Principles of phenomics in endometriosis.

BACKGROUND: Endometriosis has been associated with specific morphometric characteristics and pigmentary traits. The purpose of this study was to systematically review prior publications dealing with this aspect in order to revisit phenotypic information in the context of phenomics principles. METHODS: Comprehensive searches of Pubmed, Medline and Embase were conducted to identify studies, published from 1990 to 2011 in the English language literature, on the relationship between endometriosis and morphometric characteristics/pigmentary traits. RESULTS: We identified 11 studies on the association between endometriosis and body mass index (BMI) in the adult population and 5 studies on the same association during early life. While a modest inverse correlation was found between endometriosis and adult BMI, a stronger association was consistently demonstrated between endometriosis and early life body size, even after adjusting for confounding factors such as age, birthweight, age at menarche, parity and oral contraceptive use. Four papers have been published on the association between endometriosis and cutaneous naevi and five on the association between the disease and specific pigmentary traits. A skin phenotype characterized by the presence of naevi and freckles and by a high sensitivity to sun exposure is represented more frequently in women with endometriosis. CONCLUSIONS: Endometriosis appears to be associated with some phenotypic variations likely attributable to the strong effect of the environment on the expression and function of genes influencing the traits. Novel clues on endometriosis pathogenesis may derive from the analysis of the phenotypic traits associated with the disease.

Interferon-beta treatment in multiple sclerosis patients decreases the number of circulating T cells producing interferon-gamma and interleukin-4.

Systemic administration of interferon (IFN)-beta has been recently approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). The immunological mechanism by which IFN-beta ameliorates MS is still partially unknown. We measured the number of blood circulating CD4(+), CD4(-), CD8(+), and CD8(-) T cells secreting IFN-gamma and IL-4 in 26 RRMS patients followed for up to 9 months of an alternate day s.c. treatment with 8x16 IU of IFN-beta1b. Compared to pre-treatment values, a significant (P<0.05) reduction of CD4(+), CD4(-), CD8(+) and CD8(-) cells producing IFN-gamma and of CD4(+) and CD4(-) cells producing IL-4 was observed in MS patients. The IFN-beta-associated effect was evident soon after the beginning of the treatment and persisted for the entire follow-up period. We did not observe any effect of IFN-beta treatment on the percentage of IL-4-producing CD8(+) and CD8(-) cells nor in that of natural killer (NK) cells producing IFN-gamma. Our results show that IFN-beta treatment in MS patients induces a profound and persistent down-regulation of the number of circulating T cells secreting IFN-gamma and IL-4 thus suggesting a broader rather than a specific immunomodulatory effect of IFN-beta in MS.

Gene therapy in peripheral blood lymphocytes and bone marrow for ADA- immunodeficient patients.

Adenosine deaminase (ADA) deficiency results in severe combined immunodeficiency, the first genetic disorder treated by gene therapy. Two different retroviral vectors were used to transfer ex vivo the human ADA minigene into bone marrow cells and peripheral blood lymphocytes from two patients undergoing exogenous enzyme replacement therapy. After 2 years of treatment, long-term survival of T and B lymphocytes, marrow cells, and granulocytes expressing the transferred ADA gene was demonstrated and resulted in normalization of the immune repertoire and restoration of cellular and humoral immunity. After discontinuation of treatment, T lymphocytes, derived from transduced peripheral blood lymphocytes, were progressively replaced by marrow-derived T cells in both patients. These results indicate successful gene transfer into long-lasting progenitor cells, producing a functional multilineage progeny.

Close linkage of probe p212 (DXS178) to X-linked agammaglobulinemia.

Segregation analysis was performed in three families affected in X-linked agammaglobulinemia (XLA) with five polymorphic DNA probes linked to the disease locus. In agreement with previous studies, no recombination was observed with either pXG12 (DXS94) or S21 (DXS17). Segregation analysis was also performed with a marker, p212 (DXS178), which has been shown to be closely linked to pXG12 in normal families. No cross-over with XLA was observed in these three families and in five additional families previously analyzed with DXS17 and DXS94 (z = 5.92 at theta = 0). These data provide evidence against genetic heterogeneity in XLA and indicate the value of probe p212 for carrier detection and prenatal diagnosis of XLA. We were able to estimate the carrier status of six females (out of six) in the three previously unreported families.

Processing of tetanus toxin by human antigen-presenting cells. Evidence for donor and epitope-specific processing pathways.

Human T cell clones specific for epitopes 830-843 and 947-967 of tetanus toxin can be differentially activated in vitro when APC (PBL or LCL) from different donors are pulsed with tetanus toxin. Although PBL tested do not seem to exhibit substantial differences in the number of precursor T cells specific for these epitopes, APC from the same donors activate clone KT-2 specific for peptide 830-843 but not clone KT-30 specific for peptide 947-967. These APC express the proper restriction element because they can present the corresponding synthetic peptides. The failure to present a particular epitope might, however, be explained by the absence or presence of a protease(s) required for Ag presentation that may vary for different epitopes. Indeed, the protease inhibitor leupeptin was found to inhibit activation of KT-2 but not KT-30 T cell clone by the KK.35 B cell line normally capable of presenting either epitope. In summary, these data suggest that tetanus toxin processing and epitope formation by APC is distinct in different donors and for different epitopes.

Neonatal T4+ lymphocytes: analysis of the expression of 4B4 and 2H4 antigens.

Using monoclonal antibodies anti-2H4 and anti-4B4 we investigated by double immunofluorescence and immunorosette technique the presence of cells displaying the helper-inducer and the inducer of suppression phenotype among T4+ cord blood cells. The analysis of the estimated frequencies of subpopulations of T4+ cells shows that a high percentage of T4+ cord blood cells can coexpress both antigens in comparison to adult. Furthermore the percentage of T4+ cells with helper-inducer phenotype (2H4-4B4+) is significantly lower than that in the adult, while the percentage of T4+ cells with suppressor-inducer phenotype (2H4+4B4-) although higher, is not significantly different. These findings suggest that the relative immunoincompetence observed in the newborn may result from a variety of mechanisms including a low percentage of helper-inducer (4B4+2H4-) T4+ lymphocytes possibly also associated to an increased number of suppressor-inducer T4+ cells (2H4+4B4-).

[Disruption of successive specialized movements in a chain conditioned reflex after extirpation of individual fields of the prefrontal cortex in baboons]. / Narusheniia posledovatel'nykh spetsializirovannykh dvizhenii v tsepnom uslovnom reflekse posle udaleniia otdel'nykh polei prefrontal'noi kory u pavianov gamadrilov.

After extirpation of the field 9 and 47 disturbances of a chain instrumental reflex appear in monkeys as a fragmentation of successive acts and simplification of the forms of manipulation with experimental instruments. Disturbances of movement forms are stable. This fact to some extent is modelling human frontal pathology which is manifested in inability to perform a series of successive movements with switching over to different forms. Extirpation of the field 10 elicits disturbances of successive act only in the initial period and further the chain reflex is fully restored. Locomotor hyperactivity dominates in the behaviour. Author's initial conclusion is confirmed that the field 10 does not participate in formation and manifestation of temporal connections and has regulating influence on the organization of complex animals' behaviour.

[Behavioral reactions in simians after ablation of the pole of the frontal cortex]. / Povedencheskie reaktsii u obez'ian posle udaleniia poliusa lobnoi kory.

In 4 baboons and 3 macaques ablation of the frontal pole (area 10) as compared to other areas of the frontal cortex did not impair previously elaborated instrumental reflexes of different complexity and did not interfere with the elaboration of new ones. An increase in stability, speed, accuracy and intensity of conditioned reflexes was noted. The ablation did not result in motor or vegetative disturbances. In the general behaviour inhibitory elements disappeared along with an enhancement in motor goal-directed activity. It is suggested that frontal poles do not participate in closing-function but control conditioned reflexes and complex behaviour by means of inhibitory influences.