The X chromosome in immune functions: when a chromosome makes the difference

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Abstract

In response to various immune challenges, females show better survival than males; the X chromosome has an important role in this immunological advantage. X chromosome-linked diseases are usually restricted to males, who have only one copy of the X chromosome; however, females are more prone to autoimmune diseases, and the X chromosome may be involved in the breakdown of self tolerance. Several hypotheses have been proposed in recent years that support a role for the X chromosome in shaping autoimmune responses. Here, we review the main mechanisms responsible for increased immune activity in females. This provides a survival advantage in the face of pathogenic insult but can also enhance the susceptibility of females to autoimmunity.

Key Points

  • Females are more immunoreactive than males and, although sex hormones have an important role in immune functions, the X chromosome is fundamental in shaping sex-specific immune responses.

  • X-linked specific diseases usually affect only males, simply because they are hemizygous for X chromosome alleles. The fact that females carry two X chromosomes, and therefore two different allelic options to be used by cells, means that they have two possible physiological responses.

  • Mosaicism, caused by X chromosome inactivation, is one mechanism by which females can have an immune advantage over males, but there are also other features associated with the X chromosome that can modulate differences between female and male immune responses and even lead to immunological differences between individual females.

  • Although X chromosome inactivation is expected to balance the levels of female and male gene expression, several genes located in the non-recombining regions of the sex chromosomes can escape inactivation, and females may have elevated gene expression of these genes. Moreover, females may present extreme skewing of X chromosome inactivation and show overrepresentation of one of the parental X chromosomes.

  • Escape from X chromosome silencing and X inactivation skewing may account for immune differences between the sexes. These mechanisms may be involved in the development of autoimmunity, as skewed X chromosome inactivation or reactivation of parts of the inactive X chromosome can lead to the breakdown of self tolerance.

  • The number of X-linked genes and microRNAs with an identified role in immunity is increasing, and it is possible that naturally occurring variations in these genes and microRNAs account for immunological differences between genders.

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Figure 1: The different mechanisms regulating immunity and triggered by the sex chromosomes.
Figure 2: Sex distribution of the most important autoimmune diseases.
Figure 3: Current hypotheses attesting the involvement of X chromosome anomalies in autoimmunity.

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Acknowledgements

The authors acknowledge A. Bredan for critical review of the manuscript. Research in the authors' laboratory is sponsored by the Fund for Scientific Research-Flanders, the Interuniversity Attraction Poles Program of the Belgian Science Policy (IAP VI/18), the Belgische Vereniging tegen Kanker and the Flanders Institute for Biotechnology (VIB).

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Glossary

X chromosome inactivation

(Also known as lyonization or silencing). A process that occurs in female mammals in which gene expression from one of the pair of X chromosomes is downregulated. This ensures that the levels of X chromosome gene expression in females matches that of males.

Pseudoautosomal regions

Small regions of sequence homology located at the tips of mammalian X and Y chromosomes where recombination still occurs during male meiosis.

Cellular mosaicism

The chimeric state of female tissues that results from random X chromosome inactivation, meaning that normal mammalian females have two genetically distinct types of cells.

Inbreeding depression

(Also known as loss of heterozygosity) is the reduced fitness of a certain population that results from breeding between close genetic relatives.

Sex-determining region of the Y chromosome

(SRY). The gene located on the Y chromosome that is responsible for male sex determination in almost all placental mammals.

Imprinting

An epigenetic process that, through methylation and histone modification, tags the chromosomes inherited from the mother or the father and results in differential gene expression in a parent-of-origin-specific manner.

Gene-dosage effects

The nearly linear relationship between the phenotype and the number of copies of the relevant gene present in the genome.

Self tolerance

Tolerance to an individual's own antigens that is achieved through both central and peripheral tolerance mechanisms, including T cell deletion, anergy and immune regulation. Without central and peripheral tolerance, the immune system could not distinguish self from foreign antigens, resulting in autoimmunity.

Chronic granulomatous disease

An inherited disorder caused by defective oxidase activity in the respiratory burst of phagocytes. It results from mutations in any of four genes that are necessary to generate the superoxide radicals required for normal neutrophil function. Affected patients suffer from increased susceptibility to recurrent infections.

Hypomorphic mutations

A type of mutation that results in a reduced level of activity of the product encoded by the mutated gene.

Purifying selection

(Also know as negative selection). The selective elimination of deleterious alleles from the population within the mechanism of natural selection.

Sexual antagonism

When an allele is favoured in one sex and selected against in the other.

Hemizygous

A diploid genotype that has only one copy of a particular gene, as in X chromosome genes in a male, or when the homologous chromosome carries a deletion.

Fitness effect

The expected contribution of an individual to the next generation.

XY homologous genes

Genes common to both sex chromosomes and therefore present in two copies in both females and males.

Skewing of X chromosome inactivation

When the process of X chromosome inactivation selects for or against alleles on the active X chromosome. This nonrandom pattern of inactivation results in overrepresentation of one of the parental X chromosomes in female tissues. Mutations in the X-inactive specific transcript (XIST) gene or chromosomal rearrangements resulting from translocations from autosomes can also lead to inactivation skewing.

Wiskott–Aldrich syndrome

(WAS). A life-threatening X-linked immunodeficiency caused by mutation in the WAS gene. It is characterized by thrombocytopenia with small platelets, eczema, recurrent infections caused by immunodeficiency, and an increased incidence of autoimmune manifestations and malignancies.

Fetal microchimerism

The presence of fetal cells in the mother after pregnancy.

Haploinsufficiency

Occurs when only one copy of a certain gene is present in the genome, and both copies are required for proper function.

Isochromosome-Xq

A genetic defect that results from the total deletion of the short arm of the X chromosome owing to the fusion of two long arms.

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Libert, C., Dejager, L. & Pinheiro, I. The X chromosome in immune functions: when a chromosome makes the difference. Nat Rev Immunol 10, 594–604 (2010) doi:10.1038/nri2815

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