From: Kofi on
If you've followed my posts in, 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