Immunosenescence does not affect men and women equally [12]. The dysregulation in T-cell function, for example, that is associated with aging, occurs much more dramatically in women than in men [25,26].

Gender-specific differences in immunosenescence are at least partly attributable to sex hormones, evidenced by the fact that men and postmenopausal women have reduced T-cell immunity as compared to premenopausal women [27]. The fact that men live shorter lives, on average, than women is also partially attributed to the thymic involution produced by higher circulating levels of androgens in men [28], and a recent study has documented greater age-associated decline of less differentiated lymphocytes and increase of highly differentiated T cells in females [29].

Much is known about the influence of sex hormones on immunity in general. Androgens, estrogen, and progesterone all influence immune functions; estrogen in the form of 17β estradiol has been particularly associated with profound influences on the immune system (Table 23.2).

Females, in general, have superior immune vigilance as compared to males, with both humoral and cell-mediated arms mounting more vigorous responses to immune stimulation [30]. Women maintain higher antibody levels than men, as well as higher levels of circulating IL-1, IL-4, and INF-γ [31]. Females reject grafts faster [32]. A general pattern is observed in which estrogen enhances humoral immunity, while androgens as well as progesterone tend to suppress it [33]. Women respond to antigenic stimulation with a predominantly Th2 response, with increased antibody production [34]. Estrogen stimulates the Th2 response by stimulating Th lymphocytes to secrete type 2 cytokines which promote the synthesis of antibodies [35]. High estrogen levels associated with pregnancy also produce a shift towards Th2 response [36].

Conversely, men respond to antigenic stimulation primarily with a Th1 response [34]. Androgens stimulate Th cells to produce type 1 cytokines, which suppress Th2 activity and stimulate CD8 cells [37], a process that produces inflammation as the predominant immune response [34].

The fact that estrogen favors a stronger overall immune response, particularly with regard to antibody response in women, is a mixed blessing. Although it produces a superior resistance to infection as compared to men, it also increases the risk in women of autoimmune disease [38].

There are at least 70 documented autoimmune diseases [38], and the prevalence of autoimmune disease is rapidly rising worldwide, for reasons not completely understood [39]. Although the disorders share a pathogenic immunity against the body’s own tissues that is the product of a progressive disorganization of immune function, the precise etiology is unknown. Autoimmunity appears to be a multifactorial process in which genetic, environmental, and biochemical processes all participate.

A genetic or familial predisposition to autoimmunity clearly plays a role. Pairwise analyses examined discordant familiar risks for seven common autoimmune diseases using a large national databank that included the records of 172,242 patients. Records examined demonstrated a genetic pattern of inheritance for RA, SLE, type I diabetes, ankylosing spondylitis, Crohn’s disease, celiac disease, and ulcerative colitis. Incidence of each of the seven autoimmune diseases analyzed was associated additionally with at least three of the others [40].

Environmental factors such as pollution or occupational exposures or contact with viral, bacterial, or parasitic pathogens may trigger autoimmunity. Lifestyle differences like nutritional choices, sleep patterns, medications, and stress may also trigger illness [38].

Endogenous factors also play a role; for example, sex hormones are a major influence [31]. The most striking gender-based difference in immune system function is the remarkable female predominance of autoimmune diseases [41]. An estimated 78 % of those affected by autoimmune disease are women [34].

Gender-specific patterns in the development of autoimmune diseases suggest a strong role of sex hormones, as predominance in the female sex changes with age at disease diagnosis, lending strong support [42]. Autoimmunity in males shows less age-dependent variation. Autoimmune diseases prevalent in males typically present before the sixth decade with the appearance of autoantibodies, acute inflammation, and increase in the proinflammatory cytokines characteristic of a Th1 response.

Those that manifest primarily in females are more complicated. Autoimmune diseases that manifest early in life in females generally have a clear antibody-mediated pathology. Those with increased incidence in females that appear after the age of 50 (in menopause) tend to be characterized by a more chronic disease course and fibrotic Th-mediated pathology.

A central role for sex hormones in autoimmune disease in women is also evidenced by the dramatic differences in prevalence during the different reproductive periods of a woman’s life, which are themselves driven by profound modulation of circulating levels of sex steroids, particularly estrogen [31]. Many autoimmune diseases in which women predominate are exacerbated by the higher levels of female sex steroids in pregnancy (a period that is also characterized by a shift towards Th2 response), primarily estrogen, which worsens disease, while androgens produce beneficial effect.

Strict correlation of autoimmunity with estrogen levels, however, is not observed. Other female-predominant autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis, worsen during pregnancy [43] and improve in the postmenopausal period [44] (Table 23.3).

The influence on autoimmune disease of the decreasing levels of estrogen associated with aging in women is essentially unascertained. The declining efficacy of the immune system with age, in both genders, is accompanied by a characteristic increase in both the variety and level of circulating autoantibodies [8]. Antinuclear antibody (ANA) levels remain constant until about age 60 and then rise. About 5 % of healthy individuals of that age have high ANA titers (1:160), compared to 37 % of those over 70 years of age [45].

Although autoantibodies, found in the blood of all healthy humans, serve a useful function in a healthy adult, acting to clear away cellular debris produced by routine injury and inflammation [46], the number of different circulating autoantibodies has proven to be a good predictor of autoimmune disease. The risk of developing childhood diabetes within 5 years, for example, is only 10 % with the presence of one autoantibody specificity, but increases to as much as 80 % if there are three [34]. Autoantibody levels are normally kept in check by immune tolerance processes, but can (through age or overt disease) reach clinically significant levels, at which point the binding of self-antigens activates the complement cascade and results in cytotoxicity or other immune pathology [34]. Rising levels of antibodies, apart from the number of different specificities, are also associated with a generally increased risk of autoimmunity in old age [8].

What specifically causes the documented increase in both autoantibodies and autoimmunity in older adults is a matter of debate. With age, the normally tight orchestration of interdependent immune functions begins to decay, with progressive perturbation of immune function that can eventually lead to autoimmune disease [8]. Increased autoimmunity appears to be primarily the result of the combined effects of the reduction in naïve T cells (produced by thymus involution) in concert with an activation of self-reactive memory B cells.

B-cell activation may result from a variety of antigenic stimuli [47]. Exposure to an infectious agent with molecular mimicry of a self-antigen may prompt a memory response [16]. Cumulative exposure to a variety of antibody specificities, in the presence of chronic infections, for example, may also produce hyperstimulation of B cells. In a study of the elderly in Cameroon (where multiple chronic infections are not uncommon), the pattern of autoantibodies observed in the elderly subjects was markedly different from that in industrialized countries, suggesting a role for long-term multiple antigen exposures [48]. Normal aging can also reduce the efficiency of normal physical immune barriers, resulting in increased pathogen intrusion [49]. Innate immunity also deteriorates with age, which can contribute to chronic immune stimulation. The persistence of high antigen levels can also make co-stimulatory T cells less susceptible to downregulation [49].

Other sources of B-cell memory activation are neoantigens which are revealed by a progressive loss of tissue integrity and increased inflammation as individuals age [50]. Inappropriate activation of lymphocytes can also result from defective clearance of cellular debris, resulting in prolonged exposure to autoantigens [49]. Self-antigens may also acquire alterations that increase immunogenicity. For example, posttranslational modification of proteins increases in immunosenescence; particular modifications, such as isoaspartyl formation, can trigger an autoimmune response [49].

Improper self-antigen recognition by dendritic cells (DC) and T cells initiates, through release of specific cytokines (as described above), destructive Th1 or Th2 responses. Rheumatoid arthritis, for example, is characterized by an exaggerated Th1 self-reactive immunity, SLE by an excessive Th2 [24]. Estrogens are known to drive physiological selection of Th1 or Th2 pathways.

A perturbation in immune receptor signaling may underlie the increase in autoimmune phenomena in the elderly, particularly those that contribute to the regulation of immune tolerance. Optimal immune function necessitates a tight balance of the signaling pathways in both T- and B-cell compartments; these pathways are altered in both compartments in SLE and other autoimmune diseases [51].

Other aspects of aging can increase immune dysfunction as well: stress, with associated increased cortisol levels; sleep dysregulation and associated effects on immunity; decrease in physical activity and negative effects on immunocompetence; and nutritional deficiencies common in old age with a negative impact on immunocompetence [4].

In women, the cumulative physiological degeneration associated with normal aging is augmented by a dramatic and systemic estrogen deprivation. Estrogens generally favor immune processes involving CD4+ Th2 cells and B cells [52], thereby promoting B-cell-mediated autoimmune diseases. Physiological levels of estrogen, however, also stimulate the expansion of CD4+ CD25+regulatory T cells (Treg cells), which help maintain tolerance to self-antigens and therefore ameliorate autoimmune disease, as well as the expression of the Foxp3 gene, a marker for Treg cell function [53]. Follicular helper T cells (Tfh cells), in contrast, appear to drive autoantibody production in the germinal center and are associated with the development of systemic autoimmunity [54].

Androgens, on the other hand, encourage processes involving CD4+Th1 cells and CD8+ cells, acting to suppress or ameliorate B-cell-mediated autoimmune diseases [31]. The influence of these hormones on the immune system, therefore, produces more autoimmune pathology in women in autoimmune disease mediated by Th2-dominant processes and more in men when Th1 processes are involved (see Table 23.3).

Hormonal manipulations can alter immune reactivity and modulate disease expression [41]. Estrogens provoke involution of the thymus [38]; treatment of castrated animals with exogenous sex hormones causes massive atrophy of the thymus [55]. Thymus regeneration occurs following ovariectomy [5], and thymus involution occurs during pregnancy, which reverts after lactation ceases [56].

Estrogen-induced involution of the thymus is associated with a reduction in numbers of immature T lymphocytes [38]. Estrogen affects T-cell subset composition, as well as T-cell function and activation [12]. Oral estrogen replacement therapy has been shown to restore T-cell function [57].

Estrogen drastically reduces not only the size of the thymus but also of the bone marrow cavity as well, the sites where most deletion of autoreactive cells occurs. B cells developing at alternative sites (liver and spleen), where less stringent selection occurs, may escape normal controls [31].

Estrogens, in fact, stimulate lymphopoiesis outside of the bone marrow [58]. Mice treated with exogenous estrogen develop impressive hemopoietic centers in the liver and spleens filled with antibody-producing cells [31].

Estrogen depletion in women, characteristic of postmenopausal women, has been specifically associated with reductions in B cells and T cells [59] and Th-derived cytokines [60] as well as an impaired immune response to viral infections [61]. In vitro, estrogen stimulates Th1 cytokine production by T cells [47].

Estrogens diminish the number of monocytes, through apoptosis, as well as through a modulation of the cell cycle which delays mitosis [62]. Autoreactive B-cell apoptosis, particularly, is inhibited [63]. Estrogen however simultaneously induces a rapid maturation of B lymphocytes [38] and stimulates Th lymphocytes to secrete type 2 cytokines that promote antibody production [35,37].

It is known that many natural, pathological, and therapeutic conditions can change serum estrogen levels, including the menstrual cycle, pregnancy, menopause, use of oral contraceptives, use of hormonal replacement treatment, and disease. The estrogen withdrawal of menopause, however, is a significant hormonal transition and one with numerous physiological ramifications. The interrelationship of menopause and autoimmune diseases is complex and not yet fully understood. Recent literature has noted that autoimmune disease and/or autoimmune disease treatments can play a role in causing premature ovarian failure (POF) resulting in early menopause [64,65]. In addition, some symptoms and effects of autoimmune disease (e.g., increased cardiovascular risk, increased fracture risk, cognitive decline, urinary incontinence/irritable bladder, etc.) can be similar to those of normal aging, which increases the challenge of distinguishing the expected effects of menopause and aging from those of autoimmune disease [64,66]. These aspects of the relationship between menopause and autoimmune disease will not be discussed in this chapter, which shall rather concentrate on effects of menopause on selected autoimmune diseases.

The normal immunosenescence evidenced in both sexes may be modulated in some degree by changing levels and forms of endogenous estrogen. The production of cytokines Il-6, Il-1, and TNF-α increases after menopause, as does the physiological response to those cytokines [11]. There is a postmenopausal decrease in CD4 T and B lymphocytes, as well as decrease in the cytotoxic activity of natural killer (NK) cells [33].

In vitro analysis of three different T-cell signaling proteins (Janus kinase 2 [JAK2], Janus kinase 3 [JAK3], and CD3-zeta) found that postmenopausal levels were substantially reduced as compared to premenopausal levels [12]. In addition, Jurkat T cells exposed to premenopausal levels of E2 also formed significantly more IL-2 producing colonies as compared to those exposed to postmenopausal levels (75.3 ± 2.2 vs 55.7 ± 2.1 [P < 0.0001]) [12]. Studies suggest a normalization of cellular response after hormone replacement therapy (HRT) [11].