nostalgia: the similarities between immunological and neurological memory

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Ó 2012 John Wiley & Sons A/S Immunological Reviews 248/2012 5 Lawrence Steinman Nostalgia: the similarities between immunological and neurological memory 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 Ó 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

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Page 1: Nostalgia: the similarities between immunological and neurological memory

� 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

Page 2: Nostalgia: the similarities between immunological and neurological memory

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

Page 3: Nostalgia: the similarities between immunological and neurological memory

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

Page 4: Nostalgia: the similarities between immunological and neurological memory

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

Page 5: Nostalgia: the similarities between immunological and neurological memory

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Steinman Æ Immune and neurological memory

� 2012 John Wiley & Sons A/SImmunological Reviews 248/2012 9