Sexual dimorphism in immune response genes as a function of puberty

Rebecca Lamason,Rajeev Agarwal,John C Hall,Rashmi Rawat,Eric P Hoffman,Po Zhao,Jae Jin Chae,Antony Rosen,Adrian Davis,Phillip Cohen,Kanneboyina Nagaraju

doi:10.1186/1471-2172-7-2

Abstract

BackgroundAutoimmune diseases are more prevalent in females than in males, whereas males have higher mortality associated with infectious diseases. To increase our understanding of this sexual dimorphism in the immune system, we sought to identify and characterize inherent differences in immune response programs in the spleens of male and female mice before, during and after puberty.ResultsAfter the onset of puberty, female mice showed a higher expression of adaptive immune response genes, while males had a higher expression of innate immune genes. This result suggested a requirement for sex hormones. Using in vivo and in vitro assays in normal and mutant mouse strains, we found that reverse signaling through FasL was directly influenced by estrogen, with downstream consequences of increased CD8+ T cell-derived B cell help (via cytokines) and enhanced immunoglobulin production.ConclusionThese results demonstrate that sexual dimorphism in innate and adaptive immune genes is dependent on puberty. This study also revealed that estrogen influences immunoglobulin levels in post-pubertal female mice via the Fas-FasL pathway.

Highlights

Autoimmune diseases are more prevalent in females than in males, whereas males have higher mortality associated with infectious diseases
We have identified one such pathway, reverse signaling through FasL, as a possible source of the sexual dimorphism in immunoglobulin (Ig) levels that is seen between males and females, since this pathway is affected by estrogen levels
Assignment of functions to cluster members suggested that post-pubertal male mice preferentially expressed genes involved in innate immunity. The expression of these innate immunity genes was significantly decreased in post-pubertal female mice. These results suggest that considerable remodeling of splenic immune function occurs at the time of puberty, with the result that sexual dimorphism in immunity is permanently established in postpubertal life, with adult males showing a predominantly primitive immune response and adult females being relatively deficient in these responses

Summary

Introduction

Autoimmune diseases are more prevalent in females than in males, whereas males have higher mortality associated with infectious diseases. The innate immune system uses proteins encoded in the germline (on macrophages, mast cells, natural killer cells) to recognize conserved products of infectious non-self (i.e., microbial pathogens), but not non-infectious self (i.e., host proteins) [7,8] In contrast to this relatively inflexible system is the almost infinitely adaptable immune system of lymphocytes [9]. These two systems are known to interact closely with each other: For example, cellular and soluble components of innate immunity help the adaptive immune response to select and respond to appropriate antigens. Understanding the basis of sex differences in immune response genes is important for developing new approaches to prevention, diagnosis and treatment of infectious and autoimmune diseases

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