Effects of Menopause on Autoimmune Diseases

Miranda A Farage; Kenneth W Miller; Howard I Maibach


Expert Rev of Obstet Gynecol. 2012;7(6):557-571. 

In This Article

Aging & the Development of Autoimmunity

There are at least 70 documented autoimmune diseases[36] and the prevalence of autoimmune disease is rapidly rising worldwide, for reasons not completely understood.[37] 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 were associated additionally with at least three of the others.[38]

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.[36]

Endogenous factors also play a role; for example, sex hormones are a major influence.[29] The most striking gender-based difference in immune system function is the remarkable female predominance of autoimmune diseases.[39] An estimated 78% of those affected by autoimmune disease are women.[32]

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.[40] Autoimmunity in males show less age-dependent variation. Autoimmune diseases prevalent in males typically present before the sixth decade with the appearance of autoantibodies, acute inflammation and an 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 year (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.[29] 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 effects.

Strict correlation of autoimmunity with estrogen levels, however, is not observed. Other female-predominant autoimmune diseases, such as MS and RA, worsen during pregnancy[41] and improve in the postmenopausal period (Table 3).[42]

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.[7] Anti-nuclear antibodies levels remain constant until approximately 60 years, and then rise. Approximately 5% of healthy individuals of that age have high anti-nuclear antibody titers (1:160), compared with 37% of those over 70 years of age.[43]

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,[44] 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.[32] 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.[32] Rising levels of antibodies, apart from the number of different specificities, are also associated with a generally increased risk of autoimmunity in old age.[7]

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.[7] Increased autoimmunity appears to be primarily the result of the combined effects of the reduction in naive 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.[45] Exposure to an infectious agent with molecular mimicry of a self-antigen may prompt a memory response.[15] 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.[46] Normal aging can also reduce the efficiency of normal physical immune barriers, resulting in increased pathogen intrusion.[47] Innate immunity also deteriorates with age, which can contribute to chronic immune stimulation. The persistence of high antigen levels can also make costimulatory T cells less susceptible to downregulation.[47]

Another source of B-cell memory activation are neoantigens, which are revealed by a progressive loss of tissue integrity and increased inflammation as individuals age.[48] Inappropriate activation of lymphocytes can also result from defective clearance of cellular debris, resulting in prolonged exposure to autoantigens.[47] Self-antigens may also acquire alterations that increase immunogenicity. For example, post-translational modification of proteins increases in immunosenescence; particular modifications, such as isoaspartyl formation, can trigger an autoimmune response.[47]

Improper self-antigen recognition by DCs and T-cell initiates, through release of specific cytokines (as described above), destructive Th1 or Th2 responses. RA, for example, is characterized by an exaggerated Th1 self-reactive immunity; SLE by an excessive Th2 response.[23] 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.[49]

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 the nutritional deficiencies common in old age with a negative impact on immunocompetence.[4]