Caterina De Carolis

Glutathione: A key player in autoimmunity

Increasing attention in the physiopathology of inflammatory/immunomediated diseases has been focused on the role of reactive oxygen species (ROS), oxygen-based molecules possessing high chemical reactivity and produced by activated neutrophils during the inflammatory response. During chronic inflammation, when sustained production of ROS occurs, antioxidant defences can weaken, resulting in a situation termed oxidative stress. Moreover, antioxidant defence systems have been demonstrated to be constitutively lacking in patients affected with chronic degenerative diseases, especially inflammatory/immunomediated. Glutathione, a tripeptide, is the principal component of the antioxidant defence system in the living cells. Glutathione has been demonstrated to have diverse effects on the immune system, either stimulating or inhibiting the immunological response in order to control inflammation. The study of interactions between glutathione and the immune system has attracted many investigators. Altered glutathione concentrations may play an important role in many autoimmune pathological conditions prevalently elicited, detrimed and maintained by inflammatory/immune response mediated by oxidative stress reactions. The role of glutathione in autoimmunity will be reviewed herein.

Mild thyroid abnormalities and recurrent spontaneous abortion: diagnostic and therapeutical approach.

PROBLEM: The aim of this study is to evaluate the role of mild thyroid abnormalities in recurrent spontaneous abortion, and to assess the effects of two different therapeutical protocols.
 METHOD: A prospective study in the population of recurrent aborters with mild thyroid abnormalities, evaluating the obstetric outcome in 42 patients. Sixteen thyroid autoantibodies positive patients were treated with thyroid replacement therapy, while 11 patients received intravenous immunoglobulins (IVIG). Fifteen patients, characterized by negative antithyroid antibodies, and having underlying thyroid pathology, were treated with thyroid replacement therapy.
 RESULTS: Among patients with thyroid antibodies, 6 out of the 11 pregnancies (54.5%) treated with IVIG ended in live birth. In the thyroid supplementation group, 13 out of 16 pregnancies (81.2%) ended in live birth. Only one pregnancy loss occurred among patients with a mild underlying thyroid pathology treated with thyroid replacement therapy.
 CONCLUSIONS: Mild thyroid abnormalities are associated with an increased rate of miscarriage. This poor obstetrical prognosis seems to be related to an impaired thyroid adaptation to pregnancy. Thyroid replacement therapy appears to be more effective than IVIG in preventing a new miscarriage.

NK cells in autoimmunity: A two-edg'd weapon of the immune system☆

Natural killer (NK) cells are part of the innate-immune system and respond rapidly to a variety of insults via cytokine secretion and cytolytic activity. Their main function is first line of innate immunity across viral, bacterial and parasitic infections. NK-cells are not solely killers but can also act as regulators of adaptive immunity. It is evident from literature that NK-cells are deeply involved in autoimmunity, but the question is how and why they act as a two edged weapon. Number of circulating NK-cells can be frequently altered depending on the disease taken into consideration. Cytokine milieu, the microenvironment in which they mature and other stimuli acting on different cell surface receptors may differently trigger NK-cells response and influence their role in autoimmune diseases. Functional differences between NK-cells at different anatomical sites, the adaptability of NK-cells effector responses and genetic factors may also explain differences in such responses. Thus, NK-cell alterations may be associated with increased autoimmunity and the modulation in the number of circulating NK-cells seems to be a primary event rather than an active inflammation/drug administration consequence during inflammatory/autoimmune processes, playing a fundamental role in the pathogenesis of a number of autoimmune diseases.

GM-CSF and Pregnancy: Evidence of Significantly Reduced Blood Concentrations in Unexplained Recurrent Abortion Efficiently Reverted by Intravenous Immunoglobulin Treatment

Problem: Certain Th‐2 cytokines and granulocyte–macrophage colony‐stimulating factor (GM‐CSF) are propitious for the success of pregnancy and recurrent spontaneous abortion (RSA) is often characterized by a failure of Th‐2 type responses. These considerations as well as the use of intravenous immunoglobulin (IVIg) in RSA induced us to evaluate the levels of GM‐CSF in normal pregnancies, in pregnant women affected with unexplained RSA and the effects of IVIg treatment.

High levels of peripheral blood NK cells in women suffering from recurrent spontaneous abortion are reverted from high-dose intravenous immunoglobulins.

To determine the levels of peripheral blood natural killer (NK) cells in healthy women and recurrent aborters, and the effect of intravenous immunoglobulins (IVIGs) on these levels.

Urinary phthalate monoesters concentration in couples with infertility problems.

The widespread use of phthalates results in human exposure: phthalates are rapidly metabolized to their respective monoesters and other oxidative products, which are glucuronidated and excreted through the urine and feces. Several in vivo studies showed that some phthalates, in particular diethyl-hexyl phthalate (DEHP), diethyl phthalate (DEP), di(n-butyl)phthalate (DnBP) and n-butylbenzylphthalate (BBzP), are able to interact with the human endocrine system, interfering with the reproduction ability. In this study, 56 couples were recruited from a centre of assisted reproduction. Spot urine samples were collected and five urinary metabolites of the above phthalates were determined using an HPLC/MS/MS analytical method with isotopic dilution. The results were compared with those of 56 couples of parents of one or more children and the statistical analysis revealed a significant difference between the two groups in terms of urinary concentrations of phthalates metabolites. A further step will be the correlation of these results with information on the life styles and working conditions collected through a specifically designed questionnaire.

Anti-thyroid antibodies and antiphospholipid syndrome: evidence of reduced fecundity and of poor pregnancy outcome in recurrent spontaneous aborters.

Problem:  To determine the presence of anti‐thyroid antibodies in patients with primary antiphospholipid syndrome (APS) [antiphospholipid antibodies (aPL) + recurrent spontaneous abortion (RSA)], compare APS alone with APS and thyroid autoimmunity for fecundity and for pregnancy outcome.

Pregnancy and autoimmunity: A common problem

Successful pregnancy is considered a Th1-Th2 cooperation phenomenon (Th, T-helper), with a predominantly Th2-type lymphocytes response, together with the emerging role of interleukin (IL)-12, IL-15 and IL-18 and of other unidentified soluble factors dependent on natural killer (NK) cells. In the pathogenesis of recurrent spontaneous abortion (RSA), immunological factors have been involved such as decidual cells, complement system, cytokines and genes of the hystocompatibility complex that can determine the success or the failure of a pregnancy. A deeper insight into apparently unexplained RSA shows increasing evidences supporting both alloimmune and autoimmune mechanisms, with autoantibodies playing a major role. The best-characterised pathogenic autoantibodies are anti-phospholipid antibodies, and also other autoantibodies, such as anti-Ro/SSA and anti-La/SSB, have been found to be associated with an increased rate of abortion, poor pregnancy outcome and several other obstetric manifestations. This intriguing mixture has been unveiled only in the last few years with the discovery of novel pathogenic mechanisms that can be targeted in the prevention and treatment of obstetrical complications occurring in the course of an autoimmune disease.

NK Cells, Autoantibodies, and Immunologic Infertility: A Complex Interplay

Infertility and recurrent spontaneous abortion (RSA) are heterogeneous conditions that have been frequently explained with an immunological pathomechanism. A deeper insight into apparently unexplained infertility and RSA shows increasing evidences supporting both alloimmune and autoimmune mechanisms, in which natural killer (NK) cells and autoantibodies seem to play a relevant role. Successful pregnancy is considered as Th1–Th2 cooperation phenomenon, with a predominantly Th2-type lymphocytes response, together with the emerging role of interleukin (IL)-12, IL-15, and IL-18 and of other unidentified soluble factors dependent on NK cells. Uterine NK cells comprise the largest population at implantation site, and their activity, characteristics, and abundance suggest that they participate at the “decidualization” process that, vice versa, induces NK activation and recruitment in each menstrual cycle. However, NK cell alteration may be associated with impaired pregnancy, and the modulation in the number of circulating NK cells is most likely to be a primary event rather than an active inflammation/drug administration consequence during an inflammatory/autoimmune process, thus playing an important role in the pathogenesis of immunological infertility. Relationships within immunological infertility, recurrent spontaneous abortion, autoantibodies, and NK cells will be reviewed herein.

Smell and Autoimmunity: A Comprehensive Review

The sense of smell is an ancient sensory modality vital for sampling and perceiving the chemical composition of surrounding environments. Olfaction involves a pathway of biochemical and electrophysiological processes, which allows the conversion of molecular information into sensations. Disturbances in the olfactory function have been investigated mainly in neurological/neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases; impaired sense of smell has been associated with depressed mood. Only recently, smell capability was tested in other diseases, particularly autoimmune diseases. Shoenfeld and colleagues opened this chapter showing that patients affected with systemic lupus erythematosus (SLE) have disturbances in their olfactory functions and revealed its association with neuropsychiatric manifestations of the disease. This evidence was confirmed in experimental models and replicated in other SLE populations. The connection between autoimmunity and the sense of smell was lately emphasized by studies on patients with Sjögren’s syndrome and in patients with other autoimmune/immune-mediated diseases, such as polydermatomyositis, recurrent spontaneous abortion, and hereditary angioedema. Genetic susceptibility and hormonal and environmental factors may play a role in these conditions. Olfactory receptor gene clusters are located in proximity to key locus of susceptibility for autoimmune diseases such as the major histocompatibility complex, suggesting not only a physic linkage, but a functional association. Nonetheless, gender- and hormone-mediated effects are fundamental in the development of autoimmune diseases. The different connections between smell and autoimmunity, genes and hormones may suggest that this is another tessera of a mosaic which is waiting the answer of Oedipus.