Does evolution ‘care’ about idiotypy?

Is there an idiotypic network? Is it functional? Why do idiotypic antibodies exist at all? What is the role of anti-idiotypic antibodies in evolution

Is there a functional idiotypic network? Why do idiotypic antobdies exist? What is the role of anti-idiotypic antibodies in evolution?

The fatal attraction of idiotypy

When we started our work on the IgOme representation of the repertoire, we were committed to generating data and mining it for meaning without preconceptions. As we got the first public IgM mimotope libraries and checked the sequences against the human proteome for possible linear epitopes, we were surprised to find that an unexpectedly large fraction of the mimotopes were identical or homologous to sequences in the HCDR3 regions of other antibodies¹.

Our earlier fascination with idiotypy, for which we were shamed by the disillusioned immunological community^2,3, resurfaced like an old love. Of course, nobody has denied the existence of idiotypic antibodies, but the question of whether they are functional or merely a byproduct of the immune system’s architecture has been debated. The major obstacle seemed to be the lack of appropriate system-level methodology. Could we have a new tool at our disposal to study idiotypy in a more systematic way?

Here is what we found so far

Studying the changes in IgM repertoire in antiphospholipid syndrome (APS) patients, we found that a 0.5% of the IgM reactivities, normally found in healthy donors, are lost in APS patients. The APS specific IgM reactivties were several fold lower in number.The mimotope sequences of changed reactivities were mapping to idiotopes more often than expected, but those in healthy were also related to public reactivities while those in APS - not⁴.

Next, we tested the capacity of our optimized public IgM mimotope library to differentiate neurodegenerative diseases. The serum IgM (but not the IgG) distinguished a large cluster of public reactivities that were lost in Alzheimer’s and frontotemporal dementia, but not in other forms of dementia, and the respective mimotope sequences were non-randomly homologous to idiotopes⁵. Interestingly, the IgG reactivities better differentiated Alzheimer’s disease from frontotemporal dementia, but did not correlate with idiotypy.

Thus, IgOme maps show changes associated with autoimmune pathology with two recurrent features:

- Loss of public IgM reactivities and

- Non-random association with idiotypic reactivity.

NoteMore on the Immune Network Theory controversy;

• Here is a short essay on the state of the art of the idiotypic network theory

• Here is a synopsis of the major immunological theories

References

1.

Pashov, A. et al. Diagnostic profiling of the human public IgM repertoire with scalable mimotope libraries. Frontiers in Immunology 10, 2796 (2019).

2.

Langman, R. E. & Cohn, M. The “complete” idiotype network is an absurd immune system. Immunology Today 7, 100–101 (1986).

3.

Søren Ventegodt, Hermansen, T. D., Isack Kandel & Merrick, J. Human development XVII: Jerne’s anti-idiotypic network theory cannot explain self-nonself discrimination. in (2010).

4.

Pashova, S. et al. Restriction of the global IgM repertoire in antiphospholipid syndrome. Frontiers in Immunology 13, 865232 (2022).

5.

Pashova-Dimova, S. et al. Changes in the public IgM repertoire and its idiotypic connectivity in alzheimer’s disease and frontotemporal dementia. J Neuroimmunol 409, 578775 (2025).