Association Of Autoimmune Diseases Research Articles

Association of serum sclerostin levels with marrow adiposity in postmenopausal women with glucocorticoid-induced osteoporosis

BackgroundGlucocorticoids and sclerostin act as inhibitors of the Wnt signaling pathway, thereby hindering bone formation. Given the pathway's intricate association with mesenchymal stem cells, the hypothesis suggests that heightened sclerostin levels may be intricately linked to an augmentation in marrow adiposity induced by glucocorticoids. This study endeavored to delve into the nuanced relationship between circulating sclerostin and bone marrow adipose tissue in postmenopausal women grappling with glucocorticoid-induced osteoporosis (GIO).MethodsIn this cross-sectional study, 103 patients with autoimmune-associated diseases underwent glucocorticoid treatment, boasting an average age of 61.3 years (standard deviation 7.1 years). The investigation encompassed a thorough assessment, incorporating medical history, anthropometric data, biochemical analysis, and dual-energy X-ray absorptiometry measurements of lumbar and femoral bone mineral density (BMD). Osteoporosis criteria were established at a T-score of -2.5 or lower. Additionally, MR spectroscopy quantified the vertebral marrow fat fraction.ResultsBMD at the femoral neck, total hip, and lumbar spine showcased an inverse correlation with marrow fat fraction (r = –0.511 to – 0.647, P < 0.001). Serum sclerostin levels exhibited a positive correlation with BMD at various skeletal sites (r = 0.476 to 0.589, P < 0.001). A noteworthy correlation emerged between circulating sclerostin and marrow fat fraction at the lumbar spine (r = –0.731, 95% CI, –0.810 to –0.627, P < 0.001). Multivariate analysis brought to light that vertebral marrow fat fraction significantly contributed to sclerostin serum concentrations (standardized regression coefficient ß = 0.462, P < 0.001). Even after adjusting for age, body mass index, physical activity, renal function, BMD, and the duration and doses of glucocorticoid treatment, serum sclerostin levels maintained a significant correlation with marrow fat fraction.ConclusionsCirculating sclerostin levels exhibited a noteworthy association with marrow adiposity in postmenopausal women grappling with GIO.

Incident autoimmune diseases in association with SARS-CoV-2 infection: a matched cohort study.

To investigate whether the risk of developing an incident autoimmune disease is increased in patients with prior COVID-19 disease compared to those without COVID-19, a large cohort study was conducted. A cohort was selected from German routine health care data. Based on documented diagnoses, we identified individuals with polymerase chain reaction (PCR)-confirmed COVID-19 through December 31, 2020. Patients were matched 1:3 to control patients without COVID-19. Both groups were followed up until June 30, 2021. We used the four quarters preceding the index date until the end of follow-up to analyze the onset of autoimmune diseases during the post-acute period. Incidence rates (IR) per 1000 person-years were calculated for each outcome and patient group. Poisson models were deployed to estimate the incidence rate ratios (IRRs) of developing an autoimmune disease conditional on a preceding diagnosis of COVID-19. In total, 641,704 patients with COVID-19 were included. Comparing the incidence rates in the COVID-19 (IR=15.05, 95% CI: 14.69-15.42) and matched control groups (IR=10.55, 95% CI: 10.25-10.86), we found a 42.63% higher likelihood of acquiring autoimmunity for patients who had suffered from COVID-19. This estimate was similar for common autoimmune diseases, such as Hashimoto thyroiditis, rheumatoid arthritis, or Sjögren syndrome. The highest IRR was observed for autoimmune diseases of the vasculitis group. Patients with a more severe course of COVID-19 were at a greater risk for incident autoimmune disease. SARS-CoV-2 infection is associated with an increased risk of developing new-onset autoimmune diseases after the acute phase of infection. Key Points • In the 3 to 15 months after acute infection, patients who had suffered from COVID-19 had a 43% (95% CI: 37-48%) higher likelihood of developing a first-onset autoimmune disease, meaning an absolute increase in incidence of 4.50 per 1000 person-years over the control group. • COVID-19 showed the strongest association with vascular autoimmune diseases.

Neuromyelitis optica spectrum disorders with and without associated autoimmune diseases.

We aimed to determinate the frequency of this association and compare the features of neuromyelitis optica spectrum disorder (NMOSD) with and without associated autoimmune diseases (AD) in a Latin American (LATAM) population in clinical practice. We retrospectively reviewed the medical records of patients with NMOSD according to the 2015 diagnostic criteria. Patients from Argentina (n=77), Brazil (n=46), and Venezuela (n=17) were enrolled and classified into two groups as follows: with AD or without AD. Clinical, paraclinical (including aquaporin-4 antibodies (AQP4-ab) status), magnetic resonance imaging (MRI), and prognosis data were analyzed and compared. Kaplan-Meier (KM) and the Nelson-Aalen estimator analyses were performed to estimate both time and the cumulative hazard risk of disability reaching an EDSS≥4; and time for the first recurrence. Out of 140 patients, 33 (23.5%) patients had associated an AD at presentation. The most frequent associated AD was Hashimoto disease (n=10) followed by lupus (n=7) and Sjogren's syndrome (n=6). However, rituximab use (42.4% vs. 21.5%, p=0.02), female gender (82.2% vs. 100%, p=0.006), corticospinal lesions on MRI (0% vs. 12.5%, p=0.01) at onset, and positivity for antinuclear antibodies (21.2% vs. 48.4%, p=0.03) were significantly associated with NMOSD patients with AD in comparison to NMOSD patients without AD. No differences were found in other clinical and paraclinical aspects between groups. KM and Nelson-Aalen estimator analyses did not show differences between groups. NMOSD patients associated with AD were observed in 23.5%. In addition, NMOSD patients with and without associated AD were similar in most evaluated features.

Detection of Antinuclear Antibodies in Canine Serum by Immunoperoxidase in MDCK and Indirect Immunofluorescence in HEp2 Cells

Antinuclear antibodies are found in animals suffering from Systemic Lupus Erythematosus (SLE) and some other diseases, their presence in the blood is determined by antinuclear antibody (ANA) test using indirect immunofluorescence (IF) with HEp2 cells as a substrate. In this work, an immunoperoxidase (IP) assay was developed to evaluate the ANAs in canine sera, using canine kidney cell lines (MDCK) and compared with a commercial immunofluorescence test on Hep2 cells for this system, a fluoresceinated anti-canine Ig antibody was standardized. The study was performed on 50 sera from dogs submitted to the laboratory with different clinical diagnoses of autoimmune-associated diseases. The procedures on both cells were unified to perform comparisons of the reactions, direct sera or at different dilutions were added to a monolayer of permeabilized MDCK cells, followed by a peroxidized anti-canine IgG conjugate, and a substrate for the IP reaction. The same sera were tested on the commercial IF assay on Hep2 cell system. In 22/50 cases, the presence of LE cells in peripheral blood was determined. A high correlation was found in the detection of antinuclear antibodies between both cell lines and techniques, however there were differences in the reaction patterns in the nucleus and cytoplasm between cell lines. The diffuse nuclear pattern observed in MDCK cells was more related to the presence of high percentages of LE cells in peripheral blood. The differences found in the results were possibly associated with the presence of homologous antigens between the MDCK cells and the dog. In addition, the methodology and standardization for the use and interpretation of a reference serum was developed to unify the interpretation criteria in the laboratory.

Immunological signature of patients with thymic epithelial tumors and Good syndrome.

Thymic epithelial tumors (TETs) are frequently accompanied by Good Syndrome (GS), a rare immunodeficiency, characterized by hypogammaglobulinemia and peripheral B cell lymphopenia. TETs can be also associated to other immunological disorders, both immunodeficiency and autoimmunity. In this study, we enrolled TET patients with GS to address differences between patients with or without associated autoimmune diseases (AD). We analyzed the immunophenotype from peripheral blood of these patients focusing on selected immune cell subsets (CD4+T cells, CD8+T cells, T regulatory cells, NK cells, B-cells, monocytes, eosinophils, basophils, neutrophils) and serum levels of cytokines, chemokines and growth factors. We observed higher number of leucocytes, in particular lymphocytes, B lymphopenia and lower number of T regulatory cells in TET patients with associated AD compared to TET patients without AD. In the group of TET patients with AD, we also observed increased serum levels of IL-15, VEGF, IP-10, GM-CSF, IL-6, and MIP-1α. Thus, we identified considerable differences in the lymphocyte profiles of TET patients with and without ADs, in particular a reduction in the numbers of B lymphocytes and T-regulatory cells in the former, as well as differences in the serum levels of various immune modulators. Although the pathogenic mechanisms are still unclear, our results add new knowledge to better understand the disease, suggesting the need of surveilling the immunophenotype of TET patients to ameliorate their clinical management.

Bipolaquinones A-J, Immunosuppressive Meroterpenoids from a Soil-Derived Bipolaris zeicola.

Ten new meroterpenoids, bipolaquinones A-J (1-10), and one known congener, isocochlioquinone F (11), were isolated and identified from the fermented rice cultures of a soil-derived fungus, Bipolaris zeicola. The planar structures of 1-10 were elucidated based on extensive spectroscopic analyses (including HRESIMS and 1D and 2D NMR data), and their absolute configurations were determined by single-crystal X-ray diffraction analyses, comparison of experimental electronic circular dichroism (ECD) data, ECD calculations, and hydrolysis reaction. The immunosuppressive activity assay revealed that compounds 2, 3, and 7-10 showed significant inhibitory activity against concanavalin A (ConA)-induced T lymphocyte proliferation with IC50 values ranging from 4.1 to 9.4 μM, which furnished potential lead molecules for the design and development of new immunosuppressants for treating autoimmune-associated diseases.

Associated autoimmunity in Type 1 Diabetes and latent autoimmune diabetes of adults: The role of glutamic-acid decarboxylase autoantibodies

AimsTo determine the prevalence of Associated Autoimmune Diseases (AADs) in Latent Autoimmune Diabetes of Adults (LADA) versus autoimmune Type 1 Diabetes (T1D) and the role of glutamic-acid decarboxylase antibodies (GADA) and other factors. MethodsAdults with autoimmune diabetes mellitus (DM) were recruited from the Diabetes Center of Nikaia-Piraeus Hospital. Demographic and clinical parameters were recorded and anti-pancreatic and organ-specific antibodies were measured. ResultsOf 160 patients, 33.75% had one AAD and 24.37% had two or more. Patients with LADA had higher overall prevalence of AADs, mainly autoimmune thyroiditis and gastritis. Celiac disease was present only in T1D. GADA positive patients had higher prevalence of AADs and multiple autoimmunity, especially thyroiditis and gastritis. Patients with LADA had higher rates of positive GADA or islet-cell antibodies (ICA). After controlling for LADA, GADA remained a significant predictor of AADs. Female gender and chronological age were also significant predictors of AADs. ConclusionsAADs were present in 58.13% of patients. Patients with LADA were more prone to a generalized autoimmune disorder than those with T1D. AADs development was significantly associated with female sex, older age and positive GADA, which proved an independent marker of associated autoimmunity.

Duodenal Histological Findings and Risk of Coeliac Disease in Subjects with Autoimmune Atrophic Gastritis: A Retrospective Evaluation

Background and Aim: Autoimmune atrophic gastritis (AAG) is characterized by a variable spectrum of gastric and extra-gastric symptoms and has been associated with other autoimmune diseases. It is still unknown whether AAG patients have a higher risk of coeliac disease (CeD) or of any other particular duodenal histological damage. Our study aimed at evaluating the duodenal histological findings and the risk of CeD in patients with AAG, with and without other concurrent autoimmune diseases. Methods: We retrospectively collected all the histological findings of the adult patients undergoing upper gastrointestinal endoscopy with concurrent duodenal and gastric biopsies at our gastroenterology unit between 2015 and 2018 and who were regularly followed up at our centre. Date of endoscopy evaluation, endoscopy indication, data on previous CeD diagnosis and on other autoimmune-associated diseases, and a description of histological diagnosis were recorded. Results: Of the 2,423 evaluated endoscopies, 209 patients had an AAG diagnosis (8.6%). One hundred thirty-nine patients, aged 57.4 (standard deviation 13.2) years, were regularly followed up at our centre and were included. Of them, 4 subjects had a previous diagnosis of CeD and one had CeD diagnosis at index endoscopy. Additionally, 8 patients had an isolated increase of intraepithelial lymphocytes (IELs, 6%) and 2 villous atrophy with a normal IEL count. The risk of CeD in AAG was not modulated by the presence of other concurrent autoimmune diseases. Conclusions: We support the screening of all AAG patients with CeD autoantibodies. Findings of isolated IEL or villous atrophy are not exclusively related to CeD.

Spotlight on the June 2 issue

#### Notable in Neurology this week This issue features an article that examines the clinical phenotype of children with contactin-associated protein 2 (CASPR2) antibodies in order to delineate autoimmune disease in association with CASPR2 antibodies in childhood; another investigates the Revised Self-Monitoring Scale as a potential clinical endpoint for treatment trials for patients with behavioral variant frontotemporal dementia. A featured Special Article provides neurologic outcome quality measures for broad application across major neurologic diseases. ### Clinical significance of anti-NMDAR concurrent with glial or neuronal surface antibodies Some patients with anti-NMDAR encephalitis (NMDARE) have concurrent glial or neuronal surface antibodies. In 2 …

CASPR2 autoimmunity in children expanding to mild encephalopathy with hypertension

To delineate autoimmune disease in association with contactin-associated protein 2 (CASPR2) antibodies in childhood, we reviewed the clinical phenotype of children with CASPR2 antibodies. Retrospective assessment of patients recruited through laboratories specialized in autoimmune CNS disease. Ten children with serum CASPR2 antibodies were identified (age at manifestation 18 months to 17 years). Eight children with CASPR2 antibody titers from ≥1:160 to 1:5,120 had complex autoimmune diseases with an age-dependent clinical phenotype. Two children with structural epilepsy due to CNS malformations harbored nonspecific low-titer CASPR2 antibodies (serum titers 1:80). The clinical symptoms of the 8 children with high-titer CASPR2 antibodies were general weakness (8/8), sleep dysregulation (8/8), dysautonomia (8/8) encephalopathy (7/8), neuropathic pain (7/8), neuromyotonia (3/8), and flaccid paresis (3/8). Adolescents (3/8) showed pain, neuromyotonia, and encephalopathy, whereas younger children (5/8) displayed severe hypertension, encephalopathy, and hormonal dysfunction mimicking a systemic disease. No tumors were identified. Motor symptoms remitted with immunotherapy. Mild behavioral changes persisted in 1 child, and autism spectrum disorder was diagnosed during follow-up in a young boy. High-titer CASPR2 antibodies are associated with Morvan syndrome in children as young as 2 years. However, CASPR2 autoimmunity mimics systemic disease and hypertensive encephalopathy in children younger than 7 years. The outcome following immunotherapy was mostly favorable; long-term behavioral impairment may occur in younger children.

Gender Differences at the Onset of Autoimmune Thyroid Diseases in Children and Adolescents.

Background: The incidence of autoimmune thyroid diseases (ATD) may vary with the beginning of reproductive function, although few reports differentiate the incidence before and during the onset of puberty, examining gender bias. We analyzed onset of ATD in a pediatric population to assess gender differences in onset age, disease subtype, pubertal status, autoimmune co-morbidity, family history and treatment, focusing on the interaction between gender and pubertal stage.Patients and methods: We retrospectively recorded 382 children and adolescents with ATD. In each patient physical examination was considered. The presence of other associated autoimmune diseases (AAD) and familial predisposition was also recorded.Results: Predominant prevalence was noted in females compared to males (p < 0.001), both in Hashimoto's diseases (HD or HT) and Graves' disease (GD) (p < 0.001). Mean age at diagnosis showed no significant difference between sexes (p > 0.05). A higher prevalence in pubertal subjects was noted compared to prepubertal (p < 0.001, particularly HT in early and GD in late pubertal stage), without sexes difference intra-(prepubertal vs. pubertal) and inter-puberty groups (prepubertal vs. early pubertal vs. late pubertal). Both in HT and in GD, the prevalence of autoimmune associated diseases (AAD) was higher in males compared to females (p = 0.04), with similar distribution according to the pubertal maturation. The familial predisposition was similarly distributed in both genders (p > 0.05) and into pubertal stages (p > 0.05).Conclusions: Females are more prone to develop ATD during puberty, earlier in HT than in GD. The effect of puberty is not different between genders, suggesting the role of additional factors other than hormones. The screening for detection of ATD is recommended in all patients with positive family history and other autoimmune diseases, mostly in males. Considerations of gender in pediatrics could be important to define pathogenic mechanisms of ATD and to help in early diagnosis and clinical management.

Prospective, Multicentric Phase II Randomized Trial Comparing the Efficacy of Methotrexate or Cyclophosphamide in Large Granular Lymphocytic Leukemia: A French National Study. Report on the Interim Analysis

Introduction Large granular lymphocyte (LGL) leukemia is characterized by a clonal expansion of CD3+ cytotoxic T or CD3- NK cells. Prominent clinical features include neutropenia, anemia and autoimmune-associated diseases such as rheumatoid arthritis (RA). Although the disease is usually chronic and indolent, some patients may be symptomatic and require treatment. No standard therapy has been established due to the absence of prospective clinical trials. So far, low dose methotrexate, oral cyclophosphamide, and cyclosporine represent the 3 main options for initial therapy. In 2014, we launched a prospective clinical trial comparing methotrexate to cyclophosphamide in previously-untreated patients with LGL leukemia in need of treatment. Patients and methods The study was designed as a multicentric, national, open label, randomized, controlled trial on two parallel groups, comparing methotrexate and cyclophosphamide. Patients were included if they had at least one of the following indications of treatment: isolated severe neutropenia (ANC &amp;lt;0.5x109/L) or neutropenia (ANC &amp;lt;1.5x109/L) with infections, anemia requiring transfusions or symptomatic anemia, associated complications such as systemic diseases or auto-immune diseases resistant to steroids and/or immunomodulating agents (colchicin, disulone, hydrochloroquine). They were randomly assigned to receive either methotrexate (10 mg/m²/w) or cyclophosphamide (100 mg/d) for 4 months. Responders at M4 continued with the same treatment until M12 (cyclophosphamide was then delivered at 50 mg/d). Non-responders at M4 were randomly assigned to receive either cyclosporine (3 mg/kg/d) or the drug which had not been administered at the first randomization (methotrexate or cyclophosphamide). Response was assessed using previously published criteria (Lamy T, Blood 123:1182, 2014). Complete response (CR) was defined as a normalization of clinical exam (disappearance of splenomegaly or associated autoimmune symptoms) and a complete normalization of blood counts. Partial response (PR) was defined as an improvement in blood counts which did not meet criteria for complete remission (e.g., ANC &amp;gt;0.5x109/L or decrease of transfusion requirements). Treatment failure was defined as no response or any response which did not meet the above-mentioned criteria within four months after the beginning of treatment. To stop the trial as soon as sufficient information was collected, a sequential analysis was planned each time 20 patients were included and evaluated using the triangular test (Sébille V, Bellissant E. Fundam Clin Pharmacol. 2003;17(5):505-16). The primary endpoint was the hematological CR rate evaluated at M4 (binary endpoint). Secondary endpoints were overall response rate (ORR) at M4, M8 and M12, time to relapse. For non-responders at M4, cyclosporine was compared to the treatment which had not been administered during the first phase. Results From Nov 2013 to July 2019, 99 patients met inclusion criteria among which 96 were randomized. The baseline characteristics of these patients are shown in Table1. STAT3 mutation was observed 52% of cases. After the 4th sequential analysis performed on the first 80 patients evaluable for response at M4, the sample path remained in the continuation region of the triangular test. Thus, the trial has to be continued. At M4, 13 patients were in CR (16.3%) and 29 patients were in PR (36.3%), ORR was 52.6%, 36 patients were considered as refractory and underwent a second randomization: 18 patients received cyclosporine and 17 received methotrexate or cyclophosphamide. Conclusions This first prospective randomized clinical trial in LGL leukemia shows that the CR after first line therapy using either methotrexate or cyclophosphamide is relatively low (&amp;lt; 20%). Recruitment is still ongoing to assess if there is a difference in terms of response between the two drugs. Predictive biomarkers of response will be presented at the meeting. Regarding a 52% of incidence of Stat3 mutation (higher than that previously published), Jak/Stat targeted therapy should be prospectively evaluated in this disease. Disclosures Houot: Bristol Myers Squibb: Honoraria; Merck Sharp Dohme: Honoraria. Gyan:Pfizer: Honoraria. Feugier:janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

P3.CR-31 A Case of Thymoma with Autoimmune Hepatitis Following Preoperative Chemotherapy

We encountered a case of thymoma with autoimmune hepatitis. A 63-year-old woman was found to have an abnormal finding on chest radiography during a medical checkup, but did not seek further care. She was referred to our hospital one year later when a bilateral hilar abnormality was again found during a checkup. Chest computed tomography (CT) showed a 4.6 × 3.0 × 5.6 cm mass with calcifications in the anterior mediastinum. The tumor invaded the right lung and middle lobe, in association with a 2.0-cm daughter nodule in the head of the main tumor, with multiple pleural seeding lesions in the right thoracic cavity. Although she was asymptomatic, the anti-acetylcholine receptor antibody level was elevated to 33 nmol/L and the soluble IL-2 receptor antibody was elevated to 1,700 U/mL. The mass was diagnosed with CT-guided biopsy as a type-B2 thymic tumor (cT3N0M1a, c-Stage IV). She underwent induction chemotherapy (ADOC, 2 courses). After chemotherapy, abnormal liver enzyme levels (aspartate aminotransferase: 451 U/L, alanine aminotransferase: 529 U/L) were noted on preoperative examination. She was diagnosed with autoimmune hepatitis based on liver biopsy findings and treated with oral prednisolone 30 mg. Surgery was performed after prednisolone dose was gradually decreased to 20 mg. Extended thymectomy and pulmonary wedge resection using median sternotomy were performed. Pleural dissemination was resected using video-assisted thoracoscopic surgery. The pathological findings showed type-B3 thymic carcinoma (pT3N0M1a, p-Stage IV, Masaoka classification IVa). She was placed under observation without any additional treatment. Prednisolone dose has been gradually decreased to 15 mg without exacerbation of liver function. The anti-acetylcholine receptor antibody level decreased after surgery. Autoimmune diseases in association with thymoma are well known, but reports of autoimmune hepatitis are very rare. Autoimmune hepatitis must be considered when acute liver damage is observed.

Metabolic Stress in the Immune Function of T Cells, Macrophages and Dendritic Cells.

Innate and adaptive immune cells from myeloid and lymphoid lineages resolve host infection or cell stress by mounting an appropriate and durable immune response. Upon sensing of cellular insults, immune cells become activated and undergo rapid and efficient functional changes to unleash biosynthesis of macromolecules, proliferation, survival, and trafficking; unprecedented events among other mammalian cells within the host. These changes must become operational within restricted timing to rapidly control the insult and to avoid tissue damage and pathogen spread. Such changes occur at high energy cost. Recent advances have established that plasticity of immune functions occurs in distinct metabolic stress features. Evidence has accumulated to indicate that specific metabolic signatures dictate appropriate immune functions in both innate and adaptive immunity. Importantly, recent studies have shed light on whether successfully manipulating particular metabolic targets is sufficient to modulate immune function and polarization, thereby offering strong therapeutic potential for various common immune-mediated diseases, including inflammation and autoimmune-associated diseases and cancer. In this review, we detail how cellular metabolism controls immune function and phenotype within T cells and macrophages particularly, and the distinct molecular metabolic programming and targets instrumental to engage this regulation.

Primary immunodeficiency and autoimmune diseases

Primary immunodeficiencies consist of a group of genetically heterogeneous immune disorders affecting distinct elements of the innate and adaptive immune system. Patients with primary immunodeficiency are more prone to develop not only recurrent infections, but non-infectious complications, like inflammatory or granulomatous conditions, lymphoproliferative and solid malignancies, autoinflammatory disorders, and a broad spectrum of autoimmune diseases. The concomitant appearance of primary immunodeficiency and autoimmunity appears to be rather paradoxical, therefore making the diagnosis of immunodeficiency patients with autoimmune complications challenging. Mutations of one or more genes playing a fundamental role in immunoregulation and/or immune tolerance network are thought to be responsible for primary immunodeficiencies. The diverse immunological abnomalities along with the compensatory and excessive sustained inflammatory response result in tissue damage and finally in manifestation of organ-, cell-specific or systemic autoimmune diseases. Several forms of primary immunodeficiency disorders are characterized by a variety of specific autoimmune phenomena. This overview addresses the spectrum of autoimmune diseases associated with primary immunodeficiencies, and explores the molecular and cellular mechanisms underlying abnormalities of the immune system. The case presented finally highlights that both the recognition of autoimmune diseases in association with immunodeficiencies and the diagnosis of immunodefiency in those phenotypes with predominant autoimmunity could be challenging. Orv Hetil. 2018; 159(23): 908-918.

Induction of Haploidentical Mixed Chimerism Cures Autoimmune Type 1 Diabetes

Abstract Type 1 diabetes is an autoimmune disease in association with particular MHC, and induction of MHC-matched mixed chimerism cannot reverse autoimmunity. Haploidentical HCT has gradually become a common practice for treating non-malignant diseases, but it remains unknown whether induction of haploidentical mixed chimerism can reverse autoimmunity. In the current studies, we induced mixed chimerism in NOD mice (H2-Ag7) by transplanting bone marrow and CD4+ T-depleted spleen cells from haploidentical (B6 × B6g7) F1 donors (H2-Ab/g7). We found that haploidentical mixed chimerism eliminated insulitis as well as prevented in pre-diabetic and cured diabetes in new-onset WT NOD mice. Interestingly, although I-As was thought to be autoimmune susceptible, induction of haploidentical mixed chimerism with I-Ag7/s transplants also effectively eliminate insulitis. Furthermore, the mixed chimerism markedly reduced the percentage of host-type but not donor-type CD4+CD8+ thymocytes and increased CD11c+CD8−SIRPα+CD11b+ migratory DC that can mediate thymic negative selection in the chimeric thymus. In the peripheral, percentage of tetramer+ autoreactive host-type Tcon cells was markedly reduced and part of the residual T cells became PD-1hiIL-7Rαlo anergic/exhausted, while percentage of host-type CD4+Foxp3+ Treg cells significantly increased. Additionally, in the pancreas of mixed chimeric BDC2.5 NOD mice, Treg cells among tetramer+ autoreactive T cells increase 5–10 fold. Taken collectively, haploidentical mixed chimerism reverses autoimmunity and eliminating insulitis in NOD mice by enhancing DC mediated negative selection in thymus and augmenting expansion of Treg, especially antigen specific Treg cells, in the periphery.

Risk variation in celiac disease in a population from Southern Spain: evaluating the influence of the DQB1*02:02 allele frequency

Objectives: To date, the greatest genetic risk factor known for celiac disease (CD) is the presence of HLA-DQ2 heterodimers, specifically DQ2.5 in state of homozygosis or heterozygosis. DQ2.2 variants are the second most important risk factor when carried trans to DQ2. This study aimed to determine the prevalence and risk genotypes of HLA-DR-DQ.Material and methods: A total of 196 patients with CD and 206 healthy controls from the Province of Málaga (southern Spain) were included. The corresponding risk gradient in our population was established in accordance with the odds ratios (ORs) found.Results: The heterozygous genotype for DR7-DQ2.2/DR3-DQ2.5 presented the highest risk (OR =6.404, p = .0001) followed by the DR3-DQ2.5 homozygous genotype (OR =4.721, p = .001). An intermediate risk was found for the DQ2.5 heterozygous genotype with no other DQ risk variant (DQ8 or DQ2.2). Similarly, these three genotypes had also an increase in the risk of associated-autoimmune diseases. The DQB1*02:01 allele was the most widely represented among patients with CD respect to the control group (f = 0.479, p = .0001), with the second most common being DQB1*02:02 (f = 0.209, p = .0001).Conclusions: In addition to the gene dosage effect confirmed in our report, and in contrast with previous studies, we found a raised risk for those patients with DQ2.2 heterodimers in trans configuration to DQ2.5 compared to DQ2.5 homozygous individuals. Therefore, in our population of patients with CD the frequency of DQ2.2 acts as a factor that increases the genetic risk of developing CD.

Lower level of IL‑35 and its reduced inhibition in Th17 cells in patients with bone marrow mononuclear cells Coombs test‑positive hemocytopenia.

Interleukin (IL)-35 is the latest member of IL-12 family, which plays an important role in other autoimmune diseases. Bone marrow mononuclear cells Coombs test-positive hemocytopenia, also termed immunorelated hemocytopenia (IRH) is a type of autoimmune-associated diseases. The present study investigated the relationship of IL-35 in patients with IRH. A total of 43 patients with IRH and 19 normal controls were enrolled in the current study. Serum levels of IL-35 and IL-17 in peripheral blood were evaluated by ELISA. Regulatory T cells (Tregs) level was detected by flow cytometry and IL-35 subunits mRNA in Treg was determined using reverse transcription-quantitative polymerase chain reaction: Epstein-Barr virus induced 3 (EBI3) and IL-12α chain p35. Effect of IL-35 on T helper 17 cells (Th17) cells was determined by mix-culture of IL-35 with CD4+ T lymphocytes. Serum level of IL-35 was decreased in untreated patients with IRH compared with remission patients (P<0.01) and was significantly associated with clinical indexes. Frequency of IL-35 produced Tregs was lower and IL-35 subunits mRNA in CD4+CD25+ Tregs were decreased in patients with IRH compared with health controls (P<0.01). Serum level of IL-17 was increased in patients with IRH (P<0.01) and there was a negative correlation between IL-35 and IL-17 (r=−0.553; P<0.01). The production of Th17 cells and IL-17A mRNA expression were reduced (P<0.05) after mix-culture of CD4+ T lymphocytes with IL-35 compared with mix-culture of CD4+ T lymphocytes without IL-35. In conclusion, the present study revealed that IL-35 may be a monitoring indicator of IRH occurrence and progression. IL-35 level was lower and the inhibition on Th17 cells was reduced in the patients with IRH.

Development of new extra-glandular manifestations or associated auto-immune diseases after establishing the diagnosis of primary Sjögren's syndrome : A long-term study of the Antonius Nieuwegein Sjögren (ANS) cohort.

To investigate in a long-term study, the development of new extra-glandular manifestations (EGM) or associated auto-immune diseases (AID) from 1 year after establishing the diagnosis of primary Sjögren's syndrome (pSS). The primary goal was to examine the frequency and type of these manifestations and to find out which demographic, clinical and serological profile was most at risk. All outpatients diagnosed with primary Sjögren's syndrome were included in a retrospective study, with at least one check-up per year, from June 1991 until August 2015. Patients also fulfilling the criteria for concomitant connective tissue disorders were excluded. Data were collected with respect to the cumulative prevalence of a new EGM or associated AID. 140 patients were included in the final analysis. After 10 years of follow-up, the cumulative incidence of a new EGM or associated AID was 30.7%. The most frequent events were polyneuropathy, interstitial lung disease, (poly)arthritis, discoid lupus erythematosus (LE)/subacute cutaneous LE and Hashimoto's disease. Non-Hodgkin lymphoma was not diagnosed during the follow-up. Patients without chronic benign pain syndrome (CBP) (HR 2.13; 95% CI [0.94-4.76]; p=0.061), but in particular those with cryoglobulins (HR 2.87; 95% CI [1.20-6.86]; p=0.013), developed more events. Age at diagnosis, gender, the presence of ANA, anti-Ro/SSA, anti-La/SSB, IgM-RF, decreased levels of C3 or C4, or hypergammaglobulinaemia did not show any statistically significant differences. The burden of disease in pSS is higher than expected due to the development of EGM or associated AID. Therefore, we recommend long-term follow-up of all pSS patients, particularly those with cryoglobulinaemia.

Uncommon histiocytic disorders: Rosai–Dorfman, juvenile xanthogranuloma, and Erdheim–Chester disease

Abstract Rosai–Dorfman disease (RDD), juvenile xanthogranuloma (JXG), and Erdheim–Chester disease (ECD) are non-Langerhans cell (non-LCH) disorders arising from either a dendritic or a macrophage cell. RDD is a benign disorder that presents with massive lymphadenopathy, but can have extranodal involvement. In most cases, RDD is self-limited and observation is the standard approach. Treatment is restricted to patients with life-threatening, multiple-relapsing, or autoimmune-associated disease. JXG is a pediatric histiocytosis characterized by xanthomatous skin lesions that usually resolve spontaneously. In a minority of cases, systemic disease can occur and can be life threatening. Juvenile myelomonocytic leukemia (JMML), as well as germline mutations in NF1 and NF2, have been reported in children with JXG. Recent whole-exome sequencing of JXG cases did not show the BRAF-V600E mutation, although 1 patient had PI3KCD mutation. ECD is an adult histiocytosis characterized by symmetrical long bone involvement, cardiovascular infiltration, a hairy kidney, and retroperitoneal fibrosis. Central nervous system involvement is a poor prognostic factor. Interferon-α is the standard as front-line therapy, although cladribine and anakinra can be effective in a few refractory cases. More than one-half of ECD patients carry the BRAF-V600E mutation. Currently, &gt;40 patients worldwide with multisystemic, refractory BRAF-V600E+ ECD have been treated with vemurafenib, a BRAF inhibitor, which was found to be highly effective. Other recurrent mutations of the MAP kinase and PI3K pathways have been described in ECD. These discoveries may redefine ECD, JXG, and LCH as inflammatory myeloid neoplasms, which may lead to new targeted therapies.