Glutathione levels modulate Th1 Th2 profiles: clues to thimerosal susceptibility

[Guest guest]

This "mini-paper" is a further exploration into mechanisms

by which a small percentage of children are

susceptible to the ethylmercury in vaccinal thimerosal.

Abbreviations:

GSH = glutatione

APC = antigen-presenting cell

eHg = ethylmercury

TMS = thimerosal, a vaccine

preservative that is 49.6% eHg by weight

ASD = autism-spectrum disorders

IFN = interferon

A substantial subgroup of ASD children has immunity shifted

in the Th2 direction (1-4). This is consistent

with the facts (i) that many ASD children have recurring

or chronic candidiasis (parental reports), and (ii)

that individuals with Th2 profiles are more susceptible

to Candida infections (5).

As we contemplate why some children and not others become

neurologically and neurobehaviorally

impaired by physician-injected ethylmercury, the role

of susceptibility in the hours, days, and weeks

subsequent to each vaccinal thimerosal-injection needs

be considered. A number of studies have

documented the importance of peripheral- and CNS-glutathione

in detoxification and excretion of organic

mercury (eg, 7-12); and a common summary in these studies

is that animals or tissues low in GSH have

impaired detoxification or clearance of organic-mercury.

These findings suggest that an infant or toddler

who is low in GSH would be at increased risk for neurologic

sequelae from thimerosal's ethylmercury.

A further parallel with ASD children arises from the fact

that, in vivo, low GSH inclines toward immune

shifts in the Th2 direction. Jeff and colleagues

write: "glutathione levels in antigen-presenting

cells determine whether Th1 or Th2 response patterns

predominate. [in fact, in three different

experimental procedures, we showed that GSH depletion

inhibits Th1-associated cytokine production

and/or favors Th2-associated responses. [and] we demonstrate

clearly that the decrease in Th1 cytokine

production is due to the short-term, readily reversible

depletion of APC glutathione." (13).

These findings prompt concern for the mechanisms by which

GSH can be depleted, because identifying

mechanisms whereby GSH is lowered would provide insights

into why - even temporarily - a child would

be at greater risk for eHg neurotoxicity in the hours,

days, and weeks subsequent to a TMS-injection during

otherwise routine vaccinations. Importantly, one factor

known to lower GSH is recent or chronic infection

(14-16). Importantly, some chronic infections are called

"subclinical" because their symptoms are not

externally obvious and, in some cases, the lack of obvious

symptoms derives from subtle immune-

impairments that impair the generation of traditional

symptoms ( Burger, PhD, in P. Warren's

lab; personal communication). Overall, therefore, a child

who is sick, who was recently sick, or who has a

chronic subclinical infection would be at increased risk

of neurologic and neurobehavioral sequelae from

physician-injected eHg accompanied by vaccination.

Relatedly, the medical history of many ASD children includes,

during their infant and toddler periods: (a)

an atypically high number of otitis episodes not responsive

to antibiotics, and/or ( chronic diarrhea

(whether antibiotic-induced or not) that is often accompanied

by a reduction of beneficial microflora within

the gastrointestinal tract. These medical history patterns

provide two mechanisms whereby the eHg in

vaccinal TMS would be more neurotoxic. First, a chronic

infection that induces recurrent otitis would tend

to lower GSH. Secondly, GSH transferases are utilized

in the body's clearance of antibiotics (17). Thirdly,

a reduction of beneficial gut microflora leads to reduced

uptake of xenobiotic substances (eg, 18), which would

increase the duration of exposure to such substances

(7-11).

Conclusion: This "mini-paper" summarizes low-glutathione's

role as a risk factor for developing

neurologic and neurobehavioral sequelae from TMS injections.

Furthermore, two medical-history patterns

reported by many ASD parents - chronic otitis not responsive

to antibiotics; and/or prolonged diarrhea -

would augment organic mercury toxicity by lowering GSH

and/or by slowing the time required for organic mercury to be cleared from

the body. Furthermore, any conditions that lower GSH - whether, in any

one child, they be genetic and/or non-genetic - would incline the

child towards a Th2 pattern of immunity, which is often

reflected in a decreased CD4/CD8 ratio, a reduction of

cell-mediated immunity, and increased production

of antibodies, ie, traits associated with autism.

References follow two mini-addenda:

Caveat:

This "mini-paper" (a) is a technical discussion

relevant to an infant's and toddler's GSH-status at the time

or times a physician injects eHg into the child, and

( ought not be interpreted as medical advice regarding

chelation-therapies months or years after the TMS injections.

Cytokines ramifications of low GSH:

Some parents have purchased cytokines evaluations. Some

additional quotes from et al may be

helpful:

1. "Recent studies in a system where cultured cells

readily produce IL-4 have shown that increasing GSH

levels in the cultures decreases IL-4 production in a

dose-dependent manner..."

2. "Our data complement this. observation by showing

that IFN-gamma production predominates when

GSH levels are high and declines when APC GSH is depleted."

3. "Our findings support these earlier observations

by showing that Th2 response patterns are favored

when APC GSH is depleted."

4. ".it is the outcome of antigen presentation,

rather than the failure to present antigen, that changes

when antigens are presented by GSH-depleted APC."

5. "We find that GSH depletion decreases IL-12

production. However, although IFN-gamma production

is lost and fully recovers in parallel with APC GSH,

IL-12 pruduction is lost when GSH is depleted but

largely fails to recover under conditions that enable

GSH and IFN-gamma recovery."

6. "The dramatic changes that GSH depletion imposes

on immune responses are consistent with the

fundamental roles that GSH plays in cellular physiology."

7. "Our data demonstrate that subtle changes in

GSH levels may have profound effects on the immune

response."

8. ".the classical response-pattern differences

to challenge with parasitic organisms that have led to the

characterization of mouse strains as "Th2" or "Th1" may

simply reflect a differential sensitivity to

GSH depletion."

9. "Because parasite infection may well result

in modest GSH depletion, particularly in APC, there is

good reason to suspect that differential responsiveness

to infection could be mediated by the GSH-

dependent mechanisms we have described here."

References:

1. J Neuroimmunol 1998 May 1;85(1):106-9

Th1- and Th2-like cytokines in CD4+ and CD8+ T cells

in autism.

Gupta S, Aggarwal S, Rashanravan B, Lee T

Th1-like (IL-2, IFN-gamma) and Th2-like (IL-4, IL-6, and

IL-10) cytokines were

examined in CD4+ and CD8+ T cells in children with autism.

Intracellular

cytokines were measured using specific antibodies to

various cytokines and

anti-CD4 or anti-CD8 monoclonal antibodies by FACScan.

Proportions of

IFN-gamma+CD4+ T cells and IL-2+CD4+ T cells (Th1), and

IFN-gamma+CD8+ and

IL-2+CD8+ T cells (TC1) were significantly lower in autistic

children as

compared to healthy controls. In contrast, IL-4+CD4+

T cells (Th2) and IL-4+CD8+

T cells (TC2) were significantly increased in autism.

The proportions of IL-6+

CD4+, IL-6+CD8+ and IL-10+CD4+, IL-10+CD8+ T cells were

comparable in autism and

control group. These data suggest that an imbalance of

Th1- and Th2-like

cytokines in autism may play a role in the pathogenesis

of autism.

2. Ann Ist Super Sanita 1996;32(3):351-9

Opioid-immune interactions in autism: behavioural and

immunological assessment

during a double-blind treatment with naltrexone.

Scifo R et al

The emerging concept of opioid peptides as a new class

of chemical messengers of

the neuroimmune axis and the presence of a number of

immunological abnormalities

in infantile autism prompted us to correlate biological

(hormonal and

immunological) determinations and behavioural performances

during treatment with

the potent opiate antagonist, naltrexone (NAL). Twelve

autistic patients ranging

from 7 to 15 years, diagnosed according to DSM-III-R,

entered a double-blind

crossover study with NAL at the doses of 0.5, 1.0 and

1.5 mg/kg every 48 hours.

The behavioural evaluation was conducted using the specific

BSE and CARS rating

scales NAL treatment produced a significant reduction

of the autistic

symptomatology in seven ("responders") out of 12 children.

The behavioural

improvement was accompanied by alterations in the distribution

of the major

lymphocyte subsets, with a significant increase of the

T-helper-inducers

(CD4+CD8-) and a significant reduction of the T-cytotoxic-suppressor

(CD4-CD8+)

resulting in a normalization of the CD4/CD8 ratio. Changes

in natural killer

cells and activity were inversely related to plasma beta-endorphin

levels. It is

suggested that the mechanisms underlying opioid-immune

interactions are altered

in this population of autistic children and that an immunological

screening may

have prognostic value for the pharmacological therapy

with opiate antagonists.

3. Neuropsychobiology 1994;29(1):12-6

Lymphocyte function in autism and Rett syndrome.

Plioplys AV, Greaves A, Kazemi K, Silverman E

Division of Neurology, Mercy Hospital and Medical Center,

Chicago, IL 60616.

Peripheral blood lymphocytes from 17 patients with autism

were separated on a

Ficoll-Hypaque density gradient. Patients had normal

numbers of T and B cells

and T cell subsets. Although CD4:CD8 ratios were normal

for the whole group

(2.09 +/- 0.97), 6 patients had elevated ratios (> 2.2)

and 5 had decreased

ratios (< 1.5).

4. Immunol Invest 1990 Jun;19(3):245-51

Deficiency of suppressor-inducer (CD4+CD45RA+) T cells

in autism.

Warren RP, Yonk LJ, Burger RA, Cole P, Odell JD, Warren

WL, White E, Singh VK

CD4+ cells are a heterogenous population of lymphocytes

including at least two

distinct subpopulations: CD45RA+ cells, inducers of suppressor

T cells and

CDw29+ cells, inducers of helper function for antibody

production. To

investigate the possibility that immune abnormalities

in autism may involve

abnormal distribution of these helper subpopulations,

monoclonal antibodies were

used in flow cytometric analysis to characterize peripheral

blood lymphocytes of

36 subjects with autism. The autistic subjects as compared

to a group of 35

healthy age-matched subjects had a significantly reduced

number of lymphocytes,

a decreased number of CD2+ T cells and reduced numbers

of CD4+ and CD4+CD45RA+

lymphocytes. The numbers of B (CD20+) cells, suppressor

T (CD8+) cells, inducers

of helper function (CD4+CDw29+) and natural killer (CD56+)

cells were not

altered in the autistic subjects. Our results suggest

that an alteration in the

suppressor-inducer T-cell subset is associated with autism.

5. Curr Opin Microbiol 1999 Aug;2(4):363-7

Immunity to Candida albicans: Th1, Th2 cells and beyond.

Romani L

Resistance to Candida albicans infection in mice results

from the development of

T helper (Th) type 1 cell responses. Cytokines produced

by Th1 cells activate

macrophages and neutrophils to a candidacidal state.

The development of Th2

responses underlines susceptibility to infection, because

cytokines produced by

Th2 cells inhibit Th1 development and deactivate phagocytic

effector cells.

6. Discussion and citatations were presented into abmd

and autism treatment lists as (A) "peripheral

glutathione and elimination of organic mercury", (which

included cites 7-11 hereinbelow) and as (

"CNS-glutathione astrocytes mercury thimerosal", (based

upon cite 12)

7. J Toxicol Environ Health 1995 Nov;46(3):343-53

Mechanisms of hepatic methylmercury uptake.

Ballatori N, Truong AT

8. Arch Toxicol 1994;68(8):512-6

Acute effects of methylmercury on hepatic and renal glutathione

metabolisms in mice.

Yasutake A, Hirayama K

9. Toxicol Appl Pharmacol 1993 Mar;119(1):74-90

Physiological model for the pharmacokinetics of methyl

mercury in the growing rat.

Farris FF, Dedrick RL, PV, JC

10. Toxicol Appl Pharmacol 1992 May;114(1):88-96

Effect of lipoic acid on biliary excretion of glutathione

and metals.

Gregus Z, Stein AF, Varga F, Klaassen CD

11: J Toxicol Environ Health 1986;19(2):219-33

Toxicity, distribution, and elimination of thiol complexes

of methylmercury

after intracerebral injection.

Fair PH, Balthrop JE, Wade JL, Braddon-Galloway S

12. Brain Res 1994 Nov 21;664(1-2):133-40

Intracellular glutathione (GSH) levels modulate mercuric

chloride (MC)- and

methylmercuric chloride (MeHgCl)-induced amino acid release

from neonatal rat

primary astrocytes cultures.

Aschner M, Mullaney KJ, Wagoner D, Lash LH, Kimelberg

HK

13. Proc Natl Acad Sci 1998;95:3071-6.

Glutathione levels in antigen-presenting cells modulate

Th1 versus Th2 response patterns.

JD et al.

14. Aukrust P, et al, `Decreased levels of total and reduced

glutathione in CD4+ lymphocytes in common

variable immunodeficiency are associated with activation

of the tumor necrosis factor system: possible

immunopathogenic role of oxidative stress', Blood, 1995,

86.4.1383-1391.

15. Aukrust P, et al, persistent activvation of the tumor

necrosis factor system in subgroup of patients with

common variable immunodeficiency - possible immunological

and clinical consequences', Blood, 1996,

97.2.674-681.

16. Jaffe JS, et al, `Functional abnormalities of CD8+

t cells define a unique subset of patients with

common variable immunodeficiency', Blood, 1993, 82.1.192-2001.

17. Jpn J Exp Med 1981 Dec, 51:6355-62

Binding of antibiotics to human liver glutathione S-transferases.

Nishiya H, Komatsu T, Kunii O

..It has been confirmed that not only cationic GSH S-transferases

but also anionic

GSH S-transferases have the binding capacity to the antibiotics,

and that the extent

of binding of the antibiotics to anionic GSH S-transferases

is similar to the one to

cationic GSH S-transferases. Therefore, anionic GSH S-transferases

are supposed

to play nearly the same role as cationic GSH S-transferases

in transport of the antibiotics

in human liver. The fact that the extent of binding of

the antibiotics to human liver GSH

S-transferases is closely correlated with the extent

of biliary excretion of the antibiotics

suggests that human liver GSH S-transferases play an

important role in the transport of

certain antibiotics from plasma, through hepatocytes,

into bile.

18. Carcinogenesis 1993 May, 14:5869-74

Biological activities of the intestinal microflora in

mice treated with antibiotics or

untreated and the effects of the microflora on absorption

and metabolic activation of

orally administered glutathione conjugates of K-region

epoxides of 1-nitropyrene.

Kinouchi T, Kataoka K, Miyanishi K, Akimoto S, Ohnishi

Y