Concomitant Autoimmunity Research Articles

Concomitant autoimmunity and risk of multiple sclerosis disability worsening

BackgroundFew studies have examined the effect of concomitant autoimmune diseases on multiple sclerosis (MS) disability worsening. We set out to examine whether concomitant Crohn's Disease (CD), Ulcerative Colitis (UC), or Type 1 Diabetes (T1D) affect MS disability worsening in a nationwide cohort of MS patients as defined by reaching expanded disability scale status (EDSS) scores 3.0, 4.0 and 6.0. MethodsPatients with MS onset between January 2004 and January 2019 were identified from the Swedish MS registry and the Swedish National Patient Register. Kaplan–Meier analysis was used to estimate the median time to reach sustained disability milestones. Adjusted Cox proportional hazard regression models were used to calculate the risk of reaching disability milestones among persons with and without CD, UC, or T1D. ResultsOut of 8972 persons with MS, 88 (1.0 %) had T1D, 47 (0.8 %) had UC, and 78 (0.9 %) had CD. There was a significantly higher risk of disability progression, for persons with MS and T1D for reaching EDSS 6.0, hazard ratio (HR) = 2.21 (95 % confidence interval (CI) = 1.48 −3.31) and persons with MS and comorbid CD for reaching EDSS 3.0, HR = 2.30 (95 %CI = 1.74–3.04) and 4.0, HR = 1.59 (95 %CI = 1.09–2.32), and persons with MS and comorbid UC for reaching EDSS 3.0 HR = 1.57 (95 %CI = 1.15–2.14). As defined by Charlson's comorbidity index, the co-existence of other co-morbidities conferred a significant increase in the risk of reaching all endpoints, with HR ranging from 1.23 to 1.62. ConclusionComorbidity is associated with a significantly increased risk of reaching disability end-points, and T1D, CD, and UC increase the risk further. Thus, there appears to be a need for increased vigilance of comorbidites in persons with MS in order to optimise the long-term outcome of MS.

The 2023 Orthopaedic Research Society's International Consensus Meeting on musculoskeletal infection: Summary from the host immunity section.

Musculoskeletal infections (MSKI), which are a major problem in orthopedics, occur when the pathogen eludes or overwhelms the host immune system. While effective vaccines and immunotherapies to prevent and treat MSKI should be possible, fundamental knowledge gaps in our understanding of protective, nonprotective, and pathogenic host immunity are prohibitive. We also lack critical knowledge of how host immunity is affected by the microbiome, implants, prior infection, nutrition, antibiotics, and concomitant therapies, autoimmunity, and other comorbidities. To define our current knowledge of these critical topics, a Host Immunity Section of the 2023 Orthopaedic Research Society MSKI International Consensus Meeting (ICM) proposed 78 questions. Systematic reviews were performed on 15 of these questions, upon which recommendations with level of evidence were voted on by the 72 ICM delegates, and another 12 questions were voted on with a recommendation of "Unknown" without systematic reviews. Two questions were transferred to another ICM Section, and the other 45 were tabled for future consideration due to limitations of available human resources. Here we report the results of the voting with internet access to the questions, recommendations, and rationale from the systematic reviews. Eighteen questions received a consensus vote of ≥90%, while nine recommendations failed to achieve this threshold. Commentary on why consensus was not achieved on these questions and potential ways forward are provided to stimulate specific funding mechanisms and research on these critical MSKI host defense questions.

A-052 The Importance of Thyroid-stimulating Immunoglobulin (TSI) in the Diagnosis and Follow-up of Marine-Lenhart Syndrome

Abstract Introduction Marine-Lenhart syndrome is a rare cause of hyperthyroidism, occurring in 0.8%–2.7% of patients with Graves’ disease (GD). In this syndrome, GD, which is an autoimmune disease, coexists with one or more hyperfunctioning nodules—Toxic nodular goiter (TNG), or toxic multinodular goiter (TMNG)—which are usually thyroid adenomas. Both induce clinical hyperthyroidism, with suppressed thyroid-stimulating hormone (TSH) and elevated thyroid hormones (TH). Radioactive iodine uptake and thyroid scintigraphy are indicated when there is a nodule on ultrasonography (US) with suppressed TSH, for the differential diagnosis between GD and toxic nodules. However, in this syndrome, scintigraphy does not always define the diagnosis, as the aspects observed do not show the usual pattern. In these cases, it is necessary that a reliable autoimmune thyroid disease marker be performed in order to prove the concomitant autoimmunity. Objectives The aim of this study was to demonstrate the usefulness of thyroid-stimulating immunoglobulin (TSI) for diagnosing hyperthyroidism due to Marine-Lenhart syndrome. Methods The authors prospectively followed 19 patients with suspected Marine-Lenhart syndrome between 2018 and 2020. TSH and TH were measured by Electrochemiluminescence, Roche Diagnostics, and TSI was measured by Chemiluminescence, Siemens Diagnostics. Results All patients had TSH ≤ 0.01 mIU/L, free thyroxine (FT4) was 3.1 ± 0.9 ng/dL, and triiodothyronine (TT3) 312 ± 42.1 ng/dL. All of them had increased radioactive iodine uptake, but the scintigraphy showed nodules sometimes with increased, normo, or low uptake in relation to the adjacent tissue, a finding that is explained by the fact that, both, the nodule and the rest of the thyroid tissue, uptake the radioidine in excess and the pattern varies according to the activity of the DG and nodules in the period in which the test was performed. TSI was 3.98 ± 0.9 IU/L (Negative if <0.55). All patients had positive TSI, confirming concomitant GD with TNG/TMNG. During treatment monitoring, in 14 cases the hyperfunctioning nodules were treated by local sclerosis procedure, with percutaneous injection of ethanol. Despite complete nodular sclerosis, with normal TH but still suppressed TSH, the TSI still remained elevated. This demonstrated that, despite the successful treatment of the nodule, the underlying GD was still active, requiring complementary treatment with antithyroid drugs until TSI was negative, after 18 ± 4 months of treatment. Conclusion In atypical cases of hyperthyroidism, the TSI measurement is decisive for the diagnosis, as in the rare Marine-Lenhart syndrome. This contributes in a relevant way to the definition of the treatment, which can be different between the two causes that occur concomitantly. Likewise, during treatment follow-up, the TSI was essential in defining the need to maintain clinical treatment, even if the nodule had been already adequately treated.

Concomitant Autoimmunity in Endometriosis Impairs Endometrium-Embryo Crosstalk at the Implantation Site: A Multicenter Case-Control Study.

Endometriosis and autoimmune diseases share a hyper-inflammatory state that might negatively impact the embryo-endometrium crosstalk. Inflammatory and immune deregulatory mechanisms have been shown to impair both endometrial receptivity and embryo competence at the implantation site. The aim of this study was to investigate the potential additional impact of co-existing autoimmunity in women affected by endometriosis on the early stages of reproduction. This was a retrospective, multicenter case-control study enrolling N = 600 women with endometriosis who underwent in vitro fertilization-embryo transfer cycles between 2007 and 2021. Cases were women with endometriosis and concomitant autoimmunity matched based on age and body mass index to controls with endometriosis only in a 1:3 ratio. The primary outcome was the cumulative clinical pregnancy rate (cCPR). The study found significantly lower cleavage (p = 0.042) and implantation (p = 0.029) rates among cases. Autoimmunity (p = 0.018), age (p = 0.007), and expected poor response (p = 0.014) were significant negative predictors of cCPR, with an adjusted odds ratio of 0.54 (95% CI, 0.33-0.90) for autoimmunity. These results suggest that the presence of concomitant autoimmunity in endometriosis has a significant additive negative impact on embryo implantation. This effect might be due to several immunological and inflammatory mechanisms that interfere with both endometrial receptivity and embryo development and deserves further consideration.

May Concomitant Thyroid Autoimmunity be Associated with Better Prognosis in Thyroid Papillary Carcinoma?

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Association of concomitant autoimmunity with the disease features and long-term treatment and health outcomes in Celiac disease.

Celiac disease (CeD) is often accompanied by other autoimmune diseases (AID). However, the association of co-existing autoimmunity with the presentation and treatment success in CeD is unclear. We investigated these issues with a large and well-defined cohort of Finnish patients. Adult CeD patients (n = 806) were collected from multiple heath care sites via nationwide recruitment. They were interviewed, underwent measurement of CeD autoantibodies, and filled out questionnaires to ascertain quality of life (PGWB) and gastrointestinal symptoms (GSRS) after a median of 9.7 years on a gluten-free diet. Data were supplemented retrospectively from patient records. The results were compared between CeD patients with and without a coexisting AID. Altogether 185 patients had CeD+AID and 621 had CeD only. At CeD diagnosis, patients with CeD+AID were older (median 42 vs. 36 years, p = 0.010) and had more joint symptoms (9.1 vs. 4.2%, p = 0.011), whereas the groups were comparable in sex, family history of CeD, other presenting symptoms, proportion of screen-detected subjects, and severity of duodenal lesion. During follow-up on gluten-free diet, CeD+AID patients experienced poorer general health (median score 12 vs. 14, p < 0.001) in PGWB, more overall gastrointestinal symptoms (2.1 vs. 1.9, p = 0.001), and constipation (2.0 vs. 1.7, p < 0.001) in GSRS, whereas there was no difference in histological and serological recovery, dietary adherence, use of gluten-free oats, smoking, and presence of regular follow-up. Co-existing AID was not significantly associated with the baseline features or with most long-term outcomes in CeD. However, the increased prevalence of gastrointestinal symptoms and reduced poorer self-perceived health during treatment indicates these patients' need for special support.

Hypersensitivity Pneumonitis With and Without Autoimmune Features: A Clinical Comparative Analysis.

Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) caused by an immunological reaction to repeated inhalational exposure to antigens. The etiology and exact immunopathology are poorly understood. Autoimmunity overlapping with HP has been described but the role of concomitant autoimmunity in the clinical course and outcome of the HP is not clearly established. In this study, we examined patients diagnosed with HP and compare them to patients with concomitant HP and autoimmunity. Patients were retrospectively screened from a single-center ILD registry. Patients > 18years with an established multidisciplinary diagnosis of HP were included in the study. Patients with HP without autoimmune features and patients with HP with autoimmune features (HPAF) were assessed. We compared the demographics, clinical characteristics, treatment, and outcomes between the two groups. We used a Cox proportional hazards model to compare lung transplant-free survival outcomes of patients with HPAF to those with non-HPAF HP patients. Of 73 patients with HP, 43 were diagnosed with HPAF. Patients with HPAF had a higher echocardiographic probability of pulmonary hypertension as compared to non-HPAF HP patients [48.8 vs 23.3%, p = 0.028, Crude odds ratio (cOR) = 3.14]. Symptomatically, those with HPAF reported a higher prevalence of arthritis as compared to non-HPAF HP (20.9 vs 3.3%, p = 0.040, cOR = 7.68). No significant differences between pulmonary function tests, oxygen requirements, mortality, and lung transplantation rates were found between the two groups. There was no statistically significant difference in transplant-free survival (p = 0.836). Patients with HPAF had a higher echocardiographic probability of pulmonary hypertension as compared to patients with non-HPAF HP. The clinical characteristics and outcomes did not differ between the two groups and concomitant autoimmunity among the HP group did not portend a poorer prognosis.

O-192 Concomitant autoimmunity in endometriosis-affected women and In Vitro Fertilization (IVF) outcomes: a cohort study

Abstract Study question To evaluate whether the presence of concomitant autoimmunity in endometriosis patients may affect In Vitro Fertilization (IVF)/Intracytoplasmic Injection (ICSI) outcomes. Summary answer In ‘normo-responders’ patients autoimmunity did not affected ovarian response to gonadotrophin stimulation yet was the only significant negative predictor of cumulative pregnancy rate (CPR). What is known already In the last years, endometriosis has been redefined as a multifactorial disease with a complex pathogenesis. In this setting, a role of both innate and adaptive immune systems have been proposed in endometriosis development. The coexistence of endometriosis and autoimmunity is well-documented. Also, an increased risk of more severe stages of endometriosis in patients with autoimmunity has been recently reported. Even if autoimmunity has been associated with lower pregnancy rates and higher miscarriage rates, whether the presence of autoimmunity in endometriosis patients could act as an additive factor worsening IVF/ICSI response is still not known. Study design, size, duration Single-center, retrospective, cohort study. First IVF/ICSI cycles of endometriosis patients with or without autoimmunity carried out from 2007 to 2021 at the Fertility Unit of IRCSS San Raffaele Hospital(Milan) were included. Patients with endometriosis and concomitant autoimmunity were age-matched to endometriosis only controls. Only patients with a complete disease control following endometriosis treatment were admitted to IVF/ICSI. A total of 471 patients were enrolled. The study was conducted according to STROBE guidelines for observational studies. Participants/materials, setting, methods Endometriosis diagnosis was surgical/histopathological, yet also ovarian endometriosis at ultrasound assessment by expert operators was included. Autoimmunity was assessed by blood tests for auto-antibodies and/or rheumatological records. Stratified analysis by “expected” ovarian response at baseline according to AFC and/or AMH were performed. Expected ‘poor-responders’ were defined according to Bologna Criteria. The primary outcome was CPR. Secondary outcomes included oocytes retrieved, metaphase II(MII)oocytes and ovarian sensitivity index(OSI), the latter defined as:(number of retrieved oocytes/total gonadotrophin dose)×1000. Main results and the role of chance 113/471 cases with endometriosis and concomitant autoimmunity and 358/471 age-matched endometriosis only controls were enrolled. The mean age was 35.70±3.75 and 35.95±3.72 (p = 0.543) in cases and controls respectively. No baseline differences in endometriosis disease stage (p = 0.414), surgical treatment for endometriosis prior to IVF (p = 0.617), BMI (p = 0.866) or type of infertility (p = 0.255) were observed when comparing the two groups. In “expected normo-responders”, cases with autoimmunity had significantly higher numbers of oocytes retrieved (p = 0.007), MII oocytes (p = 0.007) and OSI index (p = 0.013) when compared to controls with endometriosis only; the CPR was 12.5% in cases vs. 17.5% in controls, thus comparable between the two groups (p = 0.143). In “expected poor-responders” no significant differences were observed neither in the number of oocytes retrieved and MII oocytes, nor in OSI index; the CPR was 12% in cases with concomitant autoimmunity compared to 7.75% in controls with endometriosis only (p = 0.256). In the generalized linear models (GLMs) of independent predictors associated with CPR, in expected ‘normo-responders’ autoimmunity was the only significant negative predictor of CPR (p = 0.004) whereas in ‘poor-responders’ only age negatively affected CPR (p = 0.001). Limitations, reasons for caution This study has a retrospective design. The interpretation of results is based on the validated yet still debated definition of poor-responders according to Bologna Criteria. Results should be interpreted with caution until replicated by future research providing multi-centric and prospective design, larger sample size and more standardized data collection. Wider implications of the findings Autoimmunity does not seem to impact neither ovarian reserve nor ovarian response to gonadotropin, as it may act a ‘competitive’ rather than ‘additive’ risk factor for infertility in endometriosis. However, in ‘normo-responders’ autoimmunity seems to reduce the chances of pregnancy following IVF/ICSI perhaps impairing endometrial receptivity and embryo implantation. Trial registration number Due to the retrospective design of the study, full IRB approval at the institution was not needed.

The Immunogenetics of Morphea and Lichen Sclerosus.

Morphea and lichen sclerosis et atrophicus (LSA) are two distinct immune-mediated diseases with a dominant presentation of dermal fibrosis and sclerosis. The two diseases have many similar clinical and histological features and tend to co-occur. Both diseases are thought to result from a derailment of the normal response to environmental triggers. Positive family history is more common in LSA than morphea but individuals with morphea have a higher frequency of concomitant and familial autoimmunity. These findings hint at the involvement of inheritance in susceptibility to LSA and morphea and thus provide a rationale for exploring the disease genetics. This chapter contains a comprehensive review of the pathogenesis of the two diseases and their known genetic associations including HLA class I and II genes.

P–349 Does concomitant autoimmunity affect IVF/ICSI outcomes in women with endometriosis? A retrospective observational study

Abstract Study question To investigate differences in In Vitro Fertilization (IVF)/Intracytoplasmic Sperm Injection (ICSI) outcomes between endometriosis women who do or don’t have a concomitant autoimmune disease. Summary answer Despite a higher oocyte yield, a trend for reduction in clinical pregnancy rates was observed in the autoimmunity group compared to women without concomitant autoimmunity. What is known already Endometriosis is an inflammatory chronic gynaecological disorder with a known detrimental impact on fertility. Endometriosis pathogenesis is still unclear. It has been postulated a role of both innate and adaptive immune system. The coexistence of endometriosis and autoimmunity is a well-documented occurrence Some recent findings have revealed an increased risk to have concomitant autoimmune disease in women with endometriosis, but no study has so far investigated whether this association could affect IVF/ICSI outcomes. Indeed, autoimmune phenomena, including proinflammatory cytokines and auto-antibody production, may result in diminished quality of oocytes/embryos with lower pregnancy rates among these patients. Study design, size, duration This was a retrospective observational study carried out at the Fertility Unit of IRCSS San Raffaele Hospital (Milan). We reviewed medical patients’ notes of women with a confirmed diagnosis of endometriosis who referred to our Fertility Unit from October 2018 to January 2021. Participants/materials, setting, methods Out of 1441 patients undergoing IVF/ICSI, 98 women had surgical/histopathological diagnosis of endometriosis. 25 of them had a clinical and/or serological diagnosis of autoimmunity. Autoimmunity was assessed by clinical data (blood tests for auto-antibodies or rheumatological records) obtained from the electronic patient files stored in the database of our Fertility Centre. Clinical pregnancy was defined as the presence of at least one intrauterine gestational sac with a viable embryo at week 6 after transfer. Main results and the role of chance 25/98 (25.5%) endometriosis women with a concomitant autoimmune disease (cases) were compared with 73/98 (74.5%) endometriosis patients without autoimmunity (controls). The mean age was 37.36±3.63 and 36.93±3.79 (p=.623) in cases and controls respectively. The mean number of oocytes retrieved was higher in cases (5.78±4.07) than in controls (3.82±2.69;p=.041); similarly, cases showed an higher number of embryos (2.13±1.93 vs. 1.19±1.37;p=.041) and blastocysts (1.89±2.02 vs. 0.85±1.61;p=.041) obtained. A total of 47 fresh embryo transfer (ET) were performed. Considering all the endometriosis patients, the clinical pregnancy rate (CPR) per cycle was 34.0% (16/47); when stratifying for the presence of autoimmunity the CPR was 23.1% (3/13) in cases, and 38.2% (13/34) in controls (p=.494). Limitations, reasons for caution This is a retrospective study based on data extraction from electronic records of our Fertility Centre. The sample size is limited and some information about past medical history could be missed. Results should be interpreted with caution until validated by future research providing more standardized data collection. Wider implications of the findings: Despite significantly higher numbers of oocytes retrieved and embryos/blastocysts formed, the presence of concomitant autoimmune disease in patients with endometriosis may impair pregnancy rates. Whether this finding is confirmed and whether it could be due to a defect in embryo/blastocysts quality or in endometrial receptivity deserves further studies. Trial registration number Not applicable

Concomitant autoimmunity may be a predictor of more severe stages of endometriosis

Pathogenesis of endometriosis is still unclear and a role of both innate and adaptive immune system has been postulated. Some recent findings have revealed an increased risk to have concomitant autoimmune disease in women with endometriosis, but no study so far has investigated whether this association could affect endometriosis severity and stage. We retrospectively reviewed medical patients’ notes of women with a confirmed diagnosis of endometriosis who referred to our endometriosis outpatient clinic between January 2015 and December 2019. Cases (endometriosis and an autoimmune disease) were matched in a 1:3 ratio by age and study period with controls (endometriosis without history of autoimmunity). At univariate logistic analysis, concomitant autoimmunity (OR 2.63, 95% CI 1.64–4.21, p < 0.001) and the number of laparoscopic procedures performed (OR 2.81, 95% CI 1.45–5.43, p = 0.002) emerged as factors significantly associated with the likelihood of stage IV endometriosis. In the multivariate logistic regression model, concomitant autoimmunity remained a significant predictor of stage IV endometriosis (OR 2.54, 95% CI 1.57–4.10, p = 0.004), whereas the association between the number of laparoscopic procedures performed and stage IV endometriosis was found to be of borderline-significance (OR 2.70, 95% 1.37–5.30, p = 0.050). Our findings suggest that endometriosis is more severe in patients who are also affected by autoimmune disturbances after controlling for relevant confounders.

Lower IgA Levels in Chronic Spontaneous Urticaria Are Associated With Lower IgE Levels and Autoimmunity.

BackgroundThe pathogenesis of chronic spontaneous urticaria (CSU) is still insufficiently understood. Recent findings suggest that immunoglobulins, in particular IgE but also IgA, play a role in the development of CSU.ObjectiveOur aim was to assess differences in clinical and laboratory markers between CSU patients with and without lower levels of serum IgA and IgE.MethodsWe analyzed the data of 606 patients with CSU by dividing them into four groups based on their IgA and IgE levels. The groups were compared for their spectrum of symptoms, disease activity, concomitant autoimmunity and routine laboratory markers. Autoreactivity was assessed by basophil activation test (BAT). Moreover, IgE-anti-thyroid peroxidase (TPO) was measured.ResultsOf the patients with lower IgE levels, 66.5% also had lower IgA levels (r=0.316, p<0.001). Patients with lower IgA and lower IgE levels showed a higher prevalence of recurrent angioedema (p=0.03, p=0.04) and concomitant autoimmunity (p=0.006, p<0.001). Autoreactivity was also found more frequently in patients with lower IgA and lower IgE levels (p=0.003, p<0.001). Reduced basophil counts were linked to both, lower IgA and lower IgE levels (p<0.001), whereas low eosinophil counts were primarily present in patients with lower IgE levels (p=0.04, p<0.001). Patients with elevated IgE-anti-TPO levels had lower IgA (p=0.007) and IgE levels (p=0.001).ConclusionLower IgA levels in CSU are linked to lower IgE levels and features of autoimmune urticaria. Our findings encourage to screen CSU patients for serum IgA and IgE levels and to further assess their role as disease biomarkers.

Combination therapy with omalizumab and an immune-suppressive agent for resistant chronic spontaneous urticaria - A real-life experience

BackgroundChronic Spontaneous Urticaria (CSU) is a relatively common immune mediated disease that can be effectively treated nowadays. Nevertheless, for some patients remission cannot be achieved following current treatment recommendations, defined as resistant CSU (r-CSU). Treating r-CSU is challenging, and, currently, there are no recommended interventions. In this real-life study we describe successful therapy of 18 r-CSU patients using an "intensified protocol" of anti-IgE-antibody (omalizumab) concomitantly with an immunosuppressant. We defined the r-CSU phenotype and compared it to omalizumab-responsive CSU (Or-CSU) phenotype. MethodsClinical and serological data of 72 CSU patients (ie, 18 r-CSU and 54 age and sex matched Or-CSU) were retrospectively collected and analyzed. All patients were diagnosed with CSU for ≥6 months and treated at the Sheba Medical Center during 2013–2018. ResultsOf 289 CSU patients, 18 (6%) were diagnosed with r-CSU and treated with the "intensified protocol" including omalizumab and cyclosporine-A (16p), methotrexate (1p), and azathioprine (1p). Of which, 14/18 (78%) achieved complete remission, 2/18 (11%) partial remission, and 2/18 (11%) no remission. During follow-up no serious adverse events were documented. r-CSU patients received higher doses of antihistamine (p < 0.0001) and omalizumab (425 ± 58 mg/month vs. 283 ± 86 mg/month; p < 0.0001) compared to Or-CSU. The r-CSU phenotype was linked with concomitant autoimmunity (p = 0.0005) and a lower level of IgE prior to initiation of therapy (p = 0.027). Conclusionr-CSU may be a distinct CSU phenotype characterized by severe disease, concomitant autoimmunity, and lower baseline-IgE levels (low "autoallergy"). An "intensified protocol" with omalizumab and an immunosuppressive agent was found to be efficacious and safe for r-CSU. Further larger studies are required to verify these results.

STAT4 sequence variant and elevated gene expression are associated with type 1 diabetes in Polish children.

IntroductionType 1 diabetes (T1D) is caused by the autoimmune destruction of pancreatic β cells, resulting from coincident genetic predisposition and some environmental triggers. Signal transducer and activator of transcription 4 (STAT4) gene encodes a transcription factor, which promotes Th1 cell differentiation, interferon γ production, and development of Th17 cells. Polymorphisms of STAT4 are associated with several autoimmune conditions, while studies in T1D provided inconsistent results. This analysis was designed to investigate the association of STAT4 rs7574865 with T1D in Polish children and to assess STAT4 expression in newly diagnosed subjects.Material and methodsRs7574865 was genotyped in 656 T1D children and 782 healthy individuals. STAT4 mRNA expression was analyzed in peripheral blood mononuclear cells (PBMCs) from 29 children with T1D and 27 age-matched controls. β-cell and thyroid-specific serum autoantibodies were assessed with radioimmunoassays.ResultsThe distribution of rs7574865 genotypes and alleles demonstrated significant difference (p = 0.002, p < 0.001, respectively) between patients vs. controls. Carriers of the minor T allele presented earlier T1D onset (p = 0.017). No differences were found in γ-cell autoantibody in genotype-stratified patients (p > 0.050), while anti-thyroid antibodies were more frequent in carriers of the minor allele(p = 0.039 for anti-thyroperoxidase, p = 0.007 for anti-thyroglobulin antibodies, respectively). STAT4 was overexpressed in PBMCs from T1D patients (p = 0.008), especially subjects with two/three circulating β-cell antibodies (p < 0.001).ConclusionsThe study confirms an association of STAT4 rs7574865 with T1D in Polish patients, and provides an evidence for its relationship with an earlier disease onset and concomitant thyroid autoimmunity. STAT4 expression appears elevated in T1D, especially with more severe reaction against β-cell antigens.

MOG-IgG-associated demyelination: focus on atypical features, brain histopathology and concomitant autoimmunity.

Antibodies to myelin oligodendrocyte glycoprotein (MOG) have been demonstrated in patients with optic neuritis (ON), encephalitis and myelitis. To describe the clinical and paraclinical features in patients with MOG-associated demyelination, focusing on unusual cases, brain biopsy and concomitant autoimmunity. A single centre retrospective observational case series, analysing demographic, clinical, laboratory, histopathology and radiological data from MOG- positive patients. We identified 20 adults. The male/female ratio was 1.5. Mean age at onset was 31.6 years and mean disease duration was 7.5 years. The most frequent presentation was myelitis (45%), followed by ON (30%). One case had simultaneous myelitis and ON. Two patients had a cortical syndrome, 1 patient had an encephalopathic presentation and 1 cryptogenic focal epilepsy. Anti-neutrophil cytoplasmic antibodies (ANCA) were found in 3 cases, while 1 patient had an antibody to glutamic acid decarboxylase (GAD). Brain biopsy was performed in 2 patients. Relapsing course was identified in 60% of patients. We also discuss 3 cases with atypical features, brain histopathology and concomitant autoimmunity. MOG- associated demyelination represents a new disease entity. Unusual cases are reported, expanding the disease spectrum. Elucidating this further should be the focus of prospective studies.

Robust Iterative Stimulation with Self-Antigens Overcomes CD8+ T Cell Tolerance to Self- and Tumor Antigens

SUMMARYThe immune system adapts to constitutive antigens to preserve self-tolerance, which is a major barrier for anti-tumor immunity. Antigen-specific reversal of tolerance constitutes a major goal to spur therapeutic applications. Here, we show that robust, iterative, systemic stimulation targeting tissue-specific antigens in the context of acute infections reverses established CD8+ T cell tolerance to self, including in T cells that survive negative selection. This strategy results in large numbers of circulating and resident memory self-specific CD8+ T cells that are widely distributed and can be co-opted to control established malignancies bearing self-antigen without concomitant autoimmunity. Targeted expansion of both self- and tumor neoantigen-specific T cells acts synergistically to boost anti-tumor immunity and elicits protection against aggressive melanoma. Our findings demonstrate that T cell tolerance can be re-adapted to responsiveness through robust antigenic exposure, generating self-specific CD8+ T cells that can be used for cancer treatment.

IL1R8 Deficiency Drives Autoimmunity-Associated Lymphoma Development.

Chronic inflammation, including that driven by autoimmunity, is associated with the development of B-cell lymphomas. IL1R8 is a regulatory receptor belonging to the IL1R family, which negatively regulates NF-κB activation following stimulation of IL1R or Toll-like receptor family members. IL1R8 deficiency is associated with the development of severe autoimmune lupus-like disease in lpr mice. We herein investigated whether concomitant exacerbated inflammation and autoimmunity caused by the deficiency of IL1R8 could recapitulate autoimmunity-associated lymphomagenesis. We thus monitored B-cell lymphoma development during the aging of IL1R8-deficient lpr mice, observing an increased lymphoid cell expansion that evolved to diffuse large B-cell lymphoma (DLBCL). Molecular and gene-expression analyses showed that the NF-κB pathway was constitutively activated in Il1r8 -/-/lpr B splenocytes. In human DLBCL, IL1R8 had reduced expression compared with normal B cells, and higher IL1R8 expression was associated with a better outcome. Thus, IL1R8 silencing is associated with increased lymphoproliferation and transformation in the pathogenesis of B-cell lymphomas associated with autoimmunity.

Reprogramming responsiveness to checkpoint blockade in dysfunctional CD8 T cells

Established T cell dysfunction is a barrier to antitumor responses, and checkpoint blockade presumably reverses this. Many patients fail to respond to treatment and/or develop autoimmune adverse events. The underlying reason for T cell responsiveness remains elusive. Here, we show that susceptibility to checkpoint blockade is dependent on the activation status of T cells. Newly activated self-specific CD8 T cells respond to checkpoint blockade and cause autoimmunity, which is mitigated by inhibiting the mechanistic target of rapamycin. However, once tolerance is established, self-specific CD8 T cells display a gene signature comparable to tumor-specific CD8 T cells in a fixed state of dysfunction. Tolerant self-specific CD8 T cells do not respond to single or combinatorial dosing of anti-CTLA4, anti-PD-L1, anti-PD-1, anti-LAG-3, and/or anti-TIM-3. Despite this, T cell responsiveness can be induced by vaccination with cognate antigen, which alters the previously fixed transcriptional signature and increases antigen-sensing machinery. Antigenic reeducation of tolerant T cells synergizes with checkpoint blockade to generate functional CD8 T cells, which eliminate tumors without concomitant autoimmunity and are transcriptionally distinct from classic effector T cells. These data demonstrate that responses to checkpoint blockade are dependent on the activation state of a T cell and show that checkpoint blockade-insensitive CD8 T cells can be induced to respond to checkpoint blockade with robust antigenic stimulation to participate in tumor control.

Leveraging TCR Affinity in Adoptive Immunotherapy against Shared Tumor/Self-Antigens.

Adoptive cellular therapy (ACT) using T-cell receptor (TCR)-engineered lymphocytes holds promise for eradication of disseminated tumors but also an inherent risk of pathologic autoimmunity if targeted antigens or antigenic mimics are expressed by normal tissues. We evaluated whether modulating TCR affinity could allow CD8+ T cells to control tumor outgrowth without inducing concomitant autoimmunity in a preclinical murine model of ACT. RIP-mOVA mice express a membrane-bound form of chicken ovalbumin (mOVA) as a self-antigen in kidney and pancreas. Such mice were implanted with OVA-expressing ID8 ovarian carcinoma cells and subsequently treated with CD8+ T lymphocytes (CTL) expressing either a high-affinity (OT-I) or low-affinity (OT-3) OVA-specific TCR. The effects on tumor growth versus organ-specific autoimmunity were subsequently monitored. High-affinity OT-I CTLs underwent activation and proliferation in both tumor-draining and pancreatic lymph nodes, leading to both rapid eradication of ID8-OVA tumors and autoimmune diabetes in all treated mice. Remarkably, the low-affinity OT-3 T cells were activated only by tumor-derived antigen and mediated transient regression of ID8-OVA tumors without concomitant autoimmunity. The OT-3 cells eventually upregulated inhibitory receptors PD-1, TIM-3, and LAG-3 and became functionally unresponsive, however, allowing the tumors in treated mice to reestablish progressive growth. Antibody-mediated blockade of the inhibitory receptors prevented exhaustion and allowed tumor clearance, but these mice also developed autoimmune diabetes. The findings reveal that low-affinity TCRs can mediate tumor regression and that functional avidity can discriminate between tumor-derived and endogenous antigen, while highlighting the risks involved in immune-checkpoint blockade on endogenous self-reactive T cells.

Childhood thyroid autoimmunity and relation to islet autoantibodies in children at risk for type 1 diabetes in the diabetes prediction in skåne (DiPiS) study

Background: The aim was to determine prevalence and age at seroconversion of thyroid autoimmunity in relation to islet autoantibodies, gender and HLA-DQ genotypes in children with increased risk for type 1 diabetes followed from birth.Methods: In 10-year-old children (n = 1874), blood samples were analysed for autoantibodies against thyroid peroxidase (TPOAb), thyroglobulin (TGAb), glutamic acid decarboxylase 65 (GADA), Zink transporter 8 (ZnT8R/W/QA), insulinoma-associated protein-2 (IA-2A), insulin (IAA) and HLA-DQ genotypes. Prospectively collected samples from 2 years of age were next analysed for TPOAb, and TGAb and, finally, in confirming samples at 11–16 years of age along with TSH and FT4. Frequencies were tested with Chi-square or Fischer’s exact tests, autoantibody levels with Wilcoxon and correlations between autoantibody levels with Spearman’s rank correlation test.Results: The prevalence of thyroid autoimmunity was 6.9%, overrepresented in girls (p < .001) also having higher TPOAb levels at 10 years (p = .049). TPOAb was associated with GADA (p = .002), ZnT8R/W/QA (p = .001) and IA-2A (p = .001) while TGAb were associated with ZnT8R/W/QA (p = .021). In boys only, TPOAb were associated with GADA (p = .002), IA-2A (p = .001), ZnT8R/W/QA (p = .001) and IAA (p = .009), and TGAb with GADA (p = .013), IA-2A (p = .005) and ZnT8R/W/QA (p = .003). Levels of IA-2A correlated to both TPOAb (p = .021) and to TGAb (p = .011). In boys only, levels of GADA and TGAb correlated (p = .009 as did levels of IA-2A and TPOAb (p = .013). The frequency and levels of thyroid autoantibodies increased with age. At follow-up, 22.3% had abnormal thyroid function or were treated with thyroxine.Conclusions: Thyroid autoimmunity and high TPOAb levels were more common in girls. In contrast, in boys only, there was a strong association with as well as correlation between levels of thyroid and islet autoantibodies. It is concluded that while girls may develop autoimmune thyroid disease (AITD) independent of islet autoantibodies, the risk for thyroid disease in boys may be linked to concomitant islet autoimmunity.