Elevated Titers Research Articles

Pulmonary and Intestinal Involvement in a Patient with Myeloperoxidase-specific Antineutrophil Cytoplasmic Antibody-positive Hermansky-Pudlak Syndrome.

A 26-year-old Japanese woman was admitted with a 1-month history of diarrhea, a high fever for a few days, and exacerbation of dyspnea. She was treated with an antifibrotic drug and long-term oxygen therapy for Hermansky-Pudlak syndrome-related pulmonary fibrosis. New ground-glass attenuation appeared on chest computed tomography (CT), and a colon biopsy showed an inflammatory cell accumulation with a high titer of myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic antibodies (ANCA). Systemic inflammation related to MPO-ANCA titer elevation was suspected. Steroid pulse therapy and intravenous cyclophosphamide improved chest CT findings and diarrhea. Therefore, immunosuppressant treatment should be considered for systemic inflammation related to MPO-ANCA.

Hcp1-loaded staphylococcal membrane vesicle vaccine protects against acute melioidosis.

Burkholderia pseudomallei is the causal agent of melioidosis, a deadly tropical infectious disease that lacks a vaccine. On the basis of the attenuated Staphylococcus aureus RN4220-Δagr (RN), we engineered the RN4220-Δagr/pdhB-hcp1 strain (RN-Hcp1) to generate B. pseudomallei hemolysin-coregulated protein 1 (Hcp1)-loaded membrane vesicles (hcp1MVs). The immunization of BALB/c mice with hcp1MVs mixed with adjuvant by a three-dose regimen increased the serum specific IgG production. The serum levels of inflammatory factors, including TNF-α and IL-6, in hcp1MV-vaccinated mice were comparable with those in PBS-challenged mice. The partial adjuvant effect of staphylococcal MVs was observed with the elevation of specific antibody titer in hcp1MV-vaccinated mice relative to those that received the recombinant Hcp1 protein (rHcp1) or MVs derived from RN strain (ΔagrMVs). The hcp1MVs/adjuvant vaccine protected 70% of mice from lethal B. pseudomallei challenge. Immunization with hcp1MVs only protected 60% of mice, whereas vaccination with rHcp1 or ΔagrMVs conferred no protection. Moreover, mice that received hcp1MVs/adjuvant and hcp1MVs immunization had low serum TNF-α and IL-6 levels and no inflammatory infiltration in comparison with other groups. In addition, all surviving mice in hcp1MVs/adjuvant and hcp1MVs groups exhibited no culturable bacteria in their lungs, livers, and spleens five days postinfection. Overall, our data highlighted a new strategy for developing B. pseudomallei vaccine and showed that Hcp1-incorporated staphylococcal MV is a promising candidate for the prevention of acute melioidosis.

Juvenile localized scleroderma: A single-centre experience from India.

Juvenile localized scleroderma (JLS) or morphoea, a rare chronic autoimmune disease predominantly affects skin, subcutaneous tissue and occasionally the adjacent muscle, fascia and bone. We report the largest single-centre cohort of patients with JLS from India. Patients who were diagnosed to have JLS were enrolled from the Paediatric Dermatology Clinic and the Paediatric Rheumatology Clinic of a tertiary care referral hospital in India. Collected data included details of the clinical profile, laboratory investigations and management. We analysed 84 patients with Juvenile localized scleroderma. Median age of disease onset was 5 years, and median age at diagnosis was 8 years. Commonest subtype was linear scleroderma (57 patients, 67.7%) followed by plaque morphoea and generalized morphoea. Fourteen patients (16.6%) were noted to have extracutaneous manifestations (ECMs). These included arthritis in eight (33.3%), brain parenchymal abnormalities in four (4.7%) and pulmonary involvement in two (8.3%) patients. Antinuclear antibody (ANA) was positive in eight/25 patients (32%; diffuse and speckled pattern in four patients each). One amongst these also had elevated anti-dsDNA titres. Positive ANA was found to have no association with ECMs (p 1.000). Patients were treated using methotrexate (61 patients; 72.6%), dexamethasone oral mini-pulse (OMP; 35 patients; 41.6%), calcipotriol (39 patients; 46.4%), topical corticosteroids (32 patients; 38%) and topical tacrolimus (three patients; 3.7%). Using linear regression analysis, administration of dexamethasone OMP and calcipotriol was found to be a predictor of good treatment response (p 0.034 and 0.019, respectively). Early use of systemic corticosteroids along with methotrexate may be more beneficial than methotrexate therapy alone.

Mixed IgG and IgM anti-GM1 ganglioside antibody positive multifocal motor neuropathy with severe secondary axonal loss in a Filipino female

Approximately 40% of patients with multifocal motor neuropathy had anti-GM1 IgM antibodies, while only 1 out of 88 patients had anti-GM1 IgG antibodies. Unlike its predominantly demyelinating IgM counterpart, the anti-GM1 IgG antibody is often seen in the axonal variant of Guillain Barre syndrome. As it affects axons, it is also associated with worse prognosis. We report here a 58-year-old woman who was admitted for 3 months history of progressive asymmetric weakness, initially involving the right-hand extensors, eventually affecting the contralateral side and the lower extremities. The electrodiagnostic examination revealed multifocal pure motor demyelinating neuropathy with severe axonal loss. On nerve ultrasound, the axons were small in non-compressive areas. The extremely elevated anti-GM1 IgM titer (1:51,200, nv<1:800) was consistent with the diagnosis of MMN. Her anti-GM1 IgG antibodies (1: 12,800, nv<1:800) was also elevated. In conclusion, the presence of concomitant anti-GM IgG and anti-GM1 IgM may lead to an MMN with more severe axonal loss.

Flavobacterium psychrophilum: Response of Vaccinated Large Rainbow Trout to Different Strains.

Although Flavobacterium psychrophilum is recognized as the causative pathogen of rainbow trout fry syndrome (RTFS), often resulting in high fry mortality, it is also responsible for bacterial cold water disease (BCWD) in large and older rainbow trout (Oncorhynchus mykiss). These older fish do not experience high mortality, but sustain, through the shedding of bacteria, a constant infection pressure at farm level, which exposes fry to an unnecessary infection risk. We have produced and assessed the immunogenicity of an experimental injection BCWD vaccine, which may be used to decrease the shedding of bacteria from older fish. A total of 800 fish were i.p.-injected: 200 fish received the bacterin with adjuvant, 200 fish received the bacterin alone, 200 fish received adjuvant alone and 200 fish were injected with physiological saline. Blood samples were taken at day 0 and at three different time points (4, 8 and 14 weeks) post-vaccination. Plasma antibody levels were measured by ELISA for reactivity against both the homologous F. psychrophilum vaccine strain (serotype Fd) and heterologous strains (serotype Th). Significantly elevated antibody titers were found against all serotypes in vaccinated fish. Welfare parameters associated with the vaccination process were evaluated by analyzing trout plasma samples for six different biochemical parameters, but no adverse effects associated with injection were indicated. The study suggests that an injection vaccine containing formalin-inactivated whole cells of F. psychrophilum (serotype Fd), adjuvanted with FIA, may also induce protection against heterologous strains. We advocate for, as the next step, the performance of field trials evaluating if the vaccination of older rainbow trout will (1) reduce the infection pressure in farms, (2) elevate the general health level in all groups and (3) minimize F. psychrophilum infection in fry at farm level. This may reduce the need for the administration of antibiotics in all age classes.

E6020, a TLR4 Agonist Adjuvant, Enhances Both Antibody Titers and Isotype Switching in Response to Immunization with Hapten-Protein Antigens and Is Diminished in Mice with TLR4 Signaling Insufficiency.

The mechanisms by which TLR4-based adjuvants enhance immunogenicity are not fully understood. We have taken advantage of a novel knock-in mouse strain that homozygously expresses two single-nucleotide polymorphisms (SNPs) that are homologous to human TLR4 (rs4986790 and rs4986791) and have been associated with LPS hyporesponsiveness in vivo and in vitro. TLR4-SNP (coexpressing mutations D298G/N397I in TLR4) mice that recapitulate the human phenotype were compared with wild-type (WT) mice for their hapten-specific Ab responses after immunization with hapten 4-hydroxy-3-nitrophenyl acetyl (NP) NP-Ficoll or NP-OVA in the absence or presence of a water-soluble TLR4 analog adjuvant, E6020. IgM and IgG anti-NP responses were comparable in WT and TLR4-SNP mice after immunization with either NP-Ficoll or NP-OVA only. E6020 significantly yet transiently improved the IgM and IgG anti-NP responses of both WT and TLR4-SNP mice to NP-Ficoll (T-independent), with modestly enhanced Ab production in WT mice. In contrast, T-dependent (NP-OVA), adjuvant-enhanced responses showed sustained elevation of NP-specific Ab titers in WT mice, intermediate responses in TLR4-SNP mice, and negligible enhancement in TLR4-/- mice. E6020-enhanced early humoral responses in WT and TLR4-SNP mice to NP-OVA favored an IgG1 response. After a second immunization, however, the immune responses of TLR4-SNP mice remained IgG1 dominant, whereas WT mice reimmunized with NP-OVA and E6020 exhibited increased anti-NP IgG2c titers and a sustained increase in the IgG1 and IgG2c production by splenocytes. These findings indicate that E6020 increases and sustains Ab titers and promotes isotype class switching, as evidenced by reduced titers and IgG1-dominant immune responses in mice with TLR4 insufficiency.

Follow-up and Evaluation of the Efficacy of the Hemostatic Treatment in Congenital FVII Deficiency during Development of Inhibitor

Introduction The development of inhibitors is an extremely rare complication in patients with factor (F)VII deficiency treated with replacement therapies such as recombinant activated FVII (rFVIIa), and represents a major therapeutic challenge in the treatment of this disorder. When inhibitors result in loss of response to high doses of rFVIIa, activated prothrombin complex concentrate (aPCC) is often used as an alternative treatment for these patients. The use of high-dose rFVIIa or aPCC might be accompanied by an increased risk of thromboembolic events, so it is important monitoring properly the effect of the hemostatic treatment Here we describe the therapeutic management and follow-up of a patient with elevated inhibitor titres, resistant to rFVIIa treatment who switched to prophylaxis with aPCC, using several global coagulation tests. Methods The coagulation status of the patient and the reponse to in vitro spiking of different doses of rFVIIa or aPCC were assessed with several global tests: Prothrombine time (PT) was tested using HemosIL®RecombiPlasTin 2G. Clot formation was evaluated with Rotational Thromboelastometry (ROTEM®) using blood with CTI (to inhibit contact activation) and activated with a low amount of Tissue Factor (TF) as trigger (dilution 1:50,000 of EXTEM reagent). The thrombin generation (TG) was tested with the Calibrated Automated Thrombogram (CAT) system using plasma collected with CTI and activated with 1 pM TF plus phospholipids (PPP-Low®, Stago). Thrombus formation under flow conditions was assessed with the Total Thrombus-formation Analysis System (T-TAS®) in AR-chips coated with collagen and thromboplastin. The Area under the flow pressure curve (AUC) was calculated over 30 min after starting. Results Three year-old girl affected by severe congenital FVII deficiency (FVII 9.1%) with significant severe bleeding history (spontaneous intracranial hemorrhage at 1st month of life). Since then she is in prophylaxis treatment with rFVIIa. At 6 months of life she developed an inhibitor (9.8 BU). Despite prophylaxis she presents frequent spontaneous mucocutaneous bleedings. When she was 2 years old she needed to be admitted at hospital because of port-A-Cath infection. Due to the administration of intensive treatment with rFVIIa during admission she developed thrombosis of peripheral venous access, so prophylaxis treatment was temporary suspended. After 5 days without prophylaxis treatment, and increasing inhibitor titres, she developed a new intracranial haemorrhage, which needed intensive treatment with continuous rFVIIa infusion (90 µg/Kg/12h), immunoglobulines and rituximab for lowering inhibitor titre. Hemostatic parameters improved during the administration of these treatments and inhibitor level was reduced. After restarting prophylaxis treatment with rFVIIa (50 µg/Kg/48h), inhibitors and a hypocoagulable state were observed with all global coagulation test showing extended PT, clotting time (CT), TG Lag-time (LT) and anomalous thrombus formation (AUC) but presented very good response to low dosis (2.5 IU/Kg) of aPCC in vitro (Table-1). At the age of three years she required admission at hospital because of port-A-Cath infection again, needing its replacement by a new one after administration of high doses of rFVIIa without bleeding complications. After this, inhibitor titre raised again (> 50 BU), presenting frequent bleeding episodes (spontaneous muscle bleedings and tonsillar bleeding), and due to the clinical worsening, treatment was modified to prophylaxis with aPCC (30 UI/Kg/48h). Despite the treatment change she continued presenting bleeding episodes, global tests continued showing an hypocoagulable state, and required 10 times higher doses in vitro of aPCC (25 IU/Kg) to restore all the monitored hemostatic parameters (Table-1), probably related to the important increase in inhibitor titre. This situation led to employing higher doses of aPCC prophylaxis (60 UI/Kg/48 h) to try to avoid bleeding episodes without increasing the risk of suffering thrombotic events. Conclusions Global coagulation tests used in this study were sufficiently sensitive methods to show an abnormal hemostatic profile in FVII-deficient patients with clinical hemorrhagic symptoms with inhibitor development, supporting their use to manage the risk of bleeding or thrombosis in this life-threatening condition. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

An AhR-Caspase Axis Mediated Antiviral Apoptosis in an Arthropod.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates immune modulation following exposure of animals to many environmental xenobiotics. However, its role in innate immune responses during viral infection is not fully understood, especially in invertebrates. In this study, a cDNA encoding an AhR homolog was cloned from an arthropod Litopenaeus vannamei (LvAhR). The expression of LvAhR was strongly upregulated in response to the challenge of white spot syndrome virus, a pathogen of highly contagious and fatal infectious disease of shrimp. The relevance of LvAhR to host defense was underlined by heightened susceptibility and elevated virus loads after AhR-silenced shrimp exposure to white spot syndrome virus. LvAhR could induce an apoptosis response through regulating the expression of L. vannamei caspase-1 (homologous to human caspase-3) by directly targeting its promoter that was required to couple with AhR nuclear translocator. Additionally, knockdown of L. vannamei caspase-1 resulted in elevated virus titers and a lower cell apoptotic rate. Thus, we demonstrate that an AhR-caspase axis restrains virus replication by promoting antiviral apoptosis, supporting a previously unidentified direct link between AhR signaling and caspase-mediated apoptosis signaling and, furthermore, suggests that the AhR-caspase axis could be a potential therapeutic target for enhancing antiviral responses in arthropods.

ATYPICAL MANIFESTATIONS OF SUBACUTE SCLEROSING PANENCEPHALITIS: CASE SERIES

Subacute Sclerosing Panencephalitis (SSPE) is a rare, progressive degenerative disease of the brain caused by reactivation of aberrant measles virus. Classical symptoms of SSPE are described as behavioral changes, declining scholastic performance, myoclonic jerks etc. However, at times it presents with varied atypical manifestations, which makes diagnosis difcult. Hereby we report two patients with unusual manifestations of SSPE. In rst case, 14-year-old boy presented with recurrent falls of 9 months duration. Initially, it was 1-2 times per week, progressing over 9 months to frequency of 40-50 falls per day. In second case, 21-year-old gentleman presented with behavioral changes and memory disturbance of 1-year duration. However, his family members noticed worsening of symptoms 1 month before presentation as he started developing involuntary jerky movements involving the right upper and lower limb. In both of them electroencephalogram (EEG) was showing long interval periodic discharges and cerebrospinal uid was showing elevated titers of anti-measles antibody overall suggesting SSPE. Hence it needs much attention for atypical presentations and also considering SSPE in differential diagnosis of unsolved atypical neurological presentations.

Screening of B-cell epitopes of Der-p1 and Der-p2 major aeroallergens by computational approach for designing immunotherapeutics

Introduction and Aim: Allergic diseases are IgE-mediated hypersensitivity reactions affecting approximately 30% of the general population globally. Dermatophagoides pteronyssinus (Der-p) is the most prevalent house dust mite (HDM) species consisting of 23 mite allergen groups. Among these, group 1 and 2 are major allergenic proteins, which causes allergic asthma in 80% of sensitized individuals, with elevated IgE titres in the serum. This study involves in silico analysis of potential B-cell epitopes of group 1 and group 2 of Der-p, which can be utilized in designing immunotherapeutic vaccines. Materials and Methods: Allergen sequences obtained from the database- International Union of Immunological Societies (IUIS), for predicting of B-cell epitopes. The physiochemical properties and secondary structures of the obtained sequence were evaluated. The sequences were further subjected to determining antigenicity, surface accessibility, and prediction of linear and discontinuous B-cell epitope by utilizing IEDB tools. Results: The linear and discontinuous B-cell epitopes of Der-p1 and Der-p2 aeroallergen were predicted. Further, Der-p1 and Der-p2 showed 6 linear epitopes each respectively. Conformational epitopes predicted were 123 of Der-p1 and 72 of Der-p2 respectively, by the ElliPro tool. Based on the structure, antigenicity, and surface accessibility, only 10% of Der-p1 and Der-p2 which binds to B-cell epitopes are linear and the majority are discontinuous. Conclusion: The linear and conformational epitopes of Der-p1 and Der-p2 are predicted using in silico tools. These identified epitopes might be useful for developing epitope-based immunotherapeutics for HDM allergy.

Imaging vitreous cortex hyalocyte response to paracentral acute middle maculopathy (PAMM) using En Face OCT.

Vitreous cortex hyalocytes (VCH) are resident macrophage cells that provide immunosurveillance, respond to tissue injury and inflammation, and help maintain the transparency of the media. In this case report we demonstrate the use of en face optical coherence tomography (OCT) to image VCH in vivo in a patient presenting with PAMM secondary to antiphospholipid syndrome. A 38-year-old female with no known medical history presented with complaints of visual disturbances in the right eye. OCT revealed hyperreflective bands in the IPL and INL nasal to the fovea. A diagnosis of PAMM was made. Work-up revealed elevated titers of antiphospholipid antibodies. En face OCT revealed a decline in the inflammatory activation over a seven-month period as evidenced by changes in VCH distribution and morphology. Our findings suggest that monitoring changes in the distribution and morphology of VCH could have a potential clinical utility for assessing disease severity, predicting recovery, and early recognition of treatment response in various inflammatory ocular pathologies such as PAMM.

ODP635 A rare case of metastatic papillary thyroid carcinoma on NTRK inhibitor with thyrotoxicosis

Abstract We present a case of 26-year-old Hispanic female with neck enlargement and worsening dyspnea. She was noted to have enlarged thyroid nodules; biopsy revealed papillary thyroid carcinoma (PTC) with ETV6-NTRK fusion by next-generation sequencing (NGS). Further work up revealed extensive bilateral milliary pulmonary metastases and Graves’ disease with elevated thyrotropin receptor antibodies and thyroid-stimulating immunoglobulin titers. Tuberculosis work up was negative and bronchoalveolar lavage revealed metastatic PTC. The patient was initiated on larotrectinib (100mg administered twice daily) as well as block-and-replace regimen with levothyroxine and methimazole. Her dyspnea improved and she successfully underwent total thyroidectomy as well as bilateral neck dissections; methimazole and thyroid hormones were discontinued thereafter. Interestingly, patient developed thyrotoxicosis post-surgery even without being on levothyroxine with elevated free T3 at 18 pg/mL (normal range 2.3–4.2), compared to 5.8 pg/mL prior to surgery. Despite discontinuation of levothyroxine, patient continued to be biochemically and clinically hyperthyroid. She was treated with methimazole for 4 months after surgery, and subsequently underwent radioactive iodine (RAI) ablation with 30 mCi of I-131 of sodium iodide. After RAI, thyroid function started to improve, prompting re-initiation of very low dose levothyroxine about 5 months after surgery. Since then, she has remained clinically stable. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Clinical Study of the Relationship between Sjögren Syndrome and T-Cell Large Granular Lymphocytic Leukemia: Single-Center Experience.

The relationship between Sjögren syndrome (SS) and T-cell large granular lymphocytic (T-LGL) leukemia remains unclear. In this paper, we report for the first time a large case series of 21 patients with primary and secondary SS associated with T-LGL leukemia. Our results suggest the importance of considering T-LGL leukemia in the diagnostic evaluation of SS patients, particularly when neutropenia occurs. We also postulate that elevated antinuclear antibody titers in patients with T-LGL leukemia indicate the need for the clinical assessment of SS. To assess whether SS affects the frequency of the signal transducer and activator of transcription 3 (STAT3) gene mutations in T-LGL leukemia, we examined STAT3 mutations by next-generation sequencing in two cohorts of patients: with SS-associated T-LGL leukemia and T-LGL leukemia in the setting of rheumatic diseases but without SS. While our results suggest that SS, per se, is not associated with an increased frequency of STAT3 mutations in T-LGL leukemia, further studies are needed to better assess the role of the STAT pathway in the development of concomitant SS and T-LGL leukemia.

GPR55 in B cells limits atherosclerosis development and regulates plasma cell maturation

Dissecting the pathways regulating the adaptive immune response in atherosclerosis is of particular therapeutic interest. Here we report that the lipid G-protein-coupled receptor GPR55 is highly expressed by splenic plasma cells (PCs), upregulated in mouse spleens during atherogenesis and human unstable or ruptured compared to stable plaques. Gpr55-deficient mice developed larger atherosclerotic plaques with increased necrotic core size compared to their corresponding controls. Lack of GPR55 hyperactivated B cells, disturbed PC maturation and resulted in IgG overproduction. B-cell-specific Gpr55 depletion or adoptive transfer of Gpr55-deficient B cells was sufficient to promote plaque development and elevated IgG titers. In vitro, the endogenous GPR55 ligand lysophsophatidylinositol (LPI) enhanced PC proliferation, whereas GPR55 antagonism blocked PC maturation and increased their mitochondrial content. Collectively, these discoveries provide previously undefined evidence for GPR55 in B cells as a key modulator of the adaptive immune response in atherosclerosis.

ODP456 A rare case of massive goiter with overlapping features of Riedel's thyroiditis and Fibrous Variant of Hashimoto's thyroiditis

Abstract Background Hashimoto's thyroiditis is the most common autoimmune disorder of the thyroid gland associated with hypothyroidism. It is distinguished by painless inflammation and elevated titers of TPO antibodies. Fibrous Variant of Hashimoto's Thyroiditis is a rare condition occurring in about 10% of cases, mainly middle-aged individuals, and characterized by an extensive fibrous proliferation without extension into the surrounding structures. Riedel's thyroiditis is a rare generalized autoimmune disorder involving B lymphocytes and IgG4-secreting plasma cells, clinically characterized by extension of the fibrous process to surrounding tissues in the neck, as well as compression symptoms like dysphagia and dyspnea. It is usually associated with mediastinal and retroperitoneal fibrosis. There is significant clinical, pathological, and laboratory test overlap between these two entities that makes the differential diagnosis difficult. Case report A 54-year-old male diagnosed with hypothyroidism on Levothyroxine, and a large goiter seen with new onset of compressive symptoms including dyspnea and dysphagia since March/April 2021. He complains of having pressure on his neck, difficulty swallowing, and worse symptoms when lying flat on a bed. His thyroid is noted to be extremely large and firm, without evident nodularity on examination. Laboratory exams were significant for TSH 3.21 (0.36-3.74), T4 0.94 (0.76-1.46), vitamin D level 13 (30-100), TPO > 9000 (0-9), IgG4 81.9 (4. 0-86. 0), and a negative ANA screen. Thyroid ultrasound showed an enlarged heterogeneous thyroid gland with no discrete nodules. Given the compressing symptoms the patient presented, he was referred to surgery for total thyroidectomy. Surgery could not be completed due to the inability to safely mobilize the gland and adherence to surrounding tissues. He then underwent a right thyroid lobule core biopsy, showing an inflammatory infiltrate composed primarily of lymphocytes and plasma cells. Atrophic thyroid follicles with prominent fibrosis were noted. IgG4 immunostaining highlights <5 positive plasma cells/HPF and IgG4/IgG <30%, excluding IgG4-related fibrosing disease in this core biopsy material. There was no evidence of malignancy. Considering the prominent fibrosis, very high TPO Ab titer, and a seeming lack of extrathyroidal involvement, Fibrous Variant of Hashimoto's Thyroiditis seems more likely, but Riedel Thyroiditis cannot be completely ruled out. He was placed on Prednisone 40 mg daily, with modest improvement of symptoms. Tamoxifen 20mg daily was later added given literature reports of additional improvement in symptoms associated with its use. Referral to a tertiary center for possible isthmusectomy may be considered if symptoms worsen. Presentation: No date and time listed

PMON317 Rapid Progression of Adrenal insufficiency in Child with Autoimmune Polyendocrine Syndrome Type 1

Abstract Background Autoimmune Polyendocrine Syndrome type 1 (APS-1) is an autosomal recessive rare disease resulting from mutations in the autoimmune regulator gene (AIRE) on chromosome 21q22.3. APS-1 was first described as a syndrome in 1946 as a triad of mucocutaneous candidiasis, primary hypoparathyroidism, and adrenal insufficiency. With an AIRE gene mutation, the immune system will have a T-regulatory cell defect, which leads to a loss of immune tolerance. This will increase the risk of autoimmune disease in the body's organs such as the pancreas, thyroid, adrenal gland, liver, intestine, skin, and parathyroid gland. Clinical case A 6-year-old male was admitted to the pediatric floor for new-onset seizures and tetany. Initial laboratory assessment was concerning for severe hypocalcemia associated with low parathyroid hormone (PTH) and hyponatremia. Blood workup showed: low serum sodium 130 mmol/L (136-144), potassium 4.1 mmol/L(3.4-4.7), carbon dioxide 16 mmol/L; ionized calcium 0.67 mmol/L (1.19-1.41), phosphorus 7.4mg/dL (4.0-7.0), PTH 9.0pg/mL (12.0-88.0). Calcium replacement and calcitriol were initiated with a resolution of symptoms. Further investigations were done for the adrenal gland given his low sodium level. He underwent an ACTH stimulation test that he passed, with a cortisol baseline of 39mcg/dl with a peak of 48mcg/dl. ACTH level was high at 120pg/mL (5-27), and a repeat in 4 weeks was normal at 11pg/ml. His renin activity was elevated at 71ng/ml/hr (1.5-3.5). Renin activity was repeated and was elevated again at 34ng/ml/hr, prompting adrenal antibody testing, which revealed an elevated titer 1: 10 (<1: 10). Due to concern for APS-1, genetic testing was obtained and revealed a pathological variant of AIRE of c.892G>A and c.967_979del consistent with APS-1. He was started on 0.1mg Florinef and was later followed routinely at an outpatient endocrinology clinic. Fifteen months after diagnosis, he had a repeat ACTH stimulation test, and his baseline cortisol was 9.1mcg/dl with a peak at 60 minutes of 9.6mcg/dl (<18). ACTH level was elevated at 425pg/ml at this time. He was started on hydrocortisone replacement. Of note, investigation of siblings revealed a 10-month-old sister with abnormal AIRE mutation and a 17-month-old sister with unexplained death. Conclusion APS-1 can affect multiple organs, and cases can significantly vary in age and the number of affected organs at presentation. The patient presented with atypical presentation as he had hypocalcemia and hypoparathyroidism as an initial abnormality. Typically, adrenal insufficiency appears in the second decade of life but, the patient has it at the time of diagnosis, and it rapidly progresses. Family history plays an essential role in investigating autoimmune disease and warrants further assessment for autoimmune markers. While typically a disease that progresses insidiously into adulthood, cases like ours demonstrate rapid autoimmune disease progression. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Rheumatoid factor IgM autoantibodies control IgG homeostasis.

Rheumatoid arthritis is an autoimmune disease characterized by joint inflammation due to autoantibodies targeting multiple self-proteins. Most patients with poor prognosis show elevated titers of IgM antibodies specifically binding to IgG. Such autoreactive antibodies are referred to as rheumatoid factor (RF). However, their biological function and contribution to disease progression remains elusive. We have recently shown that autoreactive antibodies are present in healthy individuals and play an important role in regulating physiological processes. This regulatory mechanism is determined by the class and affinity of the autoreactive antibody, as low-affinity autoreactive IgM neutralizes the recognized autoantigen while high-affinity IgM protects its autoantigen from degradation. Here, we show that RFs possessing a high affinity and mono-specificity to IgG have a stabilizing effect on IgG, whereas low-affinity polyreactive RFs neutralize IgG in vivo. These results suggest that autoreactive IgM antibodies recognizing IgG play a crucial role in regulating IgG homeostasis and that a disbalance between IgM-mediated IgG degradation and stabilization might affect the onset and progression of autoimmune diseases. Consequently, restoring this balance using low-affinity anti-IgG IgM might be a promising therapeutic approach for autoimmune diseases involving autoreactive IgG.

An atypical course of a 71-year old man with right arm weakness and ataxia: Expert commentary

Dr Khemani and colleagues have presented a diagnostically challenging case of a sporadic, adult onset ataxia (SAOA) syndrome resembling Multiple System Atrophy cerebellar type (MSA-C), with an atypical presentation of focal amyotrophy, eventually diagnosed as spinocerebellar ataxia type 3 (SCA3) [ [1] Khemani P. Elliott M. Levine T. An Atypical Clinical Course of a 71-Year-Old Man with Right Arm Weakness and Ataxia. Parkinsonism Relat Disord, 2022 Abstract Full Text Full Text PDF Scopus (0) Google Scholar ]. The patient had presented elsewhere three years prior, with a Miller Fisher syndrome (MFS) associated with an elevated antiGQ1b antibody titer. However, as the patient had become wheelchair bound over the subsequent three years, the initial diagnosis of MFS is perhaps questionable. When evaluating ataxic disorders, it is important to establish the disease onset and course accurately. As the patient had a progressive cerebellar syndrome, the possible causes could be categorized broadly as: primary autoimmune (paraneoplastic or non-paraneoplastic); or neurodegenerative (sporadic or genetic). Primary autoimmune cerebellar ataxia encompassing paraneoplastic ataxia syndromes, and immune-mediated ataxias (gluten ataxia and anti-GAD65 ataxia) may present insidiously, with accumulating disability especially if timely and appropriate immunosuppressive therapies are not instituted [ [2] Hadjivassiliou M. Graus F. Honnorat J. Jarius S. Titulaer M. Manto M. Hoggard N. Sarrigiannis P. Mitoma H. Diagnostic criteria for primary autoimmune cerebellar ataxia-guidelines from an international task force on immune-mediated cerebellar ataxias. Cerebellum. 2020; 19: 605-610 Crossref PubMed Scopus (35) Google Scholar ].

Reference intervals of thyroidstimulating hormone in pregnant women living in the central regions of the Russian Federation

Pregnancy is a condition with important structural and physiological changes in the thyroid gland. In this regard, experts of thyroid associations have recommended developing specific reference intervals taking into account the natural and socio-geographical characteristics of the region under study. To conduct an epidemiological analysis and evaluate TSH reference intervals in pregnant women living in the central regions of the Russian Federation with mild iodine deficiency. We have conducted the observational multicenter cross-sectional study included 2008 healthy pregnant women at different trimesters of pregnancy, from three regions of the Russian Federation (Moscow, Ivanovo and Smolensk). We assessed the level of thyroid-stimulating hormone, antibodies to thyroid peroxidase, antibodies to serum thyroglobulin, the level of iodine concentration in the morning portion of urine (cerium arsenic method) and we have conducted a questionnaire (date birth and gestational age). Women with elevated titers of anti-TPO and/or anti-TG antibodies were excluded from the study (245 women). As a result, we assessed high and medium levels of TSH and its overestimation with iodine sufficiency in pregnant women. The results are presented using the calculation of 2.5 and 97.5 percentiles. We confirmed the presence of iodine deficiency in the study areas. The median concentration of iodine in the urine was: in Moscow 106 μg/l, in Ivanovo 119 μg/l, in Smolensk 134 μg/l. Pregnant women were divided into 2 groups according to iodine adequacy. In the group with optimal iodine supply, the level of TSH was 0,006-3,36 in the 1st trimester, 0,20-3,74 in the 2nd trimester, and 0,33-3,68 mIU/L in the 3rd trimester. In the group with mild iodine deficiency - in the 1st trimester it was 0,11-3,00, in the 2nd trimester 0,22-3,78, in the 3rd trimester 0,07-3,04 mIU/l. Statistical analysis of the data revealed that when comparing the level of TSH by trimester, depending on the place of residence, no statistical difference was found (p = 0,239). We obtained that the level of TSH in healthy pregnant women living in the central regions of the Russian Federation does not exceed 3.8 mIU/l in all trimesters.

A RARE CAUSE OF MULTIFOCAL PNEUMONIA AND CONSTRICTIVE PERICARDITIS: COXSACKIEVIRUS A

A RARE CAUSE OF MULTIFOCAL PNEUMONIA AND CONSTRICTIVE PERICARDITIS: COXSACKIEVIRUS A