of GP patients, with α5-specific antibodies emerged in isolated cases, the answer for which is critical for understanding of etiology and progression of the GP disease.
Renal Division, Department of Medicine, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, China.
Zhao
Z
Cui
Renal Division, Department of Medicine, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, China; Peking-Tsinghua Center for Life Sciences, Beijing, China. Electronic address: mhzhao@bjmu.edu.cn.
Ming-Hui
MH
Zhao
Renal Division, Department of Medicine, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, China.
Xiao-Yu
XY
Jia
Renal Division, Department of Medicine, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, China.
Miao
M
Wang
Renal Division, Department of Medicine, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, China.
Shui-Yi
SY
Hu
Renal Division, Department of Medicine, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, China.
Su-Xia
SX
Wang
Renal Division, Department of Medicine, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, China.
Feng
F
Yu
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Center for Matrix Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
Kyle L
KL
Brown
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Center for Matrix Biology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; Vanderbilt Institute of Chemical Biology, Nashville, TN, USA. Electronic address: billy.hudson@vanderbilt.edu.
Billy G
BG
Hudson
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Center for Matrix Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
Vadim
V
Pedchenko
D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000175:diagnosis / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity; D001706:Biopsy; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D024141:Collagen Type IV / Q000737:chemistry / Q000276:immunology*; D004195:Disease Models, Animal; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D005260:Female; D006801:Humans; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008958:Models, Molecular; D011487:Protein Conformation; D021122:Protein Subunits / Q000276:immunology*; D051381:Rats; D011921:Rats, Inbred WKY
D001323:Autoantibodies; D001324:Autoantigens; D024141:Collagen Type IV; D000939:Epitopes; D021122:Protein Subunits
Antigen; Autoantibody; Collagen IV; Epitopes; Glomerular basement membrane (GBM); Goodpasture's disease; NC1 domain