Argument for the Classical Concept:

The Passive Heymann Nephritis Model   

(If the index is not shown on your left hand side: click here)

Antibodies against the rat kidney can be produced in rabbits by immunization of the rabbit with injections of a rat kidney extract into the rabbit. If these rabbit anti-rat kidney antibodies are injected into a rat they will immediately attack the rat´s glomeruli After a number of injections the rat develops glomerulonephritis with renal failure, a strong argument for the idea that an immunological reaction in the glomeruli alone can produce serious glomerulonephritis (Barabas & Lanigan 1974, Feenstra et al 1975).

Counter-Argument

This type of experimental glomerulonephritis develops in two steps. In the first stage, the heterologous phase, the rabbit anti-rat-kidney antibodies (the foreign, or heterologous antibodies) attack the rat´s glomeruli. At this stage a granular deposition of complement factors and rabbit antibodies are seen in the glomeruli. But this reaction does not result in any kidney damage and no proteinuria is seen. The second stage, the autologous phase, begins a few days later. As the injected anti-rat kidney antibodies come from another species, they are recognized as “foreign” by the rat´s immune system. Consequently, the rat starts to produce antibodies against the foreign antibodies. At this time, both rabbit and rat antibodies are seen in the glomeruli.
 

A reaction between antigen and antibody is the starting signal for inflammation. Normally, an inflammatory reaction protects us against foreign intruders such as bacteria, virus and other foreign substances. In the autologous phase the antibodies attack the foreign rabbit antibodies, that are located to the glomerular basement membrane. Therefore, the inflammation may destruct not only the intruders, but also the basement membrane.

The reason why the first reaction, the heterologous phase, does not damage the kidney but the second does, may partly be that the second involves many more antibodies, and partly because the second reaction happens to a membrane that is already damaged a little, just as a flu is harmless in healthy youngsters but can kill the old and the weak. By this way the GBM of the rat is damaged both from the immune complex formation between the injected, foreign anti-kidney antibodies and certain parts of the GBM, but also from the reactions between the rat’s own antibodies, the autologous antibodies, that are attacking the injected rabbit antibodies and thus indirectly also the GBM.

That it is the second reaction, the autologous phase that is crucial has been shown in an elegant variant of the experiment. Here, the rats were made tolerant to rabbit immunoglobulin by desensibilization before the experiment. As a result no renal damage was seen; the autologous phase had been eliminated. (Zanetti & Druet 1980).

Even if it were correct that glomerulonephritis in the passive Heymann nephritis is produced by immunological means only, the mechanism is of course highly unlikely in human beings, because no one would ever have injected anti-human antibodies. To assume that the passive Heymann nephritis is a model of human glomerulonephritis should demand that the patient produces antibodies against his own GBM, but also, at the same time, produces antibodies against his own immunoglobulins, a hitherto unknown combination of events in glomerulonephritis.

It is possible to demonstrate in another way that the rat's own anti-kidney antibodies alone are unable to hurt the kidney. If anti-kidney antibodies (extracted from a rat with active Heymann nephritis) are injected into a healthy rat, these antibodies immediately locate to the glomeruli together with complement, indicating that an antigen-antibody reaction has taken place in the glomeruli. But no kidney damage is seen, just as no damage was seen during the heterologous phase. The urine is normal as is the renal function, clearly indicating that a direct immunological attack against the glomeruli is harmless - a crucial factor is missing (Sugisaki et al 1973, Fleuren et al 1980, Abrass et al 1983, Ravnskov 1998).

Next section: Experimental Anti-GBM Nephritis