The Role of Sex in Uveitis and Ocular Inflammation

Ian Y. L. Yeung, MD; Nicholas A. Popp, BS; Chi-Chao Chan, MD

Disclosures

Int Ophthalmol Clin. 2015;55(3):111-131. 

In This Article

Discussion

In general, autoimmune diseases are mediated by Th1, Th2, and Th17 cells. Th1 cells are responsible for cell-mediated immunity, whereas Th2 cells are responsible for humoral-mediated immunity. Excessive Th1 response, via production of interferon (IFN)-[gamma] often results in tissue damage, whereas an excessive Th2 response leads to hypersensitivity through IL-4-mediated B-cell recruitment.[162] The role of Th17 cells and their production of IL-17 in autoimmunity are being studied in a variety of models.[163–169] Animal models of uveitis [experimental autoimmune uveitis (EAU)] have demonstrated that EAU is predominantly a Th1/Th17-mediated disease.[170] Further, Th17 response has been associated with the pathogenesis of VKH,[171] and IL-17 is raised in ocular sarcoidosis and in active VKH.[172–175] This matches other systemic autoimmune conditions where proinflammatory IL-17 has also been found to be overexpressed in MS,[165] rheumatoid arthritis (RA),[176] and SLE.[167,169]

However, differences in the way the sexes respond to infection and develop autoimmunity have also been described. Women primarily respond to infection and vaccination with classic Th2 mechanisms (leading to increased antibody production), whereas men develop a stronger Th1 response.[4,177] This fact has been postulated as one reason why Th2-mediated autoimmune conditions like RA are more prevalent in women.[4]

Other immunologic pathways underpinning the sex difference in autoimmunity must also be present. Increasingly, it is recognized that the gut microbiome and intestinal mucosal inflammation has a role in systemic autoimmune diseases.[178] The gut mucosa of female mice have higher concentrations of plasma cells, gut-imprinted [alpha]4[beta]7 T cells, and of CD45+ IL-17-, IL-22-, and IL-9-producing cells than male mice.[7] The microbiome has been linked to the female predominant conditions of RA and MS and is thought to have an effect on IL-17-mediated pathways.[179–181]

Overall, noninfectious uveitis tends to be more prevalent in women. However, with HLA-B27-associated disease, the uveitis tends to be more prevalent and severe in men. JIA-affected boys who are HLA-B27 positive have a 40% ocular complication rate compared with a 10% ocular complication rate in girls.[29,78,81] The explanation as for why HLA-B27 has a larger effect on ocular complications in males compared with females is still unknown, although recent evidence suggests that altered gut microbiota may play a role in HLA-B27-associated disease.[182]

It may not just be differences in the HLA gene loci to explain for the sex difference in severity of the uveitis. Interestingly, the CCR5–403 AA genotype was only found in male patients with BD. These associations may point to sex-associated genetics that have been heretofore unexplored.[183]

X chromosomes and hormone-mediated modulation may be another possible reason for the sex difference. Pregnancy illustrates this. A successful pregnancy requires the tolerance of a semiallogeneic fetus.[184,185] Increased levels of estrogen and progesterone in pregnancy results in the suppression of Th1 responses and the upregulation of Th2 responses.[186–188] Thus, it is hypothesized that pregnancy ameliorates Th1-associated autoimmune conditions like RA but exacerbates Th2-associated autoimmune conditions like SLE.[185–192] Although largely unexplored, Th17 cells may also play a role in the altered autoimmunity in pregnancy.[163,193–196] These hypotheses have been supported by animal work confirming a role for sex hormones in uveitis. Rodent EAU models showed that estrogen enhanced uveitis in females, and that these results correlated with the ocular levels of Th1 (IFN-[gamma]) and Th2 (IL-10) cytokine messengers.[197]

X chromosome inactivation may also play a significant role in sex differences in autoimmunity. It is known that a variety of immune system genes, including TLR7 and CD40R, are located on the X chromosome and that during X chromosome inactivation, approximately 15% of the genes on the second X chromosome are not completely silenced.[198,199] This incomplete inactivation has been hypothesized to be a significant cause of autoimmunity in women via the activation of TLR7 and formation of age-associated B cells are found only in the spleens of female mice and produce high levels of autoantibodies upon stimulation.[199] These age-associated B cells express IFN-[gamma]R on their surfaces and are able to respond to the high levels of IFN-[gamma] secreted in models of SLE. This hypothesis has been supported in humans by studies showing that males with Kleinfelter syndrome (XXY) have the same risk of developing SLE as females and show similar levels of X chromosome inactivation.[200]

However some sex differences in uveitis, particularly with infectious etiology, are mediated by behavioral factors. In India, Leptospira-infectious uveitis is more prevalent in men with up to 75% of patients being male.[71] Exposure to this spirochete bacterium usually occurs through farming, a task usually undertaken by men. Similarly, syphilis and HIV are more common in men. This is thought to be due to an increase, since 1999, of unsafe sexual practices mainly among homosexual males.[75,76]

Finally, how can we make use of the sex differences to aid patient management? Firstly, the above knowledge can be applied to prevent uveitis. For example, increased public education of safe sexual practices could reduce the incidence of syphilitic uveitis.[76] Increased awareness among family medicine practitioners that women are more likely to have noninfectious uveitis and autoimmune diseases should allow for early diagnosis and adequate treatment.[5] Similarly, increased awareness among pediatric rheumatologists of the increased ocular complication rate of JIA-affected boys should ensure that JIA-affected boys are referred for uveitic screening and close follow-up.[29]

One way to capitalize on the sex difference would be the use of hormonal manipulation to provide a more tailored yet efficacious therapy for future uveitis patients. Supplemental estrogen in the form of contraceptive pills has been proposed to increase the risk of SLE flares. Thus, clinicians should be judicious in their prescribing of hormonal therapy for SLE patients.[5] This contrasts with sarcoidosis, which has a second peak presentation in women over the age of 50. This increased prevalence in postmenopausal women suggests a role for sex hormone replacement. Thus hormonal therapy may be considered as a possible therapeutic adjunct for sarcoidosis patients.[36,201]

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