.....Original Citation.....
Binstock T. Gangliosides & autism: heterozygote status as immune-impairment risk
factor: hypothesis. Bit.listserv.autism; Jan 3 1998.

                                          >>>  Posting number 32992, 
                                                dated 3 Jan 1998 13:03:43

.....Abstract.....
   Gangliosides (Gsd) (i) are complex molecules that have sugar-like (saccharides)
and oil-like (lipid) components; (ii) are assembled and present in numerous tissues,
including neurons and myelin (1-9); and are linked to autism, schizophrenia, and
other neurologic disorders (10-14).
   Although in some of these articles, researchers have called attention to neuronal
Gsd as an etiologic and/or autoimmune agent (eg, 10, 12), recent data (eg, 14-24)
suggest that subtle, ganglioside-related immune-impairments may be a genetic
susceptibility factor that is more common and more significant than has been
realized, especially since heterozygote carriers have reduced levels of Gsd-related
enzymes (eg, 25-27). These findings suggest that heterozygote status may itself be
a risk factor via subtle but nonetheless significant alterations of immune function.
      At least 53 Gsd-related mutations already have been identified, in a wide
range of geneological backgrounds (28); and, whereas homozygosity would lead to
classic and well-recognized syndromes (eg, Tay-Sachs, Niemann-Pick, Sandoff (26-28),
etc), the presence of even slightly elevated levels of gangliosides (Gsd)  can alter
immune function (eg, 25).
   The immune-panels of several children whose parents participate in the St. John's
autism-list contain three traits that, preliminarily via medical-research articles,
can be linked to elevated gangliosides. These traits include i) increased levels of
antigen-specific antibodies, eg, anti-tetanus, anti-diphtheria, anti-measles
antibodies, etc (25); ii) reduced levels of Natural Killer cells (NK cells) (eg,
16-18); and iii) reduced activity of NK cells (eg, 16,22-23).

The purpose of this post and several subsequent posts shall be to present, as a
hypothesis, a rationale and citations establishing that:
        i) HETEROZYGOTE STATUS for a mutation in one or several genes
        that encode a Gsd-related enzyme may be a primary risk-factor
        present in many specific cases of autism, including cases that
        have a familiality of seemingly related disorders.
        ii) IMMUNE-IMPAIRMENT, along with other heterozygote effects upon
        Gsd-metabolism, can serve as a contributing substrate by which a
        fetus, infant, or toddler heterozygous for a Gsd-related mutation
        shall have enhanced susceptibilty and increased effects from
        otherwise "routine" infectious agents, including viruses
        of the classification herpesveridae.

For some parents, family geneology will provide strong clues as to the likelihood
of Gsd-related mutations as a risk factor. For instance, when considering mutations
in just one of the primary Gsd-enzymes, appx 1 in 30 individuals is a carrier in one
well-known risk-group; and a rate between one in 167 and one in 280 is established
for persons outside the 1-in-30 group (##). In other words, mutations in these
enzymes are not extraordinarily uncommon and, given the ganglioside/immunity
findings in recent years, heterozygote status for such a mutation may have been
causally important in a subgroup of children within the autism-spectrum.
    Such a causal mechanism may be operating in several of the children whose
immune-panel data I have been reviewing, and there is consistency with the
geneological aspects in several such families.

Teresa

who realizes that this abstract is not tightly woven and hyper-condensed, who
realizes that Gsd are diverse and numerous & their enzymes complex, & who believes
the ganglioside/immune-ramifications topic is important and worthy of consideration
by parents and other participants in this wonderful process known as the "autism
list" of St. Johns U.

References:
1) Expression of sulfated gangliosides in the central nervous system. Journal of
Neurochemistry.  68(2):878-81, 1997 Feb.
2) Functional role of glycosphingolipids in cell recognition and signaling. Journal
of Biochemistry.  118(6):1091-103, 1995 Dec.
3) Functional roles of gangliosides in bio-signaling. Behavioural Brain Research. 
66(1-2):99-104, 1995 Jan 23.
4) Brain gangliosides and memory formation. Behavioural Brain Research. 
66(1-2):105-116, 1995 Jan 23.
5) Ganglioside metabolism: enzymology, topology and regulation. Progress in Brain
Research.  101:17-29, 1994.
6) Fractionation of primary cultured cerebellar neurons: distribution of
sialyltransferases involved in ganglioside biosynthesis. Journal of Neurochemistry. 
58(4):1533-7, 1992 Apr.
7) Entry of newly synthesized gangliosides into myelin. Journal of Neurochemistry. 
58(4):1477-84, 1992 Apr.
8) Ganglioside content of astroglia and neurons isolated from maturing rat brain:
consideration of the source of astroglial gangliosides. Brain Research. 
461(1):87-97, 1988 Sep 27.
9) Lipid-metabolizing enzymes of myelin and their relation to the axon. Journal of
Lipid Research.  25(13):1548-54, 1984 Dec 15.

.......Gsd in autism & other neurologic disorders.......
10) Gangliosides in children with autism. Acta Paediatrica.  84(7):787-90, 1995 Jul.
11) A family history study of schizophrenia spectrum disorders suggests new
candidate genes in schizophrenia and autism. Psychiatric Quarterly.  65(4):287-97,
1994 Winter.
12) Cytomegalovirus infections and anti-GM2 antibodies in Guillain-Barre syndrome.
J of Neurol Neurosurg & Psychi 62(6):641-3 1997.
  To investigate whether antecedent cytomegalovirus (CMV) infections in patients
with Guillain-Barre syndrome are associated with the presence of specific
antiganglioside antibodies, acute phase serum samples from 130 patients with
Guillain-Barre syndrome and 200 controls were tested. Anti-GM2 IgM antibodies were
found more often in patients with Guillain-Barre syndrome with CMV infection (22%)
than in patients without the infection (2%) (P = 0.003). CMV infections may elicit
anti-GM2 antibodies in susceptible patients, which may contribute to the
pathogenesis of Guillain-Barre syndrome associated with CMV.
13) Abnormality of gangliosides in erythrocyte membranes of schizophrenic patients.
Clinical Physiology & Biochemistry.  6(5):281-4, 1988.
14) Glycosphingolipids as potential diagnostic markers and/or antigens in
neurological disorders. Neurochemical Research.  22(8):1071-83, 1997 Aug.

.......gangliosides & immunity.......
15) Brain-derived gangliosides regulate the cytokine production and proliferation
of activated T cells. Journal of Immunology.  157(10):4333-40, 1996 Nov 15.
16) IL-2 signalling in T and natural killer (NK) cells associated with their class
I-non-restricted killing activity. Clinical & Experimental Immunology. 
106(1):179-86, 1996 Oct.
17) Analysis of the costimulatory role of IL-2 and IL-15 in initiating proliferation
of resting (CD56dim) human NK cells. Journal of Immunology.  156(9):3254-9, 1996.
18) Gangliosides are potent immunosuppressors of IL-2-mediated T-cell proliferation
in a low protein environment. Immunology.  86(3):356-63, 1995 Nov.
19) Serum gangliosides as endogenous immunomodulators. [Review] [46 refs] Immunology
Today.  16(10):483-6, 1995 Oct.
20) Regulation of the human interleukin-2/interleukin-2 receptor system: a role for
immunosuppression. Proc of the Soc for Exp Biol & Med 206.3.176-80 1994.
21) Modulation of human myelopoiesis by human gangliosides. Experimental Hematology.

22(1):52-9, 1994 Jan.
22) Gangliosides inhibit T-lymphocyte proliferation by preventing the interaction
of interleukin-2 with its cell surface receptors. Immunology.  79(1):10-7, 1993 May.
23) Immunosuppression by human gangliosides. II. Carbohydrate structure and
inhibition of human NK activity. Cellular Immunology.  139(1):18-29, 1992 Jan.
24) Murine peritoneal macrophage gangliosides inhibit lymphocyte proliferation.
Journal of Leukocyte Biology.  50.4.393-401 1991.
25) Nanomolar concentrations of gangliosides stimulate primary humoral response. 
Biochem & Mol Biol Internat 42.1.57-63 1997.

.......ganglioside enzymes & epidemiologies.......
26) Heterozygote screening for Tay-Sachs disease: past successes and future
challenges. Current Opinion in Pediatrics.  8(6):625-9, 1996 Dec.
27) Mutational analyses of Tay-Sachs disease: studies on Tay-Sachs carriers of
French Canadian background living in New England. American Journal of Human
Genetics.  56(4):870-9, 1995 Apr.
28) Tay-Sachs disease--carrier screening, prenatal diagnosis, and the molecular era.
An international perspective, 1970 to 1993. The International TSD Data Collection
Network. JAMA.  270(19):2307-15, 1993 Nov 17.
29) A chronic GM2 gangliosidosis variant with a HEXA splicing defect: quantitation
of HEXA mRNAs in normal and mutant fibroblasts. European Journal of Human Genetics. 
5(3):129-36, 1997 May-Jun.
                                                                     eof



                                          >>> Posting number 32996, 
                                          dated 3 Jan 1998 13:51:50

.....Prelude.....
If a syndrome like autism has several causes, then exploring one causal pathway
temporarily may exclude the other pathways. The following discussion focuses upon
a group of genetic mutations that may stand as susceptibility genes whose pathway
to autism, in some autism-spectrum children, be augmented by viral or other
infections. That this mini-paper focuses upon an infection-related predispostion
does not imply that *all* autisms have the pathway discussed herein.

.....Antibodies & NK cells.....
Immune-panels from several autism-spectrum children have one or several of the
following characteristics:
   i) increased levels of antigen-specific antibodies, eg, anti-tetanus,
      anti-diphtheria, anti-measles antibodies, etc.
  ii) reduced levels of Natural Killer cells (NK cells),
 iii) reduced activity of NK cells.

There is extensive medical literature about these three processes. For instance,
Epstein-Barr virus can induce B-cell stimulation and a resulting increase in
antigen-specific antibodies (see works of LG Lum and others); and endogenous
complement is another endogenous factor that can stimulate immunoglobulin production
(20-22).
       However, as my readings continued in regard to possible causes of i,ii, and
iii, a recurrent topic began to emerge: "gangliosides", because an increase in
gangliosides can induce all three traits (cites hereinbelow); and, importantly, a
possible link between gangliosides and autism has been documented in an
epidemiological study by Ann Goodman (1) and in a more recent study examining
cerebrospinal fluid (CSF) in autistics (2).
      Physicians and some parents are well aware of severe ganglioside problems
which have been given a generic name "gangliosidoses". Tay-Sachs and Niemann-Pick
are classic examples; and many of these disorders are considered to be "autosomal
recessive", which means that both parents must have a mutated allele if the child
is to develop a severe gangliosidosis (reviewed in 3). Correspondingly, if a child
inherits only one mutated gene for a ganglioside-modifying enzyme, then he or she
is considered a "heterozygote" and usually does not develop a traditional
gangliosidosis syndrome.
      However,studies linking (i) nanomolar concentrations of gangliosides, and (ii)
impaired immune function suggest the possibility that heterozygosity for mutations
of one or several ganglioside-degradation enzymes are risk factors that increase
susceptibility for the development of autism and even for other disorders (eg,
schizophrenia, lymphoma, leukemia; see additional findings in citation 1). That
ganglioside atypicalities are a non-specific to autism (as autism-list participant
Bob Jensen so correctly points out for many identified autism-associated risk
factors), suggests that additional etiologic agents need be present. Among some
kids, and given ganglioside effects upon immune function, the additional agent (in
some kids) may well be infectious, via one or several pathogens (see below).

>From the beginning, let us acknowledge that "gangliosides" (Gsd) is a very complex
topic, and several natural processes (ie, other than gene mutations) can increase
a person's Gsd levels (eg, tumors, liver damage). However, this post focuses upon
ramifications of ganglioside-enzymes mutations in children who are heterozygous for
the mutation, thereby having a good copy of the gene, thereby escaping the full-
blown syndromes (eg, Tay-Sachs). In this context, several questions emerge:

A. Can a heterozygote (for a GSD-enzyme mutation) produce reduced levels of a
Gsd-degradation enzyme? The answer is Yes (eg, 4); and we note that if the rate of
Gsd-degredation decreases, then more Gsd are available so as to potentially
(theoretically) induce the immune-panel atypicalities seen among some
autism-spectrum children (as shall be more thoroughly examined in a subsequent post
of this series).

B. Are there ways to identify who might be at risk for having such a mutation? The
answer is Yes and No. For instance, Ashkenazi Jews are known to have a greatly
increased likelihood of having mutations within Gsd-enzyme genes (eg, see 1,2).
However, other nationalities are well represented too, eg, English, Irish, Germans,
Spaniards, French, Japanese, etc (eg, 5-10).

C. Are there tests that can identify whether or not a child is heterozygous for a
mutation of a ganglioside-enzyme gene? The answer is Yes; however, there are so many
genes involved that the preferred method of analysis is not via specific genes but
instead is via levels of enzymes (eg, 11).

D. Would there be diagnosis and/or treatment ramifications if a child were found to
be heterozygous for one or several mutations in Gsd-enzyme genes? Again, the answer
is Yes. For instance, such findings would enable better interpretation of atypical
immune-panel data; various infections might be treated somewhat differently, etc.
Importantly, "slightly more than mild" elevations of antigen-specific antibodies
(eg, anti-tetanus and/or anti-measles, etc) may not necessarily mean the presence
of ongoing subclinical infection by those pathogens, because an alternative
possibility is that of enhanced immunoglobulin production via elevated Gsd levels
(eg, 12).
 Conclusion: During the last several weeks, while perusing several autism-spectrum
medical histories and/or immune panels, several immune-related similarities prompted
intensive research. Amidst this process, the topic "gangliosides" jumped forth with
increasing frequency and, as far as I can tell at this point, with increasing
significance. 

For these reasons, I wanted to share the above rationale and the citations
hereinbelow, because this topic may be highly significant in *some* families. Let
us be clear: in most autism-spectrum kids, the presence of heterozygosity for a
Gsd-degradation enzyme's gene would probably not be a sufficient cause for inducing
the autism-spectrum phenotype. However, Gsd are a primary component of neurons (see
2 for additional citations), and the immune-impairments induced by Gsd-related
heterozygosity would diminish the child's responses against viral infections, due
to impaired Natural Killer cell activity and reductions in NK cell number.
      Furthermore, heterozygosity for a mutation of a Gsd-enzyme gene might be the
kind of "contributing factors" (along with null alleles of C4b genes; RP Warren et
al) that allow seemingly common infectious agents (eg, HSV, CMV, HHV6, Varicella,
etc) to have stronger, more prolonged, and more severe effects in *some* of the
autism-spectrum kids whose parents participate on the autism-list.

Clearly, the above rationale is a preliminary sketch. Comments are invited and
welcomed.

                                    >>> Posting number 32997, 
                                    dated 3 Jan 1998 13:54:45

REFERENCES

1) Goodman AB. A family history study of schizophrenia spectrum disorders suggests
new candidate genes in schizophrenia and autism. Psychiatric Quarterly. 
65(4):287-97, 1994 Winter.
  To limit genetic heterogeneity, this study focused on the widely extended
pedigrees of Ashkenazi Jewish schizophrenic and autistic probands, to determine if
similar causal mechanisms might obtain for both conditions. At least two previous
epidemiological studies have demonstrated increased risk for schizophrenia in
Ashkenazi Jews. The hypothesis posed is that increased prevalence of various rare
autosomal recessive diseases among the Ashkenazim might contribute to the increased
vulnerability to schizophrenia and to autism in this large genetic isolate. Rates
of amyotrophic lateral sclerosis (ALS) and bleeding disorders were significantly
increased among relatives of schizophrenic and autistic probands, compared to
relatives of normal probands. These results suggest new candidate loci in
schizophrenia and autism, particularly the chromosome 15q23-24 locus of the
hexosaminidase A gene, causing various GM2 gangliosidoses, and the 21q22.1-q22.2
loci of the antioxidant, superoxide dismutase gene, and a cytokine receptor gene.

2) Lekman A et al. Gangliosides in children with autism. Acta Paediatrica. 
84(7):787-90, 1995 Jul.
  Concentrations of the four major brain gangliosides, GM1, GD1a, GD1b and GT1b,
biochemical markers of neuronal membranes, were determined in the cerebrospinal
fluid (CSF) of 20 children with autism and in 25 controls. In addition, the
gangliosides were determined in children with different forms of non-progressive
neurological disorders lacking clinical features of autism. GM1, GD1a, GD1b and GT1b
were significantly increased in patients with autism compared with age-matched
controls and children with non-progressive neurological disorders...

3) Stanley CA. Defects in metabolism of lipids. Ch 72 in: Textbook of Pediatrics,
15th ed; Nelson WE et al editors, Saunders 1996.

4) Fernandes MJ et al. A chronic GM2 gangliosidosis variant with a HEXA splicing
defect: quantitation of HEXA mRNAs in normal and mutant fibroblasts. Eur J of Hum
Gen 5.3.129-36 1997.
  Over 72 mutations have been identified in the HEXA gene of which only four (T538C,
A590C, G805A, and C1495T) are believed to cause a chronic form of Tay-Sachs disease
(TSD). We identified a novel HEXA mutation (IVS7, -7 G-->A) leading to chronic TSD
in a Canadian patient of English ancestry. The second allele in this patient was the
exon 11 4-bp insertion mutation (/1277TATC), which is the most frequent TSD allele
in Ashkenazi Jews. The IVS7, -7 G-->A mutation introduces a new 3' splice acceptor
site 5 bp upstream of the normal intron 7 splice acceptor site. The mutation leads
to reduction of steady-state levels of HEXA mRNA by more than 80%. Two mRNA species
are produced by the IVS7, -7 G-->A allele; a normal nRNA species and an mRNA lacking
exon 8. No mRNA species that was spliced at the upstream 3' splice acceptor site was
detected. We used competitive PCR to quantitate mRNA species in fibroblasts obtained
from this patient. We compared the amounts of three identified mRNA species to HEXA
mRNA levels in cells from normal individuals and from individuals heterozygous for
/1277TATC. The steady-state level of HEXA mRNA in cells from a normal individual was
17.3 pg/microg RNA. An individual heterozygous for /1277TATC produced 8.7 pg of
normal HEXA mRNA/microg RNA. The HEXA mRNA species with the insertion mutation was
present in patient cells at 4.8% of the level of normal HEXA nRNA in homozygous
normal cells. In fibroblasts from the patient carrying the IVS7, -7 G-->A mutation,
the steady-state level of exon 8-deleted HEXA mRNA was 5.9% the level of that
produced by homozygous normal cells. The level of normal HEXA nRNA in this patient's
cells was 10.4%.

.......ganglioside disorders reflect many nationalities.......
5) Heterozygosity for Tay-Sachs disease in non-Jewish Americans with ancestry from
Ireland or Great Britain. J Med Genet 33.829-32 1996.
6) An Alu1- polymorphism in the HEXA gene is common in Ashkenazi and Sephardic Jews,
Israeli Arabs, and French Canadians of Quebec and northern New England.  Human
Mutation.  6(1):89-90, 1995.
7) GM2D gangliosidosis B1 variant in a boy of German/Hungarian descent. Clinical
Neuropathology.  12(4):196-200, 1993 Jul-Aug.
8) Further investigation of the HEXA gene intron 9 donor splice site mutation
frequently found in non-Jewish Tay-Sachs disease patients from the British Isles. 
Journal of Medical Genetics.  30(6):479-81, 1993 Jun.
9) Beta-hexosaminidase splice site mutation has a high frequency among non-Jewish
Tay-Sachs disease carriers from the British Isles. Journal of Medical Genetics. 
29(8):563-7, 1992 Aug.
10) A new point mutation in the beta-hexosaminidase alpha subunit gene responsible
for infantile Tay-Sachs disease in a non-Jewish Caucasian patient (a Kpn mutant).
Am J of Human Genetics.  47(3):568-74, 1990 Sep.

11) Natowicz MR, Prence EM. Heterozygote screening for Tay-Sachs disease: past
successes and future challenges. Current Op in Ped 8.6.625-9 1996.
  Tay-Sachs disease (TSD) is an autosomal recessive, neurodegenerative disorder
caused by a deficiency of beta-hexosaminidase A activity. Mass screening for TSD
heterozygotes has been routine in the Ashkenazi Jewish population since the early
1970s. Recent advances in the molecular genetics and epidemiology of TSD require a
reevaluation of heterozygote screening practices. The use of DNA-based analyses for
a panel of common mutations detects about 98% of TSD mutations found in the
Ashkenazi Jews and about 50% of TSD mutations found in the general non-Jewish
population; enzyme-based analysis has nearly 100% sensitivity for all populations.
We recommend 1) that members of several ethnic groups and persons with a family
history consistent with TSD be offered testing for TSD heterozygosity and 2) that
assays of enzyme activity be used as the primary screening tool, with mutation
analysis used as an adjunct tool in certain cases.

12) Dozmorov IM et al. NANOMOLAR CONCENTRATIONS OF GANGLIOSIDES STIMULATE
PRIMARY HUMORAL RESPONSE Biochem Mol Biol Internat 42.1.57-63 1997.
  Exogenous gangliosides act as immunosuppressors when applied at micromolar
concentrations corresponding to their average level in human plasma. Here we show
that at nanomolar concentrations the gangliosides GD3, GD1a and GM1 can act as
immunostimulators markedly enhancing the number of plaque-forming cells in mouse
splenocyte culture responding to sheep erythrocytes. At such low concentration these
gangliosides as well as GM3 were not able to influence significantly proliferative
responses of splenic B and T lymphocytes or of cytotoxic T-cells. Neither did they
change significantly the production of IL-1 by antigen-representing cells, or of
IL-2 by Con A-induced blasts In the splenocyte culture. It is suggested that the
stimulatory effect of low ganglioside concentrations on humoral response is due to
their influence on cooperative cell-cell interactions required for the
differentiation of B-cells into Ig-secreting cells.

13) The role of natural killer cells in viral infections. Scandinavian Journal of
Immunology.  46(3):217-24, 1997 Sep.
14) Activation and function of natural killer cell responses during viral
infections. Current Opinion in Immunology.  9(1):24-34, 1997 Feb.
15) Natural killer cells wear different hats: effector cells of innate resistance
and regulatory cells of adaptive immunity and of hematopoiesis. Seminars in
Immunology.  7(2):83-8, 1995 Apr.
16) Major histocompatibility complex class I antigens and the control of viral
infections by natural killer cells.  J Virol 69.3967-71 1995.
17) Production and differentiation of NK linkage cells in bone marrow. Natural
Immunity.  12(4-5):177-93, 1993 Jul-Oct.
18) Regulation of virus infections by natural killer cells. A review. Natural
Immunity & Cell Growth Regulation.  5(4):169-99, 1986.
19) Natural killer cells. Annual Review of Medicine 37.347-52 1986.

.......complement increases Ig production.......
20) Function of C3 in a humoral response: iC3b/C3dg bound to an immune complex
generated with natural antibody and a primary antigen promotes antigen uptake and
the expression of co-stimulatory molecules by all B cells, but only stimulates
immunoglobulin synthesis by antigen-specific B cells.     Clinical & Experimental
Immunology.  104(3):531-7, 1996 Jun.
21) Complement subcomponent C1q stimulates Ig production by human B lymphocytes.  
Journal of Immunology.  146(10):3356-64, 1991 May 15.
22) Differential effects of cytomegalovirus infection on complement synthesis by
human mesangial cells. Clinical & Experimental Immunology.  109(3):518-25, 1997 Sep.
                                                                   eof

addendum:  GANGLIOSIDES: EPILEPTIFORM ACTIVITY, IgE 

I.          gangliosides & epileptiform activity
                                          >>> Posting number 33022, 
                                          dated 3 Jan 1998 20:22:48

Interesting tidbit:

Bartolomei F.  Boucraut J.  Barrie M.  Kok J.  Dravet C.  Viallat D.
Bernard D.  Gastaut JL.
     Cryptogenic partial epilepsies with anti-GM1 antibodies: a new form
     of immune-mediated epilepsy?.
          Epilepsia.  37(10):922-6, 1996 Oct.
  PURPOSE: We wished to study immune system dysfunction which has been proposed as
a potential cause of epilepsy. Epileptogenic action of antibodies directed against
GM1 gangliosides was demonstrated in rats, but the potential role of anti-GM1
antibodies in human epilepsy has not yet been studied. METHODS: We investigated the
presence of IgG or IgM anti-GM1 antibodies in the sera of 64 patients with various
types of epileptic syndromes: idiopathic generalized epilepsy (IGE) (n = 6),
symptomatic or cryptogenic generalized epilepsy (SCGE) (n = 7), symptomatic partial
epilepsy (SPE) (n = 26), and cryptogenic partial epilepsy (CPE) (n = 25). RESULTS:
Two patients had elevated titers of IgM anti-GM1 antibodies, one patient had
elevated titers of both IgM and IgG anti-GM1 antibodies, and 1 patient had elevated
titers of IgG anti-GM1 antibodies. All 4 patients had complex partial seizures (CPS)
secondarily generalized, drug resistance, psychiatric disorders, and normal brain
imaging. Anti-GM1 antibodies were never associated with IGE, SCGE, or SPE. We
compared the reactivity of sera from these patients with the sera from 5 patients
with motor neuropathies with conduction block (MNCB) against different gangliosides
and concluded that epilepsy sera did not react with the Gal(beta 1-3)GalNAc epitope.
Two anti-GM1-positive patients were treated successfully with high-dose intravenous
immunoglobulins (IgIV). CONCLUSIONS: Our findings suggest that detection of anti-GM1
antibodies could allow identification of a subgroup of patients with partial
epilepsy associated with an autoimmune response. If anti-GM1 antibodies prove
pathogenic, they could be an important prognostic factor for drug resistance and
worsening of seizures.


II.               gangliosides & IgE
                                    >>> Posting number 33025, 
                                    dated 3 Jan 1998 20:34:52



Citation 1 suggests that elevations of ganglioside GM2 and/or GM3 might induce a
reduced level of IgE.
  "These results indicate that GM2 and GM3 inhibit IgE and IgG4
   production by inhibiting endogenous TNF-alpha production."

Citation 2 contains a nuance suggesting that enhanced ganglioside levels might
induce additional mast-cell histamine release via a mechanism related to IgE-type
receptors.
  "Gangliosides appear to specifically optimize IgE-receptor-ligand
   interaction and alterations in cellular gangliosides could thus induce
   enhanced releasability as observed in atopics."

Tc: The first citation, along with the first quote hereinabove and along with the
ganglioside posts earlier today suggest the *possibility* of four ganglioside
effects: increased antigen-specific antibodies, reduced number of NK cells, impaired
NK activity, and lower IgE.

1) Kimata H.  Differential effects of gangliosides on human IgE and IgG4 production.

European Journal of Immunology.  25(1):302-5, 1995 Jan.
Ab:   The effects of gangliosides on human IgE and IgG4 production were studied. Of
the various gangliosides tested, only GM2 and GM3 inhibited the IgE and IgG4
production induced by interleukin (IL)-4 plus hydrocortisone (HC), or that induced
by IL-13 plus HC, in human surface IgE- and IgG4-negative (sIgE-, sIgG4-) B cells
without affecting the production of IgG1, IgG2, IgG3, IgM, IgA1 or IgA2. In
contrast, GM1, GD1a, GD1b, GD3, GT1b and GQ1b were without effects. The GM2- and
GM3-mediated inhibition was specific, since each was blocked by a corresponding
antibody. Of the various factors tested. IL-6, IL-10, and tumor necrosis factor
(TNF)-alpha enhanced the IgE and IgG4 production induced by IL-4 plus HC or by IL-13
plus HC, while IL-8 and transforming growth factor (TGF)-beta inhibited these
responses. However, only TNF-alpha counteracted the GM2- and GM3-mediated inhibition
of IgE and IgG4 production, while IL-6, IL-10, anti-IL-8 monoclonal antibody and
anti-TGF-beta antibody failed to do so. Anti-TNF-alpha monoclonal antibody, but not
control IgG1, not only inhibited IgE and IgG4 production in the absence of TNF-alpha
but also blocked the counteraction of inhibition by TNF-alpha. In cultures
containing IL-4 plus HC or IL-13 plus HC. GM2 and GM3 specifically inhibited
TNF-alpha production without affecting TNF-alpha receptors, IL-6 production or IL-6
receptors. These results indicate that GM2 and GM3 inhibit IgE and IgG4 production
by inhibiting endogenous TNF-alpha production.

2) Zuberbier T.  Pfrommer C.  Beinholzl J.  Hartmann K.  Ricklinkat J.
Czarnetzki BM.  Gangliosides enhance IgE receptor-dependent histamine and LTC4
release from human mast cells.  Biochimica et Biophysica Acta.  1269(1):79-84, 1995
Oct 19.
Ab:   Releasability of mast cells and basophils to an IgE-dependent stimulus is
regulated by extra- and intracellular factors which are only partly understood. As
gangliosides are known to modulate receptor-dependent processes in various cell
types, we have evaluated the effect of these molecules on mast cell mediator
release. Human skin mast cells and the human mast cell line HMC1 were pretreated
with the gangliosides GM2, GM3 and GD1a as well as with asialo-GM3, heparin and
buffer alone (controls). After washing, the cells were stimulated with anti-IgE,
calcium ionophore A 23187, N-FMLP or substance P. All gangliosides but not
asialo-GM3 and heparin augmented anti-IgE-induced mediator release in a
dose-dependent fashion, whereas the release to A 23187, N-FMLP and substance P
remained unaffected. Only sequential but not simultaneous addition of ganglioside
and anti-IgE showed an enhancement in mediator release compared to controls.
Mediator release in both ganglioside-pretreated cells and controls was
calcium-dependent and could be inhibited by pretreatment of cells with staurosporine
or dibutyryl cAMP, indicating an unchanged signal transduction. Gangliosides appear
to specifically optimize IgE-receptor-ligand interaction and alterations in cellular
gangliosides could thus induce enhanced releasability as observed in atopics.
                                                                    eof

III.        immune hyperstimulation, Gaucher's, gangliosidoses

                              >>> Posting number 36190, 
                              dated 5 Feb 1998 11:40:03

On the autism-list, numerous parents have reported lab-tests showing enhanced levels
of antigen-specific antibodies, sometimes for antigens against which the child has
been immunized. While analysing this phenomenon in several autism-spectrum kids'
immune-panels, and perusing medical literature that might account for immune
stimulation, several phenomena came forth. 
      For instance, Epstein Barr virus (EBV) can induce "polyclonal stimulation"
that can result in elevated antibodies levels. Another example is provided by
excessive gangliosides as might result from a child's status as a gangliosidoses
heterozygote (cites and rationale provided in prior post). Gaucher's disease is
another lipid-related syndrome that can induce polyclonal immune stimulation,
thereby elevating antibodies levels and inducing shifts in antibodies production
(1).
      There are many fine reviews of Gaucher's, and a general theme is that of much
inter-personal variation. This variance would be augmented by person-specific
co-factors such as presence and timing of HHV6, EBV, CMV, etc. I am fascinated that
many immune aspects discussed on the autism list have components that med literature
indicates might be derived from ganglioside-related and lipid-related heterozygote
status that would serve as a predisposing factor which allows infectious processes
to make more headway in children having the heterozygote status.

I am not asserting that these mechanisms apply in all cases of autism, perhaps not
even in most. However, the immune panels I've perused are augmented by some of the
ongoing elevated-antibodies anecdotes provided on the autism list, thereby
suggesting that the status of a child's ganglioside-enzyme production may be
important as a contributing factor in some cases of autism-spectrum traits.

Question: If Gaucher's induces chronic immune stimulation, would
Gaucher-heterozygote status induce a "wee bit" of immune stimulation, especially in
a child who had an additional immune-stimulation factor such as a chronic infection?
My hunch: the answer is yes.

1) Shoenfeld Y et al. Gaucher's disease: a disease with chronic
stimulation of the immune system.
        Archives of Pathology & Laboratory Medicine 106.388-91 1982.
  Concentrations of IgA, IgG, and IgM were measured in 25 patients with Gaucher's
disease. The mean of each was significantly higher than that generally observed in
healthy adults. A direct correlation was noted between IgA and IgG concentrations
and age. Patients who underwent splenectomy had IgM concentrations significantly
lower than those of persons who did not. In two of 25 patients, multiple myeloma of
the nonsecretory type developed. The migration inhibition factor (MIF) test
performed with the lymphocytes of our patients was positive to glucocerebroside in
four of 17 patients, to glucocerebrosidase in four of 19 patients, and to the
extracts of the spleen of a patient with Gaucher's disease in three of eight
patients. The results of al MIF tests were negative in six control subjects with
splenomegaly of other causes. Our results suggest that in Gaucher's disease there
is chronic stimulation of the humoral immune system. The first expression of this
stimulation is the production of polyclonal immunoglobulins and, in due time, the
development of monoclonal immunoglobulin as well as multiple myeloma.

>>> Posting number 32992, dated 3 Jan 1998 13:03:43
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock 
Subject:      1 gangliosides & autism: heterozygote gangliosidoses 

>>> Posting number 32996, dated 3 Jan 1998 13:51:50
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock 
Subject:      2a gangliosides; impaired immunity: heterozygote effects

>>> Posting number 32997, dated 3 Jan 1998 13:54:45
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock 
Subject:      2b gangliosides; impaired immunity: heterozygote effects

>>> Posting number 33022, dated 3 Jan 1998 20:22:48
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock 
Subject:      gangliosides & epileptiform activity

>>> Posting number 33025, dated 3 Jan 1998 20:34:52
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock 
Subject:      gangliosides & IgE

>>> Posting number 36190, dated 5 Feb 1998 11:40:03
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock 
Subject:      immune hyperstimulation, Gaucher's, gangliosidoses