Sex-related differences in the occurrence of autoimmune diseases are well documented, with females showing a greater propensity to develop these diseases than males. Sex hormones, namely dihydrotestosterone and estrogen, have been shown to improve the severity of inflammatory diseases. Immunologically, the beneficial effects of sex hormones have been attributed to suppression of effector lymphocyte responses accompanied by an immune detour from pro-inflammatory to anti-inflammatory cytokine production. In this review, we present our view of the mechanisms of sex hormones that contribute to their ability to suppress autoimmune responses with an emphasis on the pathogenesis of experimental autoimmune encephalomyelitis.
The normal function of the immune system is to protect organisms from invasion by pathogens. When such a response is directed against the tissues themselves, autoimmunity can result. However, healthy individuals may have a range of autoimmune responses as evidenced by the detection of low levels of antibodies and T cells against autoantigens that may reflect the formation of natural antibodies or idiotypic networks [ 1 , 2 , 3 , 4 ]. Autoimmune diseases (AIDs) manifest clinically when autoimmunity brings tissue damage that disrupts the functions of affected organs [ 5 , 6 ].
AIDs are generally considered the leading cause of death in young and middle-aged women in the United States [ 7 ]. Estimates indicate a large variation in both the incidence (from less than 1 in 100,000 to more than 20 in 100,000) and prevalence (from less than 5 in 100,000 to more than 500 in 100,000) of these diseases [ 8 ]. Approximately 50 million Americans may have some form of autoimmune disease and of these, more than 75% are women [ 7 ]. The chronic nature of many of these diseases such as multiple sclerosis (MS) can have a significant impact on medical costs and quality of life [ 8 ].
MS is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) and affects approximately 2.5 million people worldwide with a female preponderance (2 to 3: 1). In the United States alone, MS affects approximately 400,000 people with 10,000 new cases diagnosed each year [ 9 , 10 , 11 ], resulting in a loss of approximately 2.5 billion to the economy [ 12 , 13 ].
Although the disease can be observed in people of any age, it is commonly diagnosed in the third to fifth decade age group.
Although no known causes have been identified, it is commonly believed that a combination of genetic susceptibility and environmental factors trigger the onset of the disease [ 9 , 11 ].
Traditionally, four types of MS have been identified. These include relapsing-remitting MS (RRMS), secondary progressive MS, primary progressive MS, and relapsing progressive MS (PRMS) [ 14 ], with RRMS being the most common (~85%) and PRMS the rarest of all (~5%) [ 11 ]. A recent classification emphasizes the combination of active or inactive and/or stable or progressive nature of the disease course [ 15 ]. The pathological diversity of lesions in white and gray matter with differential mechanistic signatures provides an additional layer to the variable clinical phenotypes [ 16 , 17 ]. Given this complex nature, the challenge is to study pathogenetic events in humans and animals; various models of experimental autoimmune encephalomyelitis (EAE) are routinely used in MS research.
Females are generally more resistant than males to viral infections because of greater antibody production [ 28 ], especially during the period between puberty and menopause [ 27 ], but conflicting reports may cast doubt on this notion. While males appear to contract some viral infections at a higher rate, such as human immunodeficiency virus, West Nile virus, hepatitis B virus, influenza virus, and Hantavirus [ 28 , 29 ], females with the same viral load as males may be at higher risk of developing acquired immunodeficiency syndrome [ 30 ]. Similarly, during the 2009 H1N1 avian influenza pandemic in Canada, women were found to have a two- to sixfold higher risk of death than men [ 31 ]. In contrast, emerging evidence suggests that mortality is more common in males than females with coronavirus-19 disease, which may be attributed to other confounding factors such as smoking and behavioral changes [ 32 , 33 , 34 ]. In general, it is known that women achieve higher antiviral immune responses than men, which may be helpful in eliminating the virus, but prolongation of this response may lead to increased disease severity [ 31 , 35 ]. For bacterial infections, however, males were found to be more susceptible than females to Mycobacterium tuberculosis (M.tb), Helicobacter pylori , Coxiella burnetii ,Pseudomonas aeruginosa infections and Salmonella typhimurium [ 36 , 37 , 38 , 39 , 40 ]. In addition, the proportion of adult males found to have symptomatic M.tb infections was two times higher than females [ 36 ]. In contrast, females are more likely than males to survive sepsis [ 41 ]. Females have a lower incidence of malaria than males [ 42 ] and experimentally, female mice were also found to be more resistant than males to Plasmodium chabaudi infection [ 43 ]. These data suggest that sex differences may vary from disease to disease of infectious origin.
Autoimmune diseases are more prevalent in females than males, and this discrepancy also exists in animal models, as shown with PLP 139-151-induced EAE in SJL mice [ 60 , 138 ]. Essentially, PLP-reactive T cells generated in males can induce EAE in males comparable to the EAE phenotype in females induced by cells generated in female SJL mice [ 138 ]. In contrast, cells from males can induce only mild disease in females [ 138 ], suggesting that the microenvironment of recipients may determine EAE outcomes. Studying the underlying mechanisms, we had previously noted that EAE-resistant male B10.S mice possess higher frequencies of PLP-specific Treg cells 139-151 than SJL mice, and depletion of Treg cells allowed B10.S mice to develop severe EAE [ 162 , 163 ]. Although these observations provide a cellular basis for EAE susceptibility and EAE resistance phenotypes, male hormones appear to play a critical role in EAE suppression. In support of this notion, a number of studies [ 124 , 125 , 132 , 136 , 164 , 165 , 166] indicate therapeutic benefits of testosterone by improving EAE severity or clinical remissions in MS patients that are accompanied by increased gray matter volume, reduced Th1/Th17 inflammatory cytokines (IFN-γ, IL-2, and IL-17A), Th1/Th17 asymmetry: Treg to Tregs ratio, shift of immune response toward Th2 type (IL-10), increased NK cell populations, and significant reductions in CNS infiltration containing CD4 T cells [ 124 , 125 , 132 , 135 , 164 , 165 , 167 ]. Based on our observations with DHT [ 161], we did not recognize the phenomenon of immune detour from pro to anti-inflammatory cytokine switch; rather, DHT was found to suppress T-cell responses regardless of their antigenic specificity involving apoptosis and/or autophagy as possible underlying mechanisms [ 161]. In addition, we performed some pilot experiments and determined that estrogen mediates DHT-like effects (data not shown). It is currently unknown whether all sex hormones mediate their functions through common pathways such as apoptosis and autophagy. Demonstrating that this concept is true could therefore expand the applications of sex hormone-dependent molecules as drug targets for a range of diseases, including metabolic syndromes, aging, and osteoporosis. Such discoveries may also potentially reduce the need to use small molecules such as selective androgen receptor modulators. As a result, it may be possible to minimize the side effects seen with sex hormones.