The immune system and the development of the brain

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 No doubt the major manner in which the immune system influences brain development is via those lymphocytes (immune cells) of the brain called glial cells.   Those glial cells which have the most unequivocal immune role to play in the brain are the tiniest ones, called microglia.  But of course,  we know now that the ramifications of the immune system in the brain are far more complex than just that.    The first person to attempt to formulate a general theory of how immune systems in the brain influence its development in a sex-specific manner was a Boston neurologist called Norman Geschwind. Geschwind's ideas on this topic were extremely speculative at the time when he first published them (1975) with an immunologist colleague named Behan and a neuropathologist named Galaburda.   He believed that because of the higher levels of circulating testosterone in the male fetus,  the human male has a weaker immune system than does the human female.  He was quite right about that,  but he mistakenly believed that the male sex was more at risk for auto immune disease.   He proposed that through mysterious effects on the trophic mechanisms of the immune system in the brain, mediated by thymic immunity, testosterone actually slows down prenatal development of the left hemisphere (but only for a while during prenatal development).   The thymus is a gland where numerous lymphocytes differentiate and become mature (other such sites include bone marrow and spleen).  This, he thought, has the effect of placing that hemisphere at risk for anomalous development,  leading to most of the male-prevalent neurological developmental disorders such as dyslexia, autism, and stuttering.   In a sense, Geschwind succeeded in popularizing the notion that the male sex may have a weaker left hemisphere than the female sex,  and a stronger right hemisphere.    This theory was all the more enticing in that it fit well with the emerging consensus to the effect that normal boys have slightly but significantly greater visuospatial skills,  whereas normal girls have slightly, and sometimes significantly greater verbal skills.  Geschwind was not in a position to identify the specific immune mechanisms involved in this proposed sex-specific developmental cascade.  He was, in a sense,  a few years ahead of his time.   It turns out that Geschwind's theory has now been, for all intents and purposes,  demolished by counter-evidence.  The saga of the Geschwind-Behan-Galaburda testosterone model represents one of the greatest misadventures in the history of behavioral neurology.  Thousands of research papers have been published, inspired by a theory that has finally been shown to be invalid,  a scientific adventure that cost many millions of dollars in futile research efforts.  If just for that,  it deserves closer scrutiny.

Geschwind and his colleagues believed that prenatal testosterone does the following things:  a) negatively influences development of the thymus which in turn negatively influences development of the immune system, producing more allergies and auto immune disorders in boys,  b) slows down and disrupts the development of the left hemisphere -leading to male preponderant traits such as left handedness, c) which in turn is associated with male-prevalent neurological developmental disorders such as dyslexia, stuttering, autism, hyperactivity,  d) and causes neural crest disorders,  leading to midline defects such as harelip,  etc. and to asymmetric hemispheric development.    This is an extreme simplification of the GBG model,  but it is enough for our purposes here. 

Now here is what I think is principally wrong with the GBG model.  1) The thymus is not more specifically weakened in utero in the male sex than are the other immune organs (bone marrow, spleen, lymph nodes). The other types of lymphocytes which are not thymo-dependent (B cells and others) are just as important with regard to sex differences.  2) The GBG model is right about the male sex having more infections,  but is wrong about the male sex having more auto immune diseases and the young boy more allergies (see chapter 7).  3) The left hemisphere of the human male is just as "developed" as the left hemisphere of the human female  -at all ages at which sex differences have been observed and replicated. Sex differences in brain anatomy cannot be expressed in terms of whole hemispheres as much as in terms of subcomponents of the hemispheres. 4) One of the most male prevalent neurodevelopmental disorders,  hyperactivity,  is at least as much a right as a left hemisphere syndrome,  -a finding which now forces us to refrain from statements to the effect of a general "weakness" of the left hemisphere in the male sex.  5) There is no histopathological or physiological evidence to date of more left than right hemisphere dysfunction in autism...  contrary to what Geschwind believed, despite the fact that language is particularly underdeveloped.  On the contrary,  it has become clear that male preponderance can be explained by the remarkably frequent occurrence of the fragile-X variant (see chapter 8 for more details on this syndrome). 6) Left handedness is related to most neurodevelopmental disorders only to the extent that could be explained by post-lesion shifting of handedness,  and left handedness is not related to any immune or auto immune parameter. 7) While the male sex is more at risk for a great many disorders (see chapter 5),  neural crest disorders (the neural crest develops into the neural tube and is the first stage of prenatal brain development) are not male-prevalent,  but rather clearly female-prevalent.  Besides,  the fetus's gonads do not start secreting testosterone,  and the fetal immune becomes functional, only after the neural crest stage of development is well over.   In fact the male fetus is slightly more at risk for just about every abnormality of neuronal development after the consolidation of the neural crest and neural tube.  

My reading of the literature relevant to the fascinating idea of immune modulation of prenatal brain development is that this promising domain is practically still virgin territory -even 20 years after the idea was so colorfully launched by Geschwind and his colleagues.    Two of the sex-dimorphic brain nuclei,  the amygdala and the bed nucleus of the stria terminalis (BNSTc) are known to be important regulators of immunity.  It is their substance-P neurotransmitter network which is both sexually dimorphic and immunoactive.  For example,  the BNST controls temperature during fever and is particularly interleukin-1 beta sensitive.  Interleukin-1 beta is an important immunosuppressant,  active in the brain.  Substance-P is very important in the perception of pain,  an inner experience which differs as a function of gender (see chapter 2).  The fascinating idea of immune modulation of prenatal brain development is a promising topic for future research.