The fine specificity and cytokine profile of T-helper cells responsive to the alpha3 chain of type IV collagen in Goodpasture’s disease

Lindsay Susan Cairns, RG Phelps, Laura Elizabeth Stuart Bowie, Andrew Michael Hall, Walaa W M Saweirs, Andrew Jackson Rees, Robert Norman Barker

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Goodpasture's disease is a severe nephritis characterized by autoantibodies to the alpha3 chain of type IV collagen, alpha3(IV)NC1, in the glomerular basement membrane. The disease is very strongly associated with HLA-DR15, the affinities of alpha3(IV)NC1 peptides for DR15 are known, and elution experiments have identified major naturally processed sequences. Here, the fine specificity and cytokine profile of alpha3(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 (chi(2) = 8.6, P = 0.004) from a panel spanning the sequence of alpha3(IV)NC1 than did those from control DR15-positive donors and were highly focused (P = 0.0002, binomial distribution) on two peptides, alpha3(71-90) and alpha3(131-150). Some peptides induced interferon-gamma, 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 (chi(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 alpha3(IV)NC1 in Goodpasture's disease is dominated by epitopes that are normally inefficiently presented because of processing constraints.

Original languageEnglish
Pages (from-to)2801-2812
Number of pages12
JournalJournal of the American Society of Nephrology
Volume14
Issue number11
DOIs
Publication statusPublished - Nov 2003

Fingerprint

Helper-Inducer T-Lymphocytes
Cytokines
Peptides
Interleukin-10
Binomial Distribution
Glomerular Basement Membrane
Nephritis
Neutralizing Antibodies
Interleukin-4
Autoantibodies
Interferon-gamma
Epitopes
Blood Cells
type IV collagen alpha3 chain
Tissue Donors
T-Lymphocytes
Antigens

Cite this

The fine specificity and cytokine profile of T-helper cells responsive to the alpha3 chain of type IV collagen in Goodpasture’s disease. / Cairns, Lindsay Susan; Phelps, RG; Bowie, Laura Elizabeth Stuart; Hall, Andrew Michael; Saweirs, Walaa W M; Rees, Andrew Jackson; Barker, Robert Norman.

In: Journal of the American Society of Nephrology, Vol. 14, No. 11, 11.2003, p. 2801-2812.

Research output: Contribution to journalArticle

Cairns, Lindsay Susan ; Phelps, RG ; Bowie, Laura Elizabeth Stuart ; Hall, Andrew Michael ; Saweirs, Walaa W M ; Rees, Andrew Jackson ; Barker, Robert Norman. / The fine specificity and cytokine profile of T-helper cells responsive to the alpha3 chain of type IV collagen in Goodpasture’s disease. In: Journal of the American Society of Nephrology. 2003 ; Vol. 14, No. 11. pp. 2801-2812.
@article{e4c98c9fc5e745028be6ab5165dc8616,
title = "The fine specificity and cytokine profile of T-helper cells responsive to the alpha3 chain of type IV collagen in Goodpasture’s disease",
abstract = "Goodpasture's disease is a severe nephritis characterized by autoantibodies to the alpha3 chain of type IV collagen, alpha3(IV)NC1, in the glomerular basement membrane. The disease is very strongly associated with HLA-DR15, the affinities of alpha3(IV)NC1 peptides for DR15 are known, and elution experiments have identified major naturally processed sequences. Here, the fine specificity and cytokine profile of alpha3(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 (chi(2) = 8.6, P = 0.004) from a panel spanning the sequence of alpha3(IV)NC1 than did those from control DR15-positive donors and were highly focused (P = 0.0002, binomial distribution) on two peptides, alpha3(71-90) and alpha3(131-150). Some peptides induced interferon-gamma, 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 (chi(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 alpha3(IV)NC1 in Goodpasture's disease is dominated by epitopes that are normally inefficiently presented because of processing constraints.",
author = "Cairns, {Lindsay Susan} and RG Phelps and Bowie, {Laura Elizabeth Stuart} and Hall, {Andrew Michael} and Saweirs, {Walaa W M} and Rees, {Andrew Jackson} and Barker, {Robert Norman}",
year = "2003",
month = "11",
doi = "10.1097/01.ASN.0000091588.80007.0E",
language = "English",
volume = "14",
pages = "2801--2812",
journal = "Journal of the American Society of Nephrology",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "11",

}

TY - JOUR

T1 - The fine specificity and cytokine profile of T-helper cells responsive to the alpha3 chain of type IV collagen in Goodpasture’s disease

AU - Cairns, Lindsay Susan

AU - Phelps, RG

AU - Bowie, Laura Elizabeth Stuart

AU - Hall, Andrew Michael

AU - Saweirs, Walaa W M

AU - Rees, Andrew Jackson

AU - Barker, Robert Norman

PY - 2003/11

Y1 - 2003/11

N2 - Goodpasture's disease is a severe nephritis characterized by autoantibodies to the alpha3 chain of type IV collagen, alpha3(IV)NC1, in the glomerular basement membrane. The disease is very strongly associated with HLA-DR15, the affinities of alpha3(IV)NC1 peptides for DR15 are known, and elution experiments have identified major naturally processed sequences. Here, the fine specificity and cytokine profile of alpha3(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 (chi(2) = 8.6, P = 0.004) from a panel spanning the sequence of alpha3(IV)NC1 than did those from control DR15-positive donors and were highly focused (P = 0.0002, binomial distribution) on two peptides, alpha3(71-90) and alpha3(131-150). Some peptides induced interferon-gamma, 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 (chi(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 alpha3(IV)NC1 in Goodpasture's disease is dominated by epitopes that are normally inefficiently presented because of processing constraints.

AB - Goodpasture's disease is a severe nephritis characterized by autoantibodies to the alpha3 chain of type IV collagen, alpha3(IV)NC1, in the glomerular basement membrane. The disease is very strongly associated with HLA-DR15, the affinities of alpha3(IV)NC1 peptides for DR15 are known, and elution experiments have identified major naturally processed sequences. Here, the fine specificity and cytokine profile of alpha3(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 (chi(2) = 8.6, P = 0.004) from a panel spanning the sequence of alpha3(IV)NC1 than did those from control DR15-positive donors and were highly focused (P = 0.0002, binomial distribution) on two peptides, alpha3(71-90) and alpha3(131-150). Some peptides induced interferon-gamma, 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 (chi(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 alpha3(IV)NC1 in Goodpasture's disease is dominated by epitopes that are normally inefficiently presented because of processing constraints.

U2 - 10.1097/01.ASN.0000091588.80007.0E

DO - 10.1097/01.ASN.0000091588.80007.0E

M3 - Article

VL - 14

SP - 2801

EP - 2812

JO - Journal of the American Society of Nephrology

JF - Journal of the American Society of Nephrology

SN - 1046-6673

IS - 11

ER -