On 2018 Jan 27, Viktor Müller commented:

While it is true that there is considerable overlap in the recognition of self and (possibly pathogenic) non-self epitopes (Calis et al [1] estimated an overlap of around one third for HLA class I alleles), this is likely to make the job of the immune system harder, rather than easier. The overlapping peptides tend to be non-immunogenic, indicating tolerance, and the immune system needs to be able to target epitopes that are distinguishable from self peptides even with the degenerate recognition of T cell receptors [1]. Furthermore, even if the recognition task was indeed reduced to self and similar peptides, this would still vastly exceed the capacity of a fixed germline-encoded receptor repertoire. The number of distinct potential epitopes (for HLA class I) is of the order of magnitude 10⁷ in humans [2] and in mice [3]; this exceeds the maximum number of germline immune receptors found in any species by several orders of magnitude.

We still maintain that "Distinguishing tumours from normal self is likely to be the most challenging task for Darwinian immunity that could only be added at advanced stages of its evolution" [4], but have never claimed the same for positive selection. Amphioxus has proto-MHC, and positive selection might indeed be an ancient characteristic of (vertebrate) Darwinian immunity. It will be instructive to elucidate whether and how the divergent adaptive system of jawless fish handles positive selection, or anything analogous to MHC restriction in general.

Finally, we note that the origin of vertebrate adaptive immunity is a notoriously difficult problem. We certainly do not know the whole truth about the complex events that took place more than half a billion years ago -- but we hope that, by surveying the most recent evidence, we have taken a small step in the right direction.

[1] Calis JJA, de Boer RJ, Keşmir C (2012) Degenerate T-cell Recognition of Peptides on MHC Molecules Creates Large Holes in the T-cell Repertoire. PLoS Comput Biol 8(3): e1002412. https://doi.org/10.1371/journal.pcbi.1002412

[2] Burroughs, N.J., de Boer, R.J. & Keşmir, C. Immunogenetics (2004) 56: 311. https://doi.org/10.1007/s00251-004-0691-0

[3] Müller, V. & Bonhoeffer, S. (2003). Quantitative constraints on the scope of negative selection. Trends Immunol 24, 132-5. https://doi.org/10.1016/S1471-4906(03)00028-0

[4] Müller V, Boer RJ de, Bonhoeffer S, Szathmáry E (2018) Biol Rev 93:505-528. https://doi.org/10.1111/brv.12355

On 2018 Jan 20, Donald Forsdyke commented:

PATHOGEN COEVOLUTION AND THE ANTIGENIC UNIVERSE

The distinction between selective and instructive (Lamarckian) systems of immunity (1) – originating with Paul Ehrlich – was clearly set out in 1957 by Talmage (2) who, with Burnet, can be considered a "father of clonal selection theory" (3, 4). Its historical omissions aside, this bold attempt to place the evolution of immune systems in a broad context raises other concerns.

Although mentioning "the complex adaptation of the immune repertoire to the antigenic environment," and the need "continuously to acquire and store open-ended information about the antigenic environment," the coevolution of that antigenic environment (e.g. the coevolution of pathogens) does not seem to have been considered.

While the authors agree with Burnet that "distinguishing tumours from normal self is likely to be the most challenging task for Darwinian immunity," it is not recognized that the most successful pathogens are those that, through mutation, can come close to self. Whereas tumours represent mutations away from self, successful pathogens represent mutations towards self (by means of which they seek to exploit 'holes' in immune repertoires; 5). In both circumstances, this greatly simplifies the evolutionary task of a host. It does not have to depend on "the open-ended nature of the receptor repertoire." It does not have to "constitute a system of 'unlimited heredity' within the immune system." It does not have to "be broad enough to recognize the 'potential universe of antigens'." The scope of its task is greatly reduced.

As long ago proposed (6), and increasingly recognized (7, 8), it would be evolutionarily advantageous for organisms to focus their immune cell receptors on 'near self' antigenic specificities, rather than to attempt to anticipate the entire universe of antigens. Organisms achieve this, not through negative, but through positive selection of their immune repertoires. From the outset, organisms and their pathogens have coevolved and it would seem incorrect to suppose for the immune system that positive selection "could only be added at advanced stages of its evolution" (9). It is fundamental to immune system evolution.

1.Muller V, Boer RJ de, Bonhoeffer S, Szathmary E (2018) Biol Rev 93:505-528. Müller V, 2018

2.Talmage DW (1957) Allergy and immunology. Ann Rev Med 8:239-256 TALMAGE DW, 1957

3.Forsdyke DR (1996) The origins of the clonal selection theory of immunity. FASEB J 9:164-166.Forsdyke DR, 1995

4.Lederberg J (2002) Instructive selection and immunological theory. Immunol Rev 185:50-53.Lederberg J, 2002

5.Calis JJA, de Boer RJ, Kesmir C (2012) Degenerate T-cell recognition of peptides on MHC molecules creates large holes in the T-cell repertoire. PLoS Comput Biol 8:e1002412.Calis JJ, 2012

6.Forsdyke DR (1975) Further implications of a theory of immunity. J Theoret Biol 52:l87-l98.Forsdyke DR, 1975

7.Vrisekoop N, Monteiro JP, Mandl JN, Germain RN (2014) Revisiting thymic positive selection and the mature T cell repertoire for antigen. Immunity 41:181-190.Vrisekoop N, 2014

8.Marrack P. et al. (2017) The somatically generated portion of T cell receptor CDR3alpha contributes to the MHC allele specificity of the T cell receptor. eLife 6:e30918.Marrack P, 2017

9.Forsdyke DR (2016) Evolutionary Bioinformatics. 3rd Edition. Springer, New York.

On 2018 Jan 20, Donald Forsdyke commented:

PATHOGEN COEVOLUTION AND THE ANTIGENIC UNIVERSE

The distinction between selective and instructive (Lamarckian) systems of immunity (1) – originating with Paul Ehrlich – was clearly set out in 1957 by Talmage (2) who, with Burnet, can be considered a "father of clonal selection theory" (3, 4). Its historical omissions aside, this bold attempt to place the evolution of immune systems in a broad context raises other concerns.

Although mentioning "the complex adaptation of the immune repertoire to the antigenic environment," and the need "continuously to acquire and store open-ended information about the antigenic environment," the coevolution of that antigenic environment (e.g. the coevolution of pathogens) does not seem to have been considered.

While the authors agree with Burnet that "distinguishing tumours from normal self is likely to be the most challenging task for Darwinian immunity," it is not recognized that the most successful pathogens are those that, through mutation, can come close to self. Whereas tumours represent mutations away from self, successful pathogens represent mutations towards self (by means of which they seek to exploit 'holes' in immune repertoires; 5). In both circumstances, this greatly simplifies the evolutionary task of a host. It does not have to depend on "the open-ended nature of the receptor repertoire." It does not have to "constitute a system of 'unlimited heredity' within the immune system." It does not have to "be broad enough to recognize the 'potential universe of antigens'." The scope of its task is greatly reduced.

As long ago proposed (6), and increasingly recognized (7, 8), it would be evolutionarily advantageous for organisms to focus their immune cell receptors on 'near self' antigenic specificities, rather than to attempt to anticipate the entire universe of antigens. Organisms achieve this, not through negative, but through positive selection of their immune repertoires. From the outset, organisms and their pathogens have coevolved and it would seem incorrect to suppose for the immune system that positive selection "could only be added at advanced stages of its evolution" (9). It is fundamental to immune system evolution.

1.Muller V, Boer RJ de, Bonhoeffer S, Szathmary E (2018) Biol Rev 93:505-528. Müller V, 2018

2.Talmage DW (1957) Allergy and immunology. Ann Rev Med 8:239-256 TALMAGE DW, 1957

3.Forsdyke DR (1996) The origins of the clonal selection theory of immunity. FASEB J 9:164-166.Forsdyke DR, 1995

4.Lederberg J (2002) Instructive selection and immunological theory. Immunol Rev 185:50-53.Lederberg J, 2002

5.Calis JJA, de Boer RJ, Kesmir C (2012) Degenerate T-cell recognition of peptides on MHC molecules creates large holes in the T-cell repertoire. PLoS Comput Biol 8:e1002412.Calis JJ, 2012

6.Forsdyke DR (1975) Further implications of a theory of immunity. J Theoret Biol 52:l87-l98.Forsdyke DR, 1975

7.Vrisekoop N, Monteiro JP, Mandl JN, Germain RN (2014) Revisiting thymic positive selection and the mature T cell repertoire for antigen. Immunity 41:181-190.Vrisekoop N, 2014

8.Marrack P. et al. (2017) The somatically generated portion of T cell receptor CDR3alpha contributes to the MHC allele specificity of the T cell receptor. eLife 6:e30918.Marrack P, 2017

9.Forsdyke DR (2016) Evolutionary Bioinformatics. 3rd Edition. Springer, New York.