>>>> Posting 1629, 14 Jan 1997 20:49:58
(part 1a of 3)
....Abstract....
CD5+ B-cells are considered to be among the first immunological cells to appear in
the developing embryo and are thought to play a special postnatal role in the
gastrointestinal tract (gi-T), wherein distinctions must be made between normal and
pathogenic microorganisms.
Neonates have an extremely limited range of nascent microflora and, as a
result, are susceptible to colonizations by pathogenic microbes present in the birth
canal, gi-T, and/or in the environment during the days, weeks, and months subsequent
to birth.
The duration of susceptibility and the likelihood of pathogenic colonization
can be increased by antibiotics, which are known to be capable of killing intestinal
microflora. If pathogenic microbes are present in sufficient quantity subsequent to
birth, what the early intestinal CD5+ B-cells perceive as "normal" can bias the
child's immunoreactivity to those specific intestinal pathogens. One result can be
increased susceptibility to future colonizations that can be non- systemic,
subacute, ongoing infections localized to the gi-T.
Depending upon the child's specific pathogenic gi-T microbes, such infections
are able to modify gut permeability and, in some cases, can result in pesistent
release of neurotoxins, some of which are known to migrate into the central nervous
system.
Volumenous anecdotal data from families with autistic children suggest the
existence of (i) many cases of altered gi-T permeability, and (ii) possibly somewhat
fewer cases of persistent colonizations by specific, pathogenic bacteria, fungi,
and/or viruses capable of negatively influencing the central nervous system.
Oftentimes, severe dietary modifications and/or antimicrobial regimens result
in significant alleviations of the child's autistic traits. The early-in-life
shaping of the CD5+ gi-T repertoire may well be a crucial causal component in the
development of some autisms and autistic-like traits. Ramifications of verifying an
early CD5 role range from prevention to better treatments as well as to increased
understandings of possible etiologies in some cases of autism.
.....Rationale.....
Immunological B-cells having the cell-surface marker CD5+ may provide clues to
infection-related etiologies in some cases of autism. CD5+ cells are considered to
be the first immunological cells to appear in the human embryo (1-2); and at least
one group of researchers having extensive experience with CD5+ B-cells has
hypothesized that these cells play an IgA-related role in modulating responses to
intestinal microbes, some of which are pathogenic and need to be immunologically
eliminated, and some of which - because they are naturally occurring and beneficial
microflora - tend to be immunologically ignored (3).
Initially, neonates have a limited range of microflora in their
gastrointestinal tract (giT; 4-5) and, as a result, are susceptible to colonizations
by pathogenic microbes (4, 6-11). Usually, such adverse colonizations do not occur;
and in the days, weeks, and months subsequent to birth, most newborns develop a full
repertoire of endogenous microflora (4-5). With possible significance to some cases
of autism, the development of natural microflora overlaps in time the development
of the child's immunological self-awareness progressively encoded in his or her CD5+
B-cells (3,12).
However, if pathogenic microbes are present in the gi-T while the CD5+ cell
line is establishing its awareness of self, a profoundly altered set of CD5+ B-cell
encodings may ensue (3). In this circumstance, the natural microflora may be absent
or may have altered presence. As a result, the pathogenic microbes can be perceived
by the nascent CD5+ B-cells as natural within the child (3).
Later, with the child's CD5+ cells interpreting certain pathogenic microbes as
normal, he or she will have become tolerized to those microbes and also tolerized
to such beneficial microbes, if any, as remained present during the pathogenic
colonization (3). As a result, the child will mount only weak or non-existent
immunological responses against those pathogenic microbes and agaist such beneficial
microflora as were present. Furthermore, if normally occurring microflora were not
present (eg, due to repeated antibiotic deflorastations of the gi-T), then most
natural microflora might always be recognized by CD5+ cells as unwanted visitors
against which to mount an immune response (3,13-14).
Furthermore, when CD5+/IgA tolerance to pathogenic gi-T microbes has occurred,
then the person is more likely to have gastrointestinal infections, which may occur
in subacute, ongoing form (15-18); and if tested for antibodies to those specific
pathogens, some children who early in life had developed tolerance to specific
microbial pathogens might display abnormally low antibody titres against toxins from
certain of those microbes (19-23).
>>>> Posting number 1631,
dated 14 Jan 1997 20:57:15
(part 1b of 3)
.....Consider an illustration specific to autism.....
In her paper concerning Clostridium tetani and autism, Ellen Bolte focuses upon
subacute tetanus infections of the GI-tract and upon the role of the Clostridium
tetani toxin (TeNT) in affecting the central nervous system in ways different from
symptoms manifested in traditional tetanus derived from a deep wound (24).
Preliminary validation of the Bolte hypothesis has come from an autistic
child's treatment with a strong antibiotic known to attack Clostridium tetani.
Several traits during the onset of the child's autism had suggested the possibility
of C. tetani involvement. and prior to a prolonged sequence with that antibiotic,
the child had been severely autistic and had had extraordinarily high titres of
anti-TeNT antibodies (child's parent, personal communication). Soon after initiating
the strong antibiotic treatment, the child began a remarkable and documented
improvement (24) with regard to autistic traits, and the improvements continue as
of the date of posting this paper.
.....CD5+, Timings of Infections, Antibodies Levels.....
Continuing with the autism-TeNT example: according to the rationales offered herein
and by Kroese et al (3), a child's having high levels of anti-TeNT antibodies
suggests (i) that his response to tetanus vaccinations occurred "normally" and (ii)
that his acquiring of Clostridium tetani colonization, if at all, occurred some time
after his CD5+ B-cell responsiveness had been established.
In contrast, according to idiotype, CD5+, and oral-tolerance rationales
(3,14,19-23,26), an autistic child who shows abnormally low anti-tetanus titres may
have acquired a subacute Clostridium tetani infection of the gi-T quite early in
life. In other words, if the infection occurred as his or her CD5+ B-cells were
establishing "self- normalcy" (13-14), then his or her subsequent immunological
reactions to C. tetani would be forever reduced.
.....Infectional Predispositions.....
Since the CD5+ B-cell line is considered to be virtually (ie, not quite totally)
permanent once its sense of "self as normal" is established (1,27), a child
pathogenically colonized by C. tetani at a very young age (i) would be forever
susceptible to subacute infections by C. tetani, and (ii) might well have an
ongoing, subacute colonization whose release of TeNT into the cns might be the
primary cause of that child's autistic traits (routes and cites in ref 24). Given
the similarities between subacute tetanus symptoms and various autistic traits (24)
and given the fact that subacute intestinal colonizations and subacute tetanus are
seldom diagnosed or even recognized by physicians (24), the role of TeNT and other
microbial toxins in the etiology of autism ought be considered, especially given
mechanisms of CD5+/IgA-related tolerance as can occur early in life if pathogenic
microbes are present in the gastrointestinal tract (3).
....Additional points....
1. In regard to the *theoretical possibility* that C. tetani colonizations may be
etiological factors in some cases of autism (24), families whose autistic child has
been tested and found to have profoundly low anti-TeNT antibodies are offered the
following precautions:
(i) Just how long a child would have to be treated with
certain strong antibiotics so as to eliminate all C. tetani
bacteria and spores is not known,
(ii) Long-term regimens of such high-powered antibiotics are
not without risk,
(iii) This document's assembling of notions is merely a
*hypothesis*, albeit a hypothesis gleaned from simple
juxtaposition of credible citations from respected journals.
2. Antibiotic regimens that eliminate beneficial microflora from the
gastrointestinal tract, especially during the time period in which the CD5+ B-cells
are developing their primary self-repertoire, would increase the likelihood that
pathogenic microbes could be present (eg, 6). Thus in young children, prolonged
antibiotic regimens can increase the long-term likelihood of subacute colonization
by pathogenic microbes. From then on, such colonizations (i) would be likelier to
occur and re-occur as subacute infections, (ii) could release low levels of TeNT or
similar neurotoxins that affect CNS function, and (iii) could be releasing those
significant levels of TeNT even while inducing abnormally low antibody responses.
3. Various ubiquitous microbes -- eg, Candida species, Staphylococci, etc -- can
achieve early colonizations during the CD5+ formative time period (15). If these
colonizations occur in a young child, he or she would be always inclined towards
subacute infections by microbes which his or her CD5+ B-cells had learned to
perceive as normal; and, due to microbial syn- ergy, co-occurring infections by
other microbes might also occur (28-29).
4. Many of the pathogenic microbes increase gut permeability (30), and some generate
neurotoxins (eg, 31). As suggested by dietary and pharmaceutical manipulations
described by parents of autistic children (32-33), a goodly proportion of those
parents may be treating sequelae to early GI-tract infections that had induced CD5+
tolerance to the pathogenic microbes. In some such cases the subsequent infections
may be subacute and ongoing; in other children, intestinal permeability may have
been forever altered even if subacute colonizations have not occurred or have been
eliminated; and the possibility exists that both altered permeability and ongoing
subacute infections may be occurring in some individuals.
....Conclusion....
When considering numerous autistic individuals, person-to-person variations in these
Cd5+/IgA-related, infection-based parameters may manifest as inter-individual
traits-differences that are so common to autism. Relatedly, the diversity of
infectional parameters may also contribute to family-to-family differences in what
works and what does not work with regard to dietary manipulations and
pharmaceuticals.
Verification of infectionally caused cases of autism and also of a CD5+
intestinal-tract role (i) could increase the number of children showing behavioral
improvements subsequent to antimicrobial and dietary therapies and, via improved
protection of beneficial microflora in very young children, (ii) could decrease the
number of children who acquire subacute colonizations by pathogenic bacteria whose
toxins and other byproducts may be causally significant to etiological pathways in
certain cases of autism and related phenotypes.
>>>> Posting number 1647,
dated 14 Jan 1997 13:22:30
(Part 2 of 3)
REFERENCES, some quotations therefrom, and interspersed comments:
1. Nunez C, Nishimoto N, Gartland GL, Billips LG, Burrows PD, Kubagawa H, Cooper MD:
B cells are generated throughout life in humans. The Journal of Immunology
156.866-72 1996.
"This analysis indicates that while bone marrow is the major
site of B cell generation, cells representative of the
earliest states in the B lineage pathway are present in
multiple nonhemopoietic tissues during embryonic development."
2. Marcos MAR, Godin I, Cumano A, Morales S, Garcia-Porrero JA, Dieterlen-Lievre F,
Gaspar ML: Developmental events from hemopoietic stem cells to B cell populations
and Ig repertoires. Immunological Reviews 137.155- 1994.
3. Kroese FGM, de Waard R, Bos NA: B-1 cells and their reactivity with the murine
intestinal microflora. Seminars in Immunology 8.11-18 1996.
[This article and its citations may be highly significant for
understanding (i) gastrointestinal pathologies present in
autism and other disorders, (ii) CD5+ cells' role in
establishing a person's "normal" matrices of microflora and
microbes, and (iii) risks that ensue if endogenous microflora
are altered early in life, eg, via extended antibiotics
regimens.]
4. Stark PL, Lee A: The microbial ecology of the large bowel of breast- fed and
formula-fed infants during the first year of life. Journal of Medical Microbiology
15.189-203 1982.
5. Macfarlane GT, Cummings JH: The colonic flora, fermentation, and large bowel
digestive function. pp51-92, Chapter 4 In: The Large Intestine: Physiology,
Pathophysiology, and Disease; edited by Phillips SF, Pemberton JH, Shorter RG; Raven
Press, Ltd; New York, 1991.
"The gastrointestinal tract of babies is inoculated with
bacteria from the mothers' vaginal and fecal flora during
birth... The newborn then acquires bacteria from the external
environment and a succession of changes occurs in the
composition of the microflora over the early weeks of life.
Feeding appears to have a strong influence on the types of
bacteria found in the infant gut. The flora of breast-fed
infants differs from those who have been bottle-fed... Breast-
fed babies harbor mainly bifido-bacteria with lesser numbers
of entero-bacteria, whereas those fed a formula diet have a
more complex microflora consisting of bifidobacteria,
bacteriodes, clostridia, and streptococci... The greater
complexity of microbial populations in the formula-fed infants
is reflected in the diversity of fermentation products formed,
including acetate, propionate, and butyrate, whereas acetate
is the main SCFA produced in breast-fed babies..."
"Conversion to an adult-type microflora occurs after weaning
and by the second year of life, the gut microflora is similar
to that of the adult. It is thought that these changes in the
gut flora are due principally to the introduction of solid
food in the diet, rather than to the effect of age per se..."
6. van der Waaij D, Berghuis-de Vries JM, Lekkerker-van der Wees JEC: Colonization
resistance of the digestive tract in conventional and antibiotic-treated mice.
Journal of Hygiene 69.405-411 1971.
7. Rolfe RD: Interactions among microorganisms of the indigenous intestinal flora
and their influence on the host. Reviews of Infectious Diseases 6(Suppl 1).s73-s79
1984.
8. Hill HR, Meier FA: Host defense factors in the gastrointestinal tract. Pediatric
Infectious Disease 5.1.s144-s147 1986.
"The migrating lymphoid cells of gastrointestinal mucosal
origin appear to home not only to the gastrointestinal tract
but also to the mammary tissue where they are also capable of
producing specific antibody and immune responses."
"The sequence of antigen exposure first via the oral and then
the systemic route appears to be critical."
9. Goldmann DA: The bacterial flora of neonates in intensive care - monitoring and
manipulation. Journal of Hospital Infection 11.(Suppl A).340-51 1988.
10. Alverdy JC, Aoys E, Moss GS: Effect of commercially available chemically defined
liquid diets on the intestinal microflora and bacterial translocation from the gut.
Journal of Parenteral and Enteral Nutrition 14.1.1-6 1990.
11. Goldmann DA: When normal flora turn nasty. Pediatric Infectious Disease Journal
15.845-7 1996.
12. Hardy RR, Hayakawa K: Development of Ly-1 B and its human homolog, Leu-1 B.
Immunological Reviews 93.53-79 1986.
[In retrospect this article's title has become somewhat
misleading because of the many terminologies, eg, Ly-1, B-1a,
B-1b, CD5+, etc, pointing toward the same group of cells.]
13. Andre C, Heremans JF, Vaerman JP, Cambiaso CL: A mechanism for the induction of
immunological tolerance by antigen feeding: antigen- antibody complexes. The Journal
of Experimental Medicine 142.1509-1519 1975.
[This study appears to be profoundly on-target with regard to
many GI-tract factors and their significances!]
14. Marshall JC, Christou NV, Meakins JL: Small-bowel bacterial overgrowth and
systemic immunosuppression in experimental peritonitis. Surgery 104.404-11 1988.
[Comments in this article may have much significance to
etiology in a subgroup of autistics having suspected or
clearly identified GI-tract involvement.]
"The endogenous gut flora has multiple and complex effects on
systemic immunity. An intact gram-negative flora is a
prerequisite for the induction of delayed-type
hypersensitivity (DTH) responses..., but it also induces a
population of splenic macrophages that suppress secondary
antibody responses... The development of specific immunologic
tolerance to orally administered antigens requires the
presence of an intact gut flora... Endotoxin of gut origin
figures prominently in a number of these immunoregulatory
effects... Our investigations were undertaken to assess the
role of the microbial flora of the proximal GI tract in the
pathogenesis of the immunosuppression associated with
intraperitoneal infection."
"We have previously shown that infusion of live E. coli into
the portal vein produces suppression of systemic immunity...
when compared with systemic infusion of the same numbers of E.
coli... Our study shows that elevated levels of E. coli in the
small-bowel lumen are associated with the same suppressive
effect."
"Endotoxin... is readily able to pass from isolated small-
bowel loops into the portal vein or intestinal lymphatics, and
[in many individuals] absorption of gut endotoxin, rather than
the translocation of viable bacteria, may well be the more
biologically significant phenomenon."
15. Marshall JC, Christou NV, Meakins JL: Immunomodulation by altered
gastrointestinal tract flora: The effects of orally administered, killed
Staphylococcus epidermis, Candida, and Pseudomonas on systemic immune responses.
Archives of Surgery 123.1465-9 1988.
[This constitutes the end of the original monograph. However, several listmate
inquiries led to additional information being presented and are included here as an
addendum, including additional citations:]
ADDENDUM
>>> Posting number 2366, dated 21 Jan 1997 08:53:57
Date: Tue, 21 Jan 1997 08:53:57 -0700
Sender: SJU Autism and Developmental Disablities List
From: Teresa Binstock
Subject: Re: CD5+ B-cells: additional citations
.....because Teresa Binstock had written.....
>>What group of researchers do have this extensive experience and could you give
me some references on development of the CD5+ and CD 5- B-Cells please.
Tor A Strand Centre of International Health
University of Bergen Norway
.....to which Teresa responded.....
Tor, I have included the primary CD5/intestines citation (from Frans Kroese and
colleagues) as well as 16 citations providing additional background about CD5+
cells, which have various acronyms in the literature -- eg, CD5+, Ly-1, Leu-1, B1a,
B-1a, et cetera.
*****
The primary article focusing upon early B cells and IgA roles in the neonatal
intestine is reference 3.
3. Kroese FGM, de Waard R, Bos NA: B-1 cells and their reactivity with the murine
intestinal microflora. Seminars in Immunology 8.11-18 1996.
[This article and its citations may be highly
significant for understanding (i) gastrointestinal
pathologies present in autism and other disorders, (ii)
CD5+ cells' role in establishing a person's "normal"
matrices of microflora and microbes, and (iii) risks
that ensue if endogenous microflora are altered early
in life, eg, via extended antibiotics regimens.]
*****
Most of the following citations focus upon ontogeny of CD5+ B cells.
<1> Beagley KW. Murray AM. McGhee JR. Eldridge JH. Peritoneal cavity CD5 (Bla)
B cells: cytokine induced IgA secretion and homing to intestinal lamina propria in
SCID mice.
Immunology & Cell Biology. 73(5):425-32, 1995 Oct.
<2> Kiyoi H. Naito K. Ohno R. Naoe T. Comparable profiles of the immunoglobulin
heavy chain complementarity determining region (CDR)-3 in CD5+ and CD5- human cord
blood B lymphocytes. Immunology. 85(2):236-40, 1995 Jun.
<3> Bhat NM. Mithal A. Bieber MM. Herzenberg LA. Teng NN. Human CD5+ B
lymphocytes (B-1 cells) decrease in peripheral blood during pregnancy.
Journal of Reproductive Immunology. 28(1):53-60, 1995 Jan.
<4> Hardy RR. Carmack CE. Li YS. Hayakawa K. Distinctive developmental origins
and specificities of murine CD5+ B cells. [Review]
Immunological Reviews. 137:91-118, 1994 Feb.
<5> Abe M. Tominaga K. Wakasa H. Phenotypic characterization of human
B-lymphocyte subpopulations, particularly human CD5+ B-lymphocyte subpopulation
within the mantle zones of secondary follicles. Leukemia. 8(6):1039-44, 1994 Jun.
<6> Zupo S. Dono M. Massara R. Taborelli G. Chiorazzi N. Ferrarini M.
Expression of CD5 and CD38 by human CD5- B cells: requirement for special stimuli.
European Journal of Immunology. 24(6):1426-33, 1994 Jun.
<7> Lankester AC. van Schijndel GM. Cordell JL. van Noesel CJ. van Lier RA.
CD5 is associated with the human B cell antigen receptor complex. European Journal
of Immunology. 24(4):812-6, 1994 Apr.
<8> Hardy RR. Hayakawa K. CD5 B cells, a fetal B cell lineage. [Review] Advances
in Immunology. 55:297-339, 1994.
<9> Kasaian MT. Casali P. Autoimmunity-prone B-1 (CD5 B) cells, natural
antibodies and self recognition. [Review] Autoimmunity. 15(4):315-29, 1993.
<10> Lydyard PM. Lamour A. MacKenzie LE. Jamin C. Mageed RA. Youinou P. CD5+
B cells and the immune system. [Review] Immunology Letters. 38(2):159-66, 1993
Oct.
<11> Kearney JF. CD5+ B-cell networks. [Review] Current Opinion in Immunology.
5(2):223-6, 1993 Apr.
<12> Schutte ME. Ebeling SB. Akkermans-Koolhaas KE. Logtenberg T.
Deletion mapping of Ig VH gene segments expressed in human CD5 B cell lines. JH
proximity is not the sole determinant of the restricted fetal VH
gene repertoire. Journal of Immunology. 149(12):3953-60, 1992 Dec 15.
<13> Bhat NM. Kantor AB. Bieber MM. Stall AM. Herzenberg LA. Teng NN. The
ontogeny and functional characteristics of human B-1 (CD5+ B) cells. International
Immunology. 4(2):243-52, 1992 Feb.
<14> Hardy RR. Variable gene usage, physiology and development of Ly-1+ (CD5+) B
cells. Current Opinion in Immunology. 4(2):181-5, 1992 Apr.
<15> Solvason N. Chen X. Shu F. Kearney JF. The fetal omentum in mice and
humans. A site enriched for precursors of CD5 B cells early in development. Annals
of the New York Academy of Sciences. 651:10-20, 1992 May 4.
<16> Davidson WF. Pierce JH. Holmes KL. Evidence for a developmental
relationship between CD5+ B-lineage cells and macrophages. [Review] Annals of the
New York Academy of Sciences. 651:112-29, 1992 May 4.
eof
>>> Posting number 2318, dated 20 Jan 1997 22:08:08
Date: Mon, 20 Jan 1997 22:08:08 -0700
Sender: SJU Autism and Developmental Disablities List
From: Teresa Binstock
Subject: IgA & CD5+: was Re: Heavy Metal Toxicity
Hillary,
IgA is the primary immunoglobulin focused upon by Kroese et al, which is reference
3 in my CD5+ paper; evidently, IgA is very significant in protecting our natural
microflora or in some cases, protecting pathogenic microbes that if present early
enough in the intestines, would always be able to colonize... (which just seems to
be another phrase for "bacterial overgrowth").
Teresa
On Mon, 20 Jan 1997, robert richardson wrote:
> ...I'll ask him then the name of the lab he's using. All I did at
> the appointment was write down the names of the various
> Ig tests. I have a good URL for IgA deficiency which I've
> found very thorough but down-to-earth. Have you seen the
> following?
>
> http://www.mssm.edu/iga-defi.html
>
> My son's immunologist liked this reference so well that he's
> now copying it to hand out to his IgA-deficient patients !!
POSTING HISTORY FOR THE CD5+ PAPER
.....CD5 POSTING #1.....
>>> Posting number 1629, dated 14 Jan 1997 20:49:58
Date: Tue, 14 Jan 1997 20:49:58 -0700
Sender: SJU Autism and Developmental Disablities List
From: Teresa Binstock
Subject: CD5+ B-cells, Intestinal Microflora, & Autism (part 1a of 3)
The following paper and its citations are posted to bit.listserv.autism
by its author, and may be shared only in its entirety, only for
non-profit purposes, and may be cited as follows:
Binstock T. Hypothesis: Intestinal microflora and CD5+ B cells: their possible
significance in some cases of autism. Bit.Listserv.Autism January 14, 1997.
.....CD5 POSTING #2.....
>>> Posting number 1631, dated 14 Jan 1997 20:57:15
Date: Tue, 14 Jan 1997 20:57:15 -0700
Sender: SJU Autism and Developmental Disablities List
From: Teresa Binstock
Subject: CD5+ B-cells, Intestinal Microflora, & Autism (part 1b of 3)
.....CD5 POSTING #3.....
>>> Posting number 1647, dated 14 Jan 1997 13:22:30
Date: Tue, 14 Jan 1997 13:22:30 -0700
Sender: SJU Autism and Developmental Disablities List
From: Teresa Binstock
Subject: CD5+ B cells, Intestinal Microflora, & Autism (Part 2 of 3)
.....CD5 POSTING #4.....
>>> Posting number 1648, dated 14 Jan 1997 20:44:45
Date: Tue, 14 Jan 1997 20:44:45 -0700
Sender: SJU Autism and Developmental Disablities List
From: Teresa Binstock
Subject: 4: CD5+ B-cells, Intestinal Microflora, & Autism (part 1 of 3)
>/pre>
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