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Pluripotent stem cells are promising candidates for cell-based regenerative therapies. To avoid rejection of transplanted cells, several approaches are being pursued to reduce immunogenicity of the cells or modulate the recipient's immune response. These include gene editing to reduce the antigenicity of cell products, immunosuppression of the host, or using major histocompatibility complex-matched cells from cell banks. In this context, we have investigated the antigenicity of H-Y antigens, a class of minor histocompatibility antigens encoded by the Y chromosome, to assess whether the gender of the donor affects the cell's antigenicity. In a murine transplant model, we show that the H-Y antigen in undifferentiated embryonic stem cells (ESCs), as well as ESC-derived endothelial cells, provokes T- and B cell responses in female recipients.

Separation of X- and Y-chromosome bearing sperm has been practiced for selection of desired sex of offspring to increase the profit in livestock industries. At present, fluorescence-activated cell sorter is the only successful method for separation of X- and Y-chromosome bearing sperm. This technology is based on the differences in DNA content between these two types of sperm and has been commercialized for bovine sperm. However, this technology still has problems in terms of high economic cost, sperm damage, and lower pregnancy rates compared to unsorted semen. Therefore, an inexpensive, convenient, and non-invasive approach for sperm sexing would be of benefit to agricultural sector. Within this perspective, immunological sperm sexing method is one of the attractive choices to separate X- and Y-chromosome bearing sperm. This article reviews the current knowledge about immunological approaches, viz., H-Y antigen, sex-specific antigens, and differentially expressed proteins for sperm sexing. Moreover, this review also highlighted the different methods for identification of X- and Y-sperm.

Background Freemartinism generally occurs in female offspring of dizygotic twins in a mixed-sex pregnancy. Most bovine heterosexual twin females are freemartins. However, about 10% of bovine heterosexual twin females are fertile. Farmers mostly cull bovine fertile heterosexual twin females due to the lack of a practical diagnostic approach. Culling of such animals results in economic and genetic-material losses both for dairy and beef industry. Methods In this study, a comparative test, including qualitative detection of SRY gene by polymerase chain reaction (PCR), quantitative detection of relative content of SRY by real-time quantitative polymerase chain reaction (qPCR), and quantitative detection of H-Y antigen, was performed to establish the most accurate diagnosis for freemartin. Twelve Holstein heterosexual twin females were used in this study, while three normal Holstein bulls and three normal Holstein cows were used as a positive and negative control, respectively. Results Polymerase chain reaction results revealed that SRY gene were absent in three heterosexual twin females and only two of them were verified as fertile in later age. The qPCR results showed that relative content of SRY was more than 14.2% in freemartins and below 0.41% in fertile heterosexual twin females. The H-Y antigen test showed no significant numerical difference between freemartin and fertile heterosexual twin female. Discussion Our results show that relative content of SRY quantified by qPCR is a better detection method for diagnosis of freemartin in Holstein cattle as compare to qualitative detection of SRY gene by PCR or quantitative detection of H-Y antigen. To the authors’ knowledge, this is the first time we applied qPCR to diagnosing freemartin by quantifying SRY gene and got relative SRY content of each freemartin and fertile heterosexual twin female. We concluded that low-level of SRY would not influence fertility of bovine heterosexual twin female.

Introduction: A normal physiology of a human being is not mere a series of functions occurring with specific intensities and timing. There are lot of factors that may change the normal physiological activity within normal limits. Finger length ratio is one of the markers of intrauterine androgen exposure and it is debated and contradicted by many authors. Digit ratio varies among the ethnicities. Many Indian studies show that there is considerable difference in finger length ratio in different population. Data regarding Central India was not found on extensive search. Aim: To find out the finger length ratio and explore the birth order effect on finger length ratio among the first two successive born in the said population. Materials and Methods: We conducted a survey on 1500 volunteer persons (800 male and 700 female) over two years of time. We measured the length of the index finger (2D) and ring finger (4D) of both the hands and asked about their birth order history to find out the digit ratio for Central India population and any existing correlation of the same with birth order. T Test and Analysis of Variance (ANOVA) were used for the measure of significance and difference among the groups. The p< 0.05 was considered to be significant. Results: Our study reports that, study population mean for right hand 2D:4D ratio was 0.976 (SD±0.031) and for left hand it was found to be 0.969 (SD±0.035). For males, mean finger length ratio for right hand was 0.967 (SD±0.033) and 0.963 (SD±0.037) for left hand. In females the mean Finger length ratio was 0.982 (SD±0.027) for right hand and 0.974 (SD±0.034) for the left hand respectively. Finger length ratio was found to be significantly less (p=0.03) in males for right hand. No significant (p=0.24) difference was observed for left hand. When assessed fraternal birth order effect among the eldest, second born with elder brother and second born with elder sister groups, no significant (p>0.05) variation for finger length ratio of right and left hands observed in both male and female population. Conclusion: Our study reports that the finger length ratio (2D:4D) for Central India population did not show significant association between finger length ratio and fraternal birth order among the first two successive born.

Introduction: A normal physiology of a human being is not mere a series of functions occurring with specific intensities and timing. There are lot of factors that may change the normal physiological activity within normal limits. Finger length ratio is one of the markers of intrauterine androgen exposure and it is debated and contradicted by many authors. Digit ratio varies among the ethnicities. Many Indian studies show that there is considerable difference in finger length ratio in different population. Data regarding Central India was not found on extensive search. Aim: To find out the finger length ratio and explore the birth order effect on finger length ratio among the first two successive born in the said population. Materials and Methods: We conducted a survey on 1500 volunteer persons (800 male and 700 female) over two years of time. We measured the length of the index finger (2D) and ring finger (4D) of both the hands and asked about their birth order history to find out the digit ratio for Central India population and any existing correlation of the same with birth order. T Test and Analysis Of Variance (ANOVA) were used for the measure of significance and difference among the groups. The p< 0.05 was considered to be significant. Results: Our study reports that, study population mean for Right hand 2D:4D ratio was 0.976 (SD ± 0.031) and for left hand it was found to be 0.969 (SD± 0.035). For males, mean finger length ratio for right hand was 0.967 (SD ±0.033) and 0.963 (SD ± 0.037) for left hand. In females the mean Finger length ratio was 0.982 (SD ± 0.027) for right hand and 0.974 (SD ± 0.034) for the left hand respectively. Finger length ratio was found to be significantly less (p= 0.03) in males for right hand. No significant (p=0.24) difference was observed for left hand. When assessed fraternal birth order effect among the eldest, second born with elder brother and second born with elder sister groups, no significant (p>0.05) variation for finger length ratio of right and left hands observed in both male and female population. Conclusion: Our study reports that the finger length ratio (2D:4D) for Central India population did not show significant association between finger length ratio and fraternal birth order among the first two successive born. [ABSTRACT FROM AUTHOR]

Enzyme-linked immunosorbent assays (ELISAs) have traditionally been used to detect alloantibodies in patient plasma samples post hematopoietic cell transplantation (HCT); however, protein microarrays have the potential to be multiplexed, more sensitive, and higher throughput than ELISAs. Here, we describe the development of a novel and sensitive microarray method for detection of allogeneic antibodies against minor histocompatibility antigens encoded on the Y chromosome, called HY antigens. Six microarray surfaces were tested for their ability to bind recombinant protein and peptide HY antigens. Significant allogeneic immune responses were determined in male patients with female donors by considering normal male donor responses as baseline. HY microarray results were also compared with our previous ELISA results. Our overall goal was to maximize antibody detection for both recombinant protein and peptide epitopes. For detection of HY antigens, the Epoxy (Schott) protein microarray surface was both most sensitive and reliable and has become the standard surface in our microarray platform. [ABSTRACT FROM AUTHOR]

ABSTRACT In many mammal species with sexual dimorphism producing sons is energetically more demanding to the mother than producing daughters. Although some studies in humans have suggested that offspring born after a brother have a smaller birth weight and adult height when compared with those born after a sister, little is known about this intergenerational cost of producing sons. We aimed to study whether the sex of preceding sibling is associated with anthropometrics of the subsequent child at birth and in young adulthood. This population-based study was carried out on two data sets derived from the Swedish registers. Information on birth weight and length was obtained for 752,723 children of both sexes. Adult weight, height and muscle strength were available for 506,326 men. Multiple linear regression analyses showed that boys and girls born after a brother were, respectively, 18 and 9 g lighter and 0.08 and 0.03 cm ( P < 0.001) shorter at birth than those born after a sister. Adjustment for gestational age decreased the magnitude of the associations [10 g and 0.04 cm ( P < 0.001) in men and nonsignificant estimates in women], suggesting that part of the lower mean birth weight and length of individuals born after a brother was due to a shorter gestation. In young adulthood, men with a preceding brother showed 0.16 kg more in weight, 0.3% higher body mass index ( P < 0.001) and a trend towards reduced height and muscle strength. Our results suggest that even though the sex of the previous child is associated with the anthropometrics of the subsequent child, the effect sizes are very small questioning whether this mechanism has adaptive value in contemporary humans. Am J Phys Anthropol 154:471-478, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

H-Y antigens are a group of minor histocompatibility antigens encoded on the Y-chromosome with homologous H-X antigens on the X-chromosome. The disparate regions of the H-Y antigens are highly immunogenic and play an important role in understanding human alloimmunity. In this review, we investigate the history of H-Y antigen discovery along with their critical contributions in transplantation and pregnancy. In hematopoietic cell transplantation, male recipients with female donors who become seropositive for B-cell responses as H-Y antibodies following transplantation have increased rates of chronic graft-versus-host disease and decreased rates of relapse. Conversely, female patients who receive male kidney allografts are more likely than other gender combinations to develop H-Y antibodies and reject their allografts. Finally, in the setting of pregnancy, mothers who initially gave birth to boys are more likely to have subsequent pregnancy complications, including miscarriages, in association with H-Y antibody development. H-Y antigens continue to serve as a model for alloimmunity in new clinical scenarios. Our development of more sensitive antibody detection and next-generation DNA sequencing promises to further advance our understanding and better predict the clinical consequences of alloimmunity. [ABSTRACT FROM AUTHOR]

BACKGROUND Approximately half recurrent miscarriage (RM) cases remain unexplained after standard investigations. Secondary RM (SRM) is, in contrast to primary RM, preceded by a birth, which increases the transfer of fetal cells into the maternal circulation. Mothers of boys are often immunized against male-specific minor histocompatibility (H-Y) antigens, and H-Y immunity can cause graft-versus-host disease after stem-cell transplantation. We proposed the H-Y hypothesis that aberrant H-Y immunity is a causal factor for SRM. METHODS This is a critical review of the H-Y hypothesis based on own publications and papers identified by systematic PubMed and EMBASE searches. RESULTS SRM is more common after the birth of a boy and the subsequent live birth rate is reduced for SRM patients with a firstborn boy. The male:female ratio of children born prior and subsequent to SRM is 1.49 and 0.76 respectively. Maternal carriage of HLA-class II alleles presenting H-Y antigens to immune cells is associated with a reduced live birth rate and increased risk of obstetric complications in surviving pregnancies in SRM patients with a firstborn boy. In early pregnancy, both antibodies against HLA and H-Y antigens are increased in SRM patients compared with controls. Presence of these antibodies in early pregnancy is associated with a lower live birth rate and a low male:female ratio in subsequent live births, respectively. Births of boys are also associated with subsequent obstetric complications in the background population. CONCLUSIONS Epidemiological, immunogenetic and immunological studies support the hypothesis that aberrant maternal H-Y immune responses have a pathogenic role in SRM. [ABSTRACT FROM AUTHOR]

Abstract: The male antigen (HY), the elevated level of fetal antigen in twin pregnancies, and the increased number of MHC mismatches in dizygotic twin pregnancies might affect immunological tolerance during pregnancy. Using the Perinatal Database of the Japanese Society for Obstetrics and Gynecology, we studied the occurrence of pregnancy-induced hypertension (PIH) and preeclampsia in mothers delivering singleton babies and in those delivering monochorionic diamniotic (MD) twin pregnancies and dichorionic diamniotic (DD) twin pregnancies at 125 centers of the perinatal network in Japan from 2001 through 2005. In singleton pregnancies, pregnant women carrying female fetuses had a significantly higher incidence of PIH and preeclampsia compared with those carrying male fetuses. In MD twin pregnancies, compared with mothers carrying male–male fetuses, those carrying female–female fetuses had significantly higher incidences of PIH and preeclampsia and a marked difference was observed in primiparous cases. In DD twin pregnancies, the incidences of PIH and preeclampsia were significantly higher in mothers with female–female fetuses than those with male–male fetuses, while those with male–female fetuses had intermediate values. The incidence of PIH and preeclampsia in MD twin pregnancies was similar to that in DD twin pregnancies with male–male fetuses or female–female fetuses. The male antigen and the increased number of MHC mismatches in DD twin pregnancies were not a risk factor for PIH and preeclampsia. Female fetal sex was a risk factor for PIH and preeclampsia. [Copyright &y& Elsevier]

Abstract: Immunological approaches to gender selection have been contemplated since the discovery of the family of male-specific H-Y antigens found only on the surface of male cells. H-Y antigens are able to elicit an immune reaction when cells or tissues from a male donor are grafted to a female recipient. We describe here the development and testing of an inexpensive approach using polyclonal antibodies against four specific H-Y outer membrane proteins male enhanced antigen 1 (MEA 1), male enhanced antigen 2 (MEA 2), sex determining region Y (SRY) and testis determining factor (TDF). Epitopes based on hydrophilic primary sequences of the proteins were synthesized, N-terminal biotin-labeled, linked to streptavidin and mixed with a Ribi adjuvant prior to immunization in rabbits. The antiserum was tested to determine affinity to swine spermatozoa using anti-motility, flow cytometry and motility and sedimentation chambers. Fluorescent microscopy and fluorescent in situ hybridization (FISH) was used to identify the percentage of motile spermatozoa that contained the Y chromosome. We found that the polyclonal antibodies had high affinity to the spermatozoa leading to a cessation of motility. Furthermore, the majority of these non-motile spermatozoa contained the Y chromosome. We conclude that the use of polyclonal antiserum against synthetic H-Y peptide antigens may be an inexpensive and simple means to inhibit the motility of swine spermatozoa bearing the Y chromosome. [Copyright &y& Elsevier]

Atypical hemolytic uremic syndrome (aHUS) is associated with complement alternative pathway defects in over half the cases. Point mutations that affect complement surface regulation are common in factor H (CFH); however, sometimes individuals have null mutations in heterozygosis. The latter are difficult to identify, although a consistently low plasma factor H (fH) concentration is suggestive; definitive proof requires demonstration that the mutant sequence is not expressed in vitro. Here, novel reagents and assays that distinguish and individually quantify the common factor H-Y402H polymorphic variants were used to identify alleles of the CFH gene, resulting in low or null expression of full-length fH and also normal or increased expression of the alternative splice product factor H-like-1 (FHL-1). Our assay identified three Y402H heterozygotes with low or absent fH-H402 but normal or increased FHL-1-H402 levels in a cohort of affected patients. Novel mutations explained the null phenotype in two cases, which was confirmed by family studies in one. In the third case, family studies showed that a known mutation was present on the Y allele. The cause of reduced expression of the H allele was not found, although the data suggested altered splicing. In each family, inheritance of low expression or null alleles for fH strongly associated with aHUS. Thus, our assays provide a rapid means to identify fH expression defects without resorting to gene sequencing or expression analysis. [ABSTRACT FROM AUTHOR]

This article discusses research into the importance of the H-Y minor histocompatibility antigen as a factor in complications relating to kidney transplant surgery. A statistical analysis of the differences in survival rates between the four possible gender combinations between recipient and donor in kidney transplants that looks for incompatibility issues is presented. The study compares the role of H-Y minor histocompatibility antigen in complications relating to kidney surgery with problems relating to sex linked variations kidney size and metabolism.

It has been speculated whether maternal immune responses against male-specific minor histocompatibility (H-Y) antigens affect pregnancies negatively. This study explores, on a population level, whether previous births of boys compared with girls are associated with a decrease in birth weight of later-born siblings. The population was identified in the Danish Birth Registry and consisted of all Danish women who gave birth to their first-born singleton from 1980 to 1998. The women were followed until 2004, and their subsequent births were recorded. A total of 545,839 second- to fourth-born children were identified. The authors used linear regression to analyze the association between sex of preceding children and birth weight of subsequent siblings. Brothers compared with sisters reduced the birth weight of later-born siblings. One or two brothers, respectively, reduced the mean birth weight of later-born boys by 29 g (p = 0.0001) and 38 g (p = 0.0001) and later-born girls by 17 g (p = 0.0001) and 21 g (p = 0.0001) compared with later-born siblings with no brothers. Part of this association was due to a shorter gestation among later-born siblings with brothers. An explanation for these results could be maternal immune reactions directed against the H-Y antigens initiated during pregnancies with boys. The findings might add to the understanding of both normal and pathologic pregnancies. [ABSTRACT FROM PUBLISHER]

The ability to discriminate and further quantify the proportion of donor and host cells is essential in hematopoietic stem cell transplant protocols. In human sex-mismatched transplants, this can be easily accomplished by the use of commercially available fluorescent in situ hybridization (FISH) probes. In many animal models, including non-human primates, this methodology is not possible due to the lack of commercially available FISH probes. In animal models, donor cell detection could be accomplished if there is a known species-specific sex determining region Y (SRY) (male) or other unique DNA sequence using either semiquantitative or quantitative real-time polymerase chain reaction (PCR). The use of real-time quantitative PCR has the obvious advantage of providing detailed enumeration of the percentage of donor cells present. We report the development of extremely sensitive primer and probe combinations for male (SRY) and major histocompatibility complex (MHC)-DQA sequences in the macaque and baboon non-human primate models. This assay has a sensitivity of a five-log range and can detect less than four target cells in the presence of 105 background cells (approximately 0.001%) and fetal DNA obtained from maternal serum from Macaca nemestrina. The SRY (male) primer and probe combination has similar sensitivity in Macaca fasicularis, Macaca mulatta, and Papio cynocephalus anubis. [ABSTRACT FROM AUTHOR]

The male-specific H-Y antigen is present on mammalian cell membranes and has been identified by various methods, including antiserum cytotoxicity. The objective of the present study was to determine the sex of in vitro produced (IVP) bovine embryos, at varying stages of development, by culturing in the presence of rat monoclonal H-Y antibodies. Embryos derived from IVM/IVF were classified according to the interval after IVF (48, 96 or 120 h) as Category 1, 2 or 3 if they had 4 to 8, <32, and >32 cells, respectively. Embryos of each category were cultured for 24 h in TCM-199 supplemented with bovine oviductal epithelial cells, fetal calf serum (FCS), and antibiotics (Control group), to which the following had been added: guinea pig serum (GPS; C′ group); H-Y antiserum (HY group); or GPS and H-Y antiserum (C′+HY group). After culture, embryos were designated as “affected” when development was arrested or one or more blastomeres was degenerate; embryos lacking these changes were designated “unaffected.” The sex of each embryo was subsequently determined by chromosome analysis. After 48 h of IVF (Category 1), within each of the four treatments, the proportion of unaffected embryos was higher than the proportion of unaffected embryos (81% versus 19%, P<0.05). Similarly, the Control, C′ and HY groups of Categories 2 and 3 embryos had different proportions of unaffected versus affected embryos (75% versus 25%, P<0.05). In all these groups, the male:female ratio did not significantly differ from 1:1. In contrast, in the C′+HY group of Categories 2 and 3 embryos, the ratio of unaffected versus affected embryos was 41% versus 59% (P<0.05) and the male:female ratio differed (P<0.05) from the expected 1:1 ratio (approximately 0.3:1 and 4.5:1 for unaffected versus affected, respectively). In conclusion, when bovine embryos were cultured in the presence of rat monoclonal H-Y antibodies and compliment, alterations occurred in embryos that were beyond the 8-cell stage; we inferred that the antibodies cross-reacted with H-Y antigens. [Copyright &y& Elsevier]

Background. Although the role of male-specific minor histocompatibility antigen H-Y has been increasingly understood in both experimental and clinical organ transplantation, little has been investigated on musculoskeletal tissue transplantation. This study was performed to describe the behavior of male-specific minor histocompatibility H-Y antigen in rat skin and whole limb transplantation.Materials and methods. Using three different strains of inbred rats (Lewis, F344, and Dark Agouti), 75 donor hindlimbs and eighteen skin grafts were isogenically transplanted to the sex-mismatched recipients. Recipients were observed up to 48 weeks postoperatively. Rejection was monitored by the appearance of the skin of the grafted limb and histology. Systemic microchimerism was assessed by polymerase chain reaction using Y-chromosome specific primers.Results. Skin rejection didn’t occur in all limb transplant recipients and histology did not show any rejection findings in all components of the limb graft through 48 weeks. Successful functional recovery was expected. Stable and high level of chimerism (>1%) was detected in the lymphoid tissues in nontreated female recipients. Male skin grafts were rejected by Lewis and F344 female recipients within 6 weeks postoperatively. All female skin grafts survived in male recipients.Conclusion. Our results suggest that H-Y antigen can induce graft rejection in rat skin graft but causes no rejection reaction in whole limb transplantation. Systemic chimerism may play an important role for acceptance of sex-mismatched limb graft. [Copyright &y& Elsevier]

The mechanisms underlying maternal tolerance of the semi-allogeneic fetus are not completely understood. The maternal immune system's response to the male antigen, H-Y is an example of the conflicting evidence that both supports and refutes the idea that the immune system in pregnant females is fundamentally different from that in non-pregnant females. Although multiple pregnancies may inactivate H-Y specific T cells, the immune system of the pregnant female can also generate a cytotoxic response to this antigen. To help understand this apparent conflict, we immunized female mice against H-Y with male spleen cells before pregnancy and examined the subsequent anti H-Y response during mid-pregnancy. The pregnant mice studied were able to mount cytotoxic immune responses to H-Y that were equivalent to those generated in their non-pregnant counterparts. Moreover the experience of pregnancy did not impair the ability to maintain immunologic memory to H-Y. The data support the idea that pregnancy does not violate general rules of antigen specific immunity, even if the antigen is expressed on the fetus. [ABSTRACT FROM AUTHOR]

The downstream effectors of the Drosophila sex determination cascade are mostly unknown and thought to mediate all aspects of sexual differentiation, physiology and behavior. Here, we employed serial analysis of gene expression (SAGE) to identify male and female effectors expressed in the head, and report 46 sex-biased genes (>4-fold/P < 0.01). We characterized four novel, male- or female-specific genes and found that all are expressed mainly in the fat cells in the head. Tsx (turn on sex-specificity), sxe1 and sxe2 (sex-specific enzyme 1/2) are expressed in males, but not females, and are dependent on the known sex determination pathway, specifically transformer (tra) and its downstream target doublesex (dsx). Female-specific expression of the fourth gene, fit ( female-specific independent of transformer), is not controlled by tra and dsx, suggesting an alternative pathway for the regulation of some effector genes. Our results indicate that fat cells in the head express sex-specific effectors, thereby generating distinct physiological conditions in the male and female head. We suggest that these differences have consequences on the male and female brain by modulating sex-specific neuronal processes. [ABSTRACT FROM AUTHOR]

The purpose of this study was to confirm a previous finding that homosexual males with older brothers weigh less at birth than do heterosexual males with older brothers. The subjects comprised 250 feminine boys referred to a child psychiatry service because of extreme cross-gender wishes or behavior and assumed, on the basis of previous research, to be prehomosexual, plus 739 control boys and 261 control girls referred to the same service for reasons unrelated to sexual orientation or gender identity disorder and assumed, from base-rate probabilities, to be preheterosexual. The feminine boys with two or more older brothers weighed 385 g less at birth than did the control boys with two or more older brothers (P = 0.005). In contrast, the feminine and control boys with fewer than two older brothers did not differ in birth weight. This finding suggests that the mechanism by which older brothers increase the odds of homosexuality in later-born males operates prior to the individual''s birth. We hypothesize that this mechanism may be immunologic, that antimale antibodies produced by human mothers in response to immunization by male fetuses could decrease the birth weight of subsequent male fetuses as well as increase their odds of homosexuality. [Copyright &y& Elsevier]

We investigated the antigenic requirements for restimulation of H-2- restricted cytolytic T lymphocytes (CTL) in vitro to determine whether H-2 I region-restricted helper T cells are required in these responses. In one set of experiments, we studied the in vitro response of (responder x nonresponder)F(1) female T cells to the male antigen H-Y. We chose to examine this response because it has been suggested that the defect in nonresponder strains is a failure of helper T cells to recognize H-Y in association with nonresponder I region determinants. However, we find that nonresponder male stimulator cells are as effective as F(1) male stimulator cells at inducing H-Y-specific CTL responses. This finding calls into question reports that secondary CTL responses to H-Y are dependent upon the activation of H-Y- specific helper T cells restricted to responder type I region determinants. In a second set of experiments, we examined the requirements for restimulation of H-2-restricted T cells specific for minor-histocompatibility antigens from long-term mixed lymphocyte cultures. These cultures were established by repeatedly restimulating cultures of specific T cells with H- 2-matched stimulator cells expressing foreign minor histocompatibility antigens. We found that H-2D-restricted T ceils, including CTL, could be restimulated with cells that were matched with the responding cells at only the D region genes. This response did not appear to result from positive allogeneic effects or from antigen processing and "representation" by responder type APC that might contaminate the cultures. Thus, we find no evidence for a requirement for I region-restricted helper T cells in these CTL responses. However, helper T cells are required because we find that CTL lines derived by limit-dilution cloning from these long-term MLC are absolutely dependent upon exogenous helper factors for growth. The most simple interpretation of these results is that the helper cells are restricted to H-2 antigens other than I region antigens or to antigens that code outside of the H-2 complex. Finally, we show that factor-dependent CTL lines must recognize their specific antigen to proliferate, even in the presence of exogenous factors. The requirement of activated CTL for antigen to proliferate provides an explanation for how specific CTL can be selectively enriched in MLC by specific antigen stimulation. Furthermore, it is at variance with reports that memory CTL or activated CTL require only interleukin 2 for restimulation.

Reports on the identification of mouse male-specific transplantation antigen, H-Y. Determination of which residues are important in defining the T-cell epitope ; Genetic basis for the antigenic difference between males and females that contributes towards a tissue transplant rejection response.

Increased levels of immune complexes are more frequently detected in the serum of newborn males than they are in the serum of newborn females. In one survey of 545 newborns, 21 of 26 (81%) of the babies with high levels of immune complexes in cord serum were boys (Farber, Cambiaso & Masson, 1981). To evaluate the hypothesis that this was due in some cases to the synthesis by the mother of antibodies directed against the 'male-specific' H-Y antigen, we tested for presence of IgG antibodies bound to H-Y antigen in serum samples from 263 newborns including 124 girls and 139 boys. Sera from five of the 10 male newborns with high levels of immune complexes contained IgG bound lo H-Y; none of the sera from newborn girls had detectable amounts of those immune complexes; and sera from women who had borne males manifested higher levels of IgG reactive with sources of soluble H-Y than sera from women who had borne females. [ABSTRACT FROM AUTHOR]

Cytotoxic T-cell response to the male-specific histocompatibility antigen (H-Y) is often used as an experimental model for studying the genetic control of the immune response. This anti-H-Y response is shown to be a complex one, with multicellular interactions involving genes of the H-2 complex, and also some genes unlinked to 1-1-2. For the analysis of the genetic control of the anti-H-Y immune response, different inbred strains have been used and classified accordingly as responders or non-responders. During the authors' studies of the genetic control of the immune response, some of the strains described as non-responders were found to behave as responders, namely strains B6.C-H-2bm/2 and B10.BR. This finding has added to the intricacy of current data on the genetic control of immune response to H-Y antigen. [ABSTRACT FROM AUTHOR]

Rats of DA strain produce H-Y antibodies in response to the stimulation by their male foetuses, About 52% of the rats following a single or multiple pregnancy and 45.5% of litters (female offspring) had detectable levels of H-Y antibodies in their blood serum. The presence of H-Y antibodies did not appear to be correlated with the stage of parity or the number of male foetuses the female bore. H-Y antibodies were detected in the serum of a 27 day post-partum female and her 27 day old female offspring but not in any of the male offspring. It is suggested that H-Y antibodies are transmitted to the foetus in utero and through the milk (colostrum). The possible significance of these findings in relation to the ontogenic role of H-Y antigen is discussed. [ABSTRACT FROM AUTHOR]

Serological assays for H-Y antigen, which is male-specific in mammals, all give slightly positive but non-negligible results when females are tested. All assays used to this day share this characteristic; furthermore they do not analyse the pattern of antigens recognized by the antisera. We used the Western blot technique in an attempt to do this, and observed that three components (relative molecular mass: 15-20 kilodaltons (kD)) were recognized both in females and in males tested, and a single specific band of 32-34 kD relative molecular mass in males. This confirms the existence of a serologically detectable male antigen on human lymphocytes, and explains the existence of a certain level of antigen expression in females tested by different techniques, including the indirect immunofluorescence and ELISA used here for comparison. [ABSTRACT FROM AUTHOR]

H-Y antigen has been defined by various immunological methods including graft rejection, T-cell mediated cytolysis, and antiserum cytotoxicity. The H-Y phenotype is normally associated with the male sex in mammals. Using specific T-cell clones, two Y-linked genes coding for H-Y epitopes have been identified in the mouse, Smcy and Uty , and one of these genes, SMCY, is also present on the human Y chromosome. Anti-H-Y antisera detect a membrane bound antigen associated with β[sub 2] -microglobulin, and a soluble protein secreted by testicular Sertoli cells. The membrane bound antigen appears to be different from the peptides detected by cytotoxic T-cells, and for the soluble antigen evidence was provided that, in mammals it may be identical with anti-Müllerian hormone. In non-mammalian vertebrates, serological H-Y antigen is associated with the heterogametic sex, and sex-reversal of the homogametic sex results in the occurrence of H-Y antigen. Originally, H-Y antigen was believed to be responsible for sex determination, thus representing the testis-determining factor (TDF) in mammals, but this hypothesis has been disproved by showing that male gonadal differentiation can also occur (in the mouse) in the absence of H-Y antigen. In the meantime, SRY is considered to be TDF. Although it was revealed that the H-Y antigens as detected by different assays are genetically heterogeneous, they are probably involved in male-specific functions in mammals, and possibly in the differentiation of the heterogametic sex in non-mammalian vertebrates. [ABSTRACT FROM AUTHOR]

Discusses the history of transplantation, immune response genes, sex determination and expression cloning of the male-specific histocompatibility antigen H-Y. Information about H-Y; H-Y as a transplantation agent; Inside T cell responses to H-Y.

Reports on the identification of a human H-Y antigen presented by HLA-B7 as an 11-residue peptide derived from SMCY protein. Role of major histocompatibility complex (MHC) in the recognition of H-Y by T lymphocytes; Isolation of endogenously processed H-Y peptides; Identification of the protein that gives rise to an H-Y antigen.

Man is a gonochoristic species with male hetero- and female homogamety. The basic plan of gonadal and genital development in both sexes is female unless testes are induced by H-Y antigen which is usually specified by the Y chromosome. Genitalia can develop in either direction in both sexes. In males testosterone produced by testicular Leydig cells causes Wolffian duct differentiation, and the anti-Müllerian hormone, produced by testicular Sertoli cells, causes Müllerian duct regression. Testosterone has to be converted to dihydrotestosterone by a 5 a-reductase in endorgans to effect normal male external genital development. Individuals without gonads or with ovaries develop female genitalia-i.e. the female is the 'uninduced' sex. Sex determination begins with parental meiosis and extends to the onset of normal gonadogenesis; sex differentiation includes all subsequent sex-developmental processes. Hermaphroditism, a rare condition, is a defect of the former process (gonadogenesis), pseudohermaphroditism, a relatively common condition of the latter (genital differentiation). Male sex development, being actively induced, is much more complicated than in females, and affords many more opportunities for mishap. Gonosomal aneuploidy rarely disturbs sex development; most intersexes have normal chromosomes. In order of frequency the most common disorders are: 1) hypospadias-technically a form of external male pseudohermaphroditism, but never referred to as such in clinical practice; 2) non-specific, secondary male pseudohermaphroditism in isolated form or as component manifestation of many malformation syndromes; 3) the adrenogenital syndrome in females. Though less common than hypospadias, the adrenogenital syndrome must always be considered first in order to save life and to prevent recurrence. Genetic abnormalities of sex determination and sex differentiation in man are discussed together with experimental data elucidating the normal processes. [ABSTRACT FROM AUTHOR]

The gonads of 4 phenotypically female individuals with XY chromosomal constitution and signs of virilisation were examined by light microscopy. Electron microscopic examination was also performed in two cases. Serological analysis of H-Y antigen titer yielded positive results. The matrix of the gonads is shown to be ovarian stroma, in which tubular and follicular structures are embedded. The epithelia of the follicles resemble granulosa cells of the ovary, the tubular epithelia are resemble Sertoli cells. Tubules and follicles both show extensive regressive changes. A varying number of Leyding cells/stroma lutein cells were found in each gonad. The different degree of development of testicular and ovarian structures in the dysgenetic gonads might be explained by a defect of the gonadal specific receptor for the H-Y antigen, this defect varying in time of occurrence, duration and severity. [ABSTRACT FROM AUTHOR]

In vitro cultures of intact chick gonads (organ cultures) and reaggregation cultures of dispersed gonad cells (roller cultures) were made. Gonads or gonad cells from 7-day-old chick embryos, at the stage when sex-specific differentiation begins, were cultured in the presence of presumed H-Y antigen-containing supernatants, or co-cultured in the presence of H-Y antigen-producing cell lines. The H-Y antigen-producing cells tested were of human, mouse, bovine and chicken origin. During organ culture, addition of supernatant of the human lymphoma cell line Daudi, or co-culture with Daudi cells, stimulated a clear proliferation of the germinal epithelium in male gonads, indicating feminization. A similar effect was obtained by treatment with estradiol. In reaggregation culture, the increase in nuclear size of germ cells was chosen as a parameter for feminization. A significant increase of germ cell nuclear size was observed in gonads cultured in the presence of Daudi supernatant. In both organ cultures and reaggregation cultures, other tested H-Y antigen sources and semi-purified H-Y antigen fractions did not exert significant effects on differentiation of the gonads or on the average area of the germ cell nuclei. These findings suggest that it is not H-Y antigen, but another protein produced by Daudi cells, that might be responsible for the sex-reversing effects. [ABSTRACT FROM AUTHOR]

Abstract: Background: The common cytokine receptor γ chain signals regulate proliferation, differentiation, and apoptosis of peripheral T cells. Objective: To investigate whether simultaneous blockade of IL-2Rβ and γ chain signaling in combination with donor splenocyte transfusion (DST) induces transplant tolerance. Materials and Methods: C57BL/6 (H-2b) mice were randomly divided into 5 groups. In group 1, female mice received only H-Y skin grafts. In group 2, female mice received transfused splenocytes (5 × 106 cells) from syngeneic male mice on day 7 before H-Y skin grafting. In group 3, on days 2 and 4 after DST, female mice received intraperitoneal injections of a mixture of anti–IL-2Rβ monoclonal antibody (mAb) and anti–γ chain mAbs (4G3, 3E12, and TUGm2; 0.5 mg). After DST, group 4 received an intraperitoneal injection of the mixture of anti–γ chain mAbs, and group 5 received intraperitoneal injection of anti–IL-2Rβ mAb (TM-β1). On day 7, H-Y skin grafting was performed. Results: Group 3 recipients accepted H-Y skin grafts for more than 100 days compared with group 1 (mean survival time [MST], 33.42 days), group 2 (MST, 14.71 days), group 4 (MST, 58.71 days), and group 5 (MST, 17.29 days). Statistical differences (P < .05) were observed between any 2 groups except groups 2 and 5. Conclusion: Blockade of γ chain signaling rather than IL-2Rβ signaling combined with DST prolongs H-Y skin graft survival. Simultaneous blockade of IL-2Rβ and γ chain signaling may strengthen this effect. [Copyright &y& Elsevier]