Could Celiac anti-TG autoantibodies cause Crohn's-like colitis by impairing macrophages?

[Kofi]

If you've followed my posts in alt.support.crohns-colitis, you know
there is plenty of evidence piling up that Crohn's is due to defective
innate immunity. Innate pathways that synthesize antimicrobials like
cathelicidin are defective via impaired butyrate uptake or low levels of
Vitamin D3 - sometimes even high iron or sugar consumption (which hit
HIF-1alpha and FOXO1, respectively). For a variety of reasons, it looks
like macrophages are also deficient. Sympathetic nerves to the gut are
defective, making it difficult to direct macrophage action. Activation
of macrophages via a TLR2/TLR4/NFKB pathway is defective. Sometimes
antibodies against GM-CSF also impair macrophage activation.

When I recently discovered that overexpression of transglutaminase 2
(TG2) results in activation of NFKB [PMID 16720350], I started wondering
if the anti-TG antibodies in Celiac might recapitulate the same problems
seen in Crohn's if for different reasons. That is to say, people eat
wheat, develop autoantibodies to TG and that takes out their macrophage
NFKB response - similar to what's seen in Crohn's. NFKB activation
would be defective in each condition, albeit for different reasons.
This would allow bacteria to encroach into the gut lining.

It looks like there's good evidence for this theory. Anti-TG antibodies
might even attack macrophages directly. If true, this puts Celiac and
Crohn's into the same family.


Immunol Lett. 2010 Feb 9

Transglutaminase 2 is expressed and active on the surface of human
monocyte-derived dendritic cells and macrophages.
Hodrea J, Demeny MA, Majai G, Sarang Z, Korponay-Szabo IR, Fesus L.
Department of Biochemistry and Molecular Biology, Apoptosis and Genomics
Research Group, Hungarian Academy of Sciences, University of Debrecen,
Nagyerdei krt. 98, Debrecen H-4012, Hungary.

The multifunctional enzyme, transglutaminase 2 (TG2), can be found
intracellularly, in the extracellular matrix and on the cell surface.
Cell surface TG2 (csTG2) could not be detected by TG2-specific
antibodies or autoantibodies on immunocompetent cells. A supposedly
csTG2-specific antibody, 6B9, was recently shown to actually react with
CD44. Though the importance of TG2-mediated deamidation of gluten in the
pathogenesis of celiac disease has been well recognized, it is not known
in which intestinal cells or cell compartment the deamidation occurs.
Duodenal dendritic cells (DCs) can be directly involved in
gluten-reactive T-cell activation. Here we use blood monocyte-derived
dendritic cells (iDC) and macrophages (MPhi) as a model for intestinal
antigen-presenting cells (APCs) and show that they contain large amounts
of TG2. We found that TG100, a commercial TG2-specific monoclonal
antibody can recognize TG2 on the surface of these cells, that is
monocyte-derived APCs express surface-associated TG2. TG2 expression was
found on the surface of individual tunica propria cells in frozen small
bowel tissue sections from both normal and celiac subjects. We also
demonstrate that the pool of TG2 on the surface of iDCs can be
catalytically active, hence it might directly be involved in the
deamidation of gliadin peptides. Bacterial lipopolysaccharide (LPS)
increased the level of TG2 on the surface of maturing DCs, supporting
the hypothesis that an unspecific inflammatory process in the gut may
expose more transglutaminase activity. Copyright (c) 2010. Published by
Elsevier B.V.

PMID: 20005901

[Kofi]

Further fleshing out this line of thought...

Clin Exp Immunol. 2010 Feb;159(2):217-23. Epub 2009 Nov 12.
 
Anti-transglutaminase antibodies in non-coeliac children suffering from
infectious diseases.
Ferrara F, Quaglia S, Caputo I, Esposito C, Lepretti M, Pastore S,
Giorgi R, Martelossi S, Dal Molin G, Di Toro N, Ventura A, Not T.
Department of Reproductive and Development Science, University of
Trieste, and Children Hospital IRCCS 'Burlo Garofolo' Trieste, Italy.

Anti-transglutaminase antibodies are the diagnostic markers of coeliac
disease. A role is suggested for infectious agents in the production of
anti-transglutaminase antibodies. The aim was to measure positive
anti-transglutaminase antibody levels in children with infectious
diseases and to compare immunological and biological characteristics of
the anti-transglutaminase antibodies derived from these children with
that from coeliac patients. Two hundred and twenty-two children
suffering from infectious diseases were enrolled prospectively along
with seven biopsy-proven coeliacs. Serum samples were tested for
anti-transglutaminase antibodies and anti-endomysium antibodies;
positive samples were tested for coeliac-related human leucocyte antigen
(HLA)-DQ2/8 and anti-viral antibodies. Purified anti-transglutaminase
antibodies from the two study groups were tested for urea-dependent
avidity, and their ability to induce cytoskeletal rearrangement and to
modulate cell-cycle in Caco-2 cells, using phalloidin staining and
bromodeoxyuridine incorporation assays, respectively. Nine of 222
children (4%) tested positive to anti-transglutaminase, one of whom also
tested positive for anti-endomysium antibodies. This patient was
positive for HLA-DQ2 and was diagnosed as coeliac following intestinal
biopsy. Of the eight remaining children, two were positive for HLA-DQ8.
Levels of anti-transglutaminase returned to normal in all subjects,
despite a gluten-containing diet. Purified anti-transglutaminase of the
two study groups induced actin rearrangements and cell-cycle
progression. During an infectious disease, anti-transglutaminase
antibodies can be produced temporarily and independently of gluten. The
infection-triggered anti-transglutaminase antibodies have the same
biological properties as that of the coeliacs, with the same in-vivo
potential for damage.

PMID: 19912255

[Kofi]

Looks like sometimes certain anti-TG antibodies can serve as TLR4
ligands, thus activating macrophages instead of suppressing them. Prior
exposure to the rotavirus might prime the immune system for this.

PLoS Med. 2006 Sep;3(9):e358
  
In celiac disease, a subset of autoantibodies against transglutaminase
binds toll-like receptor 4 and induces activation of monocytes.
Zanoni G, Navone R, Lunardi C, Tridente G, Bason C, Sivori S, Beri R,
Dolcino M, Valletta E, Corrocher R, Puccetti A.
Section of Immunology, Department of Pathology, University of Verona,
Verona, Italy.

BACKGROUND: Celiac disease is a small intestine inflammatory disorder
with multiple organ involvement, sustained by an inappropriate immune
response to dietary gluten. Anti-transglutaminase antibodies are a
typical serological marker in patients with active disease, and may
disappear during a gluten-free diet treatment. Involvement of infectious
agents and innate immunity has been suggested but never proven.
Molecular mimicry is one of the mechanisms that links infection and
autoimmunity. METHODS AND FINDINGS: In our attempt to clarify the
pathogenesis of celiac disease, we screened a random peptide library
with pooled sera of patients affected by active disease after a
pre-screening with the sera of the same patients on a gluten-free diet.
We identified a peptide recognized by serum immunoglobulins of patients
with active disease, but not by those of patients on a gluten-free diet.
This peptide shares homology with the rotavirus major neutralizing
protein VP-7 and with the self-antigens tissue transglutaminase, human
heat shock protein 60, desmoglein 1, and Toll-like receptor 4. We show
that antibodies against the peptide affinity-purified from the sera of
patients with active disease recognize the viral product and
self-antigens in ELISA and Western blot. These antibodies were able to
induce increased epithelial cell permeability evaluated by
transepithelial flux of [(3)H] mannitol in the T84 human intestinal
epithelial cell line. Finally, the purified antibodies induced monocyte
activation upon binding Toll-like receptor 4, evaluated both by surface
expression of activation markers and by production of pro-inflammatory
cytokines. CONCLUSIONS: Our findings show that in active celiac disease,
a subset of anti-transglutaminase IgA antibodies recognize the viral
protein VP-7, suggesting a possible involvement of rotavirus infection
in the pathogenesis of the disease, through a mechanism of molecular
mimicry. Moreover, such antibodies recognize self-antigens and are
functionally active, able to increase intestinal permeability and induce
monocyte activation. We therefore provide evidence for the involvement
of innate immunity in the pathogenesis of celiac disease through a
previously unknown mechanism of engagement of Toll-like receptor 4.

Publication Types:
* Research Support, Non-U.S. Gov't

PMID: 16984219