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This directly links NOD2 alleles in Crohn's with regulatory T-cell

J Immunol. 2010 Jun 15;184(12):7247-56. Epub 2010 May 7.

The pathogen recognition receptor NOD2 regulates human FOXP3+ T cell
Rahman MK, Midtling EH, Svingen PA, Xiong Y, Bell MP, Tung J, Smyrk T,
Egan LJ, Faubion WA Jr.
Division of Gastroenterology and Hepatology, Department of Internal
Medicine, Mayo Clinic, Rochester, MN 55905, USA.

The expression of pathogen recognition receptors in human FOXP3+ T
regulatory cells is established, yet the function of these receptors is
currently obscure. In the process of studying the function of both
peripheral and lamina propria FOXP3+ lymphocytes in patients with the
human inflammatory bowel disease Crohn's disease, we observed a clear
deficiency in the quantity of FOXP3+ lymphocytes in patients with
disease-associated polymorphisms in the pathogen recognition receptor
gene NOD2. Subsequently, we determined that the NOD2 ligand, muramyl
dipeptide (MDP), activates NF-kappaB in primary human FOXP3+ T cells.
This activation is functionally relevant, as MDP-stimulated human FOXP3+
T cells are protected from death receptor Fas-mediated apoptosis.
Importantly, apoptosis protection was not evident in MDP-stimulated
FOXP3+ T cells isolated from a patient with the disease-associated
polymorphism. Thus, we propose that one function of pathogen recognition
receptors in human T regulatory cells is the protection against death
receptor-mediated apoptosis in a Fas ligand-rich environment, such as
that of the inflamed intestinal subepithelial space.

PMID: 20483763

PLoS One. 2007 Mar 21;2(3):e313.
A key role of dendritic cells in probiotic functionality.
Foligne B, Zoumpopoulou G, Dewulf J, Ben Younes A, Chareyre F, Sirard
JC, Pot B, Grangette C.
Laboratoire de Bact��ries Lactiques et Immunit�� des Muqueuses, Institut
Pasteur de Lille - Institut de Biologie de Lille, Lille, France.

BACKGROUND: Disruption of the intestinal homeostasis and tolerance
towards the resident microbiota is a major mechanism involved in the
development of inflammatory bowel disease. While some bacteria are
inducers of disease, others, known as probiotics, are able to reduce
inflammation. Because dendritic cells (DCs) play a central role in
regulating immune responses and in inducing tolerance, we investigated
their role in the anti-inflammatory potential of probiotic lactic acid
bacteria. METHODOLOGY/PRINCIPAL FINDINGS: Selected LAB strains, while
efficiently taken up by DCs in vitro, induced a partial maturation of
the cells. Transfer of probiotic-treated DCs conferred protection
against 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced colitis.
Protection was associated with a reduction of inflammatory scores and
colonic expression of pro-inflammatory genes, while a high local
expression of the immunoregulatory enzyme indolamine 2, 3 dioxgenase
(IDO) was observed. The preventive effect of probiotic-pulsed DCs
required not only MyD88-, TLR2- and NOD2-dependent signaling but also
the induction of CD4+ CD25+ regulatory cells in an IL-10-independent
pathway. CONCLUSIONS/SIGNIFICANCE: Altogether, these results suggest
that selected probiotics can stimulate DC regulatory functions by
targeting specific pattern-recognition receptors and pathways. The
results not only emphasize the role of DCs in probiotic immune
interactions, but indicate a possible role in immune-intervention
therapy for IBD.
PMID: 17375199

Vitamin D signaling through its nuclear vitamin D receptor (VDR) is a
key regulator of innate immunity in humans; hormonal vitamin D,
1,25-dihydroxyvitamin D3 (1,25D) robustly stimulates expression of
pattern recognition receptor NOD2/CARD15/IBD1 gene and protein in
primary human monocytic and epithelial cells. The VDR signals through
distal enhancers in the NOD2 gene, whose function was validated by
chromatin immunoprecipitation and chromatin conformation capture assays.
A key downstream signaling consequence of NOD2 activation by agonist
muramyl dipeptide (MDP) is stimulation of NF-kappaB transcription factor
function, which induces expression of the gene encoding antimicrobial
peptide beta defensin 2 (DEFB2/HBD2). Pretreatment with 1,25D
synergistically induced NF-kappaB function and expression of genes
encoding DEFB2/HBD2 and antimicrobial peptide cathelicidin in the
presence of MDP. Importantly, this synergistic response was also seen in
macrophages from a donor wild-type for NOD2, but was absent in
macrophages from patients with Crohn's disease homozygous for
non-functional NOD2 variants. These studies provide strong molecular
links between vitamin D deficiency and the genetics of Crohn's disease,
a chronic incurable inflammatory bowel condition, as Crohn's
pathogenesis is associated with attenuated NOD2 or DEFB2/HBD2 function
[PMID 19948723]

In the rich, developed parts of the world there has been a steady and
simultaneous increase in at least three groups of disease: (1)
allergies, (2) inflammatory bowel diseases (IBD; e.g. Crohn's disease
and ulcerative colitis) and (3) autoimmunity (e.g. type 1 diabetes and
multiple sclerosis). Because the medical world is so compartmentalised
it was some time before the connection between these increases was
noticed and understood. There is now evidence that the simultaneous
increase in these diseases of immunodysregulation is at least partly
attributable to malfunction of regulatory T cells (Treg). This paper
provides an overview of relevant work in each of these fields of
medicine (though with emphasis on the allergic disorders), and concludes
that the increasing failure of Treg is a consequence of diminished
exposure to certain micro-organisms that are "old friends", because of
their continuous presence throughout mammalian evolution. These
organisms, which include saprophytic mycobacteria, helminths and
lactobacilli, are recognised by the innate immune system as harmless,
and as adjuvants for Treg induction. Polymorphisms of components of the
innate immune system such as TLR2 and NOD2 appear to define subsets of
the population that will develop immunoregulatory disorders when living
in the modern environment. A further role of the "old friends" and of
the Treg that they induce might be to maintain the levels of regulatory
IL-10 secreting macrophages and antigen-presenting cells, which are
depleted in asthma and Crohn's disease. These concepts are leading to
novel therapies based on harmless organisms or their components. Phase
I/II clinical trials have yielded some statistically significant
results, and phase II trials are in progress [PMID 15007629]