Female Autoimmune Disease Research Articles

Mechanisms underlying sex differences in autoimmunity.

Autoimmune diseases are a leading cause of disability worldwide. Most autoimmune diseases occur more often in women than men, with rheumatic autoimmune diseases being among those most highly expressed in women. Several key factors, identified mainly in animal models and cell culture experiments, are important in increasing autoimmune disease in females. These include sex hormones, immune genes including those found on the X chromosome, sex-specific epigenetic effects on genes by estrogen and the environment, and regulation of genes and messenger RNA by microRNAs found in extracellular vesicles. Evidence is also emerging that viruses as well as drugs or toxins that damage mitochondria may contribute to increased levels of autoantibodies against nuclear and mitochondrial antigens, which are common in many autoimmune diseases. The purpose of this Review is to summarize our current understanding of mechanisms that may determine sex differences in autoimmune disease.

Pregnancy complications and new-onset maternal autoimmune disease.

Autoimmune diseases disproportionately impact women and female-specific aspects of reproduction are thought to play a role. We investigated the time-varying association between pregnancy complications and new-onset autoimmune disease in females during the reproductive and midlife years. We conducted a population-based cohort study of 1704553 singleton births to 1072445 females in Ontario, Canada (2002-17) with no pre-existing autoimmune disease. Pregnancy complications were preeclampsia, stillbirth, spontaneous preterm birth and severe small for gestational age (SGA). Royston-Parmar models were used to estimate the time-varying association between pregnancy complications and a composite of 25 autoimmune diseases from date of delivery to date of autoimmune disease diagnosis or censoring at death, loss of health insurance, or 31 March 2021. Models were adjusted for baseline socio-demographics, parity and comorbidities. At 19 years (median = 10.9 years of follow-up), cumulative incidence of autoimmune disease was 3.1% in those with a pregnancy complication and 2.6% in those without complications. Adjusted hazard ratio (AHR) curves as a function of time since birth were generally L-shaped. Universally, risks were most elevated within the first 3 years after birth [at 1 year: preeclampsia AHR 1.22, 95% confidence interval (CI) 1.09-1.36; stillbirth AHR 1.36, 95% CI 0.99-1.85; spontaneous preterm birth AHR 1.30, 95% CI 1.18-1.44; severe SGA AHR 1.14, 95% CI 0.99-1.31] and plateaued but remained elevated thereafter. Prior history of pregnancy complications may be an important female-specific risk factor to consider during clinical assessment of females for possible autoimmune disease to facilitate timely detection and treatment.

Impact of sex on immune-related adverse events in patients with melanoma.

e21548 Background: The clinical success of immune checkpoint inhibitors (ICIs) has predominantly conquered the modern scenario of the fight against cancer. Sex is a well acknowledged biological variable that affects immune responses to both self and foreign antigens. Indeed, recent meta-analyses of phase II and III trials of ICIs have focused on sex-related prognostic outcomes, reporting that both the overall and the progression-free survival are greater for males than females in melanoma, urothelial, and non-small-cell lung cancer. Conversely, very few studies have investigated the impact of sex on possible correlation with ICIs adverse events (AEs). Aim of this study is to identify female-male (F-M) differences in AEs developed in melanoma patients (pts) during anti-PD-1 treatment and to explore the related biological mechanism through a gene profiling analysis. Methods: Melanoma pts underwent anti-PD-1 delivery as adjuvant as well as first line treatment, who developed AEs from grade 2 onwards, according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, have been involved in the study. Gene profiling analysis was performed using NanoString IO360 panel, RNA was extracted from whole blood. Female-male differences in AEs were tested by Fisher's exact test. Volcano plot was used for graphical gene expression of fold change. Results: A total population of 161 melanoma pts has been analysed. With a total of 73 female pts and 88 male pts, arthralgia and nausea resulted as significant statistically different between female and male (p-value = 0.03 and < 0.01 respectively), with female pts most affected. A specific gene signature in female who developed arthralgia has been identified and characterized by the following genes: BCL2, EGFR, WNT10A, CTSS, IFITM2, HLA-B. These genes are involved in intracellular pro-apoptotic pathways activation and innate and adaptive immune responses activation. It has been already acknowledged that females are able to mount stronger innate and adaptive immune responses than males, which results in faster clearance of pathogens and greater vaccine efficacy in females than in males, but also explains the greater incidence of inflammatory and autoimmune diseases in females. Conclusions: In this study, we found a significant statistically sex difference of arthralgia and nausea during anti- PD-1 treatment in melanoma pts. Arthralgia in female is associated with a peculiar gene signature, which needs further investigation. Greater consideration should be given for researches that address the biological (sex) as well as sociocultural (gender) causes of F-M discrepancies in cancer immunotherapy. International collaborations have to be hugely promoted to increase knowledge in this field.

Sexual Dimorphism in Innate Immunity: The Role of Sex Hormones and Epigenetics.

Sexual dimorphism refers to differences between biological sexes that extend beyond sexual characteristics. In humans, sexual dimorphism in the immune response has been well demonstrated, with females exhibiting lower infection rates than males for a variety of bacterial, viral, and parasitic pathogens. There is also a substantially increased incidence of autoimmune disease in females compared to males. Together, these trends indicate that females have a heightened immune reactogenicity to both self and non-self-molecular patterns. However, the molecular mechanisms driving the sexually dimorphic immune response are not fully understood. The female sex hormones estrogen and progesterone, as well as the male androgens, such as testosterone, elicit direct effects on the function and inflammatory capacity of immune cells. Several studies have identified a sex-specific transcriptome and methylome, independent of the well-described phenomenon of X-chromosome inactivation, suggesting that sexual dimorphism also occurs at the epigenetic level. Moreover, distinct alterations to the transcriptome and epigenetic landscape occur in synchrony with periods of hormonal change, such as puberty, pregnancy, menopause, and exogenous hormone therapy. These changes are also mirrored by changes in immune cell function. This review will outline the evidence for sex hormones and pregnancy-associated hormones as drivers of epigenetic change, and how this may contribute to the sexual dimorphism. Determining the effects of sex hormones on innate immune function is important for understanding sexually dimorphic autoimmune diseases, sex-specific responses to pathogens and vaccines, and how innate immunity is altered during periods of hormonal change (endogenous or exogenous).

Altered ciliary morphofunction in the oviductal infundibulum of systemic autoimmune disease-prone MRL/MpJ-Faslpr/lpr mice.

According to our previous reports, impaired oocyte pickup was observed in the oviductal infundibulum of an autoimmune disease (AD) mouse model, suggesting a relationship between female infertility and AD. This study examines the relationship between AD and infundibulum morphofunction by focusing on the epithelial cilia. Healthy MRL/MpJ and AD-prone MRL/MpJ-Faslpr/lpr mice were examined at 3 and 6months of age, representing early and late disease stages, respectively. Oocyte pickup indices decreased with AD progression indicated by splenomegaly, autoantibody production and increased T cell counts of infundibulum mucosa in MRL/MpJ-Faslpr/lpr mice. Ciliary beating frequency (CBF) and height in the infundibulum were faster and higher in MRL/MpJ-Faslpr/lpr mice than in MRL/MpJ mice at the early AD stages, although the absolute CBF values were lower at the late AD stage. At the late stage, ciliary height did not differ between mouse lines but the morphological index of cilia beating direction indicated randomized patterns in MRL/MpJ-Faslpr/lpr mice. The tracheal mucosa was also examined as a representative example of cilia morphology; its CBF decreased at the late AD stage in MRL/MpJ-Faslpr/lpr; however, there were no AD-related morphological changes. Our results demonstrate altered cilia motility in systemic and reproductive organs, with such morphological changes of the infundibulum likely impairing function, including oocyte pickup.

ImmGen report: sexual dimorphism in the immune system transcriptome

Sexual dimorphism in the mammalian immune system is manifested as more frequent and severe infectious diseases in males and, on the other hand, higher rates of autoimmune disease in females, yet insights underlying those differences are still lacking. Here we characterize sex differences in the immune system by RNA and ATAC sequence profiling of untreated and interferon-induced immune cell types in male and female mice. We detect very few differentially expressed genes between male and female immune cells except in macrophages from three different tissues. Accordingly, very few genomic regions display differences in accessibility between sexes. Transcriptional sexual dimorphism in macrophages is mediated by genes of innate immune pathways, and increases after interferon stimulation. Thus, the stronger immune response of females may be due to more activated innate immune pathways prior to pathogen invasion.

The effect of NSAIDs exposure on breast cancer risk in female patients with autoimmune diseases.

Both breast cancer and autoimmune diseases (ADs) are predominant in women. NSAIDs are common medications for AD. Evidence on the association between NSAIDs use and breast cancer risk is controversial. We investigated the association between NSAIDs exposure and breast cancer risk in female patients with AD. AD patients older than 18 years of age were enrolled from Taiwan Longitudinal Health Insurance Database 2005. The NSAID users were defined as AD patients who had ever taken NSAIDs for at least 3 months between 2000 and 2009. All individuals were followed from the date of first diagnosis of AD to the end of 2013 to evaluate the risk of breast cancer. We estimated the adjusted hazard ratio (HR) using Cox proportional hazard regression after adjusting for age, comorbidities and medications. A total of 12 331 NSAID users and 12 331 non-NSAID users were included in this study after 1: 1 individual matching. The NSAID users were less likely to develop breast cancer than the non-NSAID users (adjusted HR: 0.37; 95% confidence interval: 0.27-0.50; P < 0.001), even if they used NSAIDs with low cumulative defined daily doses (adjusted HR: 0.42; 95% confidence interval: 0.34-0.53; P < 0.001). The incidence of new-onset breast cancer in NSAID users was significantly decreased in users taking selective cyclooxygenase 2 inhibitors, diclofenac, ibuprofen and piroxicam. Lower cumulative hazard rates were found in the AD patients who used NSAIDs (P < 0.001). NSAID exposure is associated with a decreased risk of breast cancer in female AD patients.

Evaluation of Diagnostic Significance and Cost Effectiveness of ELISA and IFA for the Diagnosis of Autoimmune Disorders

Background: The presence of antinuclear antibodies (ANA) is a hallmark of autoimmune diseases. As Clinicopathological classification of autoimmune diseases is difficult without laboratory support, laboratory testing is of helps in diagnosis, treatment, prognosis, and prediction of the pathological changes by disease activity. Although different tests are available for ANA detection enzyme linked immunosorbent assay (ELISA) is the mainstay of diagnosis in most routine laboratories. Indirect immunofluorescence antinuclear antibody test (IFA) though currently the “gold standard” it is not widely practiced. Most studies have used Hep2 cells for the detection of autoantibodies by IFA. However Hep 2000 Ro is superior compared to Hep 2 which lacks capability of detecting some autoantibodies like Ro antibodies. Hence, this study was undertaken to compare the diagnostic value and cost effectiveness of ANA pattern, ELISA with profile testing for patients suspected to have autoimmune disorders. Results: In the present study we observed high prevalence of autoimmune diseases in females (75.82%).ANA-ELISA in criteria matched cases with respect to ANA-IFA had a low sensitivity (59% versus 80%), higher specificity (84% versus 70%). Statistical analysis of ELISA and IFA with respect to ANA Profile showed a very less sensitivity by ELISA over IFA (51% vs. 78%) and equal specificity (70-72%) in 142 criteria matched cases. Conclusions: Statistically significant differences between ELISA and IFA infers IFA-ANA is a very appropriate method for screening purposes also IFA have capability of finding anti-mitochondrial and other cytoplasmic antibodies, which is not possible with ELISA.

Associations between attention-deficit/hyperactivity disorder and autoimmune diseases are modified by sex: a population-based cross-sectional study

Several studies have demonstrated associations between neuropsychiatric disorders, such as attention-deficit/hyperactivity disorder (ADHD), and the immune system, including autoimmune diseases. Since ADHD and many autoimmune diseases show sex-specific properties, such associations may also differ by sex. Using Norwegian national registries, we performed a cross-sectional study based on a cohort of 2,500,118 individuals to investigate whether ADHD is associated with common autoimmune diseases. Associations between ADHD and autoimmune diseases in females and males were investigated with logistic regression and effect modification by sex was evaluated. Several subanalyses were performed. The strongest association was found between ADHD and psoriasis in females, adjusted odds ratio (adjOR) = 1.57 (95% confidence interval: 1.46–1.68) and males, adjOR = 1.31 (1.23–1.40); p value for interaction < 0.0001. Furthermore, among females, ADHD was associated with Crohn’s disease, adjOR = 1.44 (1.16–1.79) and ulcerative colitis, adjOR = 1.28 (1.06–1.54). In contrast, males with ADHD had lower odds of Crohn’s disease, adjOR = 0.71 (0.54–0.92), in addition to a trend for lower odds of ulcerative colitis, adjOR = 0.86 (0.71–1.03); p values for interaction < 0.0001 and 0.0023, respectively. In a group of females where information on smoking and body mass index was available, adjustment for these potential mediators did not substantially alter the associations. Our findings support previously reported associations between ADHD and diseases of the immune system. The associations differ by sex, suggesting that sex-specific immune-mediated neurodevelopmental processes may be involved in the etiology of ADHD.

Influence of Oral and Gut Microbiota in the Health of Menopausal Women.

Sex differences in gut microbiota are acknowledged, and evidence suggests that gut microbiota may have a role in higher incidence and/or severity of autoimmune diseases in females. Additionally, it has been suggested that oral, vaginal, and gut microbiota composition can be regulated by estrogen levels. The association of vaginal microbiota with vulvovaginal atrophy at menopause is well described in the literature. However, the relevance of oral and gut microbiota modulation in the immune system during estrogen deficiency and its effect on inflammatory diseases is not well explored. Estrogen deficiency is a condition that occurs in menopausal women, and it can last approximately 30 years of a woman’s life. The purpose of this mini- review is to highlight the importance of alterations in the oral and gut microbiota during estrogen deficiency and their effect on oral and inflammatory diseases that are associated with menopause. Considering that hormone replacement therapy is not always recommended or sufficient to prevent or treat menopause-related disease, we will also discuss the use of probiotics and prebiotics as an option for the prevention or treatment of these diseases.

Presence of Autoimmune Diseases in Alopecia Areata Patients and Their Families and Its Effect on Prognosis

Objective: We aimed to investigate the role of autoimmunity in the etiopathogenesis of alopecia areata (AA) and the effects of the coexisting autoimmune diseases on the prognosis of AA. Methods: The records of 134 AA patients diagnosed in the dermatology and venereology outpatient clinic were retrospectively analyzed for the history of concomitant autoimmune disease and the family history for autoimmune diseases. Results: Of the 134 patients, 79 were males, 55 were females. The rate of autoimmune disease was 16.4%. The rate of autoimmune disease was found significantly higher in the females (p=0.034) and in the patients with a positive family history of autoimmune disease (p=0.011). No significant relationship was found between the coexistence of an autoimmune disease and the duration, type, severity of the disease, age at disease onset, nail involvement, atopy, nevus flammeus and family history of AA. The rate of the family history of autoimmune disease within the AA patients was 16.4%. Conclusion: The high rate of autoimmune disease in AA, prominent high rate of autoimmune disease in females, high rate of family history of autoimmune disease might prove the role of the autoimmunity in the etiopathogenesis of AA and suggested AA as an autoimmune disease. The coexistence of the autoimmune disease in AA has no relationship with poor prognosis.

Female Bias in Systemic Lupus Erythematosus is Associated with the Differential Expression of X-Linked Toll-Like Receptor 8.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of anti-nuclear antibodies. SLE is one of many autoimmune disorders that have a strong gender bias, with 70–90% of SLE patients being female. Several explanations have been postulated to account for the severity of autoimmune diseases in females, including hormonal, microbiota, and gene dosage differences. X-linked toll-like receptors (TLRs) have recently been implicated in disease progression in females. Our previous studies using the 564Igi mouse model of SLE on a Tlr7 and Tlr9 double knockout background showed that the presence of Tlr8 on both X chromosomes was required for the production of IgG autoantibodies, Ifn-I expression and granulopoiesis in females. Here, we show the results of our investigation into the role of Tlr8 expression in SLE pathogenesis in 564Igi females. Female mice have an increase in serum pathogenic anti-RNA IgG2a and IgG2b autoantibodies. 564Igi mice have also been shown to have an increase in neutrophils in vivo, which are major contributors to Ifn-α expression. Here, we show that neutrophils from C57BL/6 mice express Ifn-α in response to 564 immune complexes and TLR8 activation. Bone marrow-derived macrophages from 564Igi females have a significant increase in Tlr8 expression compared to male-derived cells, and RNA fluorescence in situ hybridization data suggest that Tlr8 may escape X-inactivation in female-derived macrophages. These results propose a model by which females may be more susceptible to SLE pathogenesis due to inefficient inactivation of Tlr8.

Cardiovascular and autoimmune diseases in females: The role of microvasculature and dysfunctional endothelium

Cardiovascular (CV) diseases are becoming increasingly frequent and associated with a high incidence of CV events, disability and death. It is known that there is a relationship between CV burden and systemic autoimmune diseases (SADs) that is mainly due to inflammation and autoimmunity, but the other mechanisms underlying the high CV risk of SAD patients have not yet been fully clarified.The aim of this review article is to discuss some of the specific factors associated with the accelerated atherosclerosis (ATS) characterising SADs (female sex, the microcirculation and the endothelium) in order to highlight the importance of an early diagnosis and the prompt implementation of preventive measures, as well as the possible role of new therapeutic strategies such as vaccine immunomodulation.Finally, as the natural history of ATS begins with endothelial injury (a potentially reversible process that is influenced by various factors) and microvascular damage plays a central role in the etiopathogenesis of SADs, it underlines the crucial need for the development of reliable means of detecting sub-clinical abnormalities in the microcirculation, particularly coronary microcirculation dysfunction.

Are Full Term Pregnancies and Induced Abortions Separate Risk Factors in Female Auto-immune Diseases?

Are Full Term Pregnancies and Induced Abortions Separate Risk Factors in Female Auto-immune Diseases?

Are Full Term Pregnancies and Induced Abortions Separate Risk Factors in Female Auto-immune Diseases?

Are Full Term Pregnancies and Induced Abortions Separate Risk Factors in Female Auto-immune Diseases?

Immune Cells Have Sex and So Should Journal Articles

Males and females have the same immunological cells, proteins, and pathways in place to protect against the development of disease. The kinetics, magnitude, and skewing of the responses mounted against pathogens, allergens, toxins, or self-antigens, however, can differ dramatically between the sexes. Generally, females mount higher innate and adaptive immune responses than males, which can result in faster clearance of pathogens but also contributes to increased susceptibility to inflammatory and autoimmune diseases in females compared with males. Hormonal and genetic factors contribute significantly to sex differences in immune function and disease pathogenesis. In particular, the expression of X-linked genes and microRNA as well as sex steroid hormones signaling through hormone receptors in immune cells can affect responses to immunological stimuli differently in males and females. Despite data illustrating profound differences between the sexes in immune function, sex differences in the pathogenesis of disease are often overlooked in biomedical research. Establishing journal policies that require authors to report the sex of their cells, animals, and subjects will improve our understanding of the pathogenesis of diseases, with the long-term goal of personalizing treatments for immune-mediated diseases differently for males and females in an effort to protect us equally.

Hyperemesis, gestational hypertensive disorders, pregnancy losses and risk of autoimmune diseases in a Danish population-based cohort

The risk of some female predominant autoimmune diseases (ADs) has previously been shown to be higher in women who experience hyperemesis, gestational hypertensive disorders and idiopathic pregnancy losses. This study assessed the association between such pregnancy-related experiences and the subsequent risk of female predominant and other ADs.Our study cohort comprised 1.6 million Danish women born since 1955 for whom we had information about hyperemesis, gestational hypertensive disorders and pregnancy losses and subsequent hospital contacts for 31 ADs between 1982 and 2008. Ratios of first hospitalization rates (RRs) with 95% confidence intervals (CIs) were calculated using Poisson regression, adjusting for age, birth cohort, calendar period, marital status and childbirths.During 27.0 million person-years of follow-up 51,732 women were hospitalized with one or more ADs. Overall, compared with women without the specific pregnancy experiences, the risk of any AD was significantly increased for women with hyperemesis (RR = 1.41; 95% CI 1.30–1.51), gestational hypertensive disorders (1.21; 1.16–1.26), spontaneous abortions (1.10; 1.07–1.14), missed abortions (1.09; 1.04–1.13), stillbirths (1.25; 1.12–1.40), ectopic pregnancies (1.08; 1.02–1.14) and induced abortions (1.07; 1.04–1.09). Associations with female predominant ADs (i.e., ADs with a female:male ratio >2:1) were strongest in the first five years after the studied pregnancy experiences, but overall there was little difference between the RRs for groups of female predominant ADs and other ADs. Strong and potentially biological associations were observed for a number of specific ADs; including systemic lupus erythematosus, Graves’ disease, type 1 diabetes mellitus and pernicious anemia, and for some specific ADs associations persisted even more than five years after the abnormal pregnancy experience.Abnormal pregnancies are associated with increased risk of certain ADs, possibly because of underlying immunologic or hormonal factors that predispose to both adverse pregnancy experiences and AD development.

Association ofGnRH1Polymorphisms with Rheumatoid Arthritis in a Korean Female

Purpose: Rheumatoid arthritis (RA) is a common, chronic inflammatory arthritis that develops most often in women. Gonadal hormones may account for the sexual dimorphism in the immune response and for the greater incidence of autoimmune disease in females. Gonadotrophin- releasing hormone (GnRH), one of the gonadal hormones, plays an important role in immune system modulation. This study examined the effects of single nucleotide polymorphisms (SNP) in GnRH on gender differences in the pathophysiology of RA. Materials and Methods: The presence of SNPs rs2659590, rs2321248, rs6186, rs6185, and rs2321 049 in the human GnRH1 gene was confirmed in Korean RA patients by Taqman SNP genotyping assays A total of 153 unrelated female, Korean RA patients and 96 female Korean controls participated. Results: There were no significant associations between GnRH1 polymorph isms and RA. However, we found that the rs2659590, rs6185 and rs2321248 polymorphism might be associated with a susceptibility to aberrantly high erythrocyte sedimentation rates in female RA patients. Conclusion: Additional studies, with a larger number of patients and in different populations will be required to assess whether GnRH1 polymorph isms and these haplotypes could be used as susceptibility or resistance markers in RA. To our knowledge, this study is the first to analyze associations between SNPs of GnRH1 and RA.

Sexual Dimorphism in Autoimmune Disease

We briefly survey the concept of autoimmunity and nominate the range of autoimmune diseases that include multisystemic and organ-specific disorders, and cite prevalences of autoimmune diseases in males and females, in humans and in experimental animals. Most human autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS) and autoimmune thyroid disease, have an increased incidence and prevalence in females, but a few others such as autoimmune diabetes, the Guillain Barré syndrome (GBS) and psoriasis are increased in males. Animal models of autoimmunity show an equivalent sexual dimorphism. The possible reasons for the differing incidence and prevalence of autoimmune diseases in females and males engage our attention. Environmental exposures may differ for females and males. There are innate differences in the function of the female and male immune systems, and there is some evidence for differences between females and males in the ability of a target organ for autoimmunity to withstand damage. In seeking reasons for these differences, we review the role of sex hormones in immunity and include results of trials of hormone therapy in autoimmune diseases. The association of autoimmunity and pregnancy, a female-specific condition, is discussed, and the claimed effects of lymphoid cell microchimerism on provocation of autoimmunity are reviewed. Genetic predisposition is an important factor in autoimmune disease and we particularly focus on genes on the X and Y chromosomes, the role of X chromosome inactivation, and the interaction of the sex of the patient with other genetic factors. The possible role of epigenetic mechanisms, including environmental influences, is then surveyed. We assert that sex is a vital variable that must be considered in all immunological studies, as it should be at all levels of biological research.

Estrogen Regulates CCR Gene Expression and Function in T Lymphocytes

Estrogen has been implicated in the observed female bias in autoimmune diseases. However, the mechanisms behind this gender dimorphism are poorly defined. We have previously reported that in vivo T cell trafficking is gender- and estrogen-dependent. Chemokine receptors are critical determinants of T cell homing and immune response. In this study, we show that the female gender is associated with increased CD4(+) T cell CCR1-CCR5 gene and protein expression in mice. The increased CCR expression correlates with enhanced in vitro chemotaxis response to MIP-1beta (CCL4). In vivo treatment of young oophorectomized and postmenopausal female mice with 17beta-estradiol also increased CD4(+) T cell CCR expression. Finally, 17beta-estradiol enhances tyrosine phosphorylation in T cells stimulated with MIP-1alpha in a time-dependent manner. Our results indicate an important role of estrogen in determining T cell chemokine response that may help explain the increased susceptibility and severity of autoimmune diseases in females.