Dear Concha,

I really appreciate your answer and the link. Thank you. In fact, I am particularly interested in the architectural configuration and control of autoimmunity. It would be great to see autoimmunity and apoptosis with the eyes of an architect.  

The biomedical sciences need some kind of revolution. The introduction of Space and Euclidian geometry in resolving biomedical questions is fundamental.  Antipodal points, defining boundaries of a signal and not of a cell, open field of communication, rebuilding cell nucleus, resolve the question of space and time in brain cells or in signal memory cells and immune cells – define the roots of a signal through the biological space and build a Mathematical space that answers biological needs, explain the major problem of signal coordination at the chromatin are some intriguing questions that could be equally addressed with the eyes of an architect, a mathematician, a political scientist.  

My question is driven by a specific conception of autoimmunity built around specific nuclear compartments such the PML/AIRE NBs and associated domains in interphase and M-phase. So, there is a concrete molecular basis which is used to build a model reflecting a new perception of signal control including autoimmunity and apoptosis. This is the origin of my question. Thanks Concha, for your answer.

I think you need to make sure of the scope of what you want your terms to cover, Vassilis. Autoimmunity is probably best used to describe disorders of B cell clonal regulation that lead to autoantibody formation. In most cases T cells are probably innocent bystanders. The AIRE defect story is very atypical.

The basic problem with B cell regulation is that it is based on random diversification and selection rather than instruction - like the brain and probably most very complex regulatory systems that deal with an almost infinite number of potential environmental stimuli. The weakness with a selection system is that it involves reinforcement (positive feedback) that can potentially engage inappropriately. And if recognition systems for stimuli and regulatory signals use the same stereochemical interactions, as they must, there is a risk that they will get confused. Natural selection will ensure that confusions are weeded out down to a low level, but not completely because greater diversity will have advantages but will also increase the risk of confusion. So you inevitably end up with autoimmune disease being uncommon but not non-existent.

Apoptosis is involved in deleting autoreactive B cell clones but I do not think I would put it at the centre of the story. It may be very important for a group of autoimmune diseases involving anti-nuclear antibodies but I think it would be misleading to generalise.

Dear Jonathan,

I appreciate your analysis and your clarification.  I agree, it could be misleading to generalize in science. It is also important to accept that biomedical sciences are in search of concrete models that would allow to clarify the cause-and-effect of an observation.  Let’s take the hypothesis that we have to represent at one point of a circle autoimmunity. What would be the antipodal point?  Autoimmunity is cause-and-effect sequence and should exist a model to describe it by establishing: a) a concrete and safe cure for the case of diseases and b) a logic conception so to understand this cause-and-effect phenomenon.  

I think you agree that either in B or T cells, autoimmunity engages a selection system. You nicely said that B cell regulation is based on random diversification and selection rather than instruction.  I could say that instruction is also a selection system.

“Roitt and Doniach at University College London and others have shown that in terms of antibody-producing B lymphocytes, diseases such as rheumatoid arthritis and thyrotoxicosis are associated with loss of immunological tolerance which is the ability of an individual to ignore "self", while reacting to "non-self". “This breakage leads to the immune system's mounting an effective and specific immune response against self-determinants”.  This breakage might lead to autoimmunity.

*the term “self” and “non-self” is confusing as what could be considered as “non-self” at dt by the N-individual – the human genome is expressed to environmental stress including viral DNA, vaccination, bacterial threat etc - can turn to be “self” in dt+n and then recognized by the N+1 individual in dt+n+1 under a different environmental/genetic background as “non-self” and this might be an evolutionary perspective of autoimmune reaction leading to loss or instruction of immunological tolerance.  This can be addressed also in the light of viral infection and control of autoimmune levels and etc. The N-individual is part of a sequence of events including N+1, N+2, N+n individuals.

In the clonal deletion theory, proposed by Burnet and Medawar, self-reactive lymphoid cells are destroyed during the development of the immune system in an individual (Nobel Price 1960 acquired immunological tolerance).

So, both Roit and Burnet and others introduced in their approach of studding autoimmunity the term of “loss or destroy”.  Even if autoimmunity is driven by an ‘instructive pathway”; at the bottom line a healthy immune system has the capacity to make a decision using its “proper internal control” and decides to keep the self-intact and attack the non-self.  . If, autoimmunity engages a false elimination or destruction or an “instructive process” of a target (cell - molecule) which is involved in the autoimmune response then we have to ask what the machinery for this process is.

I could say this includes proteolytic machinery, proteasomes, ubiquitination, apoptotic machinery.  This should be the antipodal point of autoimmunity in the circle and this is illustrated best by the term apoptosis.

Last but not least, talking about AIRE, it should not be a special case and I would not considered it as a monogenic disease, as it is in general claimed. AIRE defines a spatial nuclear domain with concrete properties. So any reference to AIRE makes reference to nuclear space. In the same category, we could add PML, SP100 in PBC and more. Vassilis