Low levels of serum asymmetric antibodies as a marker of threatened pregnancy.

Tolerance to the developing fetus is thought to be accomplished through the action of several molecules that are able to modulate the maternal immune response. Among several mechanisms involved in pregnancy maintenance, progesterone-induced immunomodulation, asymmetric antibody (AAb) production, indoleamine 2,3-dioxygenase (IDO)-mediated tryptophan catabolism and Th1- to Th2-type cytokine balance have been particularly well studied. However, spontaneous abortions (SA) remain the most common complication of pregnancy, affecting 15% of women, primarily in the first trimester. Development of sensitive methods for the early diagnosis of this condition is therefore a matter of critical importance. In the present study, we investigated AAb production and IDO activity in pregnant women in order to assess their value as early markers for the diagnosis of pregnancy failure. Serum AAb percentages were significantly reduced in women who subsequently suffered from SA compared with controls (p<0.001). Levels of IL-10, IL-12 and IDO activity were also lower in the SA cases, although levels of significance were not reached. In view of these findings, low maternal serum AAb percentages during the first trimester of pregnancy may be indicative of a threat to pregnancy progression.

Chronic immune stimulation correlates with reduced phenylalanine turnover.

Neuropsychiatric symptoms like mood changes and depression are common in patients with chronic inflammatory disorders such as infections, autoimmune diseases or cancer. The pathogenesis of these symptoms is still unclear. Pro-inflammatory stimuli interfere not only with the neural circuits and neurotransmitters of the serotonergic, but also with those of the adrenergic system. The pro-inflammatory cytokine interferon-gamma stimulates the biosynthesis of 5,6,7,8-tetrahydrobiopterin (BH4), which is cofactor for several aromatic amino acid monooxygenases and thus is strongly involved in the biosynthesis of the neurotransmitter serotonin and the catecholamines dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline). In macrophages, interferon-gamma also triggers the high output of reactive oxygen species, which can destroy the oxidation-labile BH4. Recent data suggest that oxidative loss of BH4 in chronic inflammatory conditions can reduce the biosynthesis of catecholamines, which may relate to disturbed adrenergic neurotransmitter pathways in patients.

Interferon-gamma-induced conversion of tryptophan: immunologic and neuropsychiatric aspects.

Tryptophan is an essential amino acid and the least abundant constituent of proteins. In parallel it represents a source for two important biochemical pathways: the generation of neurotransmitter 5-hydroxytryptamine (serotonin) by the tetrahydrobiopterin-dependent tryptophan 5-hydroxylase, and the formation of kynurenine derivatives and nicotinamide adenine dinucleotides initiated by the enzymes tryptophan pyrrolase (tryptophan 2,3-dioxygenase, TDO) and indoleamine 2,3-dioxygenase (IDO). Whereas TDO is located in the liver cells, IDO is expressed in a large variety of cells and is inducible by the cytokine interferon-gamma. Therefore, accelerated tryptophan degradation is observed in diseases and disorders concomitant with cellular immune activation, e. g. infectious, autoimmune, and malignant diseases, as well as during pregnancy. According to the cytostatic and antiproliferative properties of tryptophan-depletion on T lymphocytes, activated T-helper type 1 (Th-1) cells may down-regulate immune response via degradation of tryptophan. Especially in states of persistent immune activation availability of free serum tryptophan is diminished and as a consequence of reduced serotonin production, serotonergic functions may as well be affected. Accumulation of neuroactive kynurenine metabolites such as quinolinic acid may contribute to the development of neurologic/psychiatric disorders. Thus, IDO seems to represent a link between the immunological network and neuroendocrine functions with far reaching consequences in regard to the psychological status of patients. These observations provide a basis for the better understanding of mood disorder and related symptoms in chronic diseases.