|
Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
June 16, 2009
Cytokines participate in neuronal development (1). Increased levels of
cytokines can adversely affect neuronal development within the CNS (eg,
2-4). Vaccinations induce increased expression of various cytokines. For
instance, anti-influenza vaccination causes transiently increased levels
of cytokines. Some cytokines expressed during pregnancy adversely affect
the fetal brain. At least one cytokine (interleukin-6; IL-6) is among
the cytokines which (a) adversely affects neuronal development and (b)
is induced by anti-influenza vaccinations (cites below).
Many of the studies documenting adverse neuronal-effects of elevated
cytokines have used non-humans animals as subjects. However, these
findings combine with the anti-influenza, vaccination-induced cytokines
in humans studies so as to suggest that administering influenza vaccines
to pregnant women may have adverse effects on at least some progeny.
Importantly, although the CDC and various medical organizations
recommend the "flu shot" for pregnant women, a Pubmed search found no
citations wherein anti-influenza vaccinations were tested in pregnant
humans in regard to (a) expression of cytokines, and (b) long-term,
possibly delayed neurobehavioral effects in the children who were
embryos or fetuses when those mothers were vaccinated.
A dearth of such studies is revealed by a Pubmed search. On June 26,
2009, three citations (5-7) were generated by the following search strategy:
influenza AND pregnant AND (vaccine OR vaccinatio*) AND (cytokin* OR
interfero* OR interleuk* OR (necrosis AND factor))
An article written in Russian may be relevant (4), but possibly more
important is the fact that vaccinologists may have thoroughly studied
neither the influenza vaccinations of pregnant women nor the effects of
those vaccinations upon the fetus and upon CNS-related development of
the child. Is there cause for concern?
Firstly, anti-influenza vaccination induces cytokine expression in
humans. For example, elevation of interleukin-6 (IL-6) after
anti-influenza vaccination has been described (eg, 8-9). This elevation
is similar but not necessarily identical to immune responses induced by
influenza infection (eg, elevated IL-6; 10-11). Furthermore, co-factors
such as current or recent cytomegalovirus infection can alter responses
to anti-influenza vaccinations (eg, 12).
Secondly, IL-6 - which is elevated in response to anti-influenza
vaccinations - can induce adverse effects regarding neuronal development
of the fetus (13). Symptoms arising from these processes can be delayed
and appear subsequent to birth (14); and some researchers find relevance
to the etiologies of some cases of autism and schizophrenia (eg, 13-14).
Furthermore, inter-individual variation would arise because
cytokine-induced effects may depend upon in-utero timings of the
inflammatory pulse (eg, 15). A murine example with relevance to
behaviors common in autistic children was offered by Urs Meyer and
colleagues, who reported that an immune challenge on gestation day 9
suppressed spatial exploration, whereas the same challenge on day 17 led
to perseverative behaviors (15).
Thirdly, other studies document adverse effects of elevated,
influenza-related cytokines within the brain. These effects include
impaired neurogenesis (16-17), seizure susceptibility (18), and altered
patterns of stress hormones (19).
Indeed, Shi and colleagues wrote, "...maternal viral infection has been
cited as the 'principal non-genetic cause of autism' (Ciaranello and
Ciaranello, 1995). What these various insults are likely to have in
common is a maternal antiviral response (Patterson, 2002)." (14). Thus
concern is justified: Would maternal cytokines induced by the
anti-influenza vaccination during pregnancy incline some fetuses towards
autism, other autism-spectrum disorders, or epilepsy?
Indeed, the various findings in animal experiments suggest fetal
CNS-damage induced by anti-influenza inflammation is plausible, perhaps
even likely for small subgroups of pregnant women. And given the
relationships outlined and citations offered in this brief essay, why
are no studies findable in Pubmed regarding cytokines expression in
pregnant women receiving vaccinations? More specifically, why are there
no search-findable studies whose primary purpose was examining cytokines
responses in women who experience the anti-influenza vaccination during
pregnancy? Furthermore, why are there no vaccinated versus unvaccinated
studies of children whose mothers received (or didn't receive) an
anti-influenza vaccination during pregnancy?
The CDC recommends that pregnant women receive "flu shots" (20). Does
this recommendations for pregnant women place some fetuses at risk? The
citations presented in this brief essay suggest the answer is Yes.
References:
1. Cytokines in neuronal development.
Jonakait GM. Adv Pharmacol. 1997;37:35-67.
2. The role of pro- and antiinflammatory cytokines in neurodegeneration.
Allan SM. Ann N Y Acad Sci. 2000;917:84-93.
3. Cytokines and acute neurodegeneration.
Allan SM, Rothwell NJ. Nat Rev Neurosci. 2001 Oct;2(10):734-44.
4. A primer on cytokines: sources, receptors, effects, and inducers.
Curfs JH et al. Clin Microbiol Rev. 1997 Oct;10(4):742-80.
http://cmr.asm.org/cgi/reprint/10/4/742?view=long&pmid=9336671
5. Induction of leukocyte interferon in pregnant women and parturients.
Eristavi ZA et al. Akush Ginekol (Mosk). 1984 Jan;(1):38-40. {Russian}
6. Safety and immunogenicity of respiratory syncytial virus purified
fusion protein-2 vaccine in pregnant women.
Munoz FM et al. Vaccine. 2003 Jul 28;21(24):3465-7.
7. T-helper type 2 polarization among asthmatics during and following
pregnancy.
Rastogi D et al. Clin Exp Allergy. 2006 Jul;36(7):892-8.
8. Effect of influenza vaccine on markers of inflammation and lipid profile.
Tsai MY et al. J Lab Clin Med. 2005 Jun;145(6):323-7.
Despite wide use of the influenza vaccine, relatively little is known
about its effect on the measurement of inflammatory markers. Because
inflammatory markers such as C-reactive protein (CRP) are increasingly
being used in conjunction with lipids for the clinical assessment of
cardiovascular disease and in epidemiologic studies, we evaluated the
effect of influenza vaccination on markers of inflammation and plasma
lipid concentrations. We drew blood from 22 healthy individuals 1 to 6
hours before they were given an influenza vaccination and 1, 3, and 7
days after the vaccination. Plasma CRP, interleukin (IL)-6, monocyte
chemotactic protein 1, tumor necrosis factor alpha, IL-2 soluble
receptor alpha, and serum amyloid A were measured, and differences in
mean concentrations of absolute and normalized values on days 1, 3, and
7 were compared with mean baseline values. There was a significant
increase in mean IL-6 (P < .01 absolute values, P < .001 normalized
values) on day 1 after receiving the influenza vaccine. The mean
increases in normalized high sensitivity CRP values were significant on
day 1 (P < .01) and day 3 (P = .05), whereas the mean increase in
normalized serum amyloid A was significant only on day 1 (P < .05). No
significant changes were seen in mean concentrations of IL-2 soluble
receptor alpha, monocyte chemotactic protein-1, or tumor necrosis
factor-alpha. Of the lipids, significant decreases in mean
concentrations of normalized triglyceride values were seen on days 1 (P
< .05), 3 (P < .001), and 7 (P < .05) after vaccination. Our findings
show that the influenza vaccination causes transient changes in select
markers of inflammation and lipids. Consequently, clinical and
epidemiologic interpretation of the biomarkers affected should take into
account the possible effects of influenza vaccination.
9. Inflammatory response after influenza vaccination in men with and
without carotid artery disease.
Carty CL et al. Arterioscler Thromb Vasc Biol. 2006 Dec;26(12):2738-44.
http://atvb.ahajournals.org/cgi/content/full/26/12/2738
OBJECTIVE: Inflammatory markers are associated with vascular disease;
however, variation in the acute phase response (APR) has not been
evaluated. We evaluated whether the APR magnitude in men with severe
carotid artery disease (CAAD) (>80% stenosis) differed from that of men
without stenosis (<15% stenosis). METHODS AND RESULTS: White males with
(n=43) and without (n=61) severe CAAD receiving clinical influenza
vaccinations were recruited. Their baseline and 24-hour after
-vaccination blood samples were assayed for C-reactive protein (CRP),
IL-6, and serum amyloid-a (SAA). In vivo APR to vaccination was
measurable and varied among subjects. Adjusted for age, smoking, oral
hypoglycemics, aspirin, and stain use, the relative 24-hour changes in
levels of ln(CRP), ln(IL-6), and ln(SAA) were higher in men with CAAD
than in men without, but only the SAA response was significant (P=0.02);
the relative SAA response was 1.6 (95% confidence interval, 1.1 to 2.5)
times higher in men with than without CAAD. The APR for all markers
appeared to be independent of baseline levels. CONCLUSIONS: Influenza
vaccination results in a mild, but measurable, APR in men with and
without CAAD. SAA APR variability may be a predictor of severe vascular
disease that is independent of basal SAA level.
10. Inflammatory responses in influenza A virus infection.
Julkunen I et al. Vaccine. 2000 Dec 8;19 Suppl 1:S32-7.
Influenza A virus causes respiratory tract infections, which are
occasionally complicated by secondary bacterial infections. Influenza A
virus replicates in epithelial cells and leukocytes resulting in the
production of chemokines and cytokines, which favor the extravasation of
blood mononuclear cells and the development of antiviral and Th1-type
immune response. Influenza A virus-infected respiratory epithelial cells
produce limited amounts of chemokines (RANTES, MCP-1, IL-8) and
IFN-alpha/beta, whereas monocytes/macrophages readily produce chemokines
such as RANTES, MIP-1alpha, MCP-1, MCP-3, IP-10 and cytokines TNF-alpha,
IL-1beta, IL-6, IL-18 and IFN-alpha/beta. The role of influenza A
virus-induced inflammatory response in relation to otitis media is being
discussed.
11. Cytokines in the pathogenesis of influenza.
Van Reeth K. Vet Microbiol. 2000 May 22;74(1-2):109-16.
Uncomplicated influenza in humans, horses or swine is characterized by
massive virus replication in respiratory epithelial cells, inflammation
and an abrupt onset of general and respiratory disease. There is now
growing evidence that the so-called early cytokines produced at the site
of infection mediate many of the clinical and pathological
manifestations. Among these cytokines are interferon-alpha (IFN-alpha),
tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) alpha and
beta, interleukin-6 (IL-6), interleukin-8 (IL-8) and monocyte-attracting
chemokines. This paper reviews: (1) in vivo examinations of the cytokine
profiles during influenza in mice, humans or swine; (2) in vivo data on
the probable role of these cytokines; and (3) selected in vitro data on
cytokine induction by the influenza virus. Examination of respiratory
secretions of experimentally infected humans or animals revealed a brisk
and concurrent rise in several of the cytokines mentioned. Moreover,
peak cytokine levels directly correlated with virus replication and
disease. In the mouse model, specific anti-cytokine strategies have
further confirmed the role of cytokines in body temperature changes,
anorexia and lung inflammation. However, cytokines were clearly not the
only factor contributing to disease, and they seemed to be essential for
resolution of the infection. Though influenza virus was shown to induce
cytokines in cell culture, in vitro experiments have also revealed
conflicting data. Furthermore, the viral genes or products that are
responsible for cytokine induction are unknown. Exactly this information
would make important contributions to our understanding of the genetic
basis of viral virulence.
12. Association between cytomegalovirus infection, enhanced
proinflammatory response and low level of anti-hemagglutinins during the
anti-influenza vaccination--an impact of immunosenescence.
Trzonkowski P et al. Vaccine. 2003 Sep 8;21(25-26):3826-36.
We assessed association between prior cytomegalovirus (CMV) infection,
proinflammatory status and effectiveness of the anti-influenza
vaccination. We examined 154 individuals during the epidemic season
dividing them according to the age, response to the vaccine and the
Senieur Protocol (SP). The anti-hemagglutinins (HI), tumour necrosis
factor alpha (TNFalpha), interleukin (IL) 1beta, IL6, IL10,
ACTH/cortisol axis, anti-CMV antibodies and CD28+CD57- lymphocytes were
assessed. Non-responders of both ages we characterised by higher levels
of anti-CMV IgG and higher percentages of CD57+CD28- lymphocytes (known
to be associated with CMV carrier status) together with increased
concentrations of TNFalpha and IL6 and decreased levels of cortisol. The
anti-influenza vaccine induced increase in TNFalpha and IL10 in the all
non-responders, while cortisol increased only in the young. Concluding,
CMV carrier status eliciting elevated proinflammatory potential could
contribute to unresponsiveness to the anti-influenza vaccine.
13. Maternal immune activation alters fetal brain development through
interleukin-6.
Smith SE et al. J Neurosci. 2007 Oct 3;27(40):10695-702.
http://www.jneurosci.org/cgi/content/full/27/40/10695
Schizophrenia and autism are thought to result from the interaction
between a susceptibility genotype and environmental risk factors. The
offspring of women who experience infection while pregnant have an
increased risk for these disorders. Maternal immune activation (MIA) in
pregnant rodents produces offspring with abnormalities in behavior,
histology, and gene expression that are reminiscent of schizophrenia and
autism, making MIA a useful model of the disorders. However, the
mechanism by which MIA causes long-term behavioral deficits in the
offspring is unknown. Here we show that the cytokine interleukin-6
(IL-6) is critical for mediating the behavioral and transcriptional
changes in the offspring. A single maternal injection of IL-6 on day
12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent
inhibition (LI) deficits in the adult offspring. Moreover,
coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA
prevents the PPI, LI, and exploratory and social deficits caused by
poly(I:C) and normalizes the associated changes in gene expression in
the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does
not result in several of the behavioral changes seen in the offspring of
wild-type mice after MIA. The identification of IL-6 as a key
intermediary should aid in the molecular dissection of the pathways
whereby MIA alters fetal brain development, which can shed new light on
the pathophysiological mechanisms that predispose to schizophrenia and
autism.
14. Maternal influenza infection causes marked behavioral and
pharmacological changes in the offspring.
Shi L et al. J Neurosci. 2003 Jan 1;23(1):297-302.
http://www.jneurosci.org/cgi/content/full/23/1/297
Maternal viral infection is known to increase the risk for schizophrenia
and autism in the offspring. Using this observation in an animal model,
we find that respiratory infection of pregnant mice (both BALB/c and
C57BL/6 strains) with the human influenza virus yields offspring that
display highly abnormal behavioral responses as adults. As in
schizophrenia and autism, these offspring display deficits in prepulse
inhibition (PPI) in the acoustic startle response. Compared with control
mice, the infected mice also display striking responses to the acute
administration of antipsychotic (clozapine and chlorpromazine) and
psychomimetic (ketamine) drugs. Moreover, these mice are deficient in
exploratory behavior in both open-field and novel-object tests, and they
are deficient in social interaction. At least some of these behavioral
changes likely are attributable to the maternal immune response itself.
That is, maternal injection of the synthetic double-stranded RNA
polyinosinic-polycytidylic acid causes a PPI deficit in the offspring in
the absence of virus. Therefore, maternal viral infection has a profound
effect on the behavior of adult offspring, probably via an effect of the
maternal immune response on the fetus.
15. The time of prenatal immune challenge determines the specificity of
inflammation-mediated brain and behavioral pathology.
Meyer U et al. J Neurosci. 2006 May 3;26(18):4752-62.
http://www.jneurosci.org/cgi/content/full/26/18/4752
Disturbance to early brain development is implicated in several
neuropsychiatric disorders including autism, schizophrenia, and mental
retardation. Epidemiological studies have indicated that the risk of
developing these disorders is enhanced by prenatal maternal infection,
presumably as a result of neurodevelopmental defects triggered by
cytokine-related inflammatory events. Here, we demonstrate that the
effects of maternal immune challenge between middle and late gestation
periods in mice are dissociable in terms of fetal brain cytokine
responses to maternal inflammation and the pathological consequences in
brain and behavior. Specifically, the relative expression of pro- and
anti-inflammatory cytokines in the fetal brains in response to maternal
immune challenge may be an important determinant among other
developmental factors for the precise pathological profile emerging in
later life. Thus, the middle and late gestation periods correspond to
two windows with differing vulnerability to adult behavioral
dysfunction, brain neuropathology in early adolescence, and of the acute
cytokine responses in the fetal brain.
16. Reduced hippocampal neurogenesis in adult transgenic mice with
chronic astrocytic production of interleukin-6.
Vallières L et al. J Neurosci. 2002 Jan 15;22(2):486-92.
http://www.jneurosci.org/cgi/content/full/22/2/486
Postnatal neurogenesis can be modulated after brain injury, but the role
of the attendant expression of inflammatory mediators in such responses
remains to be determined. Here we report that transgenically directed
production of interleukin-6 (IL-6) by astroglia decreased overall
neurogenesis by 63% in the hippocampal dentate gyrus of young adult
transgenic mice. The proliferation, survival, and differentiation of
neural progenitor cells labeled with the thymidine analog
bromodeoxyuridine were all reduced in the granule cell layer of these
mice, whereas their distribution and gliogenesis appeared normal. These
effects were not a consequence of general toxicity of the IL-6
transgene, because they were manifested in the absence of neuronal death
and of major changes in glial cell number and morphology. These findings
suggest that long-term exposure of the brain to proinflammatory
mediators such as IL-6, as is seen in certain degenerative disorders and
infections, can interfere with adult neurogenesis.
17. Inflammation is detrimental for neurogenesis in adult brain.
Ekdahl CT et al. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13632-7.
http://www.pnas.org/content/100/23/13632.long
New hippocampal neurons are continuously generated in the adult brain.
Here, we demonstrate that lipopolysaccharide-induced inflammation, which
gives rise to microglia activation in the area where the new neurons are
born, strongly impairs basal hippocampal neurogenesis in rats. The
increased neurogenesis triggered by a brain insult is also attenuated if
it is associated with microglia activation caused by tissue damage or
lipopolysaccharide infusion. The impaired neurogenesis in inflammation
is restored by systemic administration of minocycline, which inhibits
microglia activation. Our data raise the possibility that suppression of
hippocampal neurogenesis by activated microglia contributes to cognitive
dysfunction in aging, dementia, epilepsy, and other conditions leading
to brain inflammation.
18. Postnatal inflammation increases seizure susceptibility in adult rats.
Galic MA et al. J Neurosci. 2008 Jul 2;28(27):6904-13.
http://www.jneurosci.org/cgi/content/full/28/27/6904
There are critical postnatal periods during which even subtle
interventions can have long-lasting effects on adult physiology. We
asked whether an immune challenge during early postnatal development can
alter neuronal excitability and seizure susceptibility in adults.
Postnatal day 14 (P14) male Sprague Dawley rats were injected with the
bacterial endotoxin lipopolysaccharide (LPS), and control animals
received sterile saline. Three weeks later, extracellular recordings
from hippocampal slices revealed enhanced field EPSP slopes after
Schaffer collateral stimulation and increased epileptiform burst-firing
activity in CA1 after 4-aminopyridine application. Six to 8 weeks after
postnatal LPS injection, seizure susceptibility was assessed in response
to lithium-pilocarpine, kainic acid, and pentylenetetrazol. Rats treated
with LPS showed significantly greater adult seizure susceptibility to
all convulsants, as well as increased cytokine release and enhanced
neuronal degeneration within the hippocampus after limbic seizures.
These persistent increases in seizure susceptibility occurred only when
LPS was given during a critical postnatal period (P7 and P14) and not
before (P1) or after (P20). This early effect of LPS on adult seizures
was blocked by concurrent intracerebroventricular administration of a
tumor necrosis factor alpha (TNFalpha) antibody and mimicked by
intracerebroventricular injection of rat recombinant TNFalpha. Postnatal
LPS injection did not result in permanent changes in microglial (Iba1)
activity or hippocampal cytokine [IL-1beta (interleukin-1beta) and
TNFalpha] levels, but caused a slight increase in astrocyte (GFAP)
numbers. These novel results indicate that a single LPS injection during
a critical postnatal period causes a long-lasting increase in seizure
susceptibility that is strongly dependent on TNFalpha.
19. Maternal LPS induces cytokines in the amniotic fluid and
corticotropin releasing hormone in the fetal rat brain.Gayle DA et al.
Am J Physiol Regul Integr Comp Physiol. 2004 Jun;286(6):R1024-9.
http://ajpregu.physiology.org/cgi/content/full/286/6/R1024
Perinatal infections are a risk factor for fetal neurological
pathologies, including cerebral palsy and schizophrenia. Cytokines that
are produced as part of the inflammatory response are proposed to
partially mediate the neurological injury. This study investigated the
effects of intraperitoneal injections of lipopolysaccharide (LPS) to
pregnant rats on the production of cytokines and stress markers in the
fetal environment. Gestation day 18 pregnant rats were treated with LPS
(100 microg/kg body wt i.p.), and maternal serum, amniotic fluid,
placenta, chorioamnion, and fetal brain were harvested at 1, 6, 12, and
24 h posttreatment to assay for LPS-induced changes in cytokine protein
(ELISA) and mRNA (real-time RT-PCR) levels. We observed induction of
proinflammatory cytokines interleukin (IL)-1 beta, IL-6, and tumor
necrosis factor-alpha (TNF-alpha) as well as the anti-inflammatory
cytokine IL-10 in the maternal serum within 6 h of LPS exposure.
Similarly, proinflammatory cytokines were induced in the amniotic fluid
in response to LPS; however, no significant induction of IL-10 was
observed in the amniotic fluid. LPS-induced mRNA changes included
upregulation of the stress-related peptide corticotropin-releasing
factor in the fetal whole brain, TNF-alpha, IL-6, and IL-10 in the
chorioamnion, and TNF-alpha, IL-1 beta, and IL-6 in the placenta. These
findings suggest that maternal infections may lead to an unbalanced
inflammatory reaction in the fetal environment that activates the fetal
stress axis.
20. CDC - Influenza (Flu) | Key Facts About Flu Vaccine
http://www.cdc.gov/FLU/protect/keyfacts.htm
Back to Index |
