Incidence Of Autoimmune Diseases Research Articles

Causality between autoimmune diseases and breast cancer: a two-sample Mendelian randomization study in a European population

BackgroundThe incidence of autoimmune diseases and breast cancer is significantly higher in women compared to men. Previous observational studies have not conclusively determined the relationship between these two conditions. This study utilizes the Mendelian randomization approach to investigate the genetic association between autoimmune diseases and breast cancer.MethodTwo-sample Mendelian randomization was conducted on a European population using the GWAS database. The inverse variance-weighted method served as the primary analytical approach. The MR-PRESSO test was applied to detect horizontal pleiotropy. To ensure result robustness, the FDR correction method was used.ResultThe study revealed that Sjögren’s syndrome lowers the overall risk of breast cancer (OR 0.96, 95% CI [0.93–0.99], p = 0.011). Idiopathic inflammatory myopathy shows a protective effect against overall breast cancer (OR 0.98, 95% CI [0.97–0.99], p = 0.035). An association was identified between rheumatoid arthritis and overall breast cancer (OR 0.98, 95% CI [0.96–1.00], p = 0.050). No causal link was found between systemic lupus erythematosus, systemic sclerosis, and overall breast cancer. The study also suggests that Sjögren’s syndrome, rheumatoid arthritis, and idiopathic inflammatory myopathy might reduce the risk of developing HER + breast cancer. Specifically, Sjögren’s syndrome (OR = 0.90, 95% CI [0.83–0.98], p = 0.02), rheumatoid arthritis (OR = 0.94, 95% CI [0.91–0.98], p = 0.006), and idiopathic inflammatory myopathy (OR = 0.96, 95% CI [0.93–0.99], p = 0.036). Additionally, systemic lupus erythematosus was found to lower the risk of HER- breast cancer (OR = 0.95, 95% CI [0.91–0.99], p = 0.046). The study did not establish a causal relationship between these five autoimmune diseases and ER + or ER- breast cancer.ConclusionThis study found that autoimmune diseases may act as protective factors against breast cancer risk.

Calculating toxic pressure for mixtures of endocrine disruptors

Incidence of autoimmune disorders, birth defects, and neurological diseases rose over the past 50 years due to increasing variety and quantity of pollutants. To date, there appear few methods capable to evaluate and predict mixture effects by endocrine disruptors (EDs). For the first time, we have developed calculus to determine mixture effects by all kinds of EDs.Our method uses the golden ratio ϕ and draws from bifurcation and chaos theory. Using also the concept of molecular mimicry, we developed the equation: effect=100%1+e5·∑KiCi−niϕ3. We successfully tested the equation using a range of cohort studies and biomarkers, and for different pollutants like heavy metals, thyroid hormone mimickants, chromate/chlorate, etc.The equation is simple enough to use with only minor prior knowledge and understanding of basic algebra. The method is universal and calculation is data 'light', requiring only pollutant concentrations [C], potencies K and an integer n for endocrinal involvement. This study offers a comprehensive framework to assess the health effects of pollutant exposure across diverse populations, envisioning far-reaching impact, and presenting practical examples and insights.

Association of HLA Haplotypes with Autoimmune Pathogenesis in Newly Diagnosed Type 1 Romanian Diabetic Children: A Pilot, Single-Center Cross-Sectional Study.

The increasing incidence of autoimmune diseases in type 1 diabetes mellitus (T1DM) patients highlights the influence of human leukocyte antigen (HLA) haplotypes on their development. This study aims to determine genetic predisposition to autoimmune diseases in T1DM patients, including thyroid disease and celiac diseases, and explore its correlation with vitamin D deficiency. A cross-sectional study involving thirty-six T1DM children was conducted. Typing was performed for the HLA A, B, C, DP, DR, and DQ loci. Regression analysis linked DR-DQ haplotypes to T1DM and the associated conditions. The most frequent predisposing alleles and haplotypes were HLA-DR3 (70.27%), DQ2 (70.27%), DR3-DQ2 (70.27%), DQB1*02:01 (70.27%), A02 (54.05%), whereas the most prevalent protecting allele was DPB1*04:01 (52.63%). Positive correlations were observed between positive anti-thyroid peroxidase antibodies and the absence of protective alleles (DPB1*04:02, p = 0.036; DPB1*04:01, p = 0.002). Associations were found between the absence of DPB1*04:01 and anti-thyroglobulin antibodies (p = 0.03). HLA allele DPB1*03:01 was linked with vitamin D deficiency (p = 0.021). Positive anti-transglutaminase antibodies correlated with C03:03 (p = 0.026) and DRB1*04:01-DQA1*03-DQB1*03:01 (p < 0.0001) and the lack of DQA1*01:03-DQB1*06:03-DRB1*13:01 (p < 0.0001). The predisposing T1DM haplotypes were associated with the presence of anti-transglutaminase and anti-thyroid antibodies, indicating a genetic predisposition to autoimmune diseases.

Hirsutella sinensis polysaccharides and Parabacteroides goldsteinii reduce lupus severity in imiquimod-treated mice

BackgroundThe incidence of autoimmune diseases is increasing in developed countries, possibly due to the modern Western diet and lifestyle. We showed earlier that polysaccharides derived from the medicinal fungus Hirsutella sinensis produced anti-inflammatory, anti-diabetic and anti-obesity effects by modulating the gut microbiota and increasing the abundance of the commensal Parabacteroides goldsteinii in mice fed with a high-fat diet. MethodsWe examined the effects of the prebiotics, H. sinensis polysaccharides, and probiotic, P. goldsteinii, in a mouse model of imiquimod-induced systemic lupus erythematosus. ResultsThe fungal polysaccharides and P. goldsteinii reduced markers of lupus severity, including the increase of spleen weight, proteinuria, and serum levels of anti-DNA auto-antibodies and signal transducer and activator of transcription 4 (STAT4). Moreover, the polysaccharides and P. goldsteinii improved markers of kidney and liver functions such as creatinine, blood urea nitrogen, glomerulus damage and fibrosis, and serum liver enzymes. However, the prebiotics and probiotics did not influence gut microbiota composition, colonic histology, or expression of tight junction proteins in colon tissues. ConclusionsOur results indicate that H. sinensis polysaccharides and the probiotic P. goldsteinii can reduce lupus markers in imiquimod-treated mice. These prebiotics and probiotics may therefore be added to other interventions conducive of a healthy lifestyle in order to counter autoimmune diseases.

Sex- and species-specific contribution of CD99 to T cell costimulation during multiple sclerosis

BackgroundDifferences in immune responses between women and men are leading to a strong sex bias in the incidence of autoimmune diseases that predominantly affect women, such as multiple sclerosis (MS). MS manifests in more than twice as many women, making sex one of the most important risk factor. However, it is incompletely understood which genes contribute to sex differences in autoimmune incidence. To address that, we conducted a gene expression analysis in female and male human spleen and identified the transmembrane protein CD99 as one of the most significantly differentially expressed genes with marked increase in men. CD99 has been reported to participate in immune cell transmigration and T cell regulation, but sex-specific implications have not been comprehensively investigated.MethodsIn this study, we conducted a gene expression analysis in female and male human spleen using the Genotype-Tissue Expression (GTEx) project dataset to identify differentially expressed genes between women and men. After successful validation on protein level of human immune cell subsets, we assessed hormonal regulation of CD99 as well as its implication on T cell regulation in primary human T cells and Jurkat T cells. In addition, we performed in vivo assays in wildtype mice and in Cd99-deficient mice to further analyze functional consequences of differential CD99 expression.ResultsHere, we found higher CD99 gene expression in male human spleens compared to females and confirmed this expression difference on protein level on the surface of T cells and pDCs. Androgens are likely dispensable as the cause shown by in vitro assays and ex vivo analysis of trans men samples. In cerebrospinal fluid, CD99 was higher on T cells compared to blood. Of note, male MS patients had lower CD99 levels on CD4+ T cells in the CSF, unlike controls. By contrast, both sexes had similar CD99 expression in mice and Cd99-deficient mice showed equal susceptibility to experimental autoimmune encephalomyelitis compared to wildtypes. Functionally, CD99 increased upon human T cell activation and inhibited T cell proliferation after blockade. Accordingly, CD99-deficient Jurkat T cells showed decreased cell proliferation and cluster formation, rescued by CD99 reintroduction.ConclusionsOur results demonstrate that CD99 is sex-specifically regulated in healthy individuals and MS patients and that it is involved in T cell costimulation in humans but not in mice. CD99 could potentially contribute to MS incidence and susceptibility in a sex-specific manner.

CPT-11 mitigates autoimmune diseases by suppressing effector T cells without affecting long-term anti-tumor immunity

The incidence of autoimmune diseases has significantly increased over the past 20 years. Excessive host immunoreactions and disordered immunoregulation are at the core of the pathogenesis of autoimmune diseases. The traditional anti-tumor chemotherapy drug CPT-11 is associated with leukopenia. Considering that CPT-11 induces leukopenia, we believe that it is a promising drug for the control of autoimmune diseases. Here, we show that CPT-11 suppresses T cell proliferation and pro-inflammatory cytokine production in healthy C57BL/6 mice and in complete Freund’s adjuvant-challenged mice. We found that CPT-11 effectively inhibited T cell proliferation and Th1 and Th17 cell differentiation by inhibiting glycolysis in T cells. We also assessed CPT-11 efficacy in treating autoimmune diseases in models of experimental autoimmune encephalomyelitis and psoriasis. Finally, we proved that treatment of autoimmune diseases with CPT-11 did not suppress long-term immune surveillance for cancer. Taken together, these results show that CPT-11 is a promising immunosuppressive drug for autoimmune disease treatment.

Graves’ disease and the risk of five autoimmune diseases: A Mendelian randomization and colocalization study

BackgroundEpidemiological studies have consistently demonstrated a high prevalence of concurrent autoimmune diseases in individuals with Graves' disease (GD). ObjectiveThe objective of this study is to establish a causal association between GD and autoimmune diseases. MethodsWe employed a two-sample Mendelian randomization (MR) to infer a causal association between GD and five autoimmune diseases, namely rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Crohn's disease (CD), ulcerative colitis (UC), and amyotrophic lateral sclerosis (ALS), in the East Asian and European population. Genetic correlations were explored through linkage disequilibrium score regression analysis (LDSC). Finally, colocalization analyses were performed to investigate possible genetic foundations. ResultsBidirectional MR analysis indicated that genetically predicted GD increased the risk of RA (Odds Ratio (OR): 1.34, 95 % Confidence Interval (CI): 1.21 to 1.47, P < 0.001) and SLE (OR: 1.21, 95%CI: 1.08 to 1.35, P < 0.001) in the East Asian population. In contrast, we found that genetically predicted RA (OR: 1.14, 95%CI: 1.05 to 1.24, P = 0.002) and SLE (OR: 1.10, 95%CI: 1.03 to 1.17, P = 0.003) were associated with a higher risk of GD. The results have been partially validated in European cohorts. Colocalization analysis suggested the potential existence of shared causal variants between GD and other autoimmune diseases. In particular, gene ARID5B may play an important role in the incidence of autoimmune diseases. ConclusionThis study has confirmed that GD was associated with RA and SLE and found a possible key gene ARID5B. It may be necessary to strengthen detection to prevent the occurrence of comorbidities in clinical practice.

Type 1 Diabetes and Other Autoimmune Disorders in Children

The incidence of autoimmune disorders (AIDs) has been dramatically increasing in both children and adults over the past few years, and type 1 diabetes (T1D) is one of the diseases that has seen the highest growth. It is well-known that the dysimmune process may spread to other systems, leading to the onset of one or more AIDs in the same individual; however, the relationship between AIDs is not often recognized. The most frequently diagnosed AIDs in children and adolescents with T1D are thyroid diseases and celiac disease, but it is also important to consider the onset of the other conditions, such as juvenile idiopathic arthritis, multiple sclerosis, atrophic gastritis, inflammatory bowel diseases, and skin disorders such as vitiligo and psoriasis. This review aims to explore the overlap of T1D and other AIDs, focusing on the less common and lesser-known diseases. A better knowledge of these comorbidities may facilitate the identification of patients at risk to treat them in the preclinical period, before the onset of complications.

Autoimmune Disorders Associated With Surgical Remission of Cushing's Disease : A Cohort Study.

Glucocorticoids suppress inflammation. Autoimmune disease may occur after remission of Cushing's disease (CD). However, the development of autoimmune disease in this context is not well described. To determine 1) the incidence of autoimmune disease in patients with CD after surgical remission compared with patients with nonfunctioning pituitary adenomas (NFPAs) and 2) the clinical presentation of and risk factors for development of autoimmune disease in CD after remission. Retrospective matched cohort analysis. Academic medical center/pituitary center. Patients with CD with surgical remission and surgically treated NFPA. Cumulative incidence of new-onset autoimmune disease at 3 years after surgery. Assessment for hypercortisolemia included late-night salivary cortisol levels, 24-hour urine free cortisol (UFC) ratio (UFC value divided by the upper limit of the normal range for the assay), and dexamethasone suppression tests. Cumulative incidence of new-onset autoimmune disease at 3 years after surgery was higher in patients with CD (10.4% [95% CI, 5.7% to 15.1%]) than in those with NFPAs (1.6% [CI, 0% to 4.6%]) (hazard ratio, 7.80 [CI, 2.88 to 21.10]). Patients with CD showed higher prevalence of postoperative adrenal insufficiency (93.8% vs. 16.5%) and lower postoperative nadir serum cortisol levels (63.8 vs. 282.3 nmol/L) than patients with NFPAs. Compared with patients with CD without autoimmune disease, those who developed autoimmune disease had a lower preoperative 24-hour UFC ratio (2.7 vs. 6.3) and a higher prevalence of family history of autoimmune disease (41.2% vs. 20.9%). The small sample of patients with autoimmune disease limited identification of independent risk factors. Patients achieving surgical remission of CD have higher incidence of autoimmune disease than age- and sex-matched patients with NFPAs. Family history of autoimmune disease is a potential risk factor. Adrenal insufficiency may be a trigger. Recordati Rare Diseases Inc.

Vitamin D and Marine n-3 Fatty Acids for Autoimmune Disease Prevention: Outcomes Two Years After Completion of a Double-Blind, Placebo-Controlled Trial.

In the 5.3-year randomized, 2 × 2 factorial, double-blind, placebo-controlled Vitamin D and Omega-3 Trial (VITAL), vitamin D supplementation reduced autoimmune disease (AD) incidence (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.61-0.99). Omega-3 (n-3) fatty acid supplementation showed a statistically nonsignificant reduction (HR 0.85, 95% CI 0.67-1.08). We aimed to confirm further AD cases arising during and after randomization and assess sustained effects with two years of postintervention observation. Of the 12,786 men aged ≥50 and 13,085 women aged ≥55 initially randomized, we observed surviving and willing participants for two more years. We continued to confirm annual participant-reported new AD by medical record review. Cox models calculated HRs for all confirmed incident AD, (and secondary endpoints, including probable cases, and individual ADs), during the observational and randomized periods. A total of 21,592 participants (83.5%) were observed for two more years; 514 participants developed incident confirmed AD (236 since prior report), of whom 255 had been randomized to vitamin D versus 259 to vitamin D placebo (HR 0.98 [95% CI 0.83-1.17] at 7 years). AD was confirmed in 234 participants initially randomized to n-3 fatty acids versus 280 randomized to its placebo (HR 0.83 [95% CI 0.70-0.99] at 7 years). Of newly confirmed cases, 65 had onset during randomization; their inclusion changed randomized results as follows: HR 0.85 (95% CI 0.70-1.04) for vitamin D and HR 0.87 (95% CI 0.71-1.06) for n-3 fatty acids. Two years after trial termination, the protective effects of 2000 IU/day of vitamin D dissipated, but 1,000 mg/day of n-3 fatty acids had a sustained effect in reducing AD incidence.

Effect of sublingual immunotherapy on clinical and laboratory autoimmunity.

Background: There still are few data on the long-term safety of sublingual immunotherapy (SLIT). The aim of this study was to assess the appearance of autoimmune diseases in patients before and after SLIT. Materials & methods: New cases of autoimmune diseases were monitored. Patients in the SLIT group (n=816) were compared with controls (n=1096). Results: The new incidences of autoimmune diseases in the SLIT group were lower compared with the control group: 18 (2.2%) versus 58 (5.3%);p<0.05. Systemic lupus erythematosus, psoriasis and Hashimoto appeared much more often in the control group. Conclusion: SLIT had no significant effect on the induction of autoimmune diseases.

Immunological Changes with Age and Innovative Approaches to Bolster Immune Function in Older Adults

Aging is accompanied by a progressive decline in immune function, known as immunosenescence, which renders elderly individuals more susceptible to infections, reduced vaccine efficacy, and increased incidence of autoimmune diseases and cancer. This decline in immunity is characterized by alterations in both innate and adaptive immune responses, including reduced T-cell diversity, impaired function of antigen-presenting cells, and dysregulated cytokine production. Additionally, inflammaging, a chronic low-grade inflammatory state, further contributes to age-related immune dysfunction. Strategies aimed at enhancing immunity in aging individuals have garnered significant attention. Promising interventions include lifestyle modifications encompassing regular exercise, balanced nutrition, and adequate sleep, which can positively impact immune function. Furthermore, vaccination strategies tailored for the elderly, such as high-dose vaccines or adjuvanted formulations, aim to bolster vaccine efficacy. Immunomodulatory therapies, including supplementation with specific micronutrients and pharmacological interventions targeting immune senescence, hold promise for rejuvenating immune responses in older individuals. Understanding the mechanisms underlying immunosenescence and inflammaging is critical in developing targeted approaches to enhance immunity in aging populations. A holistic approach combining lifestyle interventions, vaccination strategies, and innovative immunomodulatory therapies holds potential for mitigating the impact of agerelated immune decline and improving overall healthspan in the elderly. Keywords: Immunosenescence, Aging, Immunity, Inflammaging, Elderly, Immunomodulation, Vaccination Strategies, Immune Rejuvenation, Geriatrics

Vitamin D Deficiency in Pregnancy: A Systematic Review

Vitamin D deficiency (VDD) is a common problem in reproductive-aged women and has become a major public health problem worldwide. Adverse health outcomes such as preeclampsia, low birthweight, neonatal hypocalcemia, poor postnatal growth, bone fragility, and increased incidence of autoimmune diseases have been linked to low vitamin D levels during pregnancy and infancy. A systematic literature search was performed on September 6th – 21st, 2022 using respected database. The identified articles were screened using the chosen eligibility criteria. Literature selection was performed with rest time restriction from January 1, 2017, and September 22, 2022 and restricted to only published in English articles. Three papers were evaluated in full-text after duplicates were removed. Tammo et al, Mansur et al and Moralez et al were the three studies that remained following full-text screening utilizing eligibility criteria and quality assessment showing a significant proof regarding this review. Vitamin D deficiency had wide variety of effects in pregnancy as it may increased risk of multisystem disorders in pregnancy such as preeclampsia, low birth weight in neonates, insulin resistance, gestational diabetes mellitus (GDM), and a higher risk of primary cesarean delivery. Optimal level of 30 ng/mL or more before conception and throughout the entire pregnancy with different dosages available, avoiding levels below 20 ng/ml.

Two cases of pediatric primary immunodeficiency caused by a familial moesin(MSN)gene mutation

BackgroundWe investigated two brothers who presented with repeated lung infections after 6 months of age. Lymphocytes and neutrophils were significantly decreased, and both had bronchiectasis and emphysema. ObjectiveWe sought to characterize the complete picture of lung injury in some types of primary immunodeficiency disease, followed by verification and analysis. MethodsWe performed immune function determination, a complete examination of the respiratory system, genetic analysis, and literature research. ResultsThe levels of lymphocytes, neutrophils, monocytes, and natural killer cells in the brothers were significantly decreased. The IgM and IgG levels of the older brother were decreased, while the IgM and IgA levels of the younger brother were decreased. Both brothers had bronchial wall erosion with a worm-eaten appearance and decreased lung function. Genetic testing revealed a hemizygous missense mutation (c.511C > T:p.R171W) in exon 5 of the MSN gene, which was inherited from the mother. A literature review showed that the primary immunodeficiency caused by MSN gene mutations is an X-linked recessive genetic disease with four known gene mutation sites, including nonsense and missense mutations. Nonsense mutations result in a higher incidence of autoimmune diseases and a lower degree of immune function impairment. Nonsense mutations closer to the front of the MSN gene may cause more severe disease. Neonatal disease screening can improve the early diagnosis rate, but hematopoietic stem cell transplantation (HSCT) treatment is controversial. ConclusionThe primary immunodeficiency disease caused by MSN gene mutation is an X-linked recessive genetic disease that involves structural and functional damage to the respiratory system, and the worm-eaten appearance of the bronchial wall under endoscopy may be a relatively specific sign. The general manifestations of this disease are recurrent infections from 1 month to 6 months after birth, significantly reduced counts of lymphocytes and neutrophils, and decreased cellular and humoral immune function. Different types of MSN gene mutations and nonsense mutations at different sites have different clinical phenotypes. This study enriches the known spectrum of this disease.

Salt Behind the Scenes of Systemic Lupus Erythematosus and Rheumatoid Arthritis.

Sodium is vital for human health. High salt intake is a global health problem and is associated with cardiovascular morbidity and mortality. Recent evidence suggests that both innate and adaptive immune systems are affected by sodium. In general, excess salt intake drives immune cells toward a pro-inflammatory phenotype. The incidence of autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), is steadily increasing. As excess salt induces a pro-inflammatory state, increased salt intake may have impacts on autoimmune diseases. The relationship between salt intake and autoimmune diseases is most widely studied in patients with SLE or RA. This review aimed to summarize the relationship between salt intake and SLE and RA. Most, but not all, of these studies showed that high salt intake might promote SLE by M1 macrophage shift, increase in Th17/Treg cell ratio, activation of dendritic and follicular helper T cells, and increased secretion of pro-inflammatory cytokines. In RA, apart from driving immune cells toward a pro-inflammatory state, high salt intake also influences cellular signaling pathways, including receptor activator of nuclear factor κB ligand (RANKL), Rho GTPases, and MAPK (mitogen-activated protein kinase). There is now sufficient evidence that excess salt intake may be related to the development and progression of SLE and RA, although there are still knowledge gaps. More studies are warranted to further highlight the relationship between excess salt intake, SLE, and RA. Salt intake may affect cell types and pro-inflammatory cytokines and signaling pathways associated with the development and progression of systemic lupus erythematosus and rheumatoid arthritis. Bcl-6 B-cell lymphoma, 6 Erk extracellular signal-regulated kinases, IFN-γ interferon-gamma, JNK c-Jun N-terminal kinase, IL-4 interleukin 4, IL-6 interleukin 6, MAPK mitogen-activated protein kinase, STAT signal transducer and activator of transcription, Tnf-α tumor necrosis factor, Treg T regulatory cell.

Chronic stress predisposes to the aggravation of inflammation in autoimmune diseases with focus on rheumatoid arthritis and psoriasis

The global incidence of autoimmune diseases is on the rise, and many healthcare professionals believe that chronic stress plays a prominent role in both the aggravation and remission of these conditions. It is believed that prolonged exposure to stress is associated with neuroimmune axis malfunction, which eventually dysregulates multiple immunological factors as well as deregulates autoimmune responses that play a central role in various autoimmune diseases, including rheumatoid arthritis and psoriasis. Herein, we performed validation of an 8-week long rat model of chronic unpredictable stress (CUS) which consisted of exposing groups of rats to random stressors daily for 8 weeks. Additionally, we developed a novel rat model combining 8-week long random stressor-induced CUS with CIA-triggered arthritis and IMQ-triggered psoriasis and have successfully used both these models to assess the role of chronic stress in the aggravation of arthritis and psoriasis, respectively. Notably, the 8-week CUS protocol extensively aggravated and prolonged both arthritis and psoriasis condition in the rat model by upregulating the release of different pro-inflammatory cytokines, dysregulation of immune cell responses and oxidative stress system, which were all related to severe inflammation. Further, CUS aggravated macroscopic features and the increase in destruction of joint tissue and epidermal thickness induced by CIA and IMQ, respectively, in rats. In conclusion, this study suggests that exposure to an 8-week long CUS paradigm aggravates the distinctive characteristics of rheumatoid arthritis and psoriasis in rats via amplifying the inflammatory circuits and immune cell responses linked to these autoimmune diseases.

SAT416 The Incidence Of Autoimmune Disease In Transgender People After Initiation Of Gender-Affirming Hormone Therapy

Abstract Disclosure: C. Wiepjes: Advisory Board Member; Self; Novartis Pharmaceuticals. M. Den Heijer: None. Background Autoimmune diseases are more common in women than in men, possibly caused by differences in sex hormones. Generally, estrogen has an immunoenhancing effect, while testosterone has an immunosuppressive effect. However, it is not known whether gender-affirming hormone therapy in transgender people affects the risk of developing autoimmune diseases. Therefore, we aimed to compare the incidence of autoimmune diseases in trans women and trans men during hormone therapy with rates from the general population. Methods All people who visited the gender identity clinic in Amsterdam, the Netherlands, between 1972 and 2018 were included (n=8831). The medical records were screened for the occurrence of autoimmune diseases. In addition, the cohort was linked to a nationwide health data registry with medical diagnoses, as not all people received their check-ups at our clinic and in order to compare with a control population. These additional diagnoses were available from 2012-2017 and based on Diagnosis-Treatment-Combination codes. People were excluded for analyses if they did not use gender-affirming hormones (n=3022), did not have a follow-up visit (n=345), could not be linked with the nationwide health data registry (n=630), used alternating testosterone and estradiol (n=38), or had an autoimmune disease before start of hormone therapy (n=112). Standardized incidence ratios (SIR) were computed for trans women and trans men compared with the general population. Results In total, 4684 people were included, of which 2830 trans women and 1854 trans men. Median age at start of hormone therapy was 29 years (IQR 22 to 40) in trans women and 22 years (IQR 18 to 29) in trans men. Median follow-up time was 10 years (IQR 3 to 22, max 59) in trans women (total 38326 person years) and 4 years (IQR 1 to 13, max 48) in trans men (total 16548 person years). In total, 55 trans women and 48 trans men developed an autoimmune disease, after a median duration of hormone therapy of 7 years (IQR 2 to 17) in trans women and 5 years (IQR 1 to 12) in trans men. In the analyses with first autoimmune disease between 2012 and 2017, 25 trans women had an event, while 31 cases (SIR 0.81, 95%CI 0.52 to 1.16) were expected compared to cis men and 47 cases (SIR 0.54, 95%CI 0.35 to 0.77) compared to cis women. In trans men, 27 people had an event, while 15 cases were expected compared to cis men (SIR 1.81, 95%CI 1.19 to 2.55) and 23 cases were expected compared to cis women (SIR 1.16, 95%CI 0.77 to 1.64). Conclusion The risk of developing autoimmune diseases in trans women using gender-affirming hormones was similar to the risk in cis men, whereas trans men had a similar risk as cis women. This implies that gender-affirming hormone therapy does not influence the risk of developing autoimmune diseases. For further research it is interesting to see whether the severity of autoimmune diseases changes in trans people starting gender-affirming hormones. Presentation: Saturday, June 17, 2023

FRI613 Sex Differences In Human Islet Transcriptional Responses To Inflammation

Abstract Disclosure: K.L. Webster: None. W. Wu: None. B. Webb-Robertson: None. E. Nakayasu: None. S. Sarkar: None. C. Evans-Molina: None. S.A. Tersey: None. J. Enriquez: None. S.R. Hammes: None. R.G. Mirmira: None. Higher female incidence of autoimmune disease is often attributed to sex hormone-immune cell interactions or X chromosome immune genes escaping inactivation. Type 1 diabetes (T1D), however, occurs slightly more often in males, and studies show that female sex protects beta cell health under conditions of stress. It is now thought that beta cells themselves trigger loss of immune tolerance in T1D and that the state of beta cell differentiation and health dictates their susceptibility to autoimmunity. Here, we hypothesized that sex influences beta cell response to inflammation during T1D development. We utilized prior bulk RNA sequencing data on human islets from 10 donors (6 males, 4 females) treated for 18h with or without proinflammatory cytokines (PIC: IL-1b, IFNy) to mimic T1D inflammation. Hierarchical clustering grouped samples largely by PIC treatment but also by sex. To identify differentially expressed genes (DEGs) for each sex in response to PIC, we filtered for genes with fold change&amp;gt;1.5 and false discovery rate&amp;lt;0.05. A total of 3754 DEGs were detected in male islets with PIC treatment, while just 1117 were detected in female islets. Of these, 1016 genes were shared between sexes, and many related to cytokine signaling and immune responses. Only 101 DEGs were unique to females, and these were enriched in terms related to leukocyte aggregation, glutamate signaling, and responses to steroid hormone stimuli. 2738 DEGs unique to males were enriched in terms related to inflammation, NOTCH signaling, differentiation, and estrogen biosynthesis. Notably, the gene encoding double-stranded RNA sensor MDA5 (Ifih1), whose activity induces antiviral type I IFN responses and has been linked to T1D, showed a greater average increase with PIC in males (9.99-fold vs. 6.64-fold in females, p&amp;lt;0.05). By gene set enrichment analysis, control and PIC-treated female islets were enriched in differentiation and development pathways, while male islets were enriched in protein translation and steroid metabolism. To probe the role of sex steroid signaling in islet inflammatory response, we measured expression of Esr1 (encoding ERa) via qRT-PCR in mouse islets in response to PIC (IFNy, IL-1b, TNFa). In non-diabetic C57BL6/J mice, islets from both males and females increased Esr1 with PIC (3.63- and 4.39-fold, p&amp;lt;0.05). However, in pre-diabetic NOD mice, in which female mice are highly susceptible to autoimmune diabetes, islets from neither sex increased Esr1. Interestingly, islets from C57BL6/J mice of both sexes decreased expression of Ar (encoding androgen receptor) upon PIC treatment, a response also absent in NOD mice. These data suggested that Esr1 might be protective- and Ar detrimental- for beta cell function, but not in a sex-dependent manner. Collectively, these data demonstrate a sexual dimorphism in islet response to inflammation, with evidence of a more aggressive inflammatory response in males. Presentation: Friday, June 16, 2023

Update on Obesity in Psoriasis Patients.

Psoriasis is a chronic inflammatory skin condition, with genetic, epigenetic, environmental, and lifestyle factors contributing to its onset and recurrence. Severe psoriasis has a great impact on quality of life, which is similar to that of insulin-dependent diabetes, depression, and ischemic heart disease, but with a lower mortality. There is an overlap between the rising incidences of autoimmune diseases and obesity. In recent years, research has shown that there is an association between psoriasis and obesity. Psoriasis is linked to obesity in a two-way manner, as each can precipitate the development of the other. Several adipose tissue-secreted adipokines were shown to be elevated in obese psoriasis patients, exhibiting similar mechanisms of action to those underlying the pathogenesis of psoriasis. Excess body weight can influence not only the treatment response in psoriasis, but also the adverse events, leading to decreased patient compliance. Specific human microbiome patterns have been identified for obesity and psoriasis and could represent a future therapeutic target in selected individuals.

Abstract PO-081: Patterns of immune susceptibility in young, non-smoking, oral cancer patients

Abstract Introduction: Oral squamous cell carcinoma (OSCC) is peculiarly increasing in non-smokers, many of whom are younger than traditional, smoking related OSCC. The cause of this trend is unknown, and it is unclear whether these cancers represent a distinct disease, as compared to smoking-related OSCC. We hypothesize that young non-smokers with OSCC have immunological differences that increase susceptibility to infectious and immunological disease (including cancer) as compared to smokers with OSCC. Therefore, we investigated the incidence of bacterial, viral, and autoimmune illness in young OSCC patients. Methods: We performed a retrospective cohort study at a single tertiary care institution of patients under age 55 diagnosed with OSCC from 2003-2021. Multiple encounters for the same ICD-10 code in the same year were counted as one. Bacterial infections included bacterial pneumonia (ICD-10 J13-J15), cellulitis and lymphangitis (L03), urinary tract infection (N39.0), and post-surgical infection (T81.4). Viral infections included viral pneumonia (J10-J12), skin herpesvirus (A60, A63, B00, B07), infectious mononucleosis (B27), herpes zoster-related infections (B02), HIV (B20), viral hepatitis (B15-19), CMV disease (B25), viral conjunctivitis (B30), and other unclassified viral diseases (B33-34). Autoimmune disease included rheumatoid arthritis (M05), systemic Lupus (M32, L93), psoriasis (L40), inflammatory bowel disease (K50-52), Sjogren disease (M35.0), type 1 diabetes (E10), multiple sclerosis (G35), myasthenia gravis (G70), and autoimmune thyroiditis (E06.3). When patients were known to be deceased, but date of death was unavailable, they were presumed deceased at date of last encounter. Kaplan Meier analysis was used to analyze survival. Poisson regression was used to model the incidence of illness. Results: In total, 749 patients were analyzed; 467 were never smokers (NS) and 282 were current or former smokers (S). In NS, median age (interquartile range) was 47.9 (40.4-51.9) and 267 (57.2%) were male. In S, median age was 49.3 (44.6-52.7) and 208 (73.8%) were male. Five-year OS was 89% (95% confidence interval 86-93%) in NS vs. 89% (85%-93%) in S (p=0.66). The incidence of bacterial infection was 25.9 per 1000 person-years (py) in NS vs. 37.0/1000py in S (p&amp;lt;0.01). The incidence of viral infection was 37.8/1000py in NS vs. 31.4/1000py in S (p=0.14). The incidence of autoimmune disease was 26.7/1000py in NS and 36.0/1000py in S (p=0.02). Conclusions: NS were more likely to be female vs. S. OS was similar between NS and S. The incidence of bacterial infections and autoimmune diseases were significantly higher in S vs. NS, in line with pre-existing evidence that smoking is associated with increased susceptibility to bacterial infection and increased incidence and severity of autoimmune disease. Interestingly, there was a trend towards increased viral infections in NS vs. S, although not statistically significant. In the context of pre-existing evidence showing that smoking increases risk of viral infection, this finding warrants further study. Citation Format: Maxwell Y. Lee, Fred M. Baik, John B. Sunwoo. Patterns of immune susceptibility in young, non-smoking, oral cancer patients [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-081.