Gender-Associated Differences of Perforin Polymorphisms in the Susceptibility to Multiple Sclerosis

Camiña-Tato, Montse; Morcillo-Suárez, Carlos; Bustamante, Marta F.; Ortega, Israel Díaz; Navarro, Arcadi; Muntasell, Aura; López‐Botet, Miguel; Sánchez, Àlex; Carmona, Paco; Julià, Eva; Tórtola, María Teresa; Audı́, Laura; Oksenberg, Jorge R.; Martin, Roland; Montalbán, Xavier; Comabella, Manuel

doi:10.4049/jimmunol.1000102

Cited by 26 publications

(15 citation statements)

References 41 publications

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“…Nevertheless, in two strains of mice, the sex bias in EAE is reversed (males display increased susceptibility), whereas another strain shows no sex bias (reviewed in [3]). This result echoes earlier murine research in which the effect of androgen removal on EAE was dependent on genetic background [118], and observations that autosomal gene associations with MS susceptibility are often sex-specific in humans [119,120]. …”

Section: Reviewsupporting

confidence: 85%

Sex-biased chromatin and regulatory cross-talk between sex chromosomes, autosomes, and mitochondria

Silkaitis

Lemos

2014

Biol sex dif

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Several autoimmune and neurological diseases exhibit a sex bias, but discerning the causes and mechanisms of these biases has been challenging. Sex differences begin to manifest themselves in early embryonic development, and gonadal differentiation further bifurcates the male and female phenotypes. Even at this early stage, however, there is evidence that males and females respond to environmental stimuli differently, and the divergent phenotypic responses may have consequences later in life. The effect of prenatal nutrient restriction illustrates this point, as adult women exposed to prenatal restrictions exhibited increased risk factors of cardiovascular disease, while men exposed to the same condition did not. Recent research has examined the roles of sex-specific genes, hormones, chromosomes, and the interactions among them in mediating sex-biased phenotypes. Such research has identified testosterone, for example, as a possible protective agent against autoimmune disorders and an XX chromosome complement as a susceptibility factor in murine models of lupus and multiple sclerosis. Sex-biased chromatin is an additional and likely important component. Research suggesting a role for X and Y chromosome heterochromatin in regulating epigenetic states of autosomes has highlighted unorthodox mechanisms of gene regulation. The crosstalk between the Y chromosomes and autosomes may be further mediated by the mitochondria. The organelles have solely maternal transmission and exert differential effects on males and females. Altogether, research supports the notion that the interaction between sex-biased elements might exert novel regulatory functions in the genome and contribute to sex-specific susceptibilities to autoimmune and neurological diseases.

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Section: Reviewsupporting

confidence: 85%

Sex-biased chromatin and regulatory cross-talk between sex chromosomes, autosomes, and mitochondria

Silkaitis

Lemos

2014

Biol sex dif

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“…SNP rs885822 refers to a cytosine to thymine change at nucleotide 900 of the PRF1 coding region, but causes no change in perforin protein. The two variants of the c.900C>T SNP, here denoted c.900C and c.900T, have an approximate relative allelic frequency of 40:60 in the population 16 and, therefore, can be conveniently used to distinguish the two WT PRF1 alleles in population studies.…”

Section: Resultsmentioning

confidence: 99%

Heterozygosity for the common perforin mutation, p.A91V, impairs the cytotoxicity of primary natural killer cells from healthy individuals

et al. 2015

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The production and delivery of functional perforin (PRF; PRF1 gene) by cytotoxic lymphocytes maintains immune homeostasis and tumour immune surveillance. In humans, inheritance of the common PRF1 polymorphism, p.A91V, (c.272C>T) found in 8-9% of the Caucasian population, with another mutated allele resulting in reduced PRF function or trafficking, has been shown to result in hyperinflammatory diseases and/or haematological cancers. In this study, we sought to investigate the function of p.A91V on a wild-type (WT) perforin background. We first developed an assay that distinguishes the relative levels of transcription of individual PRF1 alleles, including p.A91V. The p.A91V allele was seen to be expressed at similar levels as the WT allele in primary human natural killer (NK) cells, ruling out that allelic expression imbalance influenced their function. We then demonstrated that the p.A91V mutation results in protein misfolding and an appreciable reduction in NK-cell cytotoxicity in healthy carriers of p.A91V. We propose that this level of cytotoxic dysfunction may readily account for the predisposition to immune-mediated disease in individuals homozygous for p.A91V. Also, the fact that monoallelic mutations of PRF1 decrease NK-cell cytotoxicity should be considered in individuals presenting with the manifestations of immune deficiency states that impinge on NK-cell cytotoxicity.

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“…Other data point out a relevant role of perforin in the pathogenesis of MS. Variations in the PRF1 gene have been described in MS patients with a higher frequency than in healthy controls [24]. Other authors have described a generalized defect in the expression of perforin in a subgroup of male patients with PPMS [25]. By contrast, CD8+ T Reg content of perforin was significantly decreased in the CNS as compared to blood, which suggests that this subset does not seem to use the perforin pathway for their suppressive function in MS within the central nervous compartment.…”

Section: Resultsmentioning

confidence: 99%

Perforin Expression by CD4+ Regulatory T Cells Increases at Multiple Sclerosis Relapse: Sex Differences

Tejera-Alhambra

Alonso

Teijeiro

et al. 2012

IJMS

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Multiple sclerosis (MS) represents the leading cause of neurological deficit among young adults, affecting women more frequently than men. In MS, the extent of central nervous system lesions is determined by the net balance between self-reactive and regulatory T-cells at any given time, among other factors, as well as by the effect of inflammatory response. Here, we studied both CD4+ and CD8+ TReg in parallel in blood and CSF during MS relapse. A recruitment of both regulatory CD4+ and CD8+ T cells (TReg) within the cerebrospinal fluid (CSF) takes place during MS relapse. Not previously described, the presence of CD4+ TReg in CSF was higher in women than in men, which could account for the sexual dimorphism in the incidence of MS. A direct correlation between plasma oestradiol (E2) and IL-2 levels was observed, in line with a putative circuit of E2 and perforin expression by CD4+ TReg playing a role in MS. Also, serum IFN-alpha was higher in females, with direct correlation with serum E2 levels. This is the first study to analyze perforin expression by CD4+ TReg in MS, which was greatly enhanced in CSF, what points out a relevant role of this molecule in the suppressive effects of the CD4+ TReg in MS, and contributes to the understanding of MS pathophysiology.

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Gender-Associated Differences of Perforin Polymorphisms in the Susceptibility to Multiple Sclerosis

Cited by 26 publications

References 41 publications

Sex-biased chromatin and regulatory cross-talk between sex chromosomes, autosomes, and mitochondria

Sex-biased chromatin and regulatory cross-talk between sex chromosomes, autosomes, and mitochondria

Heterozygosity for the common perforin mutation, p.A91V, impairs the cytotoxicity of primary natural killer cells from healthy individuals

Perforin Expression by CD4+ Regulatory T Cells Increases at Multiple Sclerosis Relapse: Sex Differences

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