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The Fine Specificity and Cytokine Profile of T-Helper Cells Responsive to the 3 Chain of Type IV Collagen in Goodpasture’s Disease

Lindsay S. Cairns^*, Richard G. Phelps, Laura Bowie^*, Andrew M. Hall^*, Walaa W.M. Saweirs, Andrew J. Rees^* and Robert N. Barker^*

*Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, United Kingdom; and *Department of Clinical and Surgical Sciences (Internal Medicine), University of Edinburgh, Edinburgh, United Kingdom

Correspondence to Dr. Robert N. Barker, Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom. Phone: +44-1224-273168; Fax: +44-1224-273066;

ABSTRACT. Goodpasture’s disease is a severe nephritis characterized by autoantibodies to the 3 chain of type IV collagen, 3(IV)NC1, in the glomerular basement membrane. The disease 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 sequences. 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, binomial distribution) on two peptides, 3_71–90 and 3_131–150. 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 antibody 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 disease is dominated by epitopes that are normally inefficiently presented because of processing constraints. E-mail: r.n.barker@abdn.ac.uk

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