Cells at the maternal-fetal interface express
indoleamine 2,3 dioxygenase (IDO) to consume all local
tryptophan for the express purpose of starving adjacent maternal T cells of this most limiting and
essential amino acid. This stops local T cell proliferation to ultimately result in the most dramatic example of immune tolerance, acceptance of the fetus. By contrast, inhibition of IDO using 1-methyl-tryptophan causes a sudden catastrophic rejection of the mammalian fetus. Immunomodulatory factors including IFNgamma,
TNFalpha,
IL-1, and LPS use IDO induction in responsive antigen presenting cells (APCs) also to transmit tolerogenic signals to T cells. Thus it makes sense to consider IDO induction towards tolerance for
autoimmune diseases in general. Approaches to cell specific therapeutic IDO induction with
NAD precursor supplementation to prevent the collateral non-T cell pathogenesis due to chronic
TNFalpha-IDO activated
tryptophan depletion in
autoimmune diseases are reviewed.
Tryptophan is an
essential amino acid most immediately because it is the only precursor for the endogenous biosynthesis of
nicotinamide adenine dinucleotide (
NAD). Both
autoimmune disease and the
NAD deficiency disease pellagra occur in women at greater than twice the frequency of occurrence in men. The importance of IDO dysregulation manifest as autoimmune pellagric
dementia is genetically illustrated for
Nasu-Hakola Disease (or
PLOSL), which is caused by a mutation in the IDO antagonizing genes TYROBP/DAP12 or TREM2. Loss of function leads to psychotic symptoms rapidly progressing to
presenile dementia likely due to unchecked increases in microglial IDO expression, which depletes neurons of
tryptophan causing neurodegeneration. Administration of
NAD precursors rescued entire mental hospitals of
dementia patients literally overnight in the 1930's and
NAD precursors should help Nasu-Hakola patients as well.
NAD depletion mediated by peroxynitrate PARP1 activation is one of the few established mechanisms of
necrosis. Chronic elevation of
TNFalpha leading to necrotic events by
NAD depletion in
autoimmune disease likely occurs via combination of persistent IDO activation and iNOS-peroxynitrate activation of PARP1 both of which deplete
NAD. Pharmacological doses of
NAD precursors repeatedly provide dramatic therapeutic benefit for
rheumatoid arthritis,
type 1 diabetes,
multiple sclerosis,
colitis, other
autoimmune diseases, and
schizophrenia in either the clinic or animal models. Collectively these observations support the idea that
autoimmune disease may in part be considered as localized
pellagra manifesting symptoms particular to the inflamed target tissues. Thus pharmacological doses of
NAD precursors (
nicotinic acid/
niacin,
nicotinamide/
niacinamide, or
nicotinamide riboside) should be considered as potentially essential to the therapeutic success of any IDO-inducing regimen for treating
autoimmune diseases. Distinct among the
NAD precursors,
nicotinic acid specifically activates the
g-protein coupled receptor (GPCR) GPR109a to produce the IDO-inducing tolerogenic
prostaglandins PGE(2) and
PGD(2). Next,
PGD(2) is converted to the anti-inflammatory
prostaglandin, 15d-PGJ(2). These
prostaglandins exert potent anti-inflammatory activities through endogenous signaling mechanisms involving the GPCRs EP2, EP4, and DP1 along with
PPARgamma respectively.
Nicotinamide prevents
type 1 diabetes and ameliorates
multiple sclerosis in animal models, while nothing is known about the therapeutic potential of
nicotinamide riboside. Alternatively the direct targeting of the non-redox
NAD-dependent
proteins using
resveratrol to activate
SIRT1 or
PJ34 in order to inhibit PARP1 and prevent autoimmune pathogenesis are also given consideration.