Background. Autoimmunity to kidney antigens causes membranous nephropathy a
nd Goodpasture's disease and very likely is pivotal in many other glomerula
r diseases. We investigated the potential for central tolerance to the best
-characterized kidney autoantigen the NC1 domain of the alpha3 chain of typ
e IV collagen [alpha3(IV)NC1], which is the target of autoimmune attack in
Goodpasture's disease.
Methods. Indirect immunofluorescence on human thymus and polymerase chain r
eaction (PCR) and Southern blot analysis of cDNA reverse transcribed from R
NA extracted from human thymus and kidney.
Results. Indirect immunofluorescence on human thymus demonstrated the prese
nce of alpha3(IV)NC1 in all six thymus samples examined. The homologous col
lagen IV chain, alpha5(IV)NC1, also was detected with a similar intra-thymi
c distribution. Strikingly, thymic alpha3 and alpha5 localized around and w
ithin Hassall's corpuscles in the thymic medulla, which are structures impl
icated in T cell apoptosis and possibly negative selection. In contrast, al
pha1(IV)NC1 localized to the basement membranes of interlobular septa and b
lood vessels, as is typical of collagen IV chains situated outside the thym
us. Reverse transcription-polymerise chain reaction (RT-PCR) confirmed the
presence of mRNA encoding alpha3(IV)NC1 and alpha5(IV)NC1 in thymic tissue
establishing that the antigens were likely to have been synthesized locally
.
Conclusions. The results demonstrate that alpha3(IV)NC1 is expressed in the
human thymus, and therefore should be available for induction of alpha3(IV
)NC1-specific tolerance. This observation has the important implication tha
t patients' alpha3(IV)NC1-specific, autoreactive T cells are more likely to
recognize cryptic epitopes that are not adequately presented by thymic ant
igen-presenting cells (APC) than the major antigen-derived epitopes general
ly identified by conventional approaches.