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MMR's live viruses, interferon gamma, and blood-brain barrier permeability

Posted Jul 01 2009 5:02pm

Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
May 31, 2009

Introduction: MMR induces an extended pulse of interferon gamma (IFNg), which increases permeability of the blood-brain barrier (BBB). An inference is that more mercury will enter the brain when a toddler is injected with the both the MMR and a thimerosal-containing vaccine during the same vaccination incident. The mercury-into-brain effect is likely to be increased because viral infections increase BBB permeability. Furthermore, the MMR induces increases NK activity, but a large subgroup of autistic children has suboptimal NK cytoxicity, which suggests that some children may have atypical and suboptimal NK activity pursuant to live viruses injected during MMR incidents.

The findings summarized here call attention to plausible mechanisms by which some children regress into autism or other autism-spectrum disorders subsequent to vaccinations, especially after vaccination incidents wherein multiple vaccines were injected at virtually the same time.

Here are some quotes, citations, and abstracts in support of these concerns.

---------------

"The protective effect of the BBB is... lost during bacterial and viral infections." (1)

"TNF-alpha, IL-1beta, interferon gamma (IFN-gamma), or lipopolysaccharide (LPS)"... increased "the permeability of the tight junctions" of BBB endothelial cells (2)

Regarding MMR, "Interferon-gamma was the principal cytokine produced after primary measles immunization" (3), thus the MMR's pulse of interferon gamma (IFNg) is likely to increase BBB permeability.

"45% of a subgroup of children with autism suffers from low NK cell activity" (4),

Regarding MMR, "NK cells increased after immunization" (3), but NK activity reduced by the MMR has been described (5), and a large subgroup of autistic children has low NK cytotoxicity (5). These several findings suggest that autistic children may be more inclined towards reduced NK activity after MMR vaccinations.

Inferences from these 5 studies prompt concerns. For instance,
a) Given that IFNg increases BBB permeability (2) and the MMR induces an extended pulse of IFNg (3), would simultaneous injections of MMR and a thimerosal-containing vaccine increase the amount of mercury that enters the human brain?
b) Given that the MMR contains live viruses, and given that viruses increase BBB permeability (2), would simultaneous injections of MMR and a thimerosal-containing vaccine increase the amount of mercury that enters the human brain?
c) Given that a large subgroup of autistic children has reduced effectiveness of natural killer (NK) cells (4), and given that the MMR in healthy children causes an increase in NK activity (3), would children having impaired NK function (5) have atypical and suboptimal responses to MMR-related injections of live viruses?


References:

1: Blood brain barrier and infection.
Chaudhuri JD.
Med Sci Monit. 2000 Nov-Dec;6(6):1213-22.

The blood brain barrier (BBB) is a highly dynamic structure and consists of endothelial cells, which are characterized by the presence of tight junctions and relative lack of endocytic vesicles. The tight junctions are reinforced by the foot processes of the astrocytes. The BBB functions through these specialised structures, to maintain the environment of the brain in a steady state by regulating the influx and efflux of substances. The protective effect of the BBB is however, lost during bacterial and viral infections. The primary mechanism operative are an increase in the permeability of the BBB and/or direct invasion of the brain by microorganisms. Since the BBB is relatively impermeable to chemotherapeutic agents the treatment of CNS infections is difficult. This paper aims to examine the various mechanisms by which infection spreads to the brain, and suggest measures for successful drug delivery into the brain during infections.


2: Cytokines, nitric oxide, and cGMP modulate the permeability of an in vitro model of the human blood-brain barrier.
Wong D, Dorovini-Zis K, Vincent SR.
Exp Neurol. 2004 Dec;190(2):446-55.

The endothelial cells (EC) of the microvasculature in the brain form the anatomical basis of the blood-brain barrier (BBB). In the present study, the effects of agents that modify the permeability of a well-established in vitro model of the human BBB were studied. The monolayers formed by confluent human brain microvessel endothelial cell (HBMEC) cultures are impermeable to the macromolecule tracer horseradish peroxidase (HRP) and have high electrical resistance. Exposure of HBMEC to various cytokines including TNF-alpha, IL-1beta, interferon gamma (IFN-gamma), or lipopolysaccharide (LPS) decreased transendothelial electrical resistance (TEER) mainly by increasing the permeability of the tight junctions. Primary cultures of HBMEC express endothelial nitric oxide synthase (eNOS) and produce low levels of NO. Treatment with the NO donors sodium nitroprusside (SNP) and DETA NONOate or the cGMP agonist 8-Br-cGMP significantly increased monolayer resistance. Conversely, inhibition of soluble guanylyl cyclase with ODQ rapidly decreased the resistance, and pretreatment of HBMEC with Rp-8-CPT-cGMPS, an inhibitor of cGMP-dependent protein kinase, partially prevented the 8-Br-cGMP-induced increase in resistance. Furthermore, NO donors and 8-Br-cGMP could also reverse the increased permeability of the monolayers induced by IL-1beta, IFN-gamma, and LPS. These results indicate that NO can decrease the permeability of the human BBB through a mechanism at least partly dependent on cGMP production and cGMP-dependent protein kinase activation.

3. Kinetics of immunologic responses after primary MMR vaccination.
Pabst HF et al.
Vaccine. 1997 Jan;15(1):10-4.

To study the kinetics of humoral as well as cellular immunity to measles and to test for associated immunosuppression 124 12 month old children were studied twice, before routine MMR and either 14, 22, 30, or 38 days after vaccination. Plaque reduction neutralization (PRN) titres were determined at these time points and lymphocytes were evaluated to identify changes in proportions of phenotype, their capacity to generate cytokines and to respond to blast transformation (BT) to measles hemagglutinin (HA), tetanus toxoid and Candida antigen. The PRN titre and BT to HA plateaued at 30 days and CD8+ and NK cells increased after immunization. Interleukin 2, 4, and 10 showed no significant changes. There was mild suppression of BT at 14 and 22 days post-immunization Interferon-gamma was the principal cytokine produced after primary measles immunization, suggesting primary measles immunization induces predominantly a TH1 type response.


4: Low natural killer cell cytotoxic activity in autism: the role of glutathione, IL-2 and IL-15.
Vojdani A, Mumper E, Granpeesheh D, Mielke L, Traver D, Bock K, Hirani K, Neubrander J, Woeller KN, O'Hara N, Usman A, Schneider C, Hebroni F, Berookhim J, McCandless J.
J Neuroimmunol. 2008 Dec 15;205(1-2):148-54.

Although many articles have reported immune abnormalities in autism, NK cell activity has only been examined in one study of 31 patients, of whom 12 were found to have reduced NK activity. The mechanism behind this low NK cell activity was not explored. For this reason, we explored the measurement of NK cell activity in 1027 blood samples from autistic children obtained from ten clinics and compared the results to 113 healthy controls. This counting of NK cells and the measurement of their lytic activity enabled us to express the NK cell activity/100 cells. At the cutoff of 15-50 LU we found that NK cell activity was low in 41-81% of the patients from the different clinics. This NK cell activity below 15 LU was found in only 8% of healthy subjects (p <0.001). Low NK cell activity in both groups did not correlate with percentage and absolute number of CD16(+)/CD56(+) cells. When the NK cytotoxic activity was expressed based on activity/100 CD16(+)/CD56(+) cells, several patients who had displayed NK cell activity below 15 LU exhibited normal NK cell activity. Overall, after this correction factor, 45% of the children with autism still exhibited low NK cell activity, correlating with the intracellular level of glutathione. Finally, we cultured lymphocytes of patients with low or high NK cell activity/cell with or without glutathione, IL-2 and IL-15. The induction of NK cell activity by IL-2, IL-15 and glutathione was more pronounced in a subgroup with very low NK cell activity. We conclude that that 45% of a subgroup of children with autism suffers from low NK cell activity, and that low intracellular levels of glutathione, IL-2 and IL-15 may be responsible.


5. Natural killer cell activity during measles.
Griffin DE et al.
Clin Exp Immunol. 1990 Aug;81(2):218-24.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1535057&blobtype=pdf

Natural killer cells are postulated to play an important role in host anti-viral defences. We measured natural killer cell activity in 30 individuals with acute measles (73 +/- 21 lytic units (LU)/10(7) cells) and 16 individuals with other infectious diseases (149 +/- 95 LU) and found it reduced compared with values for adults (375 +/- 70 LU; P less than 0.001) or children (300 +/- 73 LU, P less than 0.01) without infection. Reduced natural killer cell activity was found in measles patients with (84 +/- 30 LU) and without (55 +/- 18 LU) complications and was present for at least 3 weeks after the onset of the rash. Activity was increased by in vitro exposure of cells to interleukin-2. Depressed natural killer cell activity parallels in time the suppression of other parameters of cell-mediated immunity that occurs during measles.
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