FAQs: The meaning of neuroinflammatory findings in autism
What type of immune reactions are present in the brain of autistic patients?
In our study, we have demonstrated a marked increase in neuroglial responses,
characterized by activation of microglia and astroglia, in the brains
of autistic patients. These increased neuroglial responses are likely
part of neuroinflammatory reactions associated with the central nervous
system's (CNS) innate immune system. In innate immune reactions of the
CNS, microglial activation is the main cellular response to CNS dysfunction.
This is in contrast to adaptive immune responses, in which lymphocyte
and/or antibody mediated reactions are the dominant responses. In our
sample of autistic patients, microglial and astroglial activation was
present in the absence of lymphocyte infiltration or immunoglobulin
deposition in the CNS. It also was associated with increased production
of pro-inflammatory and anti-inflammatory
cytokines such as MCP-1 and TGFß-1 by neuroglia.
neuroinflammation always present in the brain of autistic patients?
NOT necessarily. Since autism is a disorder that is highly variable
in the ways it presents, and may be associated with multiple causes,
it is possible that our sample of cases does not represent the entire
autistic spectrum. Also, some of our patients had other associated neurological
disorders frequently found in autism, such as epilepsy and mental retardation.
However, the presence of microscopic and immunological findings showing
neuroimmune reactions in all of our autistic patients and the cytokine
findings in the cerebrospinal fluid (CSF) support a potential role for
neuroglia and neuroinflammation in the CNS effects in a number of individuals
are neuroglial activation and neuroinflammation relevant to the neurobiology
The presence of increased neuroglial responses is relevant to the neurobiological mechanisms involved in autism, as both microglia and astroglia are essential for neuronal activity and synaptic [neural transmission] function, neuronal-neuroglial interactions, as well as for cerebral cortex modeling, organization and remodeling during brain development. Furthermore, microglial and astroglial activation seems to play a major role in the neuroimmune mechanisms of disease in the CNS. These cells are part of the first-line response of the innate immune system of the CNS. They contribute to the modulation of immune responses by producing both pro-inflammatory and anti-inflammatory cytokines as well as growth and differentiation factors.
microglial and astroglial reactions always bad for the brain?
NO. The microglia and astroglia in the CNS may have a two-sided role in the inflammatory responses of the brain: they can act both as direct effectors of injury and on the other hand as protectors of the brain. In some situations, microglia and astroglia may produce neurotoxic reactions that damage other cells such as neurons and oligodendrocytes in the brain. However, there is strong evidence from experimental models that in some situations, both microglia and astroglia also contribute to the repair and restoration of neuronal connections and produce growth factors to maintain normal CNS function.
microglial and astroglial activation the result of residual damage or
ongoing damage to the brain?
It remains unclear how and when microglia and astroglia become activated in the brain of autistic patients. Neuroglial responses in autism may be part of primary (intrinsic) reactions that result from disturbances in neuroglial function or neuronal-neuroglial interactions during brain development. They may also be secondary (extrinsic), resulting from unknown factors that disturb prenatal or postnatal CNS development (e.g. infections, toxins, etc). Both astrocytes and microglia are critical for brain development. MHC class II (HLA-DR antigen)-positive microglia colonize the developing CNS during the second trimester of pregnancy. It is possible that the presence of activated microglia in the brain in autism may reflect abnormal persistence of fetal patterns of development. This may be in response to genetic or environmental (e.g. intrauterine, maternal) factors. Our study of brains of autistic patients showed that regardless of age, history of epilepsy, developmental regression or mental retardation, microglial and astroglial reactions were consistently present. Our findings support the view that chronic and sustained neuroglial inflammatory responses are part of an ongoing and active process rather than a residual change. These changes may be involved in mechanisms associated with abnormal function of neurons and synapses in the brain in autism.
Although our studies did not show any difference in neuroglial activation among patients with autism with respect to history of developmental regression or mental retardation, further studies that include larger series of cases may help to clarify whether these factors contribute to the ongoing neuroinflammatory responses.
the neuroinflammation observed in autism similar to encephalitis or
NO. In meningitis and encephalitis, the most prominent
immune reaction is one of adaptive immunity, the main feature being
infiltration of the CNS by inflammatory cells such as T lymphocytes
and B lymphocytes along with the production of antibodies. There is
also activation of astroglia and microglia in meningitis and encephalitis,
but the dominant immune reaction is due to adaptive immunity. In contrast,
in autism, there is NO evidence of lymphocyte infiltration or antibody
mediated reactions; the most prominent immune response is characterized
by activation of microglia and astrocytes, features that characterize
innate immune responses within the CNS. These observations suggest that
the adaptive immune system does not play a significant pathogenic role
in this disorder, at least not during its chronic phase,
and that the main immune mechanism involves predominantly innate immune
reactions. Since our study focused on autopsy tissues, we cannot exclude
the possibility that specific immune reactions, mediated by T-cell and/or
antibody responses, occurred at the onset of disease, during prenatal
or postnatal stages of development.
there any brain region particularly affected by neuroinflammation?
Yes. Our study showed the cerebellum exhibited the most prominent neuroglial
responses. The marked neuroglial activity in the cerebellum is consistent
with previous observations that the cerebellum is a major focus of pathological
abnormalities in microscopic and neuroimaging studies of patients with
autism. Based on our observations, selective processes of neuronal degeneration
and neuroglial activation appear to occur predominantly in the Purkinje
cell layer (PCL) and granular [needs to be defined] cell layer (GCL)
areas of the cerebellum in autistic subjects. These findings that are
consistent with an active and ongoing postnatal process of neurodegeneration
and neuroinflammation. Our observations suggest that the pathological
changes observed in the cerebellum in autistic patients do not occur
exclusively during prenatal development, but appear to involve an ongoing
chronic neuroinflammatory process that involves both microglia and astroglia.
Furthermore, this process continues beyond early neurodevelopment, and
is even present at very late stages in the life of patients with autism.
These findings also support the hypothesis that selective vulnerability
of Purkinje cells plays a role in the pathological process of autism
there any other evidence to support the presence of neuroinflammation
in the brain of autistic patients?
Yes. Our study has
also demonstrated the presence of unique profiles of cytokine expression
in the brain and CSF of subjects with autism. Two pro-inflammatory chemokines,
MCP-1 and TARC, and an anti-inflammatory and modulatory cytokine, TGF-ß1,
were consistently elevated in the brain regions studied. MCP-1, a chemokine
involved in innate immune reactions and an important mediator for monocyte
and T-cell activation, and for trafficking into areas of tissue injury,
appeared to be one of the most relevant proteins found in cytokine protein
array studies. It was significantly elevated in both brain tissues and
CSF. The presence of MCP-1 is of particular interest, since it facilitates
the infiltration and accumulation of monocytes and macrophages in inflammatory
CNS disease. Our immunocytochemical studies of the cerebral cortex and
cerebellum showed that MCP-1 is produced by activated and reactive astrocytes,
showing that these cells play an effector role in the disease process
in autism. The increased expression of MCP-1 has relevance to the pathogenesis
of autism as we believe its elevation in the brain is linked to microglial
activation and perhaps also to the recruitment of additional macrophages
and microglia to areas of neurodegeneration, such as those we observed
in the cerebellum.
- . Is
the elevation of MCP-1 unique to autism?
No. Our observations
resemble findings in other neurological disorders in which elevation
of MCP-1 is associated with the pathogenesis of neuroinflammation and
neuronal injury. These diseases include HIV dementia, ALS, stroke and
multiple sclerosis. It remains unclear whether MCP-1 plays multiple
roles in the CNS or whether its presence is only associated with inflammatory
conditions. It has been speculated that MCP-1 may be involved in neuronal
survival and brain protection mechanisms in addition to monocyte activation
and trafficking or even in non-lymphocytic-mediated neuronal injury.
Expression of MCP-1 in the CNS appears to be developmentally regulated,
and previous studies have shown its expression in the cerebellum during
prenatal development, a finding that may suggest an association with
maturation of Purkinje cells. Like MHC-class II expression in microglia
during CNS modeling, MCP-1 elevation in the brain of autistic patients
may reflect persistent fetal patterns of brain development.
is the role of other cytokines found in the brain of autistic patients?
Our study found that other cytokines with pro-inflammatory and anti-inflammatory
effect were also increased in the brain of patients with autism. An
example of anti-inflammatory cytokines is TGF-ß1, a key anti-inflammatory
cytokine involved in tissue remodeling following injury. It can suppress
specific immune responses by inhibiting T-cell proliferation and maturation
and downregulates MHC class II expression. In our immunocytochemical
studies, TGF- ß1 was localized mostly within reactive astrocytes and
neurons in the cerebellum. Purkinje cells that exhibited microscopic
features of degeneration showed marked reactivity for TGF-ß1. These
findings suggest that the elevation of this cytokine in autism may reflect
an attempt to modulate neuroinflammation or remodel and repair injured
is the significance of the cerebrospinal fluid findings in autistic
Cerebrospinal fluid (CSF) studies also confirmed
a prominent inflammatory cytokine profile in patients with autism. The
presence of a marked increase of MCP-1 in CSF supports the hypothesis
that pro-inflammatory pathways are activated in the brain of autistic
patients. This increase in MCP-1 may be associated with the mechanisms
of macrophage/microglia activation observed in the brain tissue studies.
The elevation of MCP-1 in the CSF resembles observations in other conditions
in which microglia/macrophage activation is important, such as in HIV
dementia and multiple sclerosis, diseases in which neuroinflammation
plays a prominent role. In addition to the marked elevation in MCP-1,
the presence of elevated levels of IFN?, IL-8, IP-10, angiogenin and
LIF strongly supports the view that active neuroinflammatory reactions
and a network of multiple cytokines are likely involved in immune-mediated
mechanisms in the CNS of autistic patients. These cytokines play important
roles in immune mediated processes and their presence in the CSF in
autistic patients may reflect an ongoing stage of inflammatory reactions
associated with neuroglial activation and/or neuronal injury. There
was a greater increase in these cytokines in the CNS compared to the
brain tissue. The reasons for the difference is unknown.. It could be
that the brain cytokines are produced from neuroglial and neuronal sources
as demonstrated by our immunocytochemical assessment. The cytokines
in CSF could result from other sources of production, such as the meningeal
lining around the brain or choroid plexus (where CSF is produced) The
persistent elevation of cytokines in CSF also might reflect a neurodevelopmental
arrest, as some of the cytokines are normally elevated during phases
of neurodevelopment. Since the CSF is easily accessible for clinical
studies, CSF cytokine profiling may be useful in the future to diagnose,
characterize and follow the clinical course of autistic disorders.
there is neuroinflammation in the brain of some autistic patients, is
treatment with anti-inflammatory or immunomodulatory medications indicated?
At present, THERE IS NO indication for using anti-inflammatory
medications in patients with autism. Immunomodulatory or anti-inflammatory
medications such as steroids (e.g. prednisone or methylprednisolone),
immunosupressants (e.g. Azathioprine, methotrexate, cyclophosphamide)
or modulators of immune reactions (e.g. intravenous immunoglobulins,
IVIG) WOULD NOT HAVE a significant effect on neuroglial activation because
these drugs work mostly on adaptive immunity by reducing the production
of immunoglobulins, decreasing the production of T cells and limiting
the infiltration of inflammatory cells into areas of tissue injury.
Our study demonstrated NO EVIDENCE at all for these types of immune
reactions. There are ongoing experimental studies to examine the effect
of drugs that limit the activation of microglia and astrocytes, but
their use in humans must await further evidence of their efficacy and