Conservatism of the H-Y/H-W receptor

Summary Soluble H-Y antigen is taken up by cells of the homogametic gonad of cattle, dog, chicken and South African clawed frog. After in vitro exposure to mouse testis supernatant or male fetal calf serum, XX ovary cells or ZZ testis cells, which are normally H-Y^-, acquire the H-Y⁺ (H-W⁺) phenotype and absorb mouse H-Y antibody in standard serological assays. In addition, H-Y antigens of the different species can compete for attachment to target cells of a single species. In a new competitive binding radioassay, uptake of tritiated human H-Y is blocked in XX bovine fetal ovarian cells exposed to non-labeled H-Y of mouse or fetal bull. Because H-Y antigens of the different species are cross-reactive serologically, positive reaction of H-Y from one species with gonadal cells of another signifies structural conservatism of the H-Y/H-W gonadal receptor. It follows that establishment of the H-Y/H-W-receptor complex is a common and critical early event in primary sex differentiation of the vertebrates, directing the initially indifferent embryonic gonad towards the heterogametic mode, which may be testicular or ovarian, depending on the species.     

H-Y antigen in 46,XY gonadal dysgenesis

Summary Presence of H-Y antigen has been correlated with testicular differentiation, and absence of H-Y with failure of testicular differentiation, in a variety of mammalian species. To determine more precisely the relationship between expression of H-Y antigen and development of the testis, we studied the cells of phenotypic females with the 46,XY male karyotype. Blood leukocytes were typed H-Y⁺ in five XY females with gonadal dysgenesis, although in other studies blood leukocytes from XY females with gonadal dysgenesis were typed H-Y^-. Thus mere presence of H-Y antigen is not sufficient to guarantee normal differentiation of the testis. In the present paper we review evidence for an additional factor in gonadal organogenesis, the H-Y antigen receptor. We infer that testicular development requires engagement of H-Y and its receptor. It follows that XY gonadal dysgenesis is the consequence of functional absence of the H-Y testis inducer as in the following conditions: failure of synthesis of H-Y or failure of specific binding of H-Y.     

H-Y antigen expression in different tissues from transsexuals

Summary H-Y-antigen expression was analyzed in patients with transsexuality. Peripheral blood lymphocytes and various tissues were examined using the cytotoxicity assay of Goldberg et al. (1971). Peripheral blood lymphocytes from healthy male and female subjects were used as controls as well as tissues from nontranssexual individuals and from male and female C57Bl/6J mice. In three female-to-male transsexuals the peripheral blood lymphocytes were H-Y antigen positive. In these patients also their ovaries, uterus, and mammae were found to be H-Y antigen positive. Three male-to-female transsexuals were examined. The peripheral blood lymphocytes in two of these patients were found to be H-Y antigen negative. Their testes were also H-Y antigen negative, as well as the epididymus, the corpus cavernosum penis, and the cremaster muscle which was analyzed in one of them. One male-to-female transsexual had peripheral blood lymphocytes which were H-Y antigen positive; this patient had testis and corpus cavernosum penis which were also H-Y-antigen positive.     

XY female mice express H-Y antigen

Karyotypically XY individuals of the C57BL/6J-Y^POS mouse stock develop as females or hermaphrodites, but never as normal males. The aberrant sexual development results from the interaction of the C57BL/6J genetic background with the M. poschiavinus-derived Y chromosome. XY females from this stock were assayed for H-Y antigen. By the criteria of skin-grafting, the cell-mediated lympholysis test, and the popliteal lymph node assay, these XY females are antigenically indistinguishable from normal C57BL/6 males. Implications for the hypothesis that H-Y antigen induces formation of the mammalian testis are discussed.     

Cross-reactivity of lung cancer patients' leucocytes in the leucocyte migration inhibition test

Summary Panels of 3 M KCl extracts of squamous-cell carcinomas, adenocarcinomas and oat-cell carcinomas of the lung were used for a comprehensive analysis of cross-reactivity in the leucocyte migration test. Lung cancer patients' leucocytes showed positive reactivity in 69%–100% of cases (n=353). No significant differences were observed when data were grouped with respect to the histological type of the tumours used for extraction or of the tumours of the leukocyte donors. Leukocytes of patients bearing tumours of nonpulmonary origin exposed to lung cancer extract panels and leukocytes of lung cancer patients exposed to gastrointestinal cancer extract panels were definitely less reactive (35%–47% and 6%–38%, respectively). However, a high reaction frequency was found in patients with lung metastases from different nonpulmonary tumours. This group of patients also frequently showed reactivity (52%) with normal lung tissue extracts. Patients with benign lung diseases reacted positively with lung tumour extracts in 25%–39% of cases, but donors with other benign disease and healthy controls were virtually nonreactive (0–14%).Hence, a high degree of cross-reactivity occurs in the lung cancer system and restricted cross-reactivity occurs with tumours of other organs. Possible explanations for the lung-oriented reactivity of patients with lung metastases are discussed.Abbreviations LMI leucocyte migration inhibition - MI migration index - LMT leucocyte migration test - SCC squamous-cell carcinoma - OCC oat-cell carcinoma - AC adenocarcinoma     

The testis as a secretory organ for H-Y antigen

Summary After cultivation of dissociated rat testicular tissues, H-Y antigen is detectable in the medium; this is not the case if nongonadal male tissues are incubated. Release of H-Y antigen by testis cells is inhibited by the addition of cycloheximide. All tissues still type H-Y positive after culture. It is assumed that the testis actively secretes H-Y antigen. This assumption is supported by the finding that the amount of H-Y antigen in the epididymal fluid increases with the age of the animals.     

T cell surface antigen expression on lymphocytes of patients with AIDS during in vitro mitogen stimulation

Summary Surface marker expression on peripheral blood mononuclear cells (PBMC) was evaluated daily in PHA- and PWM-stimulated cultures of eight AIDS patients and eight normals. Before culture, the patients' cells showed the characteristic decrease in OKT 4+ cells (normals 40.4%, patients 22.3%; P<0.001), increase in OKT 8+ cells (normals 27.6%, AIDS 38.4%; P=0.002), increase in OKT 10+ cells (normals 15.5%, AIDS 42.8%; P=0.002), and increase in HLA-DR+ cells (normals 11.4%, AIDS 28.7%; P=0.01). The percentage of OKT 11+ cells remained unchanged, while the percentage of OKT 3+ cells dropped over the first 2 days in PHA but not in PWM cultures of both groups (PHA: normals 69.8% to 35.1%; P=0.001, AIDS 56.5 to 38.5%; P=0.001, PWM: normals 62.8%–65.9%, AIDS 66.8% to 63.9%), and recovered in both groups by day 5. In PWM cultures OKT 3+ cells increased significantly in normals but not in AIDS (normals 62.6%–77.7%; P=0.04, AIDS 61.8 to 48.7%). OKT 4 expression decreased in normal PHA cultures after 1 day (38.9% to 29.6%; P=0.05) and then recovered by day 5. Its expression increased in AIDS PHA cultures by day 5 (18.0%–41.1%; P<0.001). The final percentage of OKT 4+ cells in AIDS cultures was within the normal range (35.0%–49.0%). OKT 8 expression increased in both study groups after PHA stimulation (normals 29.5%–50.4%; P=0.002, AIDS 37.4%–50.7%; P=0.02) and in normals but not AIDS after PWM stimulation (normals 28.9%–35.5%; P=0.004, AIDS 38.5%–35.6%). Because of the relative changes in expression of OKT 4 and OKT 8, the 4/8 ratio declined in the normal PHA cultures (1.89 to 1.03; P=0.1) and increased in the AIDS cultures (0.68–1.18; P=0.09). Also, the sum of OKT 4+ and OKT 8+ cells in PHA cultures increased from 68% to 94% whist expression of OKT 11 remained unchanged, indicating co-expression of these antigens on individual cells. Both PHA- and PWM-stimulated normal cells showed an increase in OKT 10 (PHA 16.0%–53.4%; P=0.01, PWM 16.1%–33.9%; P=0.03) and HLA-DR (PHA 8.6%–27.3%; P=0.03, PWM 12.5%–26.6%; P=0.07). In AIDS PHA cultures this did not change, and in their PWM cultures OKT 10 expression declined (44.8 to 23.0%; P=0.05). The PHA- and PWM-stimulated cultures of AIDS patients showed a marked deficit in generation of Tac (PHA increased from 5.4% to 77.1% in normals and from 3.2% to 48.0% in AIDS; P=0.001; PWM increased from 6.1% to 35.3% in normals, and from 5.0% to 15.5% in AIDS; P=0.04). Analysis showed that this deficit was limited to a reduced expression on small lymphocytes and that those cells that did become lymphoblasts expressed Tac normally. These results indicate that the poor blastogenic responses in AIDS are related to failure of OKT 10, HLA-DR, and Tac to increase after stimulation.Abbreviations AIDS acquired immunodeficiency syndrome - PBMC peripheral blood mononuclear cells - PHA phytohemagglutinin - PWM pokeweed mitogen - Tac T cell activation antigen - ARC AIDS-related complex of symptoms - IL-2 interleukin 2 - GVHD graft-versus-host disease - HBSS Hank's balanced salt solution - RPMI 1640 Roswell Park Memorial Institute tissue culture medium 1640 - FITC fluorescein isothiocyanate     

Does H-Y antigen induce the heterogametic ovary?

To determine whether phylogenetically conservative H-Y antigen plays any part in gonadal differentiation among the nonmammalian vertebrates, we studied expression and binding of H-Y in the frog, Xenopus laevis. Soluble H-Y obtained from mouse testis and soluble H-W from chicken ovary bound specifically to cells of the ZZ testis from normal Xenopus males. In addition, H-Y (H-W) appeared selectively in the ovaries of ZZ genetic males that had been induced to become functional females by exposure to estradiol. Our observations suggest that H-Y (H-W) antigen may be involved in differentiation of the ZW ovary, and also that synthesis of H-Y may be regulated by sex steroids in the primitive $\text{ZW}\text{ZZ}$ species.     

Prevalence of Hypertension in Rural Areas of China: A Meta-Analysis of Published Studies

Background

Hypertension is one of the leading causes of disease burden across the world. In China, the latest nationwide survey of prevalence of hypertension was ten year ago, and data in rural areas is little known. More information about hypertension prevalence could help to improve overall antihypertensive health care. We aimed to estimate the pooled prevalence of hypertension in rural areas of China.

Methods

Comprehensive electronic searches of PubMed, Web of Knowledge, Chinese Web of Knowledge, Wangfang, Weipu and SinoMed databases were conducted to identify any study in each database published from January 1, 2004 to December 31, 2013, reporting the prevalence of hypertension in Chinese rural areas. Prevalence estimates were stratified by age, area, sex, publication year, and sample size. All statistical calculations were made using the Stata Version 11.0 (College Station, Texas) and Statsdirect Version 2.7.9.

Results

We identified 124 studies with a total population of 3,735,534 in the present meta-analysis. Among people aged 18 years old in Chinese rural areas, the summarized prevalence is 22.81% (19.41%–26.41%). Subgroup analysis shows the following results: for male 24.46% (21.19%–27.89%, for female 22.17% (18.25%–26.35%). For 2004–2006: 18.94% (14.41%–23.94%), for 2007–2009, 21.24% (15.98%–27.01%) for 2010–2013: 26.68%, (20.79%–33.02%). For Northern region 25.76% (22.36%–29.32%), for Southern region 19.30%, (15.48%–24.08%).

Conclusions

The last decade witnessed the growth in prevalence of hypertension in rural areas of China compared with the fourth national investigation, which has climbed the same level as the urban area. Guidelines for screening and treatment of hypertension in rural areas need to be given enough attention.     

Evidence for a gonad-specific receptor for H-Y antigen: binding of exogenous H-Y antigen to gonadal cells is independent of beta 2-microglobulin.

This report addresses the question whether two different types of binding exist for the reaction of H-Y antigen with the cell surface. Anti-H-Y antiserum in the presence of complement was cytotoxic only for gonadal cells expressing their own H-Y antigen, but not to ovarian cells loaded with H-Y antigen. H-Y antigen was co-redistributed with beta 2--microglobulin on newborn testicular cells, but some residual H-Y activity was found on similarly treated testis cells from 15 day old rats. After beta 2--microglobulin redistribution, testis cells maintained their binding capacity for exogenous H-Y antigen prepared from epididymal fluid or Daudi cell culture supernatants. This result suggests that exogenous H-Y antigen is bound via a gonad-specific receptor which is independent of beta 2--microglobulin and that this type of binding for H-Y antigen is different from the beta 2--m-associated expression of H-Y antigen on the cell surface.     

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

Summary 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.     

X-linked genes of the H-Y antigen system in the wood lemming (Myopus schisticolor)

Summary H-Y antigen was investigated in 18 specimens representing six different sex chromosome constitutions of the wood lemming (Myopus schisticolor). The control range of H-Y antigen was defined by the sex difference between normal XX females (H-Y negativeper definitionem) and normal XY males (H-Y positive, full titer). H-Y antigen titers of the X^*Y and X^*0 females were in the male control range, while in the X^*X and X0 females the titers were intermediary. Data were obtained with two different H-Y antigen assays: the Raji cell cytotoxicity test and the peroxidase-antiperoxidase (PAP) method. Fibroblasts, gonadal cells, and spleen cells were checked. Presence of full titers of H-Y antigen in the absence of testis differentiation is readily explained by the assumption of a deficiency of the gonadspecific receptor of H-Y antigen. Since sex reversal is inherited as an X-linked trait, genes for this receptor are most likely X-linked. The implications of our findings are discussed in connection with earlier findings concerning H-Y antigen in XY gonadal dysgenesis in man and the X0 situation in man and mouse.     

Tight linkage between myotonic dystrophy and apolipoprotein E genes revealed with allele-specific oligonucleotides

Summary The X chromosomes of individuals with isolated steroid sulphatase deficiency (X-linked ichthyosis) from ten families were studied by flow karyotype analysis. In four of the families, a small but significant reduction in the relative fluorescence of the X chromosome was detected consistent with a deletion ranging from 1.2%–3.4% of the X and amounting to a DNA loss of 1.9–5.2 million base pairs. In the remaining six families, three of which demonstrated a molecular deletion of the DNA sequence GMGX9 (DXS237), the relative fluorescence of the X chromosomes was indistinguishable from normal. The phenotypes of those with X deletions detectable by flow cytometry were similar to those of patients without such deletions.     

Geographic Distribution of Mitochondrial DNA Variations among Grivet (Cercopithecus aethiops aethiops) Populations in Central Ethiopia

Since mitochondrial DNA (mtDNA) are maternally inherited without recombination, geographic distribution of mtDNA in semiterrestrial cercopithecines is considered to be influenced by female philopatry. I examined the effect of sex difference in migration patterns on geographic distribution in a habitat whose environment has changed frequently. I investigated ten groups (n = 77) of grivets (Cercopithecus aethiops aethiops) along a 600-km stretch of the Awash River, Ethiopia. I examined the mtDNA distribution among natural local populations whose nuclear variation was already shown to have a widely homogeneous distribution. RFLP analysis of whole mtDNA genome using 17 enzymes identified ten haplotypes in five clusters (haplogroups). Sequence divergence within haplogroups ranged from 0.17%–0.38%, while divergence between haplogroups ranged between 1.0%–2.5%. Haplogroups were distributed in blocks which ranged from 120–250 km along the Awash River. The haplotype distribution pattern of males indicated that they migrate between the boundaries of these blocks. Moreover, a clumped distribution pattern suggests the history of matrilineal distribution by group fission and geographic expansion.     

H-Y antigens

H-Y antigen is defined as a male histocompatibility antigen that causes rejection of male skin grafts by female recipients of the same inbred strain of rodents. Male-specific, or H-Y antigen(s), are also detected by cytotoxic T cells and antibodies. H-Y antigen appears to be an integral part of the membrane of most male cells. In addition, H-Y antibodies detect a soluble form of H-Y that is secreted by the testis. The gene (Smcy/SMCY) coding for H-Y antigen detected by T cells has been cloned. It is expressed ubiquitously in male mice and humans, and encodes an epitope that triggers a specific T -cell response in vitro. Additional epitopes coded for by different Y-chromosomal genes are probably required in vivo for the rejection of male grafts by female hosts. The molecular nature of H-Y antigen detected by antibodies on most male cells is not yet known. Testis-secreted, soluble H-Y antigen, however, was found to be identical to Müllerian-inhibiting substance (MIS). MIS cross-reacts with H-Y antibodies and identical findings were obtained for soluble H-Y antigen and MIS, i.e., secretion by testicular Sertoli and, to a lesser degree, ovarian cells, binding to a gonad-specific receptor, induction of gonadal sex reversal in vitro and, in cattle, in vivo. H-Y antisera also detect a molecule or molecules associated with the heterogametic sex in nonmammalian vertebrates. Molecular data on this antigen or antigens are not yet available.     

Alkaline phosphatase isoenzymes in human kidney and urine,immunohistochemical, immunological and biochemical characterization

Summary Human kidney contains two antigenetically distinct isoenzymes of alkaline phosphatase (AP): a liver type and an intestinal type. The intestinal type AP is a minor component (1%–4%) of the total AP activity: it is found only in the cytoplasm. Both isoenzymes are located, found by an immunohistochemical technique, in the proximal convoluted tubules. This histochemical result eliminates the possibility that the low intestinal AP content in the kidney might only originate from blood vessels, where the intestinal isoenzyme was also found. The renal isoenzymes contribute to urinary AP. Intestinal type AP in urine of healthy persons, 10%–40% of the total AP activity, was found after high speed centrifugation predominantly in the supernatant (100,000 g), the liver type mainly in the sediment. Biochemical characterization revealed that intestinal type AP in kidney and urine are identical and differ from the isoenzyme of intestinal mucosa only slightly in their electrophoretic mobility.     

H-Y antigen in transsexuality,and how to explain testis differentiation in H-Y antigen-negative males and ovary differentiation in H-Y antigen-positive females

Summary H-Y antigen was determined in eight transsexual patients. Two of the four male-to-female transsexual patients typed as H-Y antigen-negative, while the other two typed as expected from their phenotypic and gonadal sex, namely H-Y antigen-positive. Of the four female-to-male transsexual patients, three typed as H-Y antigen-positive and one was H-Y antigen-negative, as expected. The presence of normal testes in H-Y antigen-negative males is assumed to result from a mutation of nucleotide sequences of the H-Y structural gene for antigenic determinants. Thus, an H-Y is produced with normal receptor-binding activity which can sustain the testis determination of the bipotent gonadal anlage. In the case of H-Y antigen-positive females with normal ovaries a deletion of the autosomally located H-Y structural gene is assumed. This deletion should affect sequences for repressor-binding (as was suggested for H-Y antigen-positive XX-males) and for receptor-binding activity of the H-Y antigen molecule. The resulting H-Y antigen is unable to bind to the gonadal receptor of the bipotent gonadal anlage. Thus an ovary is determined. The relevance of H-Y antigen for the aetiology of transsexualism is discussed.     

Immunological and functional aspects of H-Y antigen

Summary Male-specific H-Y antigen may be defined by graft rejection, killer cell action or antibodies. Most commonly H-Y antigen is detected in assays using H-Y antisera. In these tests errors may arise from various causes: 1) Auto- and heteroantibodies cross-reacting with target cells. 2) Restriction phenomena. 3) MHC-dependent modification of the amount of H-Y antigen present on different tissues. 4) Modification of cell surface antigens by bacteria or viruses.Regarding the third definition of H-Y antigen, four different states can be distinguished in the mammalian male. H-Y occurs (1) as an integral part of the plasma membrane; (2) unspecifically attached to the membrane of human erythrocytes; (3) free in solution; (4) bound to its gonad-specific receptor.Redistribution experiments suggest that H-Y and ₂-m are associated on the cell membrane. Coredistribution is not found of H-Y and MHC antigens. An antibody blocking technique demonstrates association of H-Y and H-2D antigens on unfixed lymphoid, but not on testicular cells. Human erythrocytes lacking ₂-m do not integrate H-Y antigen into the cell membrane. Male erythrocytes, however, absorb H-Y antigen from the serum. The origin of H-Y antigen in the serum is not clear. It may be shed from cell membranes, derive from the testis which actively secretes H-Y antigen, or both.H-Y antigen is bound by a gonad-specific receptor. This receptor is present in the gonads of both sexes. H-Y antigen is supposed to mediate testis differentiation via this receptor. Reaggregation experiments in vitro using dissociated gonads of the newborn rat demonstrate that ovarian cells reorganize into testicular structures in the presence of H-Y antigen. The assumption cannot be confirmed that addition of H-Y antiserum to testicular cells results in ovarian structures. This finding, however, does not conflict with the view that H-Y antigen is involved in testis differentiation, e.g. by inducing testis cell-specific functions via the gonad-specific receptor.     

Major histocompatibility complex class II antigen expression during potentiation of line-10 tumor immunity after intralesional administration of bacillus Calmette-Guérin

Summary Intralesional injection of BCG into an established line-10 hepatocellular carcinoma in the strain-2 guinea pig causes regression of the tumor and induction of line-10 immunity. We found that the animals were already protected for a second challenge with line-10 tumor cells 7 days after BCG treatment. We studied whether this early induction of immunity was correlated with the expression of MHC class II antigens on line-10 tumor cells and was correlated with an increased expression of MHC class II antigens on leukocytes in the primary tumor and in the regional lymph node (Ln. axillaris accessorius). The MHC class II antigens and the leukocyte subpopulations were measured with monoclonal antibodies and flow cytofluorometry. In the draining lymph node the number of nucleated cells increased about 10-fold during the first 5 days after intralesional injection of BCG. At this time the MHC class II antigen expression of these cells was increased from 21%–32% in the naive controls to 39%–53% in animals with BCG-treated tumors. This implies that the number of MHC-class-II-positive cells increased about 20-fold in the draining lymph node. Surprisingly, the increase in percentage of MHC-class-II-antigen-positive cells was mainly due to an increase of IgM-positive B cells from 8%–11% to 22%–41% and an increase of IgG-positive B cells from 7%–27% to 25%–44%. In the tumor, BCG treatment induced a small increase of MHC-class-II-antigen-positive cells from 11%–12% to 15%–20%. Probably this increase came not from tumor cells but mainly from a BCG-induced infiltration of mononuclear cells, as an increase of T cells from 14% to 20%, an increase of macrophages from 8% to 18%, and an increase of B cells from 0 to 6% was observed. We conclude that the potentiation of anti-(line-10 tumor cell) immunity correlated with a 20-fold increase of MHC-class-II-antigen-positive cells in the lymph nodes and a small increase in the number of MHC-class-II-antigen-positive tumor-infiltrating cells.