nostalgia: the similarities between immunological and neurological memory
TRANSCRIPT
� 2012 John Wiley & Sons A/SImmunological Reviews 248/2012 5
Lawrence Steinman Nostalgia: the similarities betweenimmunological and neurologicalmemory
Author’s address
Lawrence Steinman
Beckman Center for Molecular Medicine, Stanford University,
Stanford, CA, USA.
Correspondence to:
Lawrence Steinman
Beckman Center for Molecular Medicine, B002,
279 Campus Drive
Stanford University
Stanford, CA 94305, USA
Tel.: +1 650 725 6401
Fax: +1 650 725 0627
e-mail: [email protected]
Acknowledgements
The author declares no conflicts of interest.
This article introduces a series of reviews
covering Neuroimmunology appearing
in Volume 248 of Immunological Reviews
Immunological Reviews 2012
Vol. 248: 5–9
Printed in Singapore. All rights reserved
� 2012 John Wiley & Sons A/S
Immunological Reviews
0105-2896
The components of this volume of Immunological Reviews are
devoted to the subject of neuroimmunology. In this preface, I
reflect on the concept of memory, a function that is critical
for both the immune system and the nervous system. The ner-
vous and immune systems are tuned to react to external stim-
uli, and both are imbued with the profound capacity to recall
earlier events, what we term as memory. It is memory for past
antigens that allows the immune system to respond effectively
to microbial challenges through neutralization of most
microbes before they can cause harm. Diseases of memory are
associated with some profound clinical pathology in both the
immune system and nervous system. Some of these syn-
dromes have conceptual similarities, so here I compare dis-
eases involving mistaken identity, and those involving
retrograde amnesia. Such disorders are encountered in human
immune biology and neurology.
Immune memory is triggered by not only an encounter
with a portion of an antigen that binds to an affinity matured
antibody or to a T-cell receptor but also there are additional
more subtle clues that orchestrate a complex recall or memory
response. When recalling a microbial memory, the immune
system has a complex set of sensors that can discern subtle
structural motifs in the microbial world, so-called pathogen-
associated molecular patterns (PAMPs) (1, 2). These molecu-
lar cues trigger memory as they signify a previous encounter,
eliciting innate immunity and augmenting the adaptive
immune responses.
Likewise, neurological memory enables us to recall and then
to respond effectively to many complex stimuli. With some
similarity to immune memory, neurological memory can also
be triggered by subtle molecular cues, often an olfactory
stimulus. Rather famously in literature, in Proust’s Remembrance
of Things Past (3), a sweet, spongy cake, known as a madeleine,
dipped in tea triggered a complex cascade of childhood
memories. Thus, both immune memory and neurological
memory involve a transformation of the initial molecular
stimulus, into a complex response. As Proust himself wrote in
his famous work, ‘Remembrance of things past is not neces-
sarily the remembrance of things as they were’ (3). This trans-
formation of a subtle cue into a complex response determined
by past events is a common feature in both immune memory
and neurological memory, as described elsewhere.
In the immune system, we retain, sometimes with the help
of secondary or ‘booster’ immunizations, life-long immunity
to many devastating and lethal microbial infections. We may
ultimately lose our immunity to chicken pox, varicella virus,
and this puts us at risk for shingles. A ‘booster’ vaccine against
varicella taken after age 60 can largely prevent shingles. With
age, we also lose memories, and the various dementias are the
most common diseases associated with this reality, with
Alzheimer’s the most well known.
In our brains, we retain precious memories of events and
emotional states in the past. Neurological memory sculpts our
personalities, provides us with the ability to perform complex
pieces of music, ride a bike, and carry out arithmetic calcula-
tions. Immune memory efficiently leads to neutralizing
responses to deadly microbes after an initial encounter, even
though certain features on that microbe may have changed or
mutated. Fortunately from a controlled immunization in
childhood, we have the capacity to neutralize a wide variety
of microbial threats throughout our lives.
What do immune memory and neurological memory actu-
ally have in common, other than the concept given to us in lan-
guage, with the shared word ‘memory’? Is memory at the
various types of neurological synapses at all similar to memory
in the immune system? Are changes at chemical synapses in the
brain at all similar to the adaptive gene rearrangements inher-
ent in the diverse immunoglobulin and the T-cell receptors
found on memory T and B cells? The answer, at least as we
know in the early part of the 21st century, is that neurological
and immunological memory have very little in common on a
molecular level. There is some information on at least some
molecules that play a role in neurological and immunological
memory. A wonderful example is brain-derived neurotrophic
factor that aids learning and memory and is also produced by T
cells that help quell brain immunity (4). There are undoubtedly
many other molecules to be discovered that play central roles
in the two processes given the same name, memory-immuno-
logical and neurological. Beyond shared molecules, it is per-
haps instructive to consider the many functional similarities
when one looks at pathological disorders of these two parallel
systems: immune and neurological memory.
Despite a lack of detailed information that might suggest
that the two types of memories share any common molecular
mechanisms, there are some intriguing similarities between
disorders of memory in the immune and nervous system. As
the gifted writer and eminent neurologist Oliver Sacks has
written, ‘Constantly, my patients drive me to question, and
constantly my questions drive me to patients’ (5). I compare
here certain neurological disorders of memory with some
conditions where immunological memory has failed. I com-
pose this preface with a tip of my metaphorical ‘hat’ towards
Professor Sacks. These clinical anecdotes about pathological
conditions of memory, both the neurological and immuno-
logical forms of memory, serve to illuminate the many rich
intersections of these concepts in the fields of neuroscience
and immunobiology.
Molecular mimicry and mistaken identity in neurology
and immunology
A classic neurologic counterpart of mistaken identity is exem-
plified by the syndrome of prosopagnosia, where an individual
can no longer identify common objects like a face, but instead
is able to recognize a familiar face by alternative cues, or fea-
tures that are associated with the face, like the hat in Oliver
Sacks’ classic, The Man Who Mistook his Wife for a Hat (5; Fig. 1).
This fascinating neurological phenomenon shares features
with autoimmune diseases manifest when there is a failure of
recognition of self. Prosopagnosia can be seen after a stroke or
tumor and often involves damage in the fusiform gyrus in the
brain. The fusiform gyrus connects the temporal and occipital
lobes with the hippocampus, a structure so vital to memory.
Lesions here are associated with this rare and shocking behav-
ioral deficit, where mistaken identity is so profound that a hus-
band might mistake his wife of half a century for a hat! Failure
to recognize self and non-self leads to complex autoimmune
diseases, as described in many articles in this volume.
Many immunologists have elaborated how the immune sys-
tem can distinguish self from non-self. Sir McFarlane Burnet
in his 1960 Nobel Lecture wrote, ‘How can an immunized
animal recognize the difference between an injected material
like insulin or serum albumin from another species and its
own corresponding substance?’ (6) He continued, ‘If a cell or
clone is limited to one or two patterns, then it is practical to
postulate that any carrying either one or two self-reactive
patterns is eliminated, leaving only clones carrying patterns
corresponding to configurations not present in the body. This
is the form taken by the clonal selection theory and provided
two patterns is adopted as the usual number for a diploid
Steinman Æ Immune and neurological memory
� 2012 John Wiley & Sons A/S6 Immunological Reviews 248/2012
somatic cell, it provides a reasonable interpretation of the
facts’ (6).
The concept of ‘Clonal Selection’ has dominated how we
have tried to understand self versus non-self recognition over
the past half century. Yet, we now are fully aware that a vast
number of structures have shared chemical structures that are
identical between the microbial world and our own self-
constituents. A competing idea, ‘Moelcular Mimicry’, one not
mutually exclusive with Clonal Selection, accounts for how
autoimmune diseases develop. The concept of molecular
mimicry accounts for how the immune system can mistake
the identity between the shared structures of what we call
‘self’ and those in the realm of ‘non-self’, mostly constituents
of the microbial world (Fig. 1). Thus, chemical structures on
b-hemolytic streptococcus are shared with chemical features
on the basal ganglia of the brain. Infection with streptococcus
can lead to the choreoathetosis, termed Sydenham’s Chorea or
St. Vitus’s dance, seen a few weeks after such a streptococcal
infection. Indeed antibodies to streptococcus are cross-reactive
with antigens in the basal ganglia, and this cross-reaction may
be at the center of the pathogenesis of Sydenham’s Chorea (7,
8). Similar structures shared between Campylobacter jejuni and
gangliosides cause an autoimmune condition called Guillain–
Barre syndrome, resulting in autoimmune inflammation of
the peripheral nerves. Anti-GD1 and GD3 antibodies targeting
regions with similar atomic contours found on Campylobacter
jejuni and also present in the peripheral nerve axon are the basis
for this disease (9, 10).
The autoimmune immune response to carbohydrates in
Guillain–Barre and in poststreptococcal disorders like Syden-
ham’s Chorea allows us to make a bridge to neurological
memories. Immune recognition of bacterial carbohydrates
Fig. 1. Molecular mimicry shares many conceptual features with the neurological condition known as prosopagnosia, where a person forinstance mistakes his wife for a hat. Molecular mimicry can lead to autoimmune and paraneoplastic conditions described in this volume. Memoryresides in certain populations of cells, and this is well reflected in the loss of memory in HIV infection. A parallel in neurology would be transient glo-bal amnesia.
Steinman Æ Immune and neurological memory
� 2012 John Wiley & Sons A/SImmunological Reviews 248/2012 7
is exploited in the design of conjugate vaccines where bac-
terial polysaccharides are coupled to protein carriers (11).
These vaccines have proven highly effective in providing
lifelong immune memory to pneumococcus and influenza.
This recognition of the carbohydrate component of an anti-
gen is reminiscent of how neurological memory can be
triggered by an encounter with that ‘sweet Madeleine
dipped in tea’ made famous in Proust’s Remembrance of Things
Past (3).
Another example of mistaken identity occurs in the memory
loss associated with antibodies to NMDA receptors. Such anti-
bodies are expressed in ovarian teratomas and provide the
basis for one of the fascinating and rare autoimmune paraneo-
plastic syndromes associated with psychiatric disorders and
memory loss. Dodel’s review in this volume (12) describes
such antibodies. Anti-NMDA receptor antibodies are often
found in systemic lupus erythematosus and may underlie
some of the psychiatric and memory disturbances seen in
lupus. This is described in the chapter by Diamond (13).
Loss of immunological memory and transient global
amnesia
Transient global amnesia and Korsakoff’s psychosis are two
examples where loss of memory occurs in a retrograde fash-
ion. This means that memory for recent events is lost and
memory of the more distant past is retained to a much greater
degree than recall for more recent events. Transient global
amnesia often follows ischemia in the basilar circulation of
the brain. The amygdala and hippocampus are often pro-
foundly affected. Korsakoff’s psychosis results from thiamine
deficiency and is sometimes accompanied with other neuro-
logical manifestations, including paralysis of eye muscles, loss
of balance and confusion, so-called Wernicke–Korsakoff
syndrome.
With some similarity memory can be lost with various dis-
ease states. In human immunodeficiency virus (HIV) infec-
tion, there is profound loss of memory cells with ensuing loss
of the ability to combat infections for which we have previ-
ously been immune. The massive loss of CD4+ T memory cells
in HIV and simian immunodeficiency virus (SIV) is a conse-
quence of the destruction of memory T cells from the virus
(14). Like the locus for memory loss in transient global amne-
sia, the locus for memory loss in SIV resides in CCR5 CD4+ T
cells (14). One of the remarkable aspects of memory is that in
both the immune system and the nervous system, memory
may truly reside in certain cell populations, even in specific
locations. In the immune system, where transplantation is
common in various diseases, loss of immune function cer-
tainly occurs following bone marrow transplantation, for
example. People with food allergies may lose them after a
transplant. Gain of immune function also occurs with the
development of a particular allergic state, like food allergy,
from a donor of the transplant. Thus, the gain of function and
loss of function for immune memory is a very real phenome-
non (15). Immune memory and even ‘horror autotoxicus’
can occur when the immune system recognizes a portion of a
self-molecules that does not normally reside in the thymus
(16). We have not yet seen a parallel experiment performed
with gain or loss of neurological memory, but I would predict
that this may be coming soon with the era of stem cell trans-
plants to the nervous system.
This volume contains a wealth of chapters dealing with the
milieu in which immunity to the nervous system flourishes.
The chapters by Axtell and Raman (17), Goverman (18),
Kuchroo (19), and Mayo and Weiner (20) describe the
molecular basis for autoimmunity to neurological tissues. Ri-
vest (21) shares how immune responses are modulated by the
neuroendocrine axis. Other articles by Ransohoff (22) and Ka-
wakami (23) describe the remarkable mechanisms that allow
immune cells to home to the brain. Fugger (24), Hauser et al.
(25), and Hafler (26) describe the intricate genetic regulation
of brain immune interactions in pathological conditions like
multiple sclerosis. Overall, the field of neuroimmunology is
well covered in this volume. It will be exciting to see how the
fields of neuroscience and immunology continue to illuminate
those common processes like memory that are vital in each
system.
Although in 2012 there is little known about common
mechanisms and molecules that underlie the process of mem-
ory in the immune system and nervous system, we may some-
day realize there is much more than merely conceptual
connections between the physiological processes that govern
immune and neurological memory. Much more needs to be
learned. There are concepts like the synapse that have been
studied in the neurosciences and immunology. Despite major
differences between neurological and immune synapses, over
the past decade there has been an elucidation of certain shared
molecules and common cell biological features (27, 28). Like
our understanding of immune and neurological synapses, we
may begin to understand shared features between immune
and neurological memory. After all, there are actual synapses
between the nerves and immune organs, and there is even
evidence that memory processes are at work at these synapses
that mark the interface between these disparate physiological
systems (29).
Steinman Æ Immune and neurological memory
� 2012 John Wiley & Sons A/S8 Immunological Reviews 248/2012
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