Sexual dimorphism in solid and hematological malignancies.

Cancer represents a leading cause of death with continuously increasing incidence worldwide. Many solid cancer types in non-reproductive organs are significantly more frequent and deadly in males compared to females. This sex-biased difference is also present in hematologic malignancies. In this review, we present an overview about sex differences in cancer with a focus on leukemia. We discuss mechanisms potentially underlying the observed sex-biased imbalance in cancer incidence and outcome including sex hormones, sex chromosomes, and immune responses. Besides affecting the pathobiology of cancers, sex differences can also influence drug responses, most notably those to immune checkpoint blockers. Therefore, sex should become a relevant factor in clinical trial design in order to avoid over- or under-treatment of one sex.

Cell-autonomous sex differences in gene expression in chicken bone marrow-derived macrophages.

We have identified differences in gene expression in macrophages grown from the bone marrow of male and female chickens in recombinant chicken M-CSF (CSF1). Cells were profiled with or without treatment with bacterial LPS for 24 h. Approximately 600 transcripts were induced by prolonged LPS stimulation to an equal extent in the male and female macrophages. Many transcripts encoded on the Z chromosome were expressed ∼1.6-fold higher in males, reflecting a lack of dosage compensation in the homogametic sex. A smaller set of W chromosome-specific genes was expressed only in females. LPS signaling in mammals is associated with induction of type 1 IFN-responsive genes. Unexpectedly, because IFNs are encoded on the Z chromosome of chickens, unstimulated macrophages from the female birds expressed a set of known IFN-inducible genes at much higher levels than male cells under the same conditions. To confirm that these differences were not the consequence of the actions of gonadal hormones, we induced gonadal sex reversal to alter the hormonal environment of the developing chick and analyzed macrophages cultured from male, female, and female sex-reversed embryos. Gonadal sex reversal did not alter the sexually dimorphic expression of either sex-linked or IFN-responsive genes. We suggest that female birds compensate for the reduced dose of inducible IFN with a higher basal set point of IFN-responsive genes.

XX T cells and XY B cells in two patients with severe combined immune deficiency.

Immunologic evaluation of two unrelated male infants with clinical and laboratory evidence of severe combined immunodeficiency (SCID) revealed T cells with a mature phenotype in the peripheral circulation of both patients although both had biopsy evidence of thymic alymphoplasia. Both had a normal number of T cells with a cytotoxic/suppressor surface marker (OKT8) but very few T helper cells (OKT4). Lymphocyte stimulation with the mitogens PHA, Con A, and pokeweed or with allogeneic cells resulted in no proliferation. However, addition of T cell growth factor, plus the phorbol ester TPA, to lymphocytes cultured with the T cell mitogen PHA did result in some proliferation of T cells. In both cases these T cells demonstrated an XX female karyotype and were probably of maternal origin. In contrast, proliferating B cells stimulated with Epstein-Barr virus demonstrated a normal XY male karyotype. The possibility that severe combined immune deficiency in these patients was the result of graft-versus-host disease induced by maternal lymphocytes is discussed.

Effect os xid on anti-DNA B-cell precursors.

The influence of the xid gene on murine autoimmunity was investigated by precursor frequency analysis of anti-DNA-producing B cells in non-xid and congenic xid autoimmune and normal mice. Antibody responses were induced in vitro by lipopolysaccharides under limiting-dilution conditions with IgM anti-DNA and antitrinitrophenyl (TNP) determined as models of an autoantibody and nonautoantibody, respectively. All mice demonstrated high frequencies of precursors for anti-DNA without differences between the autoimmune (NZB and MRL-lpr/lpr) and nonautoimmune (CBA/J and DBA/2) strains. In these strains, the presence of the xid gene was associated with a marked reduction of anti-DNA. For NZB.xid mice, this loss of anti-DNA precursors was much greater than that for anti-TNP precursors, whose frequency was similar to that of NZB mice. In contrast, xid-bearing CBA/N, DBA/2.xid, and MRL.xid mice showed marked reductions in both anti-DNA and anti-TNP precursors relative to non-xid mice. The intact anti TNP response of NZB.xid mice may be an additional manifestation of immune abnormalities of the NZB strain and suggests that their B-cell populations differ from those of other mice in the conditions for activation. Since NZB.xid spleens had a preferential reduction of anti-DNA responses, this result suggests that in NZB mice precursors for anti-DNA antibodies are predominantly distributed in the B-cell subset affected by xid, explaining the abrogation of their autoantibody production. The equivalent number of precursors in non-xid mice indicates, however, that additional regulatory abnormalities underlie the change from precursor to autoantibody-producing B cell.

H-2-linked resistance to mastocytoma in male mice: immune response to a histocompatibility antigen on the X chromosome.

Male hybrids from a cross between female mice of strain C57BL/6Kh and males of strain DBA/2J lived longer after injection of P815 mastocytoma cells of DBA/2 origin than did their female siblings. Responses to the histocompatibility antigen on the X chromosome of the DBA/2 strain may be involved in resistance to the tumor. When the female parent was replaced with a C57BL/6Kh carrying one of several mutations in the H-2 region, this sex effect disappeared in some of the hybrid combinations. Thus, the H-2 complex appears to be involved in the regulation of the immune response to the X-linked histocompatibility antigen in this tumor model.

Genetic control of autoimmune disease: interactions between xid and Ipr.

A genetic experiment has been performed in mice to test the B cell "hyperactivity" hypothesis of autoantibody production. A backcross was designed such that some progeny carried both the sex-linked recessive gene xid, which markedly reduces the B cell hyperactivity and autoantibody production seen in NZB mice, and the autosomal recessive gene Ipr, which produces a severe lymphoproliferative/autoimmune disorder in the homozygous animal. The data indicate that although xid does not preclude any measured phenotypic expression of Ipr/Ipr disease, it may play a minor modulatory role. In addition, a background gene or genes in the CBA/N mouse, distinct from xid, modulates T cell proliferation in male backcross progeny. This experiment supports the view that autoimmune phenomena are fundamentally heterogeneous, and may involve complex cellular interactions.

Primary sex determination: genetics and biochemistry.

On the basis of widespread phylogenetic conservatism, it has been proposed that serologically-defined H-Y antigen is the inducer of primary sex differentiation in mammals, causing the initially indifferent gonad to become a testis rather than an ovary. The proposal has withstood extensive testing in a variety of biological circumstances: XX males have testes and are H-Y+ and fertile XY females lack testicular tissue and are H-Y-; soluble H-Y antigen induces testicular organogenesis in XX indifferent gonads of the fetal calf in culture; H-Y antibody blocks tubular reaggregation of dispersed XY testicular cells, causing them to organize follicular clusters. There is a gonadal receptor for H-Y antigen: fetal ovarian cells that have been exposed to soluble H-Y (released for example by testicular Sertoli cells) take up the molecule and acquire the H-Y+ phenotype; they absorb H-Y antibody in serological tests. Specific uptake of soluble H-Y does not occur in the extra-gonadal tissues. It may be inferred that H-Y antigen is disseminated during embryogenesis and bound by specific receptors in cells of the primordial gonad, and that reaction of H-Y and its receptor signals a program of testicular differentiation, regardless of karyotype. The several anomalies of primary sexual differentiation manifest in such conditions as the XX male, the XX true hermaphrodite, and the XY female can thus reasonably be viewed as specific errors of synthesis, dissemination, and binding of H-Y antigen. H-Y is secreted by 'Daudi' cells, cultured from a human XY Burkitt lymphoma. The Daudi-secreted moiety is a single hydrophobic protein of 18,000 molecular weight. Early attempts to characterize H-Y secreted by testicular Sertoli cells have yielded two molecules, one of 16,500 MW (corresponding to the Daudi-secreted 18,000 MW protein), and one of 31,000 MW. It remains to be ascertained whether both are in fact H-Y antigens, and if so, whether one is a polymer of the other, or whether each represents the product of genes with discrete testis-determining functions.

Immunological bases for superior survival of females.

Evolutionary selection has equipped females with immunoregulatory genes on the X chromosome for coping with life-threatening illness. Five immunodeficiency syndromes occur solely in males, suggesting that they arise from mutant immunoregulatory genes located on the X chromosome. These syndromes, although rare, could contribute to poorer survival of males. Females have higher serum IgM concentrations, superior ability to form antibodies to infectious agents, and experience a lower incidence of viral and bacterial infectious diseases. Preponderance of autoimmune disorders in females could arise from modified immune responses owing to estrogens. Clinical and animal studies indicate that male hormones suppress autoantibody production whereas female hormones support their production. Superior immunocompetence and survival of females is based, in part, on their being protected from mutant immunoregulatory genes located on the X chromosome.

A Y chromosome associated factor in strain BXSB producing accelerated autoimmunity and lymphoproliferation.

Strain BXSB/Mp mice develop a spontaneous lupus-like syndrome which is strikingly accelerated in males. The accelerated autoimmune disease occurs in male F1 hybrids with strains NZB/BINJ, SJL/J, and C57BL/6J when the male parent is BXSB but not in the reciprocal hybrid male nor in females. The pattern is similar in F2 hybrids with strains NZB and SJL. The accelerated disease in males occurs only when the Y chromosome is derived from recombinant inbred strain BXSB and ultimately from strain SB/Le.

Presence of H-Y antigen and testis in 46, XX true hermaphroditism, evidence for Y-chromosomal function.

Endocrinologic and serologic studies of a 2-year-old child with the chromosomal complement 46,XX and ambiguous genitalia suggested the preoperative diagnosis of true hermaphroditism. Urinary and serum androgen production in response to human chorionic gonadotrophin was in the range expected for normal males, implying presence of cryptic testicular tissue. Moreover, detection of H-Y antigen, a cell surface component associated with testicular differentiation and coded or regulated by a Y-chromosomal gene, indicated presence of Y-chromosomal material. The diagnosis of true hermaphroditism was confirmed at surgery. Assuming a constant association of H-Y antigen and testicular differentiation is established, human H-Y serology may be an important adjunct to the endocrinologic evaluation of intersex patients. Our studies support the interpretation that a Y-chromosomal translocation too small for cytologic detection accounts for testicular differentiation in 46,XX true hermaphroditism. Expression of H-Y antigen remained positive after castration.

Chronic granulomatous disease and the Kell blood groups.

Fifteen antigenic determinants are known to be related to the Kell blood group. Some boys with X-linked chronic granulomatous disease have the very rare McLeod or Ko phenotype on their red cells. Serological studies of the McLeod type suggest that the weak Kell antigens that are present differ qualitatively and quantitatively from those on red cells of common Kell type. A new antigen, Kx, has been characterized and shown to be present on red cells and neutrophil leucocytes. Lack of red-cell Kx is associated with the McLeod phenotype, lack of leucocyte Kx is associated with chronic granulomatous disease.