Vaccination-induced cytokines: schizophrenia & developmental disabilities

Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
September 07, 2009


Introduction: An increasing body of peer-reviewed evidence indicates that when a woman is pregnant, transiently elevated cytokines can induce atypical brain development in her embryo or fetus. Illnesses and vaccinations induce elevation of cytokines, and these elevations can be heightened in individuals with alleles of genes related to immune responses. An implication of citations supporting these relationships is that vaccinating pregnant women is likely to induce cognitive and behavioral pathologies in as least some children whose mothers were vaccinated while the child was in utero. Schizophrenia and developmental disabilities are pathologies that may ensue.

Stacy Bilbo & Jaclyn Schwarz have written an important review, "Early-life programming of later-life brain and behavior: a critical role for the immune system".
      The peer-reviewed paper is free online (1) and is especially relevant amid recommendations that pregnant women be vaccinated for seasonal influenza and for lab-related H1N1 swine flu. Evidence discussed by Bilbo & Schwarz prompts a question: Will vaccinating pregnant women induce cytokine elevations likely to damage the embryonic or fetal brain of at least some women?
        Published studies indicate that (i) transiently elevated cytokines can alter brain development in utero, and (ii) illnesses and vaccinations cause elevated levels of various cytokines. These two factors indicate that at least some women will have children who develop untoward traits induced in utero as a result of their mother's having been vaccinated during pregnancy.
        Because cytokines are complex (2), only two will be considered here, interleukin-6 and interleukin-1beta (IL-6, IL-1b).

Interleukin-6 and interleukin-1beta are among the cytokines elevated by influenza vaccination (3-6). These elevations parallel those induced by influenza itself.
        Current recommendations for a seasonal-influenza vaccination accompanied by one or two swine flu (H1N1) vaccinations need be considered in regard to the following: "There are several reports in humans that influenza infection induces cytokine production by the maternal immune system, the fetal immune system, and the placenta..., and each has been linked to increased risk of schizophrenia in the offspring..." (1, citing 7-9; see also 10).

In addition to increased risk for schizophrenia, maternal cytokines (especially IL-1b) induced by vaccinating pregnant women may alter the subsequent child's cognitive skills related to memory (reviewed in 1). As one researcher summarizes, "Prenatal exposure to infection appears to increase the risk of schizophrenia and other neurodevelopmental disorders." (8)

Clarification: This essay is not asserting that ALL pregnant women who receive injections of anti-influenza vaccine and/or injections of anti-H1N1 vaccine (many brands of which will contain thimerosal and/or squalene) will give birth to a child who later develops schizophrenia or a developmental disorder. Instead, the evidence cited in this essay indicates that, among women who receive one or more vaccinations during pregnancy and thereby experience cytokines elevations that affect her fetus, there will be an increased risk for having a child who, some years later, will develop schizophrenia or a developmental disability.

A pregnant woman's options are discomforting. If she develops swine flu or seasonal influenza, she may induce cytokine elevations which adversely affect her fetus. If she allows herself to be vaccinated during pregnancy, her body's reaction will include cytokine elevations which may adversely affect brain development of some fetuses - and do in ways that become apparent only during early childhood, adolescence, or young adulthood (reviewed in 1).

For individuals with a technical bent, the Bilbo and Schwarz review is recommended (1). In short, it summarizes known effects of maternal elevations of interleukin-6 and interleukin-1beta. Additionally, the review elaborates increasing evidence supporting the "two hit" hypothesis, wherein an in utero event such as transiently elevated cytokines induces fetal changes which potentiate more serious sequelae pursuant to postnatal events in the offspring (eg, illness).

Media reports tell us that the safety of swine flu vaccinations will be evaluated. However, some reports have mentioned that thimerosal or squalene may not be present in the vaccines tested early, thus raising questions about "safety" pronouncements we'll be hearing. Furthermore, if the influenza or swine flu vaccinations' adverse events include developmental disabilities and schizophrenia, which will occur some years after the vaccinating of pregnant women, the monitoring of those adverse events will be impossible in the months ahead.

More generally, we ask if vaccinologists are prone to hubris? Their willingness to inject thimerosal and squalene (MF59) despite voluminous evidence of harm caused by those substances appalls. An autism parent raises an important issue (11), are many and perhaps most vaccinologists rushing forth while ignoring advances in immunology, while ignoring findings which indicate why some individuals are more likely to experience adverse effects from vaccinations, especially during pregnancy?

Postscript: This essay calls attention to adverse effects induced by cytokines elevated by vaccinations and only briefly mentions adverse effects induced by thimerosal (12) and by squalene (13). Not considered are the additive or synergistic effects of the three components: cytokine elevations, squalene, and thimerosal.


References:

1. Early-life programming of later-life brain and behavior: a critical role for the immune system
Bilbo SD, Schwarz JM.
Frontiers in Behavioral Neuroscience 2009 3(14)1-14.
http://frontiersin.org/behavioralneuroscience/paper/10.3389/neuro.08/014.2009/pdf/

2. Cytokine
http://en.wikipedia.org/wiki/Cytokine

3. 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.
Laboratory of Medicine and Pathology, University of Minnesota

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.

4. Genetic predisposition of the interleukin-6 response to inflammation: implications for a variety of major diseases?
Bennermo M, Held C, Stemme S, Ericsson CG, Silveira A, Green F, Tornvall P.
Department of Medicine, Danderyd University Hospital, Stockholm, Sweden.
Clin Chem. 2004 Nov;50(11):2136-40.
{free online}
http://www.clinchem.org/cgi/content/full/50/11/2136

BACKGROUND: A single-nucleotide polymorphism (SNP) in the promoter region of the interleukin-6 (IL-6) gene at position -174 (G>C) has been reported to be associated with a variety of major diseases, such as Alzheimer disease, atherosclerosis, and cardiovascular disease, cancer, non-insulin-dependent diabetes mellitus, osteoporosis, sepsis, and systemic-onset juvenile chronic arthritis. However, authors of previous in vitro and in vivo studies have reported conflicting results regarding the functionality of this polymorphism. We therefore aimed to clarify the role of the -174 SNP for the induction of IL-6 in vivo. METHODS: We vaccinated 20 and 18 healthy individuals homozygous for the -174 C and G alleles, respectively, with 1 mL of Salmonella typhii vaccine. IL-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) were measured in the blood at baseline and up to 24 h after vaccination. RESULTS: Individuals with the G genotype had significantly higher plasma IL-6 values at 6, 8, and 10 h after vaccination than did individuals with the C genotype (P <0.005). There were no differences between the two genotypes regarding serum concentrations of IL-1beta and TNF-alpha before or after vaccination. CONCLUSIONS: The -174 G>C SNP in the promoter region of the IL-6 gene is functional in vivo with an increased inflammatory response associated with the G allele. Considering the central role of IL-6 in a variety of major diseases, the present finding might be of major relevance.

excerpt: Interleukin 6 (IL-6) is a key proinflammatory cytokine produced by many different cells, including leukocytes, adipocytes, endothelial cells, fibroblasts, and myocytes. IL-6 regulates production of adhesion molecules and induces secretion of monocyte chemotactic protein, an important mediator of release of other cytokines, such as tumor necrosis factor-{alpha} (TNF-{alpha}) and interleukin-1ß (IL-1ß), that subsequently amplify the inflammatory reaction(1).

excerpt: We chose vaccination as a stimulus because it has been shown to increase plasma IL-6 concentrations and to have a detrimental effect on endothelial function (24).

excerpt: The main finding of the present study was that healthy individuals homozygous for the G allele of the –174 SNP located in the promoter region of the IL-6 gene had a stronger inflammatory IL-6 response to vaccination against S. typhii compared with individuals homozygous for the C allele.

excerpt: Previous in vitro studies (2)(20) have shown that the G allele of the –174 SNP was associated with increased transcription when stimulated by endotoxin and IL-1ß.

excerpt: ...the increased IL-6 response associated with the G allele might be harmful in the development of chronic diseases, such as NIDDM and atherosclerosis, by increasing the inflammatory stress when challenged repeatedly by minor stimuli. For example, insulin resistance has been associated with the G allele (14), and the G allele has been reported more frequently among Pima Indians and Caucasians with NIDDM (13).




5. Urinary tract diseases revealed after DTP vaccination in infants and young children: cytokine irregularities and down-regulation of cytochrome P-450 enzymes induced by the vaccine may uncover latent diseases in genetically predisposed subjects.
Prandota J.
Am J Ther. 2004 Sep-Oct;11(5):344-53.

Prophylactic vaccinations may sometimes shorten the incubation period of some illnesses and/or convert a latent infection/inflammation into a clinically apparent disease. Cytokines play a major role in mediating the inflammatory process in various clinical entities and represent a potential source of tissue damage if their production is not sufficiently well controlled. It seems that irregularities in production of proinflammatory cytokines may be responsible for the abnormalities associated with full-blown clinical symptoms of various urinary tract diseases observed after DTP vaccination in 13 infants and young children hospitalized over the past 24 years. On admission, upper respiratory tract diseases, atopic dermatitis, and/or latent urinary tract infection/inflammation were found in these children. It is suggested that the whole-cell pertussis present in DTP vaccine, acting as an excessive stimulus in these patients, produced symptoms reminiscent of biologic responses to circulating proinflammatory monokines such as IL-1beta, TNF-alpha, and IL-6 because earlier it was reported that in vitro the whole-cell vaccine induced significantly more such cytokine production than did the acellular pertussis or diphtheria-tetanus-only vaccine. Analysis of the cellular immune disturbances previously reported in urinary tract infection/inflammation (increased serum and/or urinary IL-1alpha, IL-1 receptor antagonist, IL-6 and IL-8), steroid-sensitive nephrotic syndrome (increased IL-2, IFN-gamma, TNF-alpha, and decreased or increased IL-4, depending on the cells studied), and atopic dermatitis (decreased IFN-gamma and increased IL-4 production), may suggest that similar subclinical chronic cytokine-mediated abnormalities produced in the course of latent diseases revealed in our patients, combined with those caused by DTP vaccination stimulus, were responsible for the pathomechanism of these clinical entities. This speculation is in agreement with the reports on the long-lasting induction of cytokine release and down-regulation of hepatic cytochrome P-450 isoenzyme activities after administration of DTP vaccine to mice and may be supported by the fact that TH1 phenotype is associated with the up-regulation of intercellular adhesion molecule-1 and RANTES, whereas TH2 phenotype is associated with the up-regulation of the vascular cell adhesion molecule and P-selectin, which are key players in the migration into inflamed tissues and localization of lymphocytes and other allergic effector and inflammatory cells. Because several inflammatory cytokines down-regulate gene expression of major cytochrome P-450 and/or other enzymes with the specific effects on mRNA levels, protein expression, and enzyme activity, thus affecting the metabolism of several endogenous lipophilic substances such as steroids, lipid-soluble vitamins, prostaglandins, leukotrienes, thromboxanes, and exogenous substances, their irregularities in the body may eventually lead to the flare of latent diseases in some predisposed subjects. Also, interleukin genetic polymorphisms, especially the constellation of TNF-alpha and IL-6 genetic variants, might predispose some infants with infection to a more than usually intense inflammatory response in the kidneys after vaccination. It seems that the aforementioned pathomechanism may also be responsible for some cases of sudden infant death syndrome, which is often preceded by infection/inflammation.

6. IL-1beta gene polymorphisms influence hepatitis B vaccination.
Yucesoy B et al.
Vaccine. 2002 Aug 19;20(25-26):3193-6.

Considerable variability exists in the vaccine response to hepatitis B with 5-10% of healthy young adults demonstrating no or inadequate responses following a standard vaccination schedule. As the interleukin-1beta (IL-1beta) cytokine has been shown to be important in the development of immune responses, we determined whether vaccine efficacy is influenced by genetic polymorphisms associated with IL-1beta expression. Ninety-two healthy individuals who were negative for antibodies to hepatitis B antigen (anti-HBs) were vaccinated against hepatitis B according to a standardized schedule. At selected times, antibody titers and lymphoproliferative capacity to hepatitis B surface antigen (HBsAg) were determined. DNA genotyping for IL-1beta polymorphisms using a polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) technique demonstrated that both the anti-HBs titer and the T-cell lymphoproliferative response to HBsAg are significantly increased in individuals possessing the IL-1beta (+3953) minor allelic variant. Copyright 2002 Elsevier Science Ltd.

7. The relationship of amniotic fluid cytokines and preterm delivery, amniotic fluid infection, histologic chorioamnionitis, and chorioamnion infection
Hillier SL et al.
Obstet Gynecol 1993 81:941-8.

OBJECTIVE: To assess the association between cytokines in the amniotic fluid (AF) and preterm delivery, the isolation of bacteria from the AF or chorioamnion, and histologic chorioamnionitis. METHODS: Fifty afebrile women with intact membranes in preterm labor at or before 34 weeks' gestation underwent amniocentesis. Cytokine levels were measured in AF, and cultures were performed. Placentas were cultured and examined histologically. RESULTS: Thirty-two (64%) of the 50 patients delivered at or before 34 weeks' gestation. Delivery at or before 34 weeks, compared with delivery after 34 weeks, was related to increased levels of interleukin-6 (IL-6) (88 versus 12%; P < .001), interleukin-1 (IL-1) alpha (50 versus 6%; P = .004), IL-1 beta (42 versus 0%; P = .002), and prostaglandin (PG) E2 (66 versus 22%; P = .008). Bacteria were recovered from the AF of nine (18%) of the 50 patients. All of the cytokines with increased levels, plus tumor necrosis factor (TNF)-alpha, were related to bacteria in the AF. Increased IL-6, IL-1 alpha, IL-1 beta, TNF-alpha, and PGE2 were also associated with histologic chorioamnionitis among women who delivered within 1 week of amniocentesis. Elevated cytokine levels were not related to chorioamnion infection. CONCLUSIONS: Elevated AF cytokines and PGE2 predicted delivery before 34 weeks' gestation and delivery within 7 days of the amniocentesis, as well as AF infection and histologic chorioamnionitis. These findings support the hypothesis that infection is one cause of preterm delivery, operating via a mechanism involving induction of cytokine production.

8. Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid, and fetal brain
Urakubo A et al.
Schizophren Res 2001 47:27-36.

Prenatal exposure to infection appears to increase the risk of schizophrenia and other neurodevelopmental disorders. We have hypothesized that cytokines, generated in response to maternal infection, play a key mechanistic role in this association. E16 timed pregnancy rats were injected i.p. with Escherichia coli lipopolysaccharide (LPS) to model prenatal exposure to infection. Placenta, amniotic fluid and fetal brains were collected 2 and 8h after LPS exposure. There was a significant treatment effect of low-dose (0.5mg/kg) LPS on placenta cytokine levels, with significant increases of interleukin (IL)-1beta (P<0.0001), IL-6 (P<0.0001), and tumor necrosis factor-alpha (TNF-alpha) (P=0.0001) over the 2 and 8h time course. In amniotic fluid, there was a significant effect of treatment on IL-6 levels (P=0.0006). Two hours after maternal administration of high-dose (2.5mg/kg) LPS, there were significant elevations of placenta IL-6 (P<0.0001), TNF-alpha (P<0.0001), a significant increase of TNF-alpha in amniotic fluid (P=0.008), and a small but significant decrease in TNF-alpha (P=0.035) in fetal brain. Maternal exposure to infection alters pro-inflammatory cytokine levels in the fetal environment, which may have a significant impact on the developing brain.

9. Serologic evidence of prenatal influenza in the etiology of schizophrenia
Brown AS et al.
Arch Gen Psychiatry 2004 61:774-80.
{free online}
http://archpsyc.ama-assn.org/cgi/content/full/61/8/774

CONTEXT: Some, but not all, previous studies suggest that prenatal influenza exposure increases the risk of schizophrenia. These studies used dates of influenza epidemics and maternal recall of infection to define influenza exposure, suggesting that discrepant findings may have resulted from exposure misclassification. OBJECTIVE: To examine whether serologically documented prenatal exposure to influenza increases the risk of schizophrenia. DESIGN: Nested case-control study of a large birth cohort, born from 1959 through 1966, and followed up for psychiatric disorders 30 to 38 years later. SETTING: Population-based birth cohort. PARTICIPANTS: Cases were 64 birth cohort members diagnosed as having schizophrenia spectrum disorders (mostly schizophrenia and schizoaffective disorder). Controls were 125 members of the birth cohort, had not been diagnosed as having a schizophrenia spectrum or major affective disorder, and were matched to cases on date of birth, sex, length of time in the cohort, and availability of maternal serum. MAIN OUTCOME MEASURES: Archived maternal serum was assayed for influenza antibody in pregnancies giving rise to offspring with schizophrenia and matched control offspring. RESULTS: The risk of schizophrenia was increased 7-fold for influenza exposure during the first trimester. There was no increased risk of schizophrenia with influenza during the second or third trimester. With the use of a broader gestational period of influenza exposure-early to midpregnancy-the risk of schizophrenia was increased 3-fold. The findings persisted after adjustment for potential confounders. CONCLUSIONS: These findings represent the first serologic evidence that prenatal influenza plays a role in schizophrenia. If confirmed, the results may have implications for the prevention of schizophrenia and for unraveling pathogenic mechanisms of the disorder.

10. Prenatal infection as a risk factor for schizophrenia
Brown AS.
College of Physicians and Surgeons of Columbia University, NY State Psychiatric Institute
Schizophr Bull. 2006 Apr;32(2):200-2
{free online}
http://schizophreniabulletin.oxfordjournals.org/cgi/content/full/32/2/200

Accumulating evidence suggests that prenatal exposure to infection contributes to the etiology of schizophrenia. This line of investigation has been advanced by birth cohort studies that utilize prospectively acquired data from serologic assays for infectious and immune biomarkers. These investigations have provided further support for this hypothesis and permitted the investigation of new infectious pathogens in relation to schizophrenia risk. Prenatal infections that have been associated with schizophrenia include rubella, influenza, and toxoplasmosis. Maternal cytokines, including interleukin-8, are also significantly increased in pregnancies giving rise to schizophrenia cases. Although replication of these findings is required, this body of work may ultimately have important implications for the prevention of schizophrenia, the elaboration of pathogenic mechanisms in this disorder, and investigations of gene-environment interactions.

11. The “New Class” of Helper T Cells or Things We Did Not Know Just Five Years Ago
Jack Russell, 06 September 2009
http://thelenseofautism.blogspot.com/2009/09/new-class-of-helper-t-cells-or-things.html

12. Autism, mercury, other toxic metals, & glutathione
Teresa Binstock, Aug 12, 2009.
http://www.generationrescue.org/binstock/090812-autism-toxic-metals-glutathione.htm


13. Lancet recommends caution for H1N1 vaccinations; ajduvants merit concern
Teresa Binstock, Aug 09, 2009
http://www.generationrescue.org/binstock/090809-Lancet-caution-H1N1-vaccination.htm


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