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I recently presented theories on why food allergies seem to increase after
beginning and maintaining a gluten-free diet:
http://maelstrom.stjohns.edu/CGI/wa.exe?A2=ind0501d&L=celiac&P=830
I just now have come across a couple of interesting abstacts on
transforming growth factor (TGF)-beta1-producing T cells (Th3 regulatory
cells or type-3 helper T cells) which, when taken together, seem to explain
a multiple food allergy and celiac disease connection. The first abstract
shows shows a REDUCTION of TGF-beta1 and Th3 cells in the mucosa of
children with multiple food allergies compared to controls. The second
abstract shows that TGF-beta1 is INCREASED in the mucosa of children with
active celiac disease compared to controls. TGF-beta1 is believed to have
suppressive properties against autoimmune responses and properties which
enhance oral tolerance. Hence the increase of TGF-beta1 while celiac
disease is active may be responsible for the suppression of food
allergies. TGF-beta1 levels may drop-off after starting a gluten-free diet
leading to the onset of multiple food allergies.
It is also noted that generation of Th3 cells and TGF-beta1 is enhanced by
a response to the commensal bacteria inhabiting the gut. This could
explain why probiotics have an effect of reducing or eliminating food
allergies. (See Medscape article.) Active celiac disease almost certainly
disturbs the mix of commensal bacteria, and, thus, probiotics should be
included with a gluten-free diet.
Th3 cells were first noted by HL Weiner in 1994 (Science. 1994 Aug 26;265
(5176):1237-40) and first designated as "Th3" cells in 1996 (J Clin Invest.
1996 Jul 1;98(1):70-7). They are now a subject of intense research for
methods to treat allergy and autoimmune disorders.
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Role of Intestinal Flora in the Development of Allergy
Marko Kalliomäki, Erika Isolauri
Curr Opin Allergy Clin Immunol 3(1):15-20, 2003.
Posted 02/10/2003 on Medscape
(Free registration may be needed to access article.)
http://www.medscape.com/viewarticle/448473_print
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Eur J Immunol. 2003 Aug;33(8):2307-15.
Reduced transforming growth factor-beta1-producing T cells in the duodenal
mucosa of children with food allergy.
Perez-Machado MA, Ashwood P, Thomson MA, Latcham F, Sim R, Walker-Smith JA,
Murch SH.
Centre for Paediatric Gastroenterology, Royal Free and University College
School of Medicine, London, GB.
Infant food allergies are increasing, and many breast-fed infants now
sensitize to maternally-ingested antigens. As low-dose oral tolerance
requires generation of suppressor lymphocytes producing TGF-beta1 (Th3
cells), we studied these cells in duodenal biopsies after diagnostic
endoscopy. Spontaneous production of Th1, Th2 and Th3 cytokines by duodenal
lymphocytes was studied using flow cytometry in 20 children with no
eventual clinico-pathological diagnosis (controls), 30 children with
multiple food allergy, nine with celiac disease and six with inflammatory
enteropathies. Immunohistochemistry and in situ hybridization were used to
localize TGF-beta1 protein and mRNA in matched biopsies. We found no
significant Th1/Th2 skewing amongst mucosal lymphocytes in allergic
children compared to controls, although celiac and inflammatory enteropathy
patients showed increased Th1 responses. By contrast, the allergic children
showed reduction of TGF-beta1(+) lymphocytes in both epithelial and lamina
propria compartments. Reduction of TGF-beta1 expression was also seen in
mononuclear cells and epithelium in food allergy by immunohistochemistry
and in situ hybridization. The dominant mucosal abnormality in food
allergic children was, thus, not Th2 deviation but impaired generation of
Th3 cells. As generation of these cells requires innate immune response to
enteric bacteria, we suggest that changing infectious exposures may inhibit
primary establishment of basic oral tolerance mechanisms.
PMID: 12884306 [PubMed - indexed for MEDLINE]
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Scand J Immunol. 2002 Nov;56(5):530-7.
Transforming growth factor-beta (TGF-beta) and tissue transglutaminase
expression in the small intestine in children with coeliac disease.
Hansson T, Ulfgren AK, Lindroos E, DannAEus A, Dahlbom I, Klareskog L.
Department of Rheumatology, Karolinska University Hospital, Stockholm;
Pharmacia Diagnostics; and Department of Pediatrics, Uppsala University
Hospital, Uppsala, Sweden. [log in to unmask]
The production of cytokines from T cells and macrophages is of potential
importance for the histological changes apparent in coeliac disease (CoD).
Small intestinal biopsy specimens from children with CoD and disease
control subjects were investigated for their content of cytokines and
tissue transglutaminase (tTG). The transforming growth factor-beta1 (TGF-
beta1) expression was increased in the lamina propria of children with
villous atrophy. In contrast, TGF-beta3 was expressed at a higher level in
the epithelium and the lamina propria of the disease control subjects. The
tTG expression was increased in the small intestine of CoD patients as
compared with that in subjects. Interleukin-4 (IL-4) was detected in the
lamina propria of both CoD patients and controls, and some of the
investigated biopsy specimens also showed IL-4 expression in the
epithelium. We conclude that children with active CoD could have an altered
expression of TGF-beta and tTG in the small intestine and that a disturbed
regulation of TGF-beta may be of importance in the immune pathogenesis of
CoD.
PMID: 12410804 [PubMed - indexed for MEDLINE]
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Immunol Rev. 2001 Aug;182:207-14.
Induction and mechanism of action of transforming growth factor-beta-
secreting Th3 regulatory cells.
Weiner HL.
Department of Neurology, Harvard Medical School and Center for Neurologic
Diseases, Brigham & Women's Hospital, Boston, Massachusetts 02115-5817,
USA. [log in to unmask]
Th3 CD4+ regulatory cells were identified during the course of
investigating mechanisms associated with oral tolerance. Different
mechanisms of tolerance are induced following oral antigen administration,
including active suppression, clonal anergy and deletion. Low doses favor
active suppression whereas high doses favor anergy/deletion. Th3 regulatory
cells form a unique T-cell subset which primarily secretes transforming
growth factor (TGF)-beta, provides help for IgA and has suppressive
properties for both Th1 and Th2 cells. Th3 type cells are distinct from the
Th2 cells, as CD4+ TGF-beta-secreting cells with suppressive properties
have been generated from interleukin (IL)-4-deficient animals. In vitro
differentiation of Th3 cells from Th precursors from T-cell antigen
receptor (TCR) transgenic mice is enhanced by culture with TGF-beta, IL-4,
IL-10, and anti-IL-12. Th3 CD4+ myelin basic protein regulatory clones are
structurally identical to Th1 encephalitogenic clones in TCR usage, MHC
restriction and epitope recognition, but produce TGF-beta with various
amounts of IL-4 and IL-10. Because Th3 regulatory cells are triggered in an
antigen-specific fashion but suppress in an antigen-non-specific fashion,
they mediate "bystander suppression" when they encounter the fed
autoantigen at the target organ. In vivo induction of Th3 cells and low
dose oral tolerance is enhanced by oral administration of IL-4. Anti-CD86
but not anti-CD80 blocks the induction of Th3 cells associated with low
dose oral tolerance. Th3 regulatory cells have been described in other
systems (e.g. recovery from experimental allergic encephalomyelitis) but
may be preferentially generated following oral antigen administration due
to the gut immunologic milieu that is rich in TGF-beta and has a unique
class of dendritic cells. CD4+CD25+ regulatory T-cell function also appears
related to TGF-beta.
PMID: 11722636 [PubMed - indexed for MEDLINE
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