The Fine Specificity and Cytokine Profile of T-Helper Cells Responsive to the α3 Chain of Type IV Collagen in Goodpasture’s Disease

Goodpasture's disease is a severe nephritis charac- terized by autoantibodies to the 3 chain of type IV collagen, 3(IV)NC1, in the glomerular basement membrane. The dis- ease is very strongly associated with HLA-DR15, the affinities of 3(IV)NC1 peptides for DR15 are known, and elution experiments have identified major naturally processed se- quences. Here, the fine specificity and cytokine profile of 3(IV)NC1-reactive T cells from patients with Goodpasture's disease is defined. Peripheral blood mononuclear cells from patients at diagnosis proliferated in response to significantly more peptides ( 2 8.6, P 0.004) from a panel spanning the sequence of 3(IV)NC1 than did those from control DR15- positive donors and were highly focused (P 0.0002, bino- mial distribution) on two peptides, 371-90 and 3131-150. Some peptides induced interferon-, but none induced IL-4. Resolution of disease was accompanied by a striking deviation of the responses from proliferation to secretion of the T- regulatory cytokine IL-10, and addition of neutralizing anti- body confirmed that such IL-10 production was suppressive. The affinity of the peptides for DR15 molecules was positively correlated ( 2 14.6, P 0.00067) with the ability to elicit proliferation. However, unlike foreign antigens, this hierarchy is not due to responses against the major naturally processed peptides, which rarely stimulated proliferation and which have only intermediate affinity for DR15 molecules. It is inferred that the helper response to 3(IV)NC1 in Goodpasture's dis- ease is dominated by epitopes that are normally inefficiently presented because of processing constraints. Autoimmunity is thought to be important in the pathogenesis of most forms of glomerulonephritis, which together account for 25% of patients with end-stage renal failure. Current treat- ments for such autoimmune diseases are unsatisfactory, but the rational design of more effective approaches depends on un- derstanding the mechanisms by which self-tolerance to autoan- tigens can be lost and restored. Although rare, Goodpasture's disease provides a unique opportunity for these studies because it is the only glomerulonephritis in which the target of the autoimmune attack is known. Indeed, the Goodpasture antigen is one of the best defined autoantigens of pathologic relevance in any human autoimmune disease. Goodpasture's disease is characterized by pathogenic anti- glomerular basement membrane autoantibodies that are invari- ably specific for the COOH-terminal noncollagenous domain