Elevated Antibody Levels Research Articles

Comparative assessment of cardiac-specific autoantibodies levels in persons with occupational pathology caused by exposure to physical and chemical factors

Introduction. The pathology of the cardiovascular system is one of the dominant causes of mortality. It has been established that exposure to vibration and mercury is associated with the development of heart and vascular diseases. Specific autoantibodies can be used as markers of exposure effects. The aim of the work was a comparative assessment of the levels of cardiac-specific autoantibodies in individuals with vibrational disease (VD) and chronic mercury intoxication. Material and methods. We examined VD patients, with chronic mercury intoxication (CMI), who work in contact with a toxicant and in the long-term post-exposure period, and the comparison group. The relative content of specific autoantibodies to nitric oxide synthase (NOS), platelet membrane components (PMC), neutrophil cytoplasm, and vascular endothelial cell antigens (c-ANCA), plasminogen, collagen, and PAPP-A protein were studied in the patient’s blood serum. Results. In individuals with CMI, the levels of autoantibodies PCM, c-ANCA are lower for plasminogen and higher for collagen than in the comparison group and in VD patients. Elevated levels of anti-collagen antibodies were found in 70% of individuals with CMI. Among patients with CMI, elevated levels of antibodies to NOS were found in 60% of persons exposed to mercury and were not detected in the long-term post-exposure period. Discussion. The high frequency of elevated levels of antibodies to collagen and correlations between their level and the rest of the indices may indicate its important role in the development of endothelial dysfunction in persons with CMI. Elevated levels of autoantibodies to NOS in patients exposed to mercury are accompanied by a decrease in NO levels and may be an important part of the pathogenesis of endothelial dysfunction. Conclusion. The profile of cardiac-specific autoantibodies in VD patients is similar to that in the comparison group. Elevated levels of antibodies to collagen and decreased levels of antigens of platelets and plasminogen play an important role in the development of endothelial dysfunction in patients with CMI. The high frequency of hyper immunoreactivity of autoantibodies to NOS and c-ANCA, which is observed in patients with CMI who are in contact with a toxicant, decreases in the long-term post-exposure period.

Anti-vinculin antibodies in scleroderma (SSc): a potential link between autoimmunity and gastrointestinal system involvement in two SSccohorts.

Systemic sclerosis (SSc) is an autoimmune disorder and commonly presents with vascular system involvement and motility disorders in the gastrointestinal (GI) tract. Vinculin is a cytoskeletal protein that plays major roles in cell-cell adhesion and is expressed in the neuromuscular apparatus of the gut. Antibodies to vinculin have been identified as a biomarker of irritable bowel syndrome (IBS). Our aim was to evaluate serum anti-vinculin antibodies in patients with SSc. Patients were recruited from two SSc centers: group I (GI-enriched group), University of Leeds, UK, and Group II (vascular predominant), University of California, Los Angeles.Serum samples of patients recruited from two SSc centres, Group I ( GI enriched group), University of Leeds, UK and Group II (Vascularpredominant), University of California, Los Angeles) were collected. Samples from age- and sex-matched healthy volunteers (N = 88) were used ascontrols. Group I (GI-enriched group, N = 83) patients were 58 [50-67] years old; 83% were females with a median body mass index (BMI) of 20.3 (21.2 ± 4.5) [18-23]. Group II (vascular-enriched group, N = 72) patients were 58 [50-67] years old; 80% were female, and BMI was 23.9 (21.3-26.9). More subjects in group I had prominent GI involvement (N = 55, 66%) than group II (12, 16%), p ˂ 0.0001. Anti-vinculin antibody levels in SSc group I (1.3 [0.9]) were significantly higher than in HC (0.7 [0.8]; p = 0.002). When pooled, circulating anti-vinculin levels in both SSc groups remained significantly higher than in the HC group (p = 0.02). Higher anti-vinculin levels were associated with higher GI-visual analogue scale (GI-VAS) scores and specifically with GI-VAS scores of ≥ 4 (p < 0.0001). This study demonstrates that elevated anti-vinculin antibody levels are common in SSc and suggests a potential link between increased anti-vinculin levels and GI tract symptoms. • Anti-vinculin antibodies are elevated in systemic sclerosis and are relatively common. • In these SSc patients, anti-vinculin antibodies are associated with higher levels of GI symptoms in SSc. • A potential link between anti-vinculin antibodies and vascular system involvement was shown.

Combined brain/heart magnetic resonance imaging in antiphospholipid syndrome-two sides of the same coin.

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by arterial, venous, and/or small vessel thrombosis, pregnancy morbidity, and persistently elevated levels of antiphospholipid antibodies (aPL). Cardiovascular disease (CVD) in APS can present as heart valvular disease (HVD), macro-micro-coronary artery disease (CAD), myocardial dysfunction, cardiac thrombi, or pulmonary hypertension. Brain disease presents as stroke or transient ischemic attack (TIA) and less frequently as cerebral venous thrombosis, seizures, cognitive dysfunction, multiple sclerosis (MS)-like syndrome, or chorea. Infarcts and focal white matter hyperenhancement are the commonest brain (MRI) abnormalities, while myocardial ischemia/fibrosis, valvular stenosis/regurgitation, or cardiac thrombi are the main abnormalities detected by cardiovascular magnetic resonance. This review aims to present the existing evidence on brain/heart involvement and their interrelationship in APS and the role of brain/heart MRI in their evaluation. Embolic brain disease, due to HVD, CAD, and/or cardiac thrombus, or brain hypo-perfusion, due to myocardial dysfunction, are among the main brain/heart interactions in APS and they are considered determinants of morbidity and mortality. Currently, there is no evidence to support the use of combined brain/heart MRI in asymptomatic APS patients. Until more data will be available, this approach may be considered in APS patients at high risk for CVD/stroke, such as systemic lupus erythematosus with high-risk aPL profile or high scores in CVD risk prediction models; APS patients with HVD/thrombus, CAD, or heart failure; those with classic and non-criteria neurologic APS manifestations (seizures, cognitive dysfunction, MS-like syndrome); or with aggressive multi-organ disease. Key Points • Cardiovascular disease (CVD) in antiphospholipid syndrome (APS) can present as heart valvular disease (HVD), macro-micro-coronary artery disease (CAD), myocardial dysfunction, cardiac thrombi, or pulmonary hypertension. • Brain disease presents as stroke or transient ischemic attack (TIA), and less frequently as cerebral venous thrombosis, seizures, cognitive dysfunction, and multiple sclerosis (MS). • A combined brain/heart MRI may be considered in APS patients at high risk for CVD/stroke, such as systemic lupus erythematosus with high-risk aPL profile or high scores in CVD risks; APS patients with HVD/thrombus, CAD, or heart failure; those with classic and non-criteria neurologic APS manifestations (seizures, cognitive dysfunction, MS-like syndrome); or with aggressive multi-organ disease.

Serum anti-LRPAP1 is a common biomarker for digestive organ cancers and atherosclerotic diseases.

Some cancers are related to atherosclerotic diseases; therefore, these two types of disease may share some antibody biomarkers in common. To investigate this, a first screening of sera was performed from patients with esophageal squamous cell carcinoma (ESCC) or acute ischemic stroke (AIS) for serological identification of antigens using recombinant cDNA expression cloning (SEREX). The amplified luminescent proximity homogeneous assay‐linked immunosorbent assay (AlphaLISA) method, which incorporates glutathione donor beads and anti‐human IgG acceptor beads, was used to evaluate serum antibody levels. SEREX screening identified low‐density lipoprotein receptor–related protein–associated protein 1 (LRPAP1) as a target antigen of serum IgG antibodies in the sera of patients with ESCC or AIS. Antigens, including recombinant glutathione S‐transferase–fused LRPAP1 protein, were prepared to examine serum antibody levels. AlphaLISA revealed significantly higher antibody levels against the LRPAP1 protein in patients with solid cancers such as ESCC and colorectal carcinoma and some atherosclerosis‐related diseases such as AIS and diabetes mellitus compared with healthy donors. Correlation analysis revealed that the elevated serum antibody levels against LRPAP1 were associated with smoking, a well‐known risk factor for both cancer and atherosclerosis. Serum LRPAP1 antibody is therefore a common marker for the early diagnosis of some cancers and atherosclerotic diseases and may reflect diseases caused by habitual smoking.

RAPIDLY PROGRESSIVE INTERSTITIAL LUNG DISEASE IN ASSOCIATION WITH MDA5 ANTIBODY DERMATOMYOSITIS

SESSION TITLE: Medical Student/Resident Diffuse Lung Disease SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Clinically Amyopathic Dermatomyositis (CADM) is a subtype of dermatomyositis (DM) characterized by the presence of cutaneous lesions, without clinical evidence of muscle weakness. The presence of autoantibodies against Melanoma Differentiation-Associated protein 5 (MDA5) in this group is highly associated with rapidly progressive interstitial lung disease (RP-ILD) and a worse prognosis. We present a case of anti-MDA5 associated RP-ILD to illustrate the importance of screening for MDA5 in patients with CADM and DM. CASE PRESENTATION: Our patient was a 45-year-old woman with a history of hypothyroidism, seronegative inflammatory polyarthritis treated with hydroxychloroquine, and notably, a history of biopsy-proven DM with a negative myositis-specific antibodies (MSA) panel (which did not include MDA5 antibodies). She had been successfully treated for DM, and maintained in remission with oral steroids. Four years following the diagnosis of DM, she presented with insidious and gradually progressive dyspnea for over a year. Physical examination was unremarkable. Pulmonary function testing showed moderate restrictive lung disease. Chest X-ray was notable for bibasilar interstitial changes. Computed tomography (CT) scan of the chest revealed nonspecific, bilateral ground-glass opacities in the middle and lower lung zones, with associated bibasilar bronchiectasis in the affected areas (Figure 1). Bronchoscopic evaluation, including transbronchial biopsy, was performed, which was negative for malignancy or infection. Open lung biopsy was obtained via robotic-assisted thoracoscopy from the affected lobes, with histopathology revealing interstitial fibrosis with multiple fibrotic foci without clear evidence of honeycombing. The pattern was suggestive of usual interstitial pneumonia (UIP). Repeat testing for MSA revealed an elevated anti-MDA5 antibody level at 22 SI. The patient was consequently diagnosed with RP-ILD in conjunction with CADM, prompting the initiation of oral prednisone and azathioprine. DISCUSSION: Anti-MDA5 antibodies recognize the RNA helicase encoded by MDA5, a protein that is involved in innate immune processes. The presence of anti-MDA5 antibodies in patients with CADM has been linked to the presence of RP-ILD, and portends a poor prognosis. The mechanism of this autoantibody production is not fully understood. One meta-analysis found that the presence of these antibodies was 77% sensitive and 86% specific for the identification of RP-ILD. Additionally, anti-MDA5 antibodies can be utilized to predict clinical outcomes and monitor disease activity in these patients. Due to its high mortality rate from respiratory failure, immediate therapy with high-intensity combination immunosuppression is essential once the diagnosis is made. CONCLUSIONS: This case highlights the importance of screening for anti-MD5 antibodies in patients with CADM to elucidate their risk of developing RP-ILD. Reference #1: Li L, Wang Q, Yang F, et al. Anti-MDA5 antibody as a potential diagnostic and prognostic biomarker in patients with dermatomyositis. Oncotarget. 2017;8(16):26552–26564. doi:10.18632/oncotarget.15716 Reference #2: Chen, Z., Cao, M., Plana, M.N., Liang, J., Cai, H., Kuwana, M. and Sun, L. (2013), Utility of Anti–Melanoma Differentiation–Associated Gene 5 Antibody Measurement in Identifying Patients With Dermatomyositis and a High Risk for Developing Rapidly Progressive Interstitial Lung Disease: A Review of the Literature and a Meta-Analysis. Arthritis Care & Research, 65: 1316-1324. doi:10.1002/acr.21985 DISCLOSURES: No relevant relationships by Komal Ejaz, source=Web Response No relevant relationships by Dan Kazmierski, source=Web Response No relevant relationships by Bassel Noumi, source=Web Response No relevant relationships by Pius Ochieng, source=Web Response No relevant relationships by NISHANT SHARMA, source=Web Response No relevant relationships by Yichen Wang, source=Web Response

Association of antibody titers and 5-HTTLPR gene polymorphisms in pediatric autoimmune neuropsychiatric disorder associated with streptococci

Introduction. It has been hypothesized that pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) etiology results from an abnormal immune response to streptococcal infection. There is evidence that the serotonergic system is involved in both obsessive-compulsive disorder (OCD) physiopathology and immunological processes. In the 5’ promoter region of 5-HTT, gene encoding for the serotonin transporter we can find the 5-HTTLPR polymorphism that has been associated with OCD. Being PANDAS a disorder with OCD symptoms and likely immune abnormalities, 5-HTT polymorphisms may be particularly relevant for this disorder. Objective. This study aimed to test the association between the 5-HT genotypes and the presence of serum antibodies in patients with PANDAS. Method. We compared the genotype frequencies and serum anti-streptococcal, anti-neural, and anti-enolase antibodies titers between 56 patients with PANDAS and 20 healthy controls from Mexico and Cuba. Results. Antibody titers were higher (anti-enolase, anti-streptococcal) in PANDAS patients compared to healthy controls. No differences in anti-neural antibody levels between both groups were detected. The anti-enolase and anti-neural antibody titer increased according to the polymorphism of the PANDAS patients as follows: LL &gt;SL &gt;SS. Discussion and conclusion. This is the first study evaluating the association between the 5-HTTLPR genotypes and antibody titers in PANDAS patients. Associations between polymorphisms in serotonergic genes and immune response could provide valuable information about the interaction between both systems. Our results suggest an association between the S allele and elevated antibody levels in PANDAS patients.

Elevated levels of anti-carbamylated protein antibody in patients with rheumatoid arthritis: association with disease activity and bone destruction

To measure the serum levels of anticarbamylated protein (CarP) antibodies in patients with rheumatoid arthritis (RA) in China and to evaluate the association of anti-CarP antibodies with clinical parameters and...

Oral immunization of trout fry with recombinant Lactococcus lactis NZ3900 expressing G gene of viral hemorrhagic septicaemia virus (VHSV)

This study has investigated the ability of Lactococcus lactic (NZ3900) carried G gene of viral haemorrhagic septicaemia virus (VHSV) under nisin-controlled gene expression (NICE) system in rainbow trout (O.Mykiss). Two groups of trout fry (7 ± 0.65 g) were immunized with 1 × 1010 cfu/g and 1 × 108 cfu/g recombinant L. lactis NZ3900, two groups of fish were fed 1 × 1010 cfu/g and 1 × 108 cfu/g L. lactis vector free, and one group was fed by the basal diet as a control. Oral immunization was done on days 1–7 and boosting was performed on days 15–21. The relative expression of IFN-1 and MX-1 genes significantly increased in head kidney of vaccinated fish depend on vaccine dosage compared to the control group. Fish in vaccinated group also showed elevated VHSV-specific antibody levels compared to the control groups. Relative percent survival (RPS), under virulent isolate VHSV challenge were estimated 62%, 78% for 108 cfu/g 1010 cfu/g feed vaccinated groups 21 days post-vaccination, while groups fed similar doses of L. lactis vector free illustrated 22% and 27% RPSs, respectively. The significant reduction of viral loads (transcript levels of N gene) were detected in the immunized groups. Increased weight gain and decreased feed consumption in vaccinated group attributed to the probiotic effect were also observed. In conclusion, our results demonstrate the ability of recombinant L. lactis as oral vaccine against VHS in rainbow trout, which can be considered as effective method against different fish pathogens.

Smoking and Epstein\u2013Barr virus infection in multiple sclerosis development

It is unclear whether smoking interacts with different aspects of Epstein–Barr virus (EBV) infection with regard to multiple sclerosis (MS) risk. We aimed to investigate whether smoking acts synergistically with elevated EBNA-1 antibody levels or infectious mononucleosis (IM) history regarding MS risk. Two Swedish population-based case–control studies were used (6,340 cases and 6,219 matched controls). Subjects with different smoking, EBNA-1 and IM status were compared regarding MS risk, by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Potential interaction on the additive scale was evaluated by calculating the attributable proportion due to interaction (AP). Current and past smokers had higher EBNA-1 antibody levels than never smokers (p < 0.0001). There was an additive interaction between current smoking and high EBNA-1 antibody levels (AP 0.3, 95% CI 0.2–0.4), but not between past smoking and high EBNA-1 antibody levels (AP 0.01, 95% CI − 0.1 to 0.1), with regard to MS risk. An interaction also occurred between current smoking and IM history (AP 0.2, 95% CI 0.004–0.4), but not between past smoking and IM history (AP − 0.06, 95% CI − 0.4 to 0.3). Current smoking increases EBNA-1 antibody levels and acts synergistically with both aspects of EBV infection to increase MS risk, indicating that there is at least one pathway to disease in which both risk factors are involved.

To evaluate the presence of subclinical thyroid disorder in type 2 diabetes mellitus

Objectives: Our objective is to determine the prevalence of subclinical thyroid disorders in patients with type 2 diabetes mellitus (T2DM) and to analyze the clinical and metabolic profile of patients with this dual endocrine disorder. Methods and Results: Sixty consecutive type 2 diabetic patients without clinical manifestations of thyroid disorders were screened for SCH and subclinical hyperthyroidism using serum free T 3, free T 4 and thyroid stimulating hormone (TSH) levels. Individuals of subclinical thyroid disease were further screened for thyroperoxidase (TPO) antibodies. SCH was detected in 13% of type 2 diabetic patients and none had subclinical hyperthyroidism in our study. SCH was common among females with type 2 diabetes (84.6%). Elevated TPO antibody levels were present in 84.6% SCH patients. Diabetic retinopathy among SCH patients showed significant association with higher serum TSH levels. Left ventricular diastolic dysfunction was present in 30.8% of SCH patients. Conclusion: SCH is common among type 2 diabetic patients, especially in females. It is most commonly secondary to autoimmune thyroid disease. Microvascular complications are commonly observed in this group of patients with dual endocrinal disorder and treating physician should be aware of the impact and should routinely screen SCH to prevent complications.

Protein-based, but not viral vector alone, HIV vaccine boosting drives an IgG1-biased polyfunctional humoral immune response.

The RV144 HIV-1 vaccine trial results showed moderate reduction in viral infections among vaccinees as well as induction of antibody-dependent cellular cytotoxicity and vaccine-specific IgG and IgG3 responses directed at variable loop regions 1 and 2 of the HIV envelope protein. However, with the recent failure of the HVTN 702 clinical trial, comprehensive profiling of humoral immune responses may provide insight for these disappointing results. One of the changes included in the HVTN 702 study was the addition of a late boost, aimed at augmenting peak immunity and durability. The companion vaccine trial RV305 was designed to permit the evaluation of the immunologic impact of late boosting with either the boosting protein antigen alone, the canarypox viral vector ALVAC alone, or a combination of both. Although previous data showed elevated levels of IgG antibodies in both boosting arms, regardless of ALVAC-HIV vector incorporation, the effect on shaping antibody effector function remains unclear. Thus, here we analyzed the antibody and functional profile induced by RV305 boosting regimens and found that although IgG1 levels increased in both arms that included protein boosting, IgG3 levels were reduced compared with the original RV144 vaccine strategy. Most functional responses increased upon protein boosting, regardless of the viral vector-priming agent incorporation. These data suggest that the addition of a late protein boost alone is sufficient to increase functionally potent vaccine-specific antibodies previously associated with reduced risk of infection with HIV.

Understanding Fluctuating Hearing Loss

Understanding Fluctuating Hearing Loss

An Erythrocyte Membrane-Associated Antigen, PvTRAg-26 of Plasmodium vivax: A Study of Its Antigenicity and Immunogenicity.

Background: Plasmodium tryptophan-rich (TR) proteins have been proposed as potential vaccine candidate antigens. Among them, P. vivax tryptophan-rich antigens (PvTR-Ags), which have positionally conserved tryptophan residues in a TR domain, are highly antigenic in humans. Several of these antigens, including PvTRAg-26, have exhibited erythrocyte-binding activities.Methods: Subclasses of IgG antibodies against PvTRAg-26 were detected by enzyme-linked immunosorbent assay in 35 P. vivax infected patients and mice immunized with the recombinant antigen to characterize its antigenicity and immunogenicity. Moreover, the antigen-specific immune responses and Th1/Th2-type cytokine patterns of splenocytes from the immunized animals were determined in vitro. The subcellular localization of PvTRAg-26 in ring-stage parasites was also detected by indirect immunofluorescence assay.Results: The IgG1 and IgG3 levels in P. vivax-infected patients were significantly higher than those in uninfected individuals. In the PvTRAg-26-immunized mice, elevated levels of antigen-specific IgG antibodies were observed, dominated by the IgG1 subclass, and Th1-type cytokines were remarkably increased compared with Th2-type cytokines. Additionally, the subcellular location of the PvTRAg-26 protein was closely associated with the caveola-vesicle complex on the infected-erythrocyte membrane in the early ring stage of P. vivax.Conclusions: PvTRAg-26, a P. vivax TR antigen, with high antigenicity and immunogenicity, induces Th1-cytokine response and increases production of IgG1 antibodies. This immune profiling study provided a substantial evidence that PvTRAg-26 may be a potential candidate for P. vivax vaccine development.

Hashimoto's Encephalopathy Mimicking Viral Encephalitis: A Case Report.

Hashimoto’s encephalopathy (HE) is a rare neuropsychiatric syndrome characterized by elevated levels of anti-thyroid antibodies. Diverse manifestations make timely diagnosis of HE difficult. Herein, we report a case of HE, in which the clinical symptoms and laboratory test results mimicked viral encephalitis. A 59-year-old male patient, who presented with a fever, headache, slow and unclear speech, sentence confusion, elevated levels of anti-thyroid antibodies in the serum, an increased white blood cell count, and positivity for anti-thyroid antibodies in the CSF, was finally diagnosed with HE and responded well to a small dose of methylprednisolone. This report helps bring the attention of clinicians to the fact that HE should be considered when cases of unexplained encephalopathy are encountered.

Immunological features in anti-U1-ribonucleoprotein antibody positive patients with systemic scleroderma

In anti-U1-ribonucleoprotein (anti-U1-RNP) antibody positive patients with systemic scleroderma (SSD), the clinical picture and course of the disease have specific features: there is a preponderance of its limited form; inflammatory damage to the joints and muscles comes to the fore; and cutaneous manifestations are mild. Moreover, a high frequency (68%) of interstitial lung disease is found. At the same time, the autoimmune profile in this group has been little studied.Objective:to investigate the level of major autoantibodies (autoAbs) in anti-U1RNP antibody positive patients with SSD and to compare the frequency of the autoAbs in this group and in the groups of patients with SSD phenotypes associated with anti-centromere antibodies (ACA) and anti-topoisomerase I (anti-Scl70) antibodies.Patients and methods. The investigation enrolled a total of 144 patients meeting the 2013 ACR/EULAR SSD classification criteria. Forty-four anti-U1RNP antibody positive patients were found to have autoAbs, rheumatoid factor (RF), anti-cyclic citrullinated peptide (ACCP), anti-Ro, anti-La, anti-double-stranded DNA (anti-dsDNA), anti-Smith (anti-Sm), anti-cardiolipin (aCL), anti-histidyl tRNA synthetase (anti-Jo1), anti-Scl70, and anti-RNA polymerase III (anti-RNAP-III) antibodies, and ACA in two points. The study group (anti-U1RNP antibody positive patients with SSD) and the comparison groups (anti-Scl70 and ACA positive patients) were comparatively analyzed.Results and discussion. Anti-U1RNP antibody positive patients with SSD were commonly observed to have overlaps (34%) with rheumatoid arthritis and systemic lupus erythematosus, as well as concurrence with Sjögren’s syndrome (SS) (32.5%). The study group was found to have frequently RF (27%), anti-Ro (41%), anti-dsDNA (50%) antibodies, rarely anti-Sm (9%), ACCP (9%), anti-La (7%), ACA (11%), anti-Scl70 (9%), and aCL (2%) antibodies. Anti-Jo1 and anti-RNAP-III antibodies were not detected in any patient. SSD patients who were highly positive for anti-U1RNP antibodies (more than 2 upper limits of the reference range) significantly more frequently exhibited RF, anti-Ro and anti-dsDNA antibodies (p&lt;0.01). Over time, anti-U1RNP antibodies detected at the onset of the disease persisted in 75% of patients. autoAbs were observed to disappear in patients with a low baseline titer of anti-U1RNP antibodies. Re-examination demonstrated that the detection rate of other autoAbs remained high in the group of patients who were highly positive for anti-U1RNP antibodies. Comparison of the three groups showed that the specific feature of the study group was the more frequent presence of other autoAbs, among which anti-Ro antibodies were most important. Their presence was associated with SS.Conclusion. In addition to clinical features, patients with SSD and anti-U1RNP antibody overproduction differ from those with major SSD phenotypes by the more frequent presence of other autoAbs. Persons who are highly positive for anti-U1RNP show the steady-state elevated levels of RF, anti-Ro and anti-dsDNA antibodies and the rare detection of SSD-specific autoAbs (ACA, anti-Scl70 and anti-RNAP-III).

IL-5Rα marks nasal polyp IgG4- and IgE-expressing cells in aspirin-exacerbated respiratory disease

The cause of severe nasal polyposis in aspirin-exacerbated respiratory disease (AERD) is unknown. Elevated antibody levels have been associated with disease severity in nasal polyps, but upstream drivers of local antibody production in nasal polyps are undetermined. We sought to identify upstream drivers and phenotypic properties of local antibody-expressing cells in nasal polyps from subjects with AERD. Sinus tissue was obtained from subjects with AERD, chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), CRS without nasal polyps, and controls without CRS. Tissue antibody levels were quantified via ELISA and immunohistochemistry and were correlated with disease severity. Antibody-expressing cells were profiled with single-cell RNA sequencing, flow cytometry, and immunofluorescence, with IL-5Rα function determined through IL-5 stimulation and subsequent RNA sequencing and quantitative PCR. Tissue IgE and IgG4 levels were elevated in AERD compared with in controls (P< .01 for IgE and P< .001 for IgG4 vs CRSwNP). Subjects with AERD whose nasal polyps recurred rapidly had higher IgE levels than did subjects with AERD, with slower regrowth (P= .005). Single-cell RNA sequencing revealed increased IL5RA, IGHG4, and IGHE in antibody-expressing cells from patients with AERD compared with antibody-expressing cells from patients with CRSwNP. There were more IL-5Rα+ plasma cells in the polyp tissue from those with AERD than in polyp tissue from those with CRSwNP (P= .026). IL-5 stimulation of plasma cells invitro induced changes in a distinct set of transcripts. Our study identifies an increase in antibody-expressing cells in AERD defined by transcript enrichment of IL5RA and IGHG4 or IGHE, with confirmed surface expression of IL-5Rα and functional IL-5 signaling. Tissue IgE and IgG4 levels are elevated in AERD, and higher IgE levels are associated with faster nasal polyp regrowth. Our findings suggest a role for IL-5Rα+ antibody-expressing cells in facilitating local antibody production and severe nasal polyps in AERD.

Cladribine Treatment Improved Homocysteine Metabolism and Increased Total Serum Antioxidant Activity in Secondary Progressive Multiple Sclerosis Patients.

Hyperhomocysteinemia plays a crucial role in the pathogenesis of many diseases of the central nervous system (CNS). The nervous system is particularly sensitive to high homocysteine (Hcy) level mainly due to its prooxidative and cytotoxic effects. Cladribine, a drug recently registered for the treatment of multiple sclerosis (MS), possesses additionally neuroprotective effects which are independent of its peripheral immunosuppressant action. Accumulating evidence suggests that oxidative stress and homocysteine thiolactone-mediated protein homocysteinylation play a causal role in MS. Both of these processes may be attenuated by paraoxonase 1 (PON1). Therefore, in the present study, we aimed to examine whether the beneficial effects of the drug in MS patients with a secondary progressive (SP) clinical course, treated with cladribine subcutaneously (s.c.), may be related to its ability to modify serum PON1 activity, Hcy concentration, and protein homocysteinylation, as well as to correct total antioxidant status. A total of 118 subjects were enrolled into the study: (1) patients with a SP type of MS, SP-MS (n = 40); (2) patients with a relapsing-remitting (RR) type of MS, RR-MS (n = 30); and (3) healthy people (n = 48). Patients with SP-MS were treated with cladribine. The drug was given in SP-SM patients s.c. six times every 6 weeks up to a total mean cumulative dose of 1.8 mg/kg. PON1 activity was assessed spectrophotometrically. The level of Hcy, homocysteine thiolactone (HTL) attached to plasma proteins (N-Hcy-protein), and antibodies against homocysteinylated proteins was assessed with an enzyme immunoassay. The total antioxidant activity of the serum was assessed with the ferric-reducing activity of plasma (FRAP) method. Basically, there was no difference in PON1 activity between untreated SP-MS, RR-MS, and control subjects. Serum Hcy was significantly higher in RR-MS patients (p < 0.001) and in SP-MS patients (p < 0.01) compared to the control group. The N-Hcy protein level was higher in RR-MS patients (p < 0.05) in comparison to the control group. Moreover, the elevated level of antibodies against homocysteinylated proteins was observed in the serum of patients with SP-MS. The total antioxidant capacity of serum was lower in MS patients vs. the control group (p < 0.001). After cladribine treatment, the activity of PON1 did not change in SP-MS patients, whereas cladribine treatment decreased the level of total Hcy (p < 0.05). Treatment with cladribine increased the total serum antioxidant activity in SP-MS patients (p < 0.01). The Expanded Disability Status Scale (EDSS) score did not change in SP-MS patients. Cladribine treatment in the SP-MS group attenuates hyperhomocysteinemia-induced protein homocysteinylation (n.s.). It also stabilises the neurological condition of SP-MS patients. The stabilisation of a neurological condition observed in SP-MS patients after cladribine treatment may be partially related to its ability to reduce elevated Hcy level and to improve serum antioxidant potential.

Familial dysalbuminemic hyperthyroxinemia confounding management of coexistent autoimmune thyroid disease.

SummaryFamilial dysalbuminemic hyperthyroxinemia (FDH) is a cause of discordant thyroid function tests (TFTs), due to interference in free T4 assays, caused by the mutant albumin. The coexistence of thyroid disease and FDH can further complicate diagnosis and potentially result in inappropriate management. We describe a case of both Hashimoto’s thyroiditis and Graves’ disease occurring on a background of FDH. A 42-year-old lady with longstanding autoimmune hypothyroidism was treated with thyroxine but in varying dosage, because TFTs, showing high Free T4 (FT4) and normal TSH levels, were discordant. Discontinuation of thyroxine led to marked TSH rise but with normal FT4 levels. She then developed Graves’ disease and thyroid ophthalmopathy, with markedly elevated FT4 (62.7 pmol/L), suppressed TSH (<0.03 mU/L) and positive anti-TSH receptor antibody levels. However, propylthiouracil treatment even in low dosage (100 mg daily) resulted in profound hypothyroidism (TSH: 138 mU/L; FT4: 4.8 pmol/L), prompting its discontinuation and recommencement of thyroxine. The presence of discordant thyroid hormone measurements from two different methods suggested analytical interference. Elevated circulating total T4 (TT4), (227 nmol/L; NR: 69–141) but normal thyroxine binding globulin (TBG) (19.2 µg/mL; NR: 14.0–31.0) levels, together with increased binding of patient’s serum to radiolabelled T4, suggested FDH, and ALB sequencing confirmed a causal albumin variant (R218H). This case highlights difficulty ascertaining true thyroid status in patients with autoimmune thyroid disease and coexisting FDH. Early recognition of FDH as a cause for discordant TFTs may improve patient management.Learning points:The typical biochemical features of familial dysalbuminemic hyperthyroxinemia (FDH) are (genuinely) raised total and (spuriously) raised free T4 concentrations due to enhanced binding of the mutant albumin to thyroid hormones, with normal TBG and TSH concentrations.Given the high prevalence of autoimmune thyroid disease, it is not surprising that assay interference from coexisting FDH may lead to discordant thyroid function tests confounding diagnosis and resulting in inappropriate therapy.Discrepant thyroid hormone measurements using two different immunoassay methods should alert to the possibility of laboratory analytical interference. The diagnosis of FDH is suspected if there is a similar abnormal familial pattern of TFTs and increased binding of radiolabelled 125I-T4 to the patient’s serum, and can be confirmed by ALB gene sequencing.When autoimmune thyroid disease coexists with FDH, TSH levels are the most reliable biochemical marker of thyroid status. Measurement of FT4 using equilibrium dialysis or ultrafiltration are more reliable but less readily available.

Late-Onset Wilson’s Disease Mimics Hashimoto Encephalopathy

A 48-year-old woman presented with a 1-day history of aggressive behavior. Hashimoto encephalopathy was first suspected based on elevated levels of serum anti-thyroid peroxidase antibody. Her clinical symptoms did not improve despite treatment with intravenous corticosteroid. Abdominal computed tomography revealed liver cirrhosis, and brain T2-weighted magnetic resonance imaging revealed midbrain hyperintensity, and she was finally diagnosed with Wilson’s disease. The Wilson’s disease should be considered in the differential diagnosis in adults presenting with unexplained hepatic, neurological, or psychiatric abnormalities.

Lung Metastases From Papillary Thyroid Cancer With Persistently Negative Thyroglobulin and Elevated Thyroglobulin Antibody Levels During Radioactive Iodine Treatment and Follow-Up: Long-Term Outcomes and Prognostic Indicators

Background: The lung is the most frequent site of distant metastasis from differentiated thyroid cancer (DTC). However, lung metastasis from papillary thyroid cancer (PTC) with persistently negative thyroglobulin (Tg) and elevated Tg antibody (TgAb) levels is an extremely rare entity, and the prognosis is therefore elusive. We investigated the clinical characteristics, long-term outcomes, and prognostic factors of lung metastases in PTC patients with persistently negative thyroglobulin (Tg) and elevated Tg antibody (TgAb) levels during radioactive iodine (131I) treatment and follow-up.Methods: We retrospectively reviewed 10,482 patients with DTC who underwent postoperative 131I treatment from 2007 to 2017 at Shanghai Sixth's People's Hospital. The relationships between progression-free survival (PFS) and several variables were assessed by univariate and multivariate analyses using the Kaplan–Meier method and a Cox proportional hazards model, respectively.Results: Forty-seven patients with PTC were enrolled in this study (4.48‰ of all patients with DTC). The median age at the initial diagnosis of lung metastasis was 39.6 ± 15.4 years, and the patients comprised 14 male and 33 female patients (male: female ratio = 1.00:2.36). Twenty-five patients had 131I avidity and 22 had non-131I avidity. At the end of the 5-years follow-up, 12 patients exhibited progressive disease (PD), and 2 patients had died. At the end of the 10-years follow-up, 21 patients showed PD and five patients had died. The 5- and 10-year PFS rates were 74.47 and 53.32%, respectively; the 5- and 10-years overall survival (OS) rates were 95.74 and 89.36%, respectively. The timing of diagnosis of lung metastases, maximal size of lung metastases, and 131I avidity were significantly associated with the 5-years PFS rate (P = 0.035, P = 0.030, and P<0.001, respectively). Only 131I avidity was associated with the 10-years PFS rate (P < 0.001). The multivariate analyses also showed that non-131I avidity were the independent poor prognostic factors for 10-years PFS at the end of follow-up (P < 0.001).Conclusions: Lung metastases from PTC in patients with persistently negative Tg and elevated TgAb levels had an excellent prognosis and survival rate during 131I treatment and follow-up. The loss of 131I avidity remained the strongest independent predictor of a poor prognosis and survival in these patients.