The innate immune system of the liver: May it explain the stronger viral clearance in female sex?


  • Potential conflict of interest: Nothing to report.

To the Editor:

We have read with great interest the article by Grebely et al., published in Hepatology, in which they show the stronger spontaneous clearance of acute hepatitis C virus (HCV) in the female sex.[1] Mechanisms underlying gender dimorphism in viral clearance remain poorly understood. The researchers pointed out that females have an increased magnitude of immune and inflammatory responses and that this may be a result of the binding of sex steroids to specific receptors in different cells. It should be stressed that experimental studies in infected chimpanzees with HCV have emphasized the role of the innate immune system, namely, Kupffer cells (KCs), in clearance.[2] In this species, as well as in rodents or humans, it is taken for granted that KCs are equally abundant in males and females. In our opinion, differences in the number of KCs could also help explain the stronger viral clearance in females.

In recent years, we have been devoted to the study of the microanatomy of the liver, by unbiased stereological methods.[3, 4] We have studied male and female Wistar rat livers (n = 5 per group) of 2, 6, 12, and 18 months. Using a systematic random sampling design, we obtained 30-μm sections that were immunostained against ED2 (1:100; AbD Serotec, Kidlington, UK).[3] Cells were counted unbiasedly in optical disectors in order to obtain the numerical density of KCs in the liver. On average, we counted 423 and 299 KCs per male and female rat liver, respectively. The numerical density is presented in Fig. 1. A two-way analysis of variance showed significant differences related with gender (P < 0.001) and aging (P < 0.05). The former were more marked in young animals, in which females had 54% more KCs than males. To the best of our knowledge, this is the first insight of gender dimorphism of KCs in vivo. A recent study showed that young female rodents have ≈50% more macrophages in their pleural and peritoneal cavities, which are more efficient in phagocytosis.[5] It is compelling to extrapolate our data between species; therefore, it would be interesting to immunomark KCs against CD68 and evaluate whether such gender dimorphism also exists for the human liver.

Figure 1.

Numerical density of KCs (per mm3) in male and female Wistar rats throughout aging. Data are expressed and mean ± standard deviation and were corrected for shrinking. Paired symbols indicate significant differences after Tukey's posthoc test (* ε Φ: P < 0.01; Ψ: P < 0.05).

  • Ricardo Marcos, DVM, Ph.D.1

  • Carla Correia-Gomes, DVM, Ph.D., MRCVS2

  • 1Institute of Biomedical Sciences Abel Salazar University of Porto Porto, Portugal

  • 2Epidemiology Research Unit SRUC Inverness United Kingdom