Abnormal Autoimmune Function Research Articles

Transcriptome analysis of the potential molecular mechanism of enteritis in intestine and hepatopancreas of Litopenaeus vannamei

The prawn, Litopenaeus vannamei (L. vannamei), is the most widely farmed species in the world but the incidence of enteritis in L. vannamei has increased in recent years. However, the pathogenesis of enteritis remains unclear. In this study, high-throughput sequencing was used to analyze the hepatopancreatic and intestinal transcriptome of healthy and enteritis-affected individuals from the same pond. In total, 1209 and 1608 differently-expressed genes (DEGs) were detected in the hepatopancreatic and intestinal transcriptomes, respectively. Significantly changed genes were enriched in the intestinal immune network for IgA Production, Lysosomes, Sphingolipid Metabolism and the Peroxisome Signaling Pathway. Expression of the integrin α4β7 gene was significantly increased in the intestine of L. vannamei with enteritis, while expression of 38 DEGs associated with the lysosome was significantly down-regulated. Furthermore, the expression of sphingolipid metabolism-related enzymes and superoxide dismutase (SOD) genes was also significantly decreased, indicating that abnormal autoimmune function, weak intestinal resistance to external pathogenic microbial invasion, and self-healing ability were important factors associated with enteritis in L. vannamei. In addition, the expression of trypsin and pancreatic lipase was decreased in the hepatopancreas of L. vannamei with enteritis. This study provided new insights into the possible molecular pathogenesis of enteritis in L. vannamei.

Etiology of granulomatous lobular mastitis based on metagenomic next-generation sequencing

Objectives: We aimed to comprehensively explore the etiology of granulomatous lobular mastitis (GLM) to optimize treatment programs.Methods: We collected 30 fresh mastitis samples for metagenomic next-generation sequencing, morphological observation, and analysis of the clinical information.Results: Of the 30 samples, 25 were GLM; pathogens were detected in 17, these were: Corynebacterium kroppenstedtii (10 of 25, 40%); C. kroppenstedtii and Pseudomonas oleovorans (3 of 25, 12%); C. kroppenstedtii and human gammaherpesvirus 4 (1 of 25, 4%); Acinetobacter baumannii and C. kroppenstedtii (1 of 25, 4%); P. oleovorans (1 of 25, 4%); and Tepidiphilus thermophilus (1 of 25, 4%). Abnormal sex hormone levels (mainly prolactin) and/or autoimmune function were found in 12 of the 25 samples. Lipophilic antibiotics (rifampicin) were found to work effectively in patients with slow-healing wounds after surgery.Conclusions: The main pathogenic factor of GLM is C. kroppenstedtii infection, but other unusual pathogens (P. oleovorans, human gammaherpesvirus 4, A. baumannii, T. thermophilus) are likely to be closely related to GLM, particularly human gammaherpesvirus 4 (Epstein-Barr virus)-associated mastitis, which may be a new entity of mastitis. Abnormal levels of sex hormones and autoimmune function are also common causes. Therefore, lipophilic antibiotics (rifampicin) and prolactin inhibitors may be an effective treatment.

Dehydroepiandrosterone improves the ovarian reserve of women with diminished ovarian reserve and is a potential regulator of the immune response in the ovaries.

Diminished ovarian reserve (DOR) has a high morbidity rate worldwide and has become a primary cause of infertility. DOR is a daunting obstacle in in vitro fertilization (IVF) and leads to poor ovarian response, high cancellation rates, poor IVF outcomes, and low pregnancy rates. Abnormal autoimmune function may also contribute to DOR. Dehydroepiandrosterone (DHEA) is a C19 androgenic steroid. DHEA is secreted mainly by the adrenal gland, and its secretion declines with age. DHEA has a pro-inflammatory immune function that opposes cortisol. The cortisol to DHEA ratio increases with age, which may lead to decreased immune function. DHEA supplementation helps improve this situation. A number of clinical case control studies and several prospective randomized clinical trials have observed a positive effect of DHEA supplementation in women with DOR. However, the underlying mechanism by which DHEA improves ovarian reserve remains unclear. DHEA functions as an immune regulator in many different tissues in mammals and may also play an important role in regulating the immune response in the ovaries. The conversion of DHEA to downstream sex steroids may allow it to regulate the immune response there. DHEA can also enhance the Th1 immune response and regulate the balance of the Th1/Th2 response. DHEA treatment can increase selective T lymphocyte infiltration in mice, resulting in a decline in the CD4+ T lymphocyte population and an upregulation of the CD8+ T lymphocyte population in ovarian tissue, thus regulating the balance of CD4+/CD8+ T cells. This review mainly focuses on how DHEA supplementation affects regulation of the immune response in the ovaries.

Is the immunological noise of abnormal autoimmunity an independent risk factor for premature ovarian aging?

The risk for premature ovarian failure increases in association with two principal known etiologies: in the presence of excessive triple CGG expansions on the FMR1 (fragile X) gene (genetic etiology) and in association with a variety of autoimmune conditions (autoimmune etiology). To what degree milder forms of premature ovarian aging are also associated with these two etiologies is, however, unknown. We, therefore, investigated 119 consecutive, so identified, infertile women and statistically correlated by linear and logistic regression analyses ovarian function parameters to markers of a possible genetic etiology (number of CGG triple repeats on the FMR1 gene) and to markers of possible abnormal immune function (immune panel). Sixty (50.4%) of 119 participants demonstrated at least one immune abnormality. Both groups did not differ statistically in age, mean follicle-stimulating hormone, estradiol, and antimüllerian hormone levels, although antimüllerian hormone suggested a trend toward higher levels in autoimmune participants (P = 0.19). Autoimmune participants also demonstrated lower mean triple CGG expansion sizes (P < 0.05) and included fewer women with greater than or equal to 35 triple repeats (relative risk, 4.0; 95% CI, 1.3-11.9; P < 0.01), previously reported to demarcate increased risk for premature ovarian aging. Even minimal evidence of abnormal autoimmune function ("immunological noise") seems to increase risk toward premature ovarian aging, often manifesting as infertility. Evidence of abnormal autoimmune function, such as increased CGG triple expansion sizes, in young women, therefore, warrants vigilance for development of prematurely diminished ovarian reserve and infertility.

Autoimmune function and number of triple CGG expansions on the FMR1 gene as independent risk factors for premature ovarian senescence

OBJECTIVE: Preliminary data suggest that numbers of triple CGG expansions on the FMR1 gene and the presence of autoimmune laboratory abnormalities distinguish two specific geno- and phenotypes amongst women with premature ovarian senescence (Gleicher et al., Fertil Steril, doi:10/1016/j.fernstert.2008.01.099). This study attempted in a larger patient sample and with higher statistical power, to confirm whether increasing triple CGG expansions sizes and abnormal autoimmune function represent independent risk factors for premature ovarian senescence. DESIGN: Cohort study. MATERIALS AND METHODS: 119 new, consecutive infertility patients with diminished ovarian reserve were investigated for number of CGG triple expansions on the FMR1 gene and evidence of abnormal autoimmune function. Statistical correlations were calculated with the higher of two allele triple repeat counts, designated as allele-2. Below (<) versus above (≥) 35 triple repeats defined the cut off between normal and elevated triple repeats, which denotes genetic risk for premature ovarian senescence (Gleicher et al., Fertil Steril, doi:10/1016/j.fertnstert.2008.01.098). To prevent statistical distortions from only few high triple repeat expansion sizes, associated with pre- and full fragile X mutations, this study was restricted to <55 triple repeats, the upper limit of the intermediate zone. RESULTS: 59/119 women showed no evidence of autoimmunity and 60 did. Mean ages (36.8 ± 5.2 vs. 36.0 ± 4.8 years), baseline follicle stimulating hormone (FSH) (13.6 ± 11.2 vs. 16.0 ± 26.0 mIU/ml), estradiol (51.4 ± 26.8 vs. 52.5 ± 26.2 pg/ml) and anti-Müllerian hormone (AMH) (0.97 ± 1.0 vs. 1.4 ± 2.0 ng/ml) did not differ significantly between both groups. CGG triple repeats on allele-1 also did not differ (28.5 ± 5.6 vs. 27.4 ± 4.4). Allele-2, however demonstrated significantly higher mean allele counts in non-immune than autoimmune patients (33.3 ± 5.6 vs 31.3 ± 4.2; p < 0.05). CONCLUSIONS: These data confirm a high prevalence of abnormal autoimmune function in infertile women with diminished ovarian reserve. They also suggest that abnormal autoimmune function helps to define two etiologically distinct patient subgroups of women with premature ovarian senescence, one autoimmune, defined by abnormal autoimmune function, and the second genetic, defined by abnormal triple CGG expansion sizes.

Relevance of low expansion CGG triple repeats numbers on the FMR1 gene to functional ovarian reserve

OBJECTIVE: A large majority of individuals demonstrate 29-30 CGG repeats on the FMR1 gene. Thirty CGG repeats have also been reported as the switching point between positive and negative effects of the translation product of the FMR1 gene. A minority amongst all ethnicities demonstrate higher or lower expansion sizes. Higher expansion sizes have been statistically correlated to risk towards premature ovarian senescence and diminished ovarian reserve, which seems independent of risk towards premature ovarian senescence associated with abnormal autoimmune function. Whether lower expansions sizes also correlate with ovarian function was subject of this study. DESIGN: Cohort study. MATERIALS AND METHODS: 300 consecutive new infertility patients, of which 81 demonstrated ≤28 triple CGG repeats on the lower count allele (allele-1), represented the study population. Triple CGG expansion sizes on allele-1 were statistically correlated by linear and logistic regression analyses to ovarian reserve parameters [FSH and AMH] in women with ≤28 repeats (low expansion sizes) and ≥ 34 repeats (high expansion sizes), thus excluding women with > 28 – 33 repeats, representing the distribution peak for most humans and, therefore, a large majority of all women (Fu et al, Cell 1991). RESULTS: Low expansion size did not differ from high expansion size patients in age, FSH and AMH levels. Neither FSH nor AMH statistically correlated in linear regression with triple CGG expansions ≤28 repeats. Logistic regression demonstrated, however, that an AMH level ≤0.8 ng/ml (indicative of diminished ovarian reserve at all ages) was significantly associated with triple CGG repeats on allele-1 (p<0.001). An increase by 5 triple expansions ≤28 repeats reduced risk for diminished ovarian reserve by 40%, while an increase by 5 triple expansions in women with ≥34 repeats increased risk by 50% (p= 0.002, each). CONCLUSIONS: High (≥34) and low expansion sizes (≤28) statistically correlate with risk towards diminished ovarian reserve. This for the first time explains the unusual distribution pattern of triple CGG repeats in the population, characterized by a large peak at 29-30 repeats. As Chinese women demonstrate, CGG distribution patterns vary between ethnicities, which may relate to reported differences in prevalence of premature ovarian senescence and IVF outcomes.

Does autoimmunity play a causative role in the pathophysiology of premature ovarian aging (POA)?

Does autoimmunity play a causative role in the pathophysiology of premature ovarian aging (POA)?

Female infertility due to abnormal autoimmunity: frequently overlooked and greatly underappreciated. Part II

Part II of this article continues the presentation of evidence in support of the major impact of abnormal autoimmune function on human female reproduction. After concentrating on nonorgan-specific autoimmune conditions in Part I of this series, this article addresses organ-specific autoimmune conditions that cause female infertility. Based on literature searches, autoimmunity to endocrine organs appears to represent a significant cause of female infertility. This autoimmunity can be directed at both nonsteroid- and steroid-producing endocrine organs and can present as single-organ disease or in the form of multiple autoimmune endocrinopathies. As with nonorgan-specific autoimmunity, organ-specific autoimmunity demonstrates typical presentations, which include familial occurrence, genetic predisposition, commonality of occurrence with other autoimmune conditions and transition through pre-/subclinical stages on the way to overt clinical expression. In contrast to nonorgan-specific autoimmune conditions, or...

Gender as risk factor for autoimmune diseases

Most autoimmune diseases occur significantly more frequently in women than men. This female preponderance for abnormal autoimmune function has largely gone unexplained. Many investigations have concentrated on the effects of female and male sex hormones on immune function, by suggesting that estrogens favor the antibody production-enhancing Th2 response and, by doing so, possibly, increase the risk towards abnormal autoimmune function. Others have suggested that women are genetically predisposed towards abnormal autoimmune function, possibly because the X chromosome may confer susceptibility towards tolerance breakdown. Recent developments have, however, opened new research avenues. The possible association between persistent fetal–maternal microchimerism and the development of autoimmune diseases has attracted special interest. Since, in analogy to allogeneic organ transplantation, fetal–maternal (and maternal–fetal) microchimerism may play an important role in the immunologic tolerance of the fetal semi-allograft, female preponderance for autoimmune diseases may be understood as a consequence of increased allogeneic cell traffic in females (in comparison to males), increased risk for long-term microchimerism and, therefore, as a consequence of the former two, the development of abnormal autoimmunity. Under an evolutionary view point the occurrence of autoimmune diseases, in general, can be seen as the price to be paid for successful reproduction. In view of increased exposure to cell traffic, women, of course, would be expected to pay a higher price, reflected in more autoimmunity.

The impact of abnormal autoimmune function on reproduction: Maternal and fetal consequences

The impact of abnormal autoimmune function on reproductive success has remained a highly controversial issue. This is, at least partially, due to the relative lack of demographic data from women with established autoimmune diseases. We, therefore, investigated 163 women with proven autoimmune diseases and 73 controls in a demographic study of reproductive success and impact of abnormal autoimmunity on pregnancy and offspring. Women with autoimmune diseases experienced fewer pregnancies overall ( p = 0.04) and fewer pregnancy losses ( p = 0.05). Offspring from women with autoimmune diseases demonstrated a significantly increased prevalence of confirmed autoimmune diseases ( p = 0.04; OR 3.759; 95%CL 1.04–1.27), which increased further if suspected, but not yet confirmed, cases were added ( p = 0.001; OR 8.592; 95%CL 1.05–55.0). Women with autoimmune diseases exhibited a trend towards lower cesarean section delivery during their own birth and a significantly increased prevalence of disease in vaginally delivered offspring ( p = 0.014; OR 6.041; 95%CL 1.32–38.22). Autoimmune diseases impair female fecundity even before the diseases become clinically overt. Offspring are at increased risk to develop autoimmune diseases, though they may differ from those of their mothers. This risk appears to correlate with mode of delivery and may be the consequence of varying cell traffic dynamics with vaginal and cesarean section deliveries.

The immunological "Wars of the Roses": disagreements amongst reproductive immunologists.

The relevance of abnormal autoimmune function to reproductive function in the female has over recent years become an increasingly controversial and contentious issue. Opposing views have led to a polarization of opinions which, at times, resulted in publications of rather vocal opinions by individuals as well as societal committees. This communication is an attempt to reconcile these, at times diametrically opposing opinions, in a concept of (auto)immune-driven reproduction failure, which could explain and unify these opposing opinions and, thus, hopefully end the ongoing "immunological wars of the roses".

Autoantibodies in infertility: current opinion.

The concept of autoimmune-related infertility has remained controversial. Traditionally, abnormal autoimmune function has been implicated as a contributing factor to female as well as male infertility. In the female, abnormal autoimmunity primarily relates to autoantibody activity against ovarian tissue components, whereas in the male, abnormal autoimmunity, believed to be clinically relevant, is mostly directed against the spermatozoon itself. Historically, abnormal autoimmune function has been seen as a rather organ-specific process in both female and male infertility, with either ovarian or testicular antigens as the primary targets. In recent years it has, however, also been recognized that additional, and possibly less organ-specific, processes of autoimmune nature may play a role. For example, female infertility patients have demonstrated a significantly higher incidence of nonorgan-specific autoantibody abnormalities. The incidence of such autoantibody abnormalities appears to be positively correlated to increasing intractability of infertility (Gleicher et al., 1993). On the other hand, there is doubt as to whether such non-organ-specific autoantibodies themselves cause disease or only serve as epiphenomena for a still undefined immunological defect which causes infertility (Gleicher, 1994). Lastly, the newly evolving field of neuroimmunology needs to be considered here. Since reproductive function is under neuroendocrine control, autoimmune processes that affect the hypothalamic–pituitary–gonadal axis at the central nervous system (CNS) level will have considerable impact on infertility. This review will therefore report on autoimmune abnormalities at CNS and gonadal levels and on non-organ-specific abnormalities systemically. It will also separate female from male findings since they are usually distinct, though both can often be found in a single couple presenting with an infertility problem.

Antithyroid antibodies and the association with non-organ-specific antibodies in recurrent pregnancy loss

The purpose of our study was to evaluate the incidence of antithyroid antibodies and non-organ-specific antibodies in women who have had three or more recurrent spontaneous abortions. Sera from 45 women for the presence of antithyroid antibodies to thyroglobulin and thyroid peroxide and for the non-organ-specific autoantibodies to 6 phospholipids, 5 histones, and 4 polynucleotides were analyzed. Sera from 100 apparently health blood donors served as controls. The test results of 14 (31%) of 45 study subjects were positive for one or both antithyroid antibodies compared with 19 (19%) of controls. Five (11%) of 45 patients had positive test results for one or more non-organ-specific antibodies, and 4 (8%) of 45 had positive test results for the lupus anticoagulant by either activated partial thromboplastin, tissue thromboplastin time, or both. Only 3 (21%) of 14 subjects whose test results were positive for thyroid antibodies also demonstrated non-organ-specific autoantibodies. The incidence of antithyroid antibodies in women who have had recurrent abortions appears not to be significantly increased compared with a normal random control population. Antithyroid antibodies do occur, however, with significantly greater frequencies in women with recurrent spontaneous abortions than non-organ-specific autoantibodies (p = 0.02). Organ-specific and non-organ-specific autoantibodies may serve as independent markers of risk for repeated pregnancy loss in patient populations where pregnancy loss is associated with abnormal autoimmune function.

Autoantibodies in normal and abnormal pregnancy.

Abnormal autoimmune function has been associated with reproductive failure for decades. In fact, all medical conditions historically associated with pregnancy loss (and on occasion infertility) are now recognized to have an autoimmune etiology. It is therefore quite surprising that only less than a decade ago a correlation between the presence of abnormal autoantibodies and pregnancy loss was reported for the first time. Since reproductive failure, similar to other abnormal autoimmune states, is not a monoclonal event, we have established that affected patients demonstrate polyclonal autoantibody abnormalities including a variety of nonorganospecific as well as organspecific autoantibody groupings. For example, patients with repeated pregnancy loss will exhibit abnormal levels of anti-phospholipid antibodies (PA). In normal pregnancy natural autoantibodies do not follow the standard immunoglobulin (Ig) pattern, characterized by a decrease in levels despite a probably mild increase in production, which is excessively compensated by the vasodilatation of pregnancy. PA, especially, demonstrate a mild increase during pregnancy, though levels only in the peripartal period may reach abnormally high titers (in comparison to nonpregnant controls). This dichotomy between total Ig and natural autoantibodies is interesting since it suggests that autoantibodies may be under distinct control. In fact, we have suggested that this observed elevation of autoantibodies may be the result of an antigenic stimulus by self-like antigen, represented by the maternal growth of the parasitic fetus. In abnormal pregnancies, especially those associated with maternal hypertension and fetal growth retardation (IUGR), autoantibody levels do reach highly abnormal levels.(ABSTRACT TRUNCATED AT 250 WORDS)

The reproductive autoimmune failure syndrome

The association between reproductive failure and abnormal autoimmune function has been recognized for decades in association with such established autoimmune diseases as systemic lupus erythematosus. Recent investigations have expanded this association to women who demonstrate similar humoral abnormalities as patients with defined autoimmune diseases but do not express any of the clinical symptoms required for the diagnosis of an autoimmune disease. The observation that abnormal autoimmune function in clinically asymptomatic patients can lead to reproductive failure has led us to define the reproductive autoimmune failure syndrome as a diagnostic entity. The present article summarizes evidence suggesting that the occurrence of reproductive autoimmune failure syndrome may be teleologically related to the woman's need for increased self-tolerance in face of antigenic exposure to the maternal haplotype of the fetus during normal pregnancy. This need for increased self-tolerance is documented by higher normal autoantibody levels in women than in men and may also be responsible for the highly increased incidence of autoimmune diseases in women in comparison with men. Under this concept, abnormal autoimmune function may lead to reproductive failure at different stages of the reproductive process, depending on the quality and possibly quantity of the abnormal autoimmune response.