In Goodpasture's disease, CD4(+) T cells escape thymic deletion and are reactive with the autoantigen alpha3(IV)NC1.
Goodpasture's disease is characterized by rapidly progressive glomerulonephritis and pulmonary hemorrhage, in association with circulating and deposited anti-glomerular basement membrane antibodies that recognize the alpha3 chain of type IV collagen [alpha3(IV)NC1] (known as the Goodpasture antigen). Unlike many other autoimmune diseases, recurrences are rare. In experimental models and human studies, both humoral and cellular mechanisms have been demonstrated to be involved in disease pathogenesis. However, there are few data on the characteristics of the autoreactive T cells or the mechanisms of tolerance to the autoantigen in human patients. It was demonstrated, using immunohistochemical analyses and reverse transcription-PCR, that the Goodpasture antigen is expressed in normal human thymus. Using limiting dilution analyses, the frequencies of circulating autoreactive T cells in patients and control subjects were assessed. During acute disease, there were increased frequencies of CD4(+) T cells reactive with alpha3(IV)NC1 (ranging from 1:6300 to 1:65,000), which decreased with time. There was a significant difference between patients during their acute disease phase and control subjects with respect to the frequency index for alpha3(IV)NC1-specific CD4(+) T cells (P < 0.05, Mann Whitney U test). The decrease in autoreactive CD4(+) T-cell numbers during recovery may be the reason why recurrences are infrequent and may explain the loss of pathogenic autoantibodies with time, because of a lack of T-cell help.
Salama
Alan D
AD
Renal Section, Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
Chaudhry
Afzal N
AN
Renal Section, Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
Ryan
James J
JJ
Renal Section, Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
Eren
Efram
E
Department of Immunology, Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
Levy
Jeremy B
JB
Renal Section, Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
Pusey
Charles D
CD
Renal Section, Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
Lightstone
Liz
L
Renal Section, Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
Lechler
Robert I
RI
Department of Immunology, Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
D000208:Acute Disease; D019867:Anti-Glomerular Basement Membrane Disease / Q000473:pathology / Q000503:physiopathology*; D001324:Autoantigens / Q000032:analysis* / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000502:physiology*; D024141:Collagen Type IV / Q000032:analysis* / Q000276:immunology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D012016:Reference Values; D013950:Thymus Gland / Q000276:immunology*; D013997:Time Factors
D001324:Autoantigens; D024141:Collagen Type IV; C057112:type IV collagen alpha3 chain