01/02.2020 | THE SCIENTIST 19tumors. The brain blebs may be formed in
response to the infiltration of T cells into
the space between blood vessels and neu-
ral tissue, Anderson suggests, while the
cell fragments they contain could come
from the astrocytes that make up the glia
limitans—the final wall of defense sepa-
rating neural tissue from foreign and toxic
substances circulating in the blood.
Lymphocytic cuffs, meanwhile, are
common in diseases such as skeletal
muscle polymyositis, a type of chronic
muscle inflammation. That disease has
many traits of autoimmune disorders,
in which the body perceives and attacks
parts of itself as foreign, and it’s a disease
that Anderson had often seen in biop-
sies. “I’ve seen many [cuffs] under the
microscope,” he says. “So I know what a
T-lymphocyte attack of an organ looks
like.” The cuffs also show up in response
to toxins, or antigens given off by a virus,
and cause brain inflammation.
The finding of both cuffs and blebs in
the postmortem brains of autistic people
suggests that the individuals’ T cells were
also responding to some antigen—either a
molecule considered foreign even though
it’s created by the person’s own body, or
a viral or bacterial one encountered in
utero, Anderson says. Except for rare
cases in which an autism-linked genetic
mutation can be identified, the cause of
ASD is unknown. According to the new
data, a majority of the unexplained cases
could have arisen as an autoimmune dis-
order or an inflammatory condition trig-
gered during pregnancy, Anderson and
colleagues concluded in a recent paper
(Ann Neurol, 86:885–98, 2019).
“It’s really a very striking finding,”
says Dan Littman, an immunologist at
New York University Langone Health
who was not involved in the work. The
team’s results, he notes, fit well with
recent animal research showing a con-
nection between the immune system and
autism—specifically that interleukin-17
(IL-17), a signaling molecule produced
by T cells to help fend off pathogens, can
cause rodents to exhibit behaviors associ-
ated with autism. In 2016, Littman and
colleagues reported that blocking theproduction of IL-17 in pregnant mice
prevented their pups from developing an
autism-like condition (Science, 351:933–
39). “ Yo u could imagine that if cytokine-
producing cells in the central nervous
system are localizing in particular places,
they could be contributing to behavioral
changes,” Littman says.
The findings also dovetail with what
little has been described in the way of
neuropathological features of autism in
humans, Anderson says. Fifteen years
ago, Carlos Pardo-Villamizar of Johns
Hopkins University and colleagues
studied postmortem brain tissues and
cerebrospinal fluid from individuals
with autism and found signs of neuro-
inflammation in the cerebral cortex,
white matter, and cerebellum—regions
essential for sensory perception and for
motor skills such as balance and coor-
dination (Ann Neurol, 57:67–81, 2005).
Transcriptional profiling of postmortem
brains from individuals with autism
revealed elevated levels of messenger
RNAs that make inflammatory proteins
(Neurobiol Dis, 30:303–11, 2008), and
more-recent data support the conclu-
sion that the brains of individuals with
autism are typically in an inflammatory
state (PNAS, 116:21659–65, 2019).
While the Boston team’s discovery of
T cell–induced inflammation associated
with autism is noteworthy, the astrocyte
blebs are particularly intriguing, notes
Duke University neuroscientist Staci
Bilbo, who did not participate in the new
study. The development of the blebs in
reaction to the cuffs “points to a role for
the blood-brain barrier breaking down,”
something rarely studied in autism, she
says. Looking further into the interaction
between the cuffs and the blebs could
reveal not only how, but why T cells are
getting into the brain, giving clues to
the origins of autism in cases driven by
immune dysfunction.
Anderson says his team has already
started follow-up experiments, running
transcriptome profiling of the cuffs and
blebs. Infiltration of T cells into the space
between blood vessels and neural tissue,
and the subsequent generation of blebs,“almost for sure is going to trigger the
expression of unique genes and proteins”
in the astrocytes and “may dissociate
autism even more specifically from other
conditions,” he says. His team is also look-
ing at the receptors on the T cells in the
cuffs to determine what’s provoking the
immune cells to swarm. The research-
ers are studying all of the genes linked to
autism and to autoimmunity as well—an
analysis that has begun to reveal “a signa-
ture of an autoimmune genetics within the
existing autism genetics,” Anderson says.
“It’s a multi-pronged approach.”
—Ashley YeagerFRIENDLY FIRE: Swarms of lymphocytes (pur-
ple) in the space between blood vessels and
neural tissue are more common in postmortem
brain samples from people with autism (below)
than in samples from controls (above).
(Scale bar: 40μm)M.M. DISTASIO ET AL.,
ANN NEUROL
, 86:885–98, 2019.