A Gender Gap in Autoimmunity

Whitacre, Caroline C.; Reingold, Stephen C.; O'Looney, P; Blankenhorn, Elizabeth; Brinley, Floyd J.; Collier, Elaine; Duquette, Pierre; Fox, Howard S.; Giesser, Barbara; Gilmore, Wendy; Lahita, Robert G.; Nelson, J. Lee; Reiss, Carol Shoshkes; Riskind, Peter; Voskuhl, Rhonda R.

doi:10.1126/science.283.5406.1277

Cited by 774 publications

(559 citation statements)

References 3 publications

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“…The difference between men and women reported here suggests the involvement of sexually dimorphic steroid hormones, such as testosterone and estrogen that can have both inhibitory and stimulatory effects on different arms of the immune system [28,40]. However, peptide hormones such as insulin-like growth factor I, and prolactin may also be of interest because receptors for both are expressed by lymphocytes [41,42].…”

Section: Discussionmentioning

confidence: 93%

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Dominant effector memory characteristics, capacity for dynamic adaptive expansion, and sex bias in the innate Vα24 NKT cell compartment

2003

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V § 24 natural killer T (NKT) cells are innate immune cells that recognize self and nonself glycolipids presented by CD1d molecules, and play immunoregulatory roles in autoimmunity and tumor immunity. We have investigated the circulating V § 24 NKT cells in a large cohort of human subjects. CCR7 -CD45RO + effector memory cells dominated both CD4 + and CD4 -NKT subsets, while a minority displayed a central memory phenotype. CD4 -central memory NKT cells, however, were atypical in that they largely lacked CD62L expression. Overall, CD4 -NKT cells displayed a functional phenotype with effector characteristics, while the CD4 + subset appeared immunoregulatory. Interestingly, NKT cell numbers in blood varied widely between subjects, and elevated numbers of these cells were much more common in women than in men. The CD4 + subset dominated the NKT cell compartment in both sexes, while circulating NKT cell numbers above 0.1% were associated with an expanded CD4 -subset. Although NKT cell numbers were generally stable over time, we describe a dynamic fivefold expansion that was associated with a skewing of the NKT CD4 + :CD4 -ratio that persisted after numbers returned to base line. Thus, the two NKT cell subsets display different properties and dynamics that will influence their function as innate immunoregulatory and effector cells.

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Section: Discussionmentioning

confidence: 93%

“…Many autoimmune diseases are more prevalent in women and the mechanisms behind this sex bias are unclear [28]. Because V § 24 NKT cells are involved in regulation of immune tolerance and autoimmunity (reviewed in [1]), we were interested in comparing the circulating pool of these cells in men and women.…”

Section: Sex Bias In Circulating Nkt Cellsmentioning

confidence: 99%

Dominant effector memory characteristics, capacity for dynamic adaptive expansion, and sex bias in the innate Vα24 NKT cell compartment

2003

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“…Similar to other autoimmune diseases, MS is sexually dimorphic in that it occurs two times more frequently in women than in men [250]. This sexual dimorphism may be due to multiple factors; certainly gender-related differences in immune responsiveness are part of the cause, but sex hormones are likely to play a significant role ( [64,110]) as indicated by a series of observations: (a) the first clinical symptoms of MS develop post-puberty; (b) increased levels of sex hormones produced during pregnancy are associated with a significant reduction in the severity of MS; (c) MS clinical symptoms are often exacerbated postpartum, a time characterized by significant alternations in sex hormone levels; (d) MS symptoms are altered also during the menstrual cycle ( [1,16,45,127,188]).…”

Section: Estrogens and Multiple Sclerosismentioning

confidence: 99%

“…In addition, estrogen effect on immune function might be biphasic: specifically, low doses of estrogens promote Th1 responses and increase cell-mediated immunity, while high doses result in increased Th-2 responses ( [28,129]). Accordingly, women are more likely to develop a Th1 response to infective agents than men, so they are more susceptible to autoimmune diseases, except during pregnancy where women exhibit a pronounced Th2 response ( [5,183,250]). …”

Section: Estrogens and Multiple Sclerosismentioning

confidence: 99%

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Vegeto

Benedusi

Maggi

2008

Frontiers in Neuroendocrinology

262

201

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a b s t r a c tRecent studies highlight the prominent role played by estrogens in protecting the central nervous system (CNS) against the noxious consequences of a chronic inflammatory reaction. The neurodegenerative process of several CNS diseases, including Multiple Sclerosis, Alzheimer's and Parkinson's Diseases, is associated with the activation of microglia cells, which drive the resident inflammatory response. Chronically stimulated during neurodegeneration, microglia cells are thought to provide detrimental effects on surrounding neurons. The inhibitory activity of estrogens on neuroinflammation and specifically on microglia might thus be considered as a beneficial therapeutic opportunity for delaying the onset or progression of neurodegenerative diseases; in addition, understanding the peculiar activity of this female hormone on inflammatory signalling pathways will possibly lead to the development of selected anti-inflammatory molecules. This review summarises the evidence for the involvement of microglia in neuroinflammation and the anti-inflammatory activity played by estrogens specifically in microglia.

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“…The disease is normally diagnosed in young adulthood with women outnumbering men 2:1. 8 Its etiology is unknown, although environmental and genetic factors contribute to pathogenesis. Susceptibility genes have not been clearly identified, although the major histocompatibility complex HLA, particularly the DR2 haplotype, has been implicated.…”

Section: Introductionmentioning

confidence: 99%

Cell-based gene therapy experiments in murine experimental autoimmune encephalomyelitis

Louie

Weiner

et al. 2005

Gene Ther

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With the ultimate goal of developing a novel treatment for multiple sclerosis (MS), we have developed a cell-based gene therapy protocol for the treatment of murine experimental autoimmune encephalomyelitis (EAE), a powerful animal model for MS. We have determined that transduced fibroblasts secreting encephalogenic epitopes, when injected into mice with EAE, cause a striking abrogation of disease. Both myelin basic protein (MBP) and proteolipid protein mini-gene constructs expressed in syngeneic fibroblast cells were capable of ameliorating ongoing EAE induced by MBP protein. These experiments are crucial since they suggest that not all encephalogenic epitopes need be secreted for the control of disease. We also demonstrate the success of this protocol when transduced syngeneic, and most importantly, allogeneic cells are sequestered within an implantable chamber. Furthermore, we find that through modifying antigen expression by changing the signal sequence of the mini-gene construct, we were able to significantly reduce the dose of cells required for treatment. These improvements to the minigene delivery system are critical for the eventual translation of our protocol to the clinic.

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A Gender Gap in Autoimmunity

Cited by 774 publications

References 3 publications

Dominant effector memory characteristics, capacity for dynamic adaptive expansion, and sex bias in the innate Vα24 NKT cell compartment

Dominant effector memory characteristics, capacity for dynamic adaptive expansion, and sex bias in the innate Vα24 NKT cell compartment

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Cell-based gene therapy experiments in murine experimental autoimmune encephalomyelitis

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