Sex Differences in the Immune System Become Evident in the Perinatal Period in the Four Core Genotypes Mouse.

We have used the four core genotypes (FCG) mouse model, which allows a distinction between effects of gonadal secretions and chromosomal complement, to determine when sex differences in the immune system first appear and what influences their development. Using splenic T cell number as a measure that could be applied to neonates with as yet immature immune responses, we found no differences among the four genotypes at postnatal day 1, but by day 7, clear sex differences were observed. These sex differences were unexpectedly independent of chromosomal complement and similar in degree to gonadectomized FCG adults: both neonatal and gonadectomized adult females (XX and XY) showed 2-fold the number of CD4+ and 7-fold the number of CD8+ T cells versus their male (XX and XY) counterparts. Appearance of this long-lived sex difference between days 1 and 7 suggested a role for the male-specific perinatal surge of testicular testosterone. Interference with the testosterone surge significantly de-masculinized the male CD4+, but not CD8+ splenic profile. Treatment of neonates demonstrated elevated testosterone limited mature cell egress from the thymus, whereas estradiol reduced splenic T cell seeding in females. Neonatal male splenic epithelium/stroma expressed aromatase mRNA, suggesting capacity for splenic conversion of perinatal testosterone into estradiol in males, which, similar to administration of estradiol in females, would result in reduced splenic T cell seeding. These sex steroid effects affected both CD4+ and CD8+ cells and yet interference with the testosterone surge only significantly de-masculinized the splenic content of CD4+ cells. For CD8+ cells, male cells in the thymus were also found to express one third the density of sphingosine-1-phosphate thymic egress receptors per cell compared to female, a male characteristic most likely an indirect result of Sry expression. Interestingly, the data also support a previously unrecognized role for non-gonadal estradiol in the promotion of intra-thymic cell proliferation in neonates of both sexes. Microarray analysis suggested the thymic epithelium/stroma as the source of this hormone. We conclude that some immune sex differences appear long before puberty and more than one mechanism contributes to differential numbers and distribution of T cells.

Genetic basis of XX male syndrome and XX true hermaphroditism: evidence in the dog.

Serological analysis of white blood cells from the members of a family of American cocker spaniels indicates that a form of abnormal sexual development, in which individuals with a female karyotype have testes or ovotestes, is caused by anomalous transmission of male-determining H-Y genes.

H-Y antigen and the genetics of sex determination.

Widespread phylogenetic conservation of H-Y antigen indicates persistence of a vital function. It has been proposed that this function is the primary determination of mammalian sex. According to this proposal, the indifferent embryonic gonad is induced to differentiate as a testis in the presence of H-Y antigen, and as an ovary in the absence of H-Y antigen. But presence of H-Y antigen does not guarantee testicular differentiation. Other factors may be required: a gene that activates the H-Y structural locus, and another gene that codes for specific H-Y antigen receptors.

Broken or maladaptive? Altered trajectories in neuroinflammation and behavior after early life adversity.

Exposure to adversity and stress early in development yields vulnerability to mental illnesses throughout the lifespan. Growing evidence suggests that this vulnerability has mechanistic origins involving aberrant development of both neurocircuitry and neuro-immune activity. Here we review the current understanding of when and how stress exposure initiates neuroinflammatory events that interact with brain development. We first review how early life adversity has been associated with various psychopathologies, and how neuroinflammation plays a role in these pathologies. We then summarize data and resultant hypotheses describing how early life adversity may particularly alter neuro-immune development with psychiatric consequences. Finally, we review how sex differences contribute to individualistic vulnerabilities across the lifespan. We submit the importance of understanding how stress during early development might cause outright neural or glial damage, as well as experience-dependent plasticity that may insufficiently prepare an individual for sex-specific or life-stage specific challenges.

Study of H-Y antigen in abnormal sex determination with monoclonal antibody and an ELISA.

A newly developed enzyme-linked immunosorbent assay (ELISA) has been applied to the study of H-Y antigen in cases of XY, XYY, and X,dicY gonadal dysgenesis, testicular feminization syndrome, XXXXY syndrome, and XX true hermaphroditism. Monoclonal H-Y antibody was absorbed with cells from each of eight patients and from normal male and female controls, and then reacted with a plated antigen source in a system subsuming the addition of biotinylated secondary antibody, avidin-biotin-enzyme complex and substrate, and thereby the generation of a color. Positive absorption decreased the reaction, and this allowed sensitive measurement of H-Y phenotype in an electronic optical density reader. The ELISA obviates many of the technical difficulties encountered in complement-mediated cytotoxicity systems and can be used in the study of clinical cases of aberrant sex determination and in the evaluation of current models of the genetics of sex determination.

Male antigen defined serologically does not identify a factor responsible for testicular development.

To test the proposal that the serologically detected male antigen (SDMA; which may or may not be the same as H-Y) was responsible for triggering the indifferent gonad to differentiate into the testis in mammals, H-Y negative sex-reversed XXSxr' male mice were investigated for the presence of SDMA. Serum from C57BL/6 female mice immunized against tissue from XXSxr' males did not contain SDMA specific antibody as detected by the complement-mediated sperm cytotoxicity assay. Thus, although SDMA is a male-specific factor and may play a role in male sex determination, it does not identify the testis-determining factor (TDF).

H-Y antigen and disorders of sexual differentiation.

The process of sexual differentiation has been further clarified by the discovery of histocompatibility -Y(H-Y) antigen. A patient with abnormal sexual differentiation whose workup included testing for H-Y antigen is presented. The discovery and clinical applicability of H-Y antigen in intersex patients are presented.

[Clinical, cytogenetical, histological, immunological and hormonal studies in a case of true hermaphroditism (author's transl)]. / Etudes cliniques, cytogénétiques, histologiques, immunologiques et hormonales chez un hermaphrodite.

A true hermaphrodite with ambiguous genitalia and 46 XX caryotype was investigated during adolescence. At 13 years testosterone concentrations (ng/ml) were 6 and 390 respectively in peripheral and right ovotestis venous blood. After removal of the right gonad, large fluctuations of estradiol levels (40 to 220 pg/ml) were observed. But the testosterone secretion by the left ovotestis was low, although responsive to hCG. A significant LH surge was induced by ethinyl-estradiol load before removal of the left gonad. The 5 alpha-reductase activity was normal in the pubic skin and the levels of cytosolic receptors of testosterone and DHT were high in the left gonad. The presence of H-Y antigen was demonstrated on lymphocytes.

[Expression of fetal antigens of gonocytes in the investigation of pathogenesis of germinal cell neoplasia]. / Ekspresja antygenów plodowych w gonocytach przy badaniach nad patogeneza nowotworów jadra pochodzenia zarodkowego.

Expression of fetal antigens of germinal cells reacting with antibodies M2A and TRA-1-60 has been studied in fetal germinal cells-gonocytes (G) persisted in gonads of prepubertal boys because of male pseudohermaphroditism (MP) and in germinal carcinoma cells in situ (CIS) of adult men. The presence of G and CIS cells was detected immunohistochemically by identification of placental like alkaline phosphatase (PLAP). CIS cells showed expression of M2A in all adult men and additionally TRA-1-60 in one case. These antigens were present in G cells only in 2 out of 6 G bearing testes of boys with MP (30%). G cells were not found in testes of 3 other older boys with MP. So, in 1/3 cases of children with MP G cells show similar features like CIS cells during the prepubertal period indicating that they are able to enter malignant transformation in early prepubertal testis. Although total frequency of occurrence of G cells in MP boys was 2/3 (60%), their malignant transformation may be lower.

Identification of candidate genes and physiological pathways involved in gonad deformation in whitefish (Coregonus spp.) from Lake Thun, Switzerland.

In 2000, fishermen reported the appearance of deformed reproductive organs in whitefish (Coregonus spp.) from Lake Thun, Switzerland. Despite intensive investigations, the causes of these abnormalities remain unknown. Using gene expression profiling, we sought to identify candidate genes and physiological processes possibly associated with the observed gonadal deformations, in order to gain insights into potential causes. Using in situ-synthesized oligonucleotide arrays, we compared the expression levels at 21,492 unique transcript probes in liver and head kidney tissue of male whitefish with deformed and normally developed gonads, respectively. The fish had been collected on spawning sites of two genetically distinct whitefish forms of Lake Thun. We contrasted the gene expression profiles of 56 individuals, i.e., 14 individuals of each phenotype and of each population. Gene-by-gene analysis revealed weak expression differences between normal and deformed fish, and only one gene, ictacalcin, was found to be up-regulated in head kidney tissue of deformed fish from both whitefish forms, However, this difference could not be confirmed with quantitative real-time qPCR. Enrichment analysis on the level of physiological processes revealed (i) the involvement of immune response genes in both tissues, particularly those linked to complement activation in the liver, (ii) proteolysis in the liver and (iii) GTPase activity and Ras protein signal transduction in the head kidney. In comparison with current literature, this gene expression pattern signals a chronic autoimmune disease in the testes. Based on the recent observations that gonad deformations are induced through feeding of zooplankton from Lake Thun we hypothesize that a xenobiotic accumulated in whitefish via the plankton triggering autoimmunity as the likely cause of gonad deformations. We propose several experimental strategies to verify or reject this hypothesis.

Identification of prostate-specific antigen in the vaginal secretions of a male pseudohermaphrodite.

Prostatic glycoprotein was detected in the vaginal fluid of a male pseudohermaphrodite with use of an enzyme-linked immunosorbent assay. Following orchiectomy, prostatic glycoprotein concentrations fell from levels greater than 60 to less than 10.0 ng/ml. The decline in prostatic glycoprotein levels postoperatively implies that prostatic glycoprotein expression is controlled by androgens.

Positive H-Y antigen testing in a case of XY gonadal absence syndrome.

H-Y antigen testing was positive in a case of pseudohermaphroditism due to XY gonadal absence syyndrome. In conclusion, H-Y antigen may be present even in the absence of testes. Also, the syndrome could not have originated from a defect in the H-Y antigen system.

Increase of lymphocytic H-Y antigen in female 21-hydroxylase deficiency.

H-Y antigen was found to be increased in lymphocytes from 10 female 21-hydroxylase deficiencies, suggesting a correlation between the degree of virilization of these patients and their H-Y + lymphocytes proportions. Furthermore, these findings demonstrate the ability of a 46,XX female subject to produce, in some circumstances, an excess of H-Y antigen.

H-Y antigen expression in a case of XX true hermaphroditism.

Cells from an XX true hermaphrodite expressed a reduced amount of H-Y antigen when compared with normal XY cells and with cells from his father, who had an XY/XX chromosomal constitution. His mother had a normal karyotype and was H-Y negative. The four brothers of the patient were clinically and karyotypically normal. An X-Y interchange followed by random inactivation of the X chromosome is proposed to explain the H-Y antigen titer found in the patient.

H-Y antigen in a fertile XY female horse.

The presence of significantly reduced levels of H-Y antigen in the blood of an XY mare is consistent with the view that H-Y genes comprise a system of testis determinants. Loss or suppression of a critical portion of H-Y genes and subthreshold expression of H-Y antigen could account for a failure of testicular differentiation, thereby allowing a measure of ovarian development in an XY embryo.

Recessive male-determining genes.

The autosomal dominant gene polled (P) causes hornlessness in goats. Chromosomal females (XX) that are P/P homozygotes develop testes or ovotestes. Thus with respect to its testis-determining properties, P or a closely linked gene acts as an autosomal recessive. Polled intersex goats are H-Y+. This finding is consistent with the view that there may be a cluster of testis-determining H-Y genes on the Y chromosome, and that translocation of a subcritical portion of these genes may generate a recessive mode of sex determination.

H-Y antigen negative patients with testicular tissue and 46,XY karyotype.

H-Y antigen could not be detected on lymphocytes from two male pseudohermaphrodites with 46,XY karyotypes and testicular tissue. One of the patients had additional assays performed on fibroblasts grown from the skin, and the gonadal ridge--these were also negative. The H-Y antiserum was raised in rats, with Raji cells the target of cytotoxicity tests. In these patients. the substance that promoted testicular differentiation does not have serologic H-Y antigen detectable by the assay used. It appears that H-Y antigen that is commonly measured in neutralization reactions may not be the only form of testicular organizing factor present.