Many years ago Mary Lyon suggested that, in order to maintain equivalent expression of X-encoded genes between males and females, one of the X chromosomes in each female cell should be inactive Escape of these genes is clearly important for female health, as illustrated by Turner syndrome, a chromosomal disorder of females caused by complete or partial loss of an X chromosome Interestingly, patients with Turner syndrome have a higher risk of developing autoimmune diseases than do females in general However, patients with Turner syndrome exhibit a greater risk of autoimmune diseases characterized by male predominance 72 , and Turner syndrome rarely overlaps with the profoundly female-biased disease SLE 73 — Symptoms that appear in patients with Klinefelter syndrome also suggest a role for genes on the partially inactivated X chromosome in the immune system.
Males with this disorder have two X and one Y chromosome. It has been reported that there is a fold increase in the prevalence of SLE in these males compared with the general male population As such, males with the XXY karyotype have a risk of developing SLE that is similar to that of the general female population. In addition, several reports suggest that expression of genes from the partially inactive X chromosome can play a role in autoimmunity 77 , Thus, Turner and Klinefelter syndromes indicate that aberrations in the content of X chromosomes in the host do affect autoimmune disease, although the one-to-one linkage between numbers of X and Y chromosomes and particular diseases is still unclear.
Studies establishing a role for X-linked genes lead to the question of whether there are any candidate genes located on the X chromosome that could potentially play a role in the development of autoimmunity. The role of intracellular TLRs in the development of autoimmunity has been extensively studied and is reviewed by others in this issue. In brief, it is well accepted that TLR7 and TLR9 are among the critical players during the development of lupus-like autoimmunity TLR9 deficiency leads to the worsening of the disease 47 , 48 , whereas TLR7-deficient animals are partially protected from lupus Several studies have demonstrated that the dosage of Tlr7 and Tlr8 plays an important role in the development of both murine and human lupus.
For instance, a recent study performed by Umiker and colleagues suggests a role for X-linked Tlr8 dosage in the development of SLE in Igi mice Likewise Tlr7 dosage has been demonstrated to play a role in the development of SLE in mice and humans 85 — Together these data suggest that Tlr7 and Tlr8 , due to their localization on X chromosome, might be overexpressed in females and thus lead to the elevated risk for the development of anti-RNP antibodies and lupus.
Our group has recently described another role for Tlr7 in autoimmunity. In particular, we have identified a subset of B cells age-associated B cells [ABCs], discussed in greater detail below , which appear in both aged female wild-type and young autoimmune mice The appearance of these cells is dependent on intact TLR7 signaling. It is possible that, due to its location on the X chromosome, Tlr7 is overexpressed in females, leading to the accumulation of ABCs in a gender-dependent manner, thereby contributing to female-biased autoimmunity.
Further studies will be required to formally test this hypothesis. Because X chromosome inactivation XCI occurs in early embryonic development, one of two X chromosomes in each cell is inactivated. This is a random and permanent process and, as a result, most females contain a mix of cells expressing the X chromosome of maternal or paternal origin Interestingly, skewed XCI is associated with autoimmune diseases.
Significant XCI skewing has also been observed in patients with RA and those with autoimmune thyroiditis 90 , However, these studies were performed using unseparated PBMCs; therefore, it is still unclear whether different immune cells exhibit similar XCI skewing with age. It has been reported that miRNAs are differentially expressed between males and females in both gonadal and non-gonadal tissues 95 — Several studies indicate numerous dysregulated miRNAs in human and murine lupus, suggesting a role for miRNAs in the development of the disease 98 , It is not entirely clear what drives differential expression of miRNAs in males and females.
Although the functions of the majority of X-linked miRNAs remain unknown, some of these miRNAs are reported to play a role in the regulation of immune responses or are associated with autoimmunity — Overall the data indicate that the presence of a second X chromosome in females can markedly affect the expression levels of multiple genes and miRNAs, which might be crucial for the development of female-biased autoimmunity.
The significance of the microbiota for the development of T1D in NOD mice was recently recognized Another group has reported that hormones mediate sex-based microbiota differences. Castration of male NOD mice reversed the microbiotic differences usually observed between male and female NOD animals These data indicate that sex hormones influence the microbiota in a sex-specific way. In turn, the microbiota causes changes in gene expression that may lead to sex bias in the development of autoimmunity Figure 1.
An effect of the microbiota has been also reported for the models of ankylosing spondylitis and RA , ; however, no effect has been observed in the severity or the prevalence of lupus in GF MRL lpr mice , which indicates that not all autoimmune diseases are affected by microbiota.
Most autoimmune diseases do not develop in childhood but instead affect adults between 40 to 60 years of age. Do male and female immune systems age similarly? Is it possible that some age-related differences occur in sex-dependent fashions, leading to the sex-biased predisposition to autoimmunity? Two reports indicate that aging affects female and male immune systems differently.
Another recent study performed on ethnically Japanese populations of males and females of different ages reported similar age-related changes in immune cell populations. Our group and others have also studied the differences in immune cell populations in aged male and female mice. These data indicate that aged female mice accumulate ABCs 49 , — , a subset of B cells defined by the expression of cell surface CD11c and the transcription factor T-bet 49 , , These data lead us to hypothesize that age-associated biological changes in females both contribute to the appearance of ABCs and occur during the onset of autoimmunity.
Both processes are sex dependent, which suggests that the same mechanism is involved. This finding is particularly intriguing because the Tlr7 gene is encoded on the X chromosome, offering a potential explanation for the sex bias in the appearance of these cells It is often noted that some of the female-biased autoimmune diseases are diagnosed in middle-aged individuals, rather than earlier in life when factors such as sex hormones are at peak levels.
Some explanations for this paradox have been mentioned above, but it is also worth pointing out that the initial event in autoimmune disease, a breakage in tolerance to self, may actually occur long before the clinical manifestations of the illnesses are manifest. Therefore the crucial problem may indeed occur at a time when estrogens and androgens are at their peak concentrations in the host. As detailed above, numerous studies have been performed in an attempt to identify the factors that drive sex bias in autoimmunity. It is important to ask where these reports will lead the field in terms of possible therapeutic interventions.
What are the possible outcomes of these studies? The data on the hormonal effects have to be considered when hormonal replacement therapy or treatment with testosterone is used on autoimmune patients. Moreover, the potential immunosuppressive effects of testosterone might make the hormone a useful treatment for patients with autoimmune disorders.
The data on differential gene expression between genders suggest new potential targets for drug development. It is likely that the factors reviewed here act simultaneously. Overexpressed X-linked genes and sex hormones probably act together in a synergistic manner, leading to a greater female-biased predisposition to autoimmunity. At the same time male hormones in combination with a single X chromosome significantly reduce the risk of autoimmunity. In summary, it is critical to consider all of these factors while developing novel therapeutics for sex-biased autoimmune diseases.
The data reviewed here indicate that immune responses in males and females are differentially regulated by several factors that lead to differences in gene expression profiles Figure 1. It is important to appreciate both the cause and the outcome of these changes in order to improve our understanding of sex differences in autoimmunity and immune responses in general. More work is required on how sex-specific factors like sex hormones and X chromosome numbers affect particular populations of immune cells and ultimately lead to the development of autoimmunity, in order to generate novel therapeutic targets for autoimmune disorders that have no cure at the present.
Go to JCI Insight. Top Abstract Introduction Sex hormones affect the incidence of autoimmunity Sex hormone effects on gene expression and autoimmunity IFNs and feedback loops involving sex hormones Other immune-associated genes affected by sex hormones X-linked genes in the sexual dimorphism of autoimmunity X chromosome—encoded microRNAs in sexual dimorphism Gut microbiota: sex differences and influence on autoimmunity Sex-dependent changes in the aging immune system Possible therapeutic interventions Concluding remarks Acknowledgments Footnotes References Version history.
First published April 27, - Version history. Abstract Autoimmune diseases occur when the immune system attacks and destroys the organs and tissues of its own host. Figure 1 Sex-specific factors that lead to sex bias in autoimmunity. Conflict of interest: The authors have declared that no conflict of interest exists. Reference information: J Clin Invest. Oertelt-Prigione S. The influence of sex and gender on the immune response. Autoimmun Rev. View this article via: PubMed Google Scholar. Therefore, the presence of an IgM antibody directed against the hepatitis B core antigen anti-HBc-IgM is helpful in the differentiation of acute vs chronic infection Table 2.
Antibody to HBsAg anti-HBs is produced in people with resolved infection and is the only serologic marker present in vaccinated individuals. The appearance of HBV markers occurs in a predictable pattern. HBV DNA red bars is detectable very early in infection and declines until approximately 36 weeks after infection onset. HBV antigens green bars appear within 4—6 weeks after exposure and serve as good markers of acute infection.
HBV antibodies appear approximately 6 weeks after infection. IgG antibodies to the core and surface antigens generally persist for life and serve as a marker of chronic or past infection. Summary of interpretations of HBV virologic and serologic test results. Major efforts to vastly decrease the incidence of HBV infection include strategies aimed at increasing vaccination rates and preventing vertical transmission of HBV from a mother to her infant. The Advisory Committee on Immunization Practices ACIP recommends vaccination of infants at birth, of all previously unvaccinated children and adolescents, and of previously unvaccinated adults who are at increased risk of infection 68 , Current guidelines for the treatment of HBV infection are reviewed elsewhere More than 3 million people in the US are chronically infected with blood-borne HCV, and global prevalence is increasing worldwide.
Chronic HCV infection causes considerable morbidity due to increased risk of liver cirrhosis, hepatocellular carcinoma, and liver failure. Because there is no effective vaccine for HCV, current efforts are focused on effective screening measures and treatment of infected individuals, and several recent advances in these areas may improve the clinical outcomes of infected patients. In the past, screening for HCV was recommended for individuals, such as intravenous drugs users, considered at high risk for HCV transmission. However, chronic HCV infection is frequently asymptomatic, and many infected individuals are unaware of their diagnosis Therefore, the CDC has recently updated screening guidelines to include one-time HCV antibody testing for any individual born between and , even in the absence of identifiable risk factors.
It has been demonstrated that people in this cohort are approximately 6 times more likely to have been exposed to HCV than adults in other age cohorts 74 , For a review of performance characteristics of these assays, we refer the reader to Kamili et al. However, this method is no longer widely used and is unavailable in the US. Once a diagnosis is confirmed, HCV genotype 1—6, with numerous subtypes should be determined, as the specific molecular makeup of the virus has important implications for treatment options.
The treatment of HCV infection is rapidly evolving from an interferon-based therapy to an interferon-free regimen that is based on direct-acting antiviral agents. These new therapeutics have markedly increased rates of sustained virologic response and more acceptable side effect profiles. Physicians have swiftly embraced therapy with direct-acting antiviral agents, so management of HCV for both clinicians and laboratorians is rapidly evolving 78 — More than subtypes of human papillomaviruses HPVs cause infection of human epithelial or mucosal surfaces, depending on tissue tropism.
Subtypes 6 and 11 are most often associated with genital warts, whereas infection with high-risk subtypes including 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68 are linked to cervical and rectal neoplasia The burden of HPV infection is high in the US and worldwide, with an estimated overall prevalence of Approximately half a million cases of cervical cancer are diagnosed annually.
HPV infection is usually asymptomatic and self-limiting. When symptoms are present, they may manifest as benign raised lesions in the genital area. Cervical cancers that arise from HPV infection may present as abnormal cervical cytology screening or with irregular vaginal bleeding. HPV is spread by contact with infected mucosal surfaces.
Therefore, vaginal and anal intercourse are major risk factors for transmission of the virus The incidence of cervical cancer has steadily declined since the initiation of widespread screening in the US and other developed countries 85 , Despite this decline, a survey estimated that Beginning at 21 years of age, cervical cytological screening is recommended to detect invasive cervical cancer. Annual screening is no longer recommended.
Instead, women should be screened every 3 years until age Specimens for HPV testing include the same swab used for cytology testing, a separate swab, or the residual fluid from liquid-based cytology testing SurePath cytology specimens, however, are not FDA cleared, owing to higher than acceptable rates of false-negative tests that may be due to degradation of HPV nucleic acid in the cytology fluid Owing to the high negative predictive value of coscreening, women screened with Pap and HPV testing should be screened every 5 years 89 , Currently available nucleic acid amplification tests for detection of human papilloma virus a.
Prevention of cervical cancer resulting from HPV infection is possible with vaccination. All 3 of these vaccines cover the oncogenic subtypes 16 and 18, and the quadrivalent vaccine additionally covers subtypes 6 and 11, which are the most common causes of genital warts. The quadrivalent and 9-valent vaccines are approved for use in males. Data from a CDC survey indicates that Coverage of boys was even lower, with Vaginitis is a common gynecologic condition, especially during a woman's reproductive years.
It is characterized by abnormal vaginal discharge, itching, or odor. While most cases of vaginitis are caused by vulvovaginal candidiasis, many can be attributed to sexually transmitted infections caused by bacterial vaginosis and trichomoniasis. Bacterial vaginosis BV occurs upon depletion of Lactobacillus species and overgrowth of other bacteria that results in a dysbiosis of the normal vaginal flora BV is the most common cause of abnormal vaginal discharge in women presenting for clinical care.
The cause of the microbial inequality that triggers BV is a subject of ongoing controversy, but women with BV are at increased risk of acquiring and transmitting other STIs 96 , Although considered the historical gold standard, gram staining of vaginal discharge is infrequently used for BV diagnosis. The stain may reveal the presence of bacterial morphologies characteristically associated with BV. In spite of this, the use of clinical criteria for diagnosis is more common because of the time, expense, and expertise required for the gram staining method.
Current molecular testing methods for BV provide an incomplete picture for diagnosis and are focused on the presence or absence of a few BV-associated microorganisms. However, detection of these organisms alone is not adequate to establish the diagnosis, and results should be correlated with clinical signs and symptoms of BV. Because of the complex polymicrobial nature of BV, culture has no role in the diagnosis of infection. Owing to the increased risk of acquisition of other STIs, treatment is advised for symptomatic women. The recommended regimen consists of topical or oral metronidazole or topical clindamycin Trichomoniasis is an infection of the urogenital tract caused by the protozoan Trichomonas vaginalis.
It is one of the most common nonviral causes of STI, with a prevalence of 3. Although most infections are asymptomatic, some women experience diffuse yellow-green discharge and vulvar irritation. The organism has been linked to adverse pregnancy outcomes, including increased risk of preterm birth, premature rupture of membranes, and delivery of an infant with decreased birth weight in infected women There is insufficient data to support routine screening for T.
Screening for trichomoniasis is not recommended as part of routine prenatal care in asymptomatic women 20 , — However, because of possible adverse outcomes in pregnancy, pregnant women exhibiting symptoms of T. Diagnostic testing for trichomoniasis is usually done in conjunction with Chlamydia and gonorrhea testing.
Detection of trichomonads by wet-mount microscopy is low cost and convenient and thus commonly used. The gold standard for detection of T.
FDA-cleared NAAT assays are available that test vaginal, cervical, or urine specimens from women and, recently, urine specimens from men. Diagnostic sensitivity may be increased by following an algorithm in which a negative wet mount is followed by NAAT In addition, less sensitive rapid antigen tests are available at the point of care that are FDA approved for vaginal secretions in women.
Diagnostic methods and therapeutic guidelines for STIs are rapidly evolving.
Ann Intern Med ; : — 91 , W Customer Service. The award, which will sit alongside the Public Service Medal he won in , was awarded for Dr Parkinson's "eminent service to the Australian community Ann Intern Med ; : 58 — In the past, screening for HCV was recommended for individuals, such as intravenous drugs users, considered at high risk for HCV transmission. If you have had a miscarriage or termination of pregnancy, you must wait six-weeks before you are eligible to donate.
This evolution, in combination with changing epidemiology, development of novel therapeutics, and advancements in diagnostic methods, has resulted in changing practices in laboratory testing and, subsequently, management of disease. Thus, both awareness and understanding of testing methods are necessary for accurate and timely diagnosis of these important causes of infection. Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: a significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; b drafting or revising the article for intellectual content; and c final approval of the published article.
Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest. Skip to main content. Review Article Review. Melanie L. Yarbrough , Carey-Ann D. DOI: Louis, MO View this table: View inline View popup. Table 1. Clinical features and screening recommendations for common STIs. Cervicitis and Urethritis Inflammation of the cervix is characterized by a purulent endocervical exudate and easily induced cervical bleeding. Genital Ulcerative Disease Genital ulcers can have infectious or noninfectious etiologies.
SYPHILIS Syphilis, which is caused by the bacterium Treponema pallidum , is divided into primary, secondary, and tertiary stages of infection, depending on clinical manifestation. Screening and diagnostic testing. Human Immunodeficiency Virus Approximately 1. Timeline of virologic and serologic markers of HIV infection. Viral Hepatitis Hepatitis may result from many infectious and noninfectious causes. Appearance of virologic and serologic markers in acute HBV infection.
Table 2. Human Papilloma Virus More than subtypes of human papillomaviruses HPVs cause infection of human epithelial or mucosal surfaces, depending on tissue tropism. Table 3. Vaginitis Vaginitis is a common gynecologic condition, especially during a woman's reproductive years.
Conclusion Diagnostic methods and therapeutic guidelines for STIs are rapidly evolving. References 1. The estimated direct medical cost of selected sexually transmitted infections in the United States, Sex Transm Dis ; 40 : — Centers for Disease Control and Prevention. Sexually transmitted disease surveillance Gonococcal infections in newborns and in adolescents. Adv Exp Med Biol ; : — LeFevre ML. Ann Intern Med ; : — Sexually transmitted infections among US women and men: prevalence and incidence estimates, Clinic-based testing for rectal and pharyngeal Neisseria gonorrhoeae and Chlamydia trachomatis infections by community-based organizations—five cities, United States, The cost-effectiveness of screening men who have sex with men for rectal chlamydial and gonococcal infection to prevent HIV infection.
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