IDENTIFICATION OF THE ALPHA-3 CHAIN OF TYPE-IV COLLAGEN AS THE COMMONAUTOANTIGEN IN ANTIBASEMENT MEMBRANE DISEASE AND GOODPASTURE-SYNDROME

Antiglomerular basement membrane (GEM) antibodies can cause glomerulon ephritis or pulmonary hemorrhage by themselves or Goodpasture syndrome when they occur together. It is unknown if variations in antibody rea ctivity contribute to the different patterns of organ involvement seen in this disease. This study examines the reactivity of the alpha 1-al pha 6 NCl domains of Type IV collagen, the putative autoantigen, in se ra from patients with anti-GEM antibodies after various clinical prese ntations of lung hemorrhage and renal injury. Serum or plasma containi ng anti-GEM antibodies from 35 patients with combined glomerulonephrit is and pulmonary hemorrhage, 19 with glomerulonephritis alone, and 4 w ith pulmonary hemorrhage alone were compared with samples from 19 norm al controls and 32 patients with other kidney diseases. Four different immunologic assays were performed with bovine alpha 1-alpha 6(IV) and recombinant human type alpha 1-alpha 5(IV) collagen NCl domains. The study found that the anti-GEM antibodies from all patients reacted wit h the alpha 3(IV) NCl (85% exclusively). Additional limited reactivity with the alpha 1(IV) NCl and alpha 4(IV) NCl was found in 15 and 3%, respectively. This non-alpha 3(IV) NCl reactivity was most frequent in the patients with anti-GBM antibodies and glomerulonephritis alone. N one of the patients had reactivity to other basement membrane componen ts like laminin, fibronectin, heparan sulfate proteoglycan, entactin, or the 7S and triple helical fragments of Type IV collagen. The observ ed alpha-chain NCl reactivity was confined to patients with anti-GEM a ntibodies with no additional reactivities detected among a large numbe r of other kidney diseases controls, The correlation of alpha 1-alpha 6(1V) NCl reactivity in a large number of patients with anti-GEM antib odies defined by classic assays definitively establishes that reactivi ty to alpha 3(IV) NCl domains is both sufficient and necessary for the expression of autoimmune disease directed to the NCl domain of Type I V collagen. On the basis of the evidence, the classification of antiba sement membrane disease and Goodpasture syndrome as anti-Type IV colla gen disease is proposed.