Italian Association of Clinical Endocrinologists (AME) 20th National Congress

The proceedings contain 9 papers. The topics discussed include: dulaglutide and NAFLD risk reduction;correlation between plasmatic long pentraxin PTX3 and nodular thyroid disease: a preliminary report;the fructose-bisphosphate aldolase a act as autoantigen in primary autoimmune hypophysitis;cortisol deficiency in Lenvatinib treatment;side effects of mitotane treatment: a retrospective study in 35 patients with adrenocortical carcinoma in adjuvant therapy;non-functioning pituitary adenoma: do predictor factors exist?;incidence and features of adrenal crisis in a series of 133 patients with Addison's disease;serological evidence and self-reported outcomes in patients with adrenal insufficiency during the first waves of COVID-19 in the North-East Italy;and persistent effects of spironolactone after its withdrawal in patients with hyperandrogenic skin disorders.

Thyroid Eye Disease Following COVID-19 Infection in a Patient with a History of Graves' Disease

Introduction: Autoimmune and inflammatory thyroid diseases have been reported following SARS-CoV-2 infection or vaccination, but thyroid eye disease (TED) post-COVID-19 infection is less common. We describe a case of TED following SAR-CoV-2 infection in a patient with a history of Graves' disease. Case Description: A 59-year-old female with history of Graves' disease status post radioiodine ablation therapy in 2002. She developed post-ablative hypothyroidism which has been stable on levothyroxine 88 mcg daily. In January 2021, the patient's husband and daughter were diagnosed with COVID-19 infection. A few days later, the patient developed an upper respiratory tract infection associated with loss of sense of smell and taste consistent with COVID-19 infection. Three days later, she developed bilateral watery eyes which progressed to eye redness, eyelid fullness, retraction, and pain with eye movement over 1-month duration. Her eye examination was significant for severe periocular soft tissue swelling, lagophthalmos and bilateral exophthalmos. The laboratory workup was consistent with normal TSH 0.388 mIU/L (0.358-3.740 mIU/L) and positive TSI 1.01 (0.0-0.55). The patient was referred to an Ophthalmologist for evaluation of TED. He noted bilateral exophthalmos, no restrictive ocular dysmotility or compressive optic neuropathy (clinical activity score 4/7 points). CT scan of orbit showed findings compatible with thyroid orbitopathy. Based on clinical activity score of 4, treatment with Teprotumumab was recommended pending insurance approval. Discussion(s): Many cases of new-onset Graves' hyperthyroidism have been reported after COVID-19, with only a few associated with TED. Our patient has been in remission for 20 years before she developed COVID-19 infection with occurence of TED.This suggests that COVID-19 infection may have played a role. SARS-CoV-2 may act through several mechanisms, including breakdown of central and peripheral tolerance, molecular mimicry between viral and self-antigens, stimulation of inflammasome with release of type I interferon. In our patient, treatment with Teprotumumab was indicated due to Graves' orbitopathy clinical activity score greater than or equal to 3. In conclusion, it is very uncommon for TED to present after COVID-19 infection. Our case reinforces the speculative hypothesis that SARS-CoV-2 virus could have triggered an autoimmune response against eye antigens. There is a need for increased awareness about the link between COVID-19 and autoimmunity to help better define the management of patients.Copyright © 2023

The peptide link between pathogens and human centromere proteins

This work tested the hypothesis that infection causes unexplained production of anti-centromere protein antibodies (ACA) via autoimmune cross-reactivity. To further examine the clinical origin of ACA, the overlapped peptides between human pathogens, including viruses, bacteria and fungi and centromere proteins (CENP-A, CENP-B and CENP-C) were assessed. We found a broad overlap of pathogenetic peptides with human centromere proteins. These data indicate potential immune cross-reactivity between pathogens and human centromere proteins. Additionally, the current findings corroborate a molecular and mechanistic framework for autoimmune disorders related to infection. Moreover, preliminary evidence for a potential role of infection in ACA-related autoimmune diseases was presented. © 2022 The Scandinavian Foundation for Immunology.

Autoantibody discovery across monogenic, acquired, and COVID-19-associated autoimmunity with scalable PhIP-seq.

Phage immunoprecipitation sequencing (PhIP-seq) allows for unbiased, proteome-wide autoantibody discovery across a variety of disease settings, with identification of disease-specific autoantigens providing new insight into previously poorly understood forms of immune dysregulation. Despite several successful implementations of PhIP-seq for autoantigen discovery, including our previous work (Vazquez et al., 2020), current protocols are inherently difficult to scale to accommodate large cohorts of cases and importantly, healthy controls. Here, we develop and validate a high throughput extension of PhIP-seq in various etiologies of autoimmune and inflammatory diseases, including APS1, IPEX, RAG1/2 deficiency, Kawasaki disease (KD), multisystem inflammatory syndrome in children (MIS-C), and finally, mild and severe forms of COVID-19. We demonstrate that these scaled datasets enable machine-learning approaches that result in robust prediction of disease status, as well as the ability to detect both known and novel autoantigens, such as prodynorphin (PDYN) in APS1 patients, and intestinally expressed proteins BEST4 and BTNL8 in IPEX patients. Remarkably, BEST4 antibodies were also found in two patients with RAG1/2 deficiency, one of whom had very early onset IBD. Scaled PhIP-seq examination of both MIS-C and KD demonstrated rare, overlapping antigens, including CGNL1, as well as several strongly enriched putative pneumonia-associated antigens in severe COVID-19, including the endosomal protein EEA1. Together, scaled PhIP-seq provides a valuable tool for broadly assessing both rare and common autoantigen overlap between autoimmune diseases of varying origins and etiologies.

A RARE CASE OF PLEURODYNIA AFTER THE COVID-19 VACCINE

SESSION TITLE: Rare Cases with Masquerading Pulmonary Symptoms SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 01:35 pm - 02:35 pm INTRODUCTION: COVID vaccinations have been encouraged by many healthcare providers but many adverse effects have also been reported. The adverse effects of the vaccine can vary based on each individual. Common adverse effects of the vaccine included fatigue, fever, chills, sore throat, muscle pain, headache, rash at injection site. Pleurodynia, also known as Devil's Grip, is a viral myalgia which causes sharp chest pain or the sensation of a grip around one's chest. Pleurodynia treatment is mostly supportive like anti-inflammatories (NSAIDS), pain management, and antibiotics (if bacterial inflammation is suspected). CASE PRESENTATION: We present a case report of a 63-year-old female who presented with complaints of pleuritic chest pain worse with inspiration. She had a history of atrial fibrillation and HTN. Patient had received the Pfizer COVID booster vaccine a few days prior to onset of the pleuritic chest pain. She was obese and had a 40 pack year smoking history. She was on room air saturating 92% with no increased work of breathing. Lung sounds were diminished due to body habitus but clear. Chest x-ray showed low lung volumes with no evidence of acute pulmonary disease. Computed Tomography Angiography (CTA) chest showed no pulmonary embolism and small left partially loculated pleural effusion with peripheral airspace opacities abutting the pleura. Acute coronary syndrome was ruled out and other cardiac workup was negative. COVID PCR was negative. Patient was treated empirically for bacterial infection with ceftriaxone and azithromycin. She was given NSAIDS to decrease inflammation and pain. Patient's symptoms improved significantly with treatment. She was discharged on NSAIDS and advised to follow up outpatient with her primary care and pulmonology. DISCUSSION: Research studies have indicated that the COVID vaccines (like Pfizer) can cause exacerbation of inflammatory or autoimmune conditions. Multiple mechanisms may be responsible for myocarditis, pericarditis, and other inflammatory conditions post vaccines. One mechanism describes that lipid particles of SARS mRNA vaccines can induce inflammation by activating the NLR pyrin domain containing 3 inflammasome of mRNA which are recognized by toll like receptors and cytosolic inflammasome components leading to inflammation. Another mechanism explains that viral proteins can cause immune cross reactivity with self-antigens expressed in the myocardium leading to an inflammatory process. CONCLUSIONS: As per current literature review there are no case reports about pleurodynia post COVID vaccination but pericarditis and myocarditis have been described. Further research studies are indicated to assess the cause and pathophysiology of pleurodynia post COVID vaccine. Physicians should have a high index of clinical suspicion for pleurodynia when assessing a patient with pleuritic chest pain with a recent history of COVID vaccination. Reference #1: 1. Analysis of COVID 19 Vaccine Type and Adverse Effects Following Vaccination. Beatthy, A;Peyser, N;Butcher, X. AMA Netw Open. 2021;4(12):e2140364. doi:10.1001/jamanetworkopen.2021.40364 Reference #2: 1. Association of Group B Coxsackieviruses with Cases of Pericarditis Myocarditis, or Pleurodynia by Demonstration of Immunoglobulin M Antibody. Schmidt, N;Magoffin, R;& Lennette, E. Infection and Immunty Journal. 1973 Sep;8(3): 341–348. PMCID: PMC422854 Reference #3: 3. Autoimmune phenomena following SARS-CoV-2 vaccination. Ishay, Y;Kenig, A;Toren, T;Amer, R;et. al. International Journal of Immuno-pharmacology. 2021 Oct;99: 107970. DISCLOSURES: No relevant relationships by Olufunmilola Ajala No relevant relationships by Arij Azhar No relevant relationships by Louis Gerolemou No relevant relationships by Wael Kalaji No relevant relationships by Steven Miller No relevant relationships by Kunal Nangrani No relevant relationships by Gaurav Parhar No relevant relationships by iran Zaman

A TOUCH OF THE HEART AND THE TOOLS FOR DIAGNOSIS

SESSION TITLE: Infections In and Around the Heart Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: Myocarditis is inflammation of the heart muscle, and its onset is usually followed by an inciting event such as a viral infection. Here, we report a case of myocarditis in an adolescent male with no significant medical history who presented with chest pain after his second dose of the covid vaccine. CASE PRESENTATION: An 18-year old male presented with no significant past medical/surgical history presented with chest pain. His only triggering event was receiving the second dose of his covid vaccine. A physical examination, chest x-ray, electrocardiogram, and echocardiogram revealed no significant findings. His laboratory findings were positive for myocardial damage with elevated troponin. All other laboratories for autoimmune and inflammation were negative. He was transferred to another facility for cardiac MRI, which subsequently had findings consistent with myocarditis. He remained asymptomatic, and laboratories were normalized. He was discharged and, on follow-up, remained asymptomatic. DISCUSSION: Covid vaccine-induced myocarditis has become a prominent issue. As of March 2022, there are 2323 preliminary reports of myocarditis/pericarditis following either mRNA vaccine, with most cases being young male adolescents. Prior vaccination, such as the smallpox vaccine, has a well-documented history of causing myocarditis, initially thought to be a rare occurrence, it had a prevalence as high as 10% when reviewed. A similar pattern may be observed with the covid vaccine;thus, this complication can be significantly underestimated, and physicians must be vigilant. Thus, cardiac MRI should be pursued if clinically suspected. It has been shown to provide reliable clinical information even in the early phases of inflammation as well as the extent of the inflammatory process, and it avoids invasive procedures1 It can also be used prognostically to monitor disease status. Myocarditis may be immune-related. Key observations include increased systemic reactogenicity and immunogenicity in younger study participants in Pfizer-biotech clinical trials. However, another report showed no difference in spike antibody between patients with myocarditis and those without myocarditis post-covid mRNA vaccine, arguing against a hyperimmune response2. Another plausible mechanism is molecular mimicry between the spike protein and self-antigens, showing cross-reactivity between human peptides in the body, including alpha-myosin3, which may explain why only mRNA covid vaccine causes this complication. Currently, there is no causal relationship, but numerous hypotheses are being examined. CONCLUSIONS: Myocarditis must be recognized as a complication of the covid vaccine and a possible differential of chest pain,specifically in young men in the current pandemic.Early referral of cardiac MRI, if unavailable at centers, is essential for diagnosis and prognostication,given the unknown sequela of this disease. Reference #1: M. Giulia Gagliardi and Bruno Polletta Paolo Di Renzi, Gagliardi, M. G., M. Giulia Gagliardi Department of Cardiology and Cardiac Surgery, Polletta, B., Bruno Polletta Department of Cardiology and Cardiac Surgery, Renzi, P. D., & Paolo Di Renzi Department of Radiology Fatebenefratelli-Isola Tiberina Hospital. (1999, January 26). MRI for the diagnosis and follow-up of Myocarditis. Circulation. Retrieved April 13, 2022, from https://www.ahajournals.org/doi/full/10.1161/circ.99.3.457/a Reference #2: Muthukumar, A., Alagarraju Muthukumar Department of Pathology (A.M., Narasimhan, M., Madhusudhanan Narasimhan Department of Pathology (A.M., Li, Q.-Z., Quan-Zhen Li Department of Immunology (Q.-Z.L.), Mahimainathan, L., Lenin Mahimainathan Department of Pathology (A.M., Hitto, I., Imran Hitto https://orcid.org/0000-0002-9928-4175 Department of Pathology (A.M., Fuda, F., Franklin Fuda Department of Pathology (A.M., Batra, K., Kiran Batra Department of Radiology (K.B.), Jiang, X., Xuan Jiang Department of Internal Medicine (Q.-Z.L., Zhu, C., Chengsong Zhu Department of Internal Medicine (Q.-Z.L., Schoggins, J., … Al., E. (2021, June 16). In-depth evaluation of a case of presumed myocarditis after the second dose of COVID-19 mrna vaccine. Circulation. Retrieved March 31, 2022, from https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.056038 Reference #3: Vojdani, A., & Kharrazian, D. (2020, August). Potential antigenic cross-reactivity between SARS-COV-2 and human tissue with a possible link to an increase in autoimmune diseases. Clinical immunology (Orlando, Fla.). Retrieved March 31, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246018/ DISCLOSURES: No relevant relationships by Aaron Douen No relevant relationships by Sudhanva Hegde No relevant relationships by Marc Sukhoo-Pertab

PROGRESSIVE ASCENDING WEAKNESS AFTER THE PFIZER/BIONTECH COVID-19 VACCINE

SESSION TITLE: Autoimmune Disorders: Both Primary and Secondary SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 10:15 am - 11:10 am INTRODUCTION: Myasthenia gravis (MG) occurs sporadically with no known causes. We present a rare case of new onset MG s/p COVID-19 vaccination. CASE PRESENTATION: A healthy 46-year-old female presented with progressing LE weakness for 3 months. Symptoms started 5 days after her initial Pfizer COVID-19 vaccine. Her workup showed negative neuroimaging, bland basic CSF studies from LP, with negative MS profile and AChR Ab. She presented again in 1 month with difficulty rising from a seated position, raising her arms above her head with blurry vision. Exam showed bilateral ptosis that improved with an ice pack test, weakness is worst in proximal muscles, but normal reflexes. Workup was again negative. Pyridostigmine was added after discharge (DC). 2 months after, she was admitted to the ICU for acute progressive fatiguability and dyspnea. EMG/NCS of the ulnar nerve showed 60-70% electrical decrement. She underwent therapeutic PLEX. Prednisone was added at DC followed by mycophenolate. 2 weeks later, she was again admitted with myasthenic crisis. She again underwent PLEX with improvement and intubation was avoided. Biweekly PLEX was started at DC. Testing for AChR, MuSK, and LRP4 Abs were initially negative, but AChR Abs were present 6 months later. She then underwent thymectomy showing hyperplasia. DISCUSSION: MG exacerbations have been attributable to infections (50%) and medications (30%). This has worsened during the COVID-19 pandemic especially when medications such as azithromycin were used to treat acute infections. While vaccine-induced flares or onset of autoimmune diseases have been described in literatures, new onset MG following vaccines is rare, limited to 1 to 3 case reports. No case, to our knowledge, correlated to the 1st dose like our patient. The temporal relationship between the COVID-19 vaccination and onset of MG symptoms in our patient could represent a correlation, but does not prove causality. Perhaps a more plausible theory is that the vaccine may have unmasked a previously unrecognized disease in high-risk patient. We ask if the COVID vaccine induces a similar cytokine storm, which hyperstimulates the immune system to a point that breaks immunologic self-tolerance. Interestingly, our patient was initially seronegative, but the presence of AChR Ab was confirmed after sensitive cell-based assays testing. Our patient may have had pre-existing self-antigens to the AChR that were released after receiving the Pfizer COVID-19 vaccine. CONCLUSIONS: The rate of COVID-19 vaccinations will soon surpass that of infections placing vulnerable individuals at risk for MG onset. Recognizing this risk will open discussions about vaccine safety. In doing so, we can begin to formulate new parameters for post-vaccination monitoring. The risks of and complications from acute COVID-19 still outweigh the rare adverse events from vaccines;thus, eligible patients should be offered the COVID-19 vaccine. Reference #1: Guidon AC, Amato AA. COVID-19 and neuromuscular disorders. Neurology. 2020 Jun 2;94(22):959-969. doi: 10.1212/WNL.0000000000009566. Epub 2020 Apr 13. PMID: 32284362. Reference #2: Tagliaferri AR, Narvaneni S, Azzam MH, Grist W. A Case of COVID-19 Vaccine Causing a Myasthenia Gravis Crisis. Cureus. 2021;13(6):e15581. Published 2021 Jun 10. doi:10.7759/cureus.15581 Reference #3: Chavez A, Pougnier C. A Case of COVID-19 Vaccine Associated New Diagnosis Myasthenia Gravis. Journal of Primary Care & Community Health. January 2021. doi:10.1177/21501327211051933 DISCLOSURES: No relevant relationships by andrew bui No relevant relationships by Sharonya Shrivastava

THE ROLE of MOLECULAR MIMICRY in SARS-COV-2 RELATED AUTOIMMUNE RHEUMATIC DISEASES

Background: Several studies suggested that SARS-CoV-2 infection may induce autoantibodies related to autoimmune rheumatic diseases (ARD). Objectives: To determine whether polyclonal antibodies from SARS-CoV-2 unin-fected patients with ARDs cross-react with SARS-CoV-2 and vice versa. Methods: 90 sera positive at high-titres for 23 common autoantibodies (all sera stored before 2018), were tested for reactivity against proteins of SARS-CoV-2 (spike protein S1, nucleocapsid NC etc) by ELISA and CMIA. Vice versa, 10 monoclonal antibodies against S1 protein (most of them against RBD) were tested for autoantibody reactivity by indirect immunofuorescence, ELISA, immunoblot and dot/line immunoassays coated with different antigens. Ten post-COVID sera with high titers of anti-Spike abs were tested by ELISAs for reactivity against various autoantigens related to ARDs. Results: 88 out of 90 samples (%), were totally unreactive to SARS-CoV-2 proteins;2 sera, one anti-CCP and one anti-CENP reacted against S protein. All sera tested negative for neutralized abs against SARS-CoV-2. None of 10 sera from SARS-CoV-2 infected patients reacted with different autoantigens by molecular assays. None of the 10 monoclonal abs against S1 protein reacted with 23 different self-antigens. On HEp2 cells as substrate for IIF, 3 of the 10 monoclonal abs gave a low-titre coarse speckled pattern. No reactivity was found by IIFL using tissue substrates. Conclusion: Our data do not suggest a dominant role for molecular mimicry and immunological cross reactivity as a trigger of autoantibodies related to ARDs.

HIGH PREVALENCE of SERUM AUTOANTIBODIES in SEVERELY ILL COVID-19 PATIENTS HOSPITALIZED in the INTENSIVE CARE UNIT

Background: Coronavirus Disease-19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is characterized by a wide range of clinical manifestations 1. Although COVID-19 was initially considered a respiratory infection, it was shortly recognized as a multisystemic disorder associated with heightened infammatory responses, including autoimmune phenomena 1. The presence of autoantibodies (AAbs) has been described in COVID-19 patients, highlighting the state of immune dysregulation in COVID-19 1. The clinical signifcance of AAbs, however, is still elusive. Objectives: To assess the prevalence of AAbs in critically ill, mechanically ventilated COVID-19 patients admitted to the intensive care unit (ICU) and investigate whether AAbs influence the clinical outcome of these patients. Methods: The current study evaluated prospectively from March 8th, 2021 to May 10th, 2021 the presence of AAbs against nuclear antigens (ANA), extracta-ble nuclear antigens (ENA), neutrophil cytoplasmic antigens (ANCA), cyclic cit-rullinated peptides (anti-CCP), double stranded-DNA (anti-dsDNA), cardiolipin (anti-CL), β2-glycoprotein-I (anti-β2-GPI), thyroid peroxidase (anti-TPO), and thyroglobulin (anti-TG) in critically ill COVID-19 patients upon admission in the ICU (n=217). Samples from 60 COVID-19 patients that were available 15 days after ICU admission were further analyzed for the evaluation of de novo AAbs production. Serum samples of age and sex matched healthy individuals before the COVID-19 pandemic were used as a control group (n=117). Results: COVID-19 patients treated in ICU had more commonly at least one AAb compared to age and sex matched controls (174/217, 80.2% vs 73/217, 62,4%, p< 0,001). More specifcally, COVID-19 patients expressed more frequently ANAs (48.4% vs 21.4%, p<0.001), anti-dsDNA (5.1% vs 0%, p=0.01), anti-CCP (8.3% vs 1.7%, p=0.014) and anti-CL IgM AAbs (21.7% vs 9.4%, p=0.005) than controls. The majority of critical COVID-19 patients who were positive for AAbs (144, 82.8%) expressed reactivity in up to three autoantigens with the most prominent being ANA, anti-phospholipid, ANCA and anti-TPO AAbs. AAbs-positive patients demonstrated more robust anti-SARS-CoV-2 humoral responses compared to AAbs-negative patients [detectable anti-SARS-CoV-2 S1-protein IgG antibodies: 150 (86.2%) vs 28 (65.1%), p=0.001;adequate neutralizing activity: 159 (91.4%) vs. 33 (76.7%), p=0.007]. The two groups, however, did not differ in terms of clinicoepidemiologic characteristics or the incidence of death in the ICU. Convalescent COVID-19 patients (n=111) compared to those who died (n=106), did not differ in the prevalence of serum AAbs or antibody responses against SARS-CoV-2. Differences were only shown in clinicolaboratory parameters including patients' age, comorbidities, O2 saturation, infammatory markers, and in-hospi-tal prognostic scores as expected. Paired samples testing (n=60) revealed that 45 patients had at least one newly induced AAb, 28 patients lost at least one reactivity and only 6 patients didn't show any seroconversion. The most common new-onset AAb reactivity was against anti-CL (IgG isotype) (n=21) followed by ANA (n=20), anti-β2-GPI (IgG isotype) (n=11), myositis-related antigens (n=13) and ENAs (n=9);nevertheless, no associations with clinicoepidemiologic features or COVID-19 outcome were revealed. Conclusion: Patients with severe COVID-19 express AAbs more commonly than age and sex matched controls, suggesting that SARS-COV-2 infection may induce a hitherto unknown B-cell autoreactivity. The presence of autoantibodies does not play a role in the outcome of SARS-COV-2 infection. However, further studies are needed to defne their role in future development of systemic autoimmune disorders or the long-COVID syndrome.

C-Reactive Protein: Friend or Foe? Phylogeny From Heavy Metals to Modified Lipoproteins and SARS-CoV-2.

Animal C-reactive protein (CRP) has a widespread existence throughout phylogeny implying that these proteins have essential functions mandatory to be preserved. About 500 million years of evolution teach us that there is a continuous interplay between emerging antigens and components of innate immunity. The most archaic physiological roles of CRP seem to be detoxication of heavy metals and other chemicals followed or accompanied by an acute phase response and host defense against bacterial, viral as well as parasitic infection. On the other hand, unusual antigens have emerged questioning the black-and-white perception of CRP as being invariably beneficial. Such antigens came along either as autoantigens like excessive tissue-stranded modified lipoprotein due to misdirected food intake linking CRP with atherosclerosis with an as yet open net effect, or as foreign antigens like SARS-CoV-2 inducing an uncontrolled CRP-mediated autoimmune response. The latter two examples impressingly demonstrate that a component of ancient immunity like CRP should not be considered under identical "beneficial" auspices throughout phylogeny but might effect quite the reverse as well.

A master autoantigen-ome links alternative splicing, female predilection, and COVID-19 to autoimmune diseases.

Chronic and debilitating autoimmune sequelae pose a grave concern for the post-COVID-19 pandemic era. Based on our discovery that the glycosaminoglycan dermatan sulfate (DS) displays peculiar affinity to apoptotic cells and autoantigens (autoAgs) and that DS-autoAg complexes cooperatively stimulate autoreactive B1 cell responses, we compiled a database of 751 candidate autoAgs from six human cell types. At least 657 of these have been found to be affected by SARS-CoV-2 infection based on currently available multi-omic COVID data, and at least 400 are confirmed targets of autoantibodies in a wide array of autoimmune diseases and cancer. The autoantigen-ome is significantly associated with various processes in viral infections, such as translation, protein processing, and vesicle transport. Interestingly, the coding genes of autoAgs predominantly contain multiple exons with many possible alternative splicing variants, short transcripts, and short UTR lengths. These observations and the finding that numerous autoAgs involved in RNA-splicing showed altered expression in viral infections suggest that viruses exploit alternative splicing to reprogram host cell machinery to ensure viral replication and survival. While each cell type gives rise to a unique pool of autoAgs, 39 common autoAgs associated with cell stress and apoptosis were identified from all six cell types, with several being known markers of systemic autoimmune diseases. In particular, the common autoAg UBA1 that catalyzes the first step in ubiquitination is encoded by an X-chromosome escape gene. Given its essential function in apoptotic cell clearance and that X-inactivation escape tends to increase with aging, UBA1 dysfunction can therefore predispose aging women to autoimmune disorders. In summary, we propose a model of how viral infections lead to extensive molecular alterations and host cell death, autoimmune responses facilitated by autoAg-DS complexes, and ultimately autoimmune diseases. Overall, this master autoantigen-ome provides a molecular guide for investigating the myriad of autoimmune sequalae to COVID-19 and clues to the rare adverse effects of the currently available mRNA and viral vector-based COVID vaccines.

Paradoxical sex-specific patterns of autoantibody response to SARS-CoV-2 infection.

BACKGROUND: Pronounced sex differences in the susceptibility and response to SARS-CoV-2 infection remain poorly understood. Emerging evidence has highlighted the potential importance of autoimmune activation in modulating the acute response and recovery trajectories following SARS-CoV-2 exposure. Given that immune-inflammatory activity can be sex-biased in the setting of severe COVID-19 illness, the aim of the study was to examine sex-specific autoimmune reactivity to SARS-CoV-2 in the absence of extreme clinical disease. METHODS: In this study, we assessed autoantibody (AAB) reactivity to 91 autoantigens previously linked to a range of classic autoimmune diseases in a cohort of 177 participants (65% women, 35% men, mean age of 35) with confirmed evidence of prior SARS-CoV-2 infection based on presence of antibody to the nucleocapsid protein of SARS-CoV-2. Data were compared to 53 pre-pandemic healthy controls (49% women, 51% men). For each participant, socio-demographic data, serological analyses, SARS-CoV-2 infection status and COVID-19 related symptoms were collected by  an electronic survey of questions. The symptoms burden score was constructed based on the total number of reported symptoms (N = 21) experienced within 6 months prior to the blood draw, wherein a greater number of symptoms corresponded to a higher score and assigned as more severe burden. RESULTS: In multivariable analyses, we observed sex-specific patterns of autoreactivity associated with the presence or absence (as well as timing and clustering of symptoms) associated with prior COVID-19 illness. Whereas the overall AAB response was more prominent in women following asymptomatic infection, the breadth and extent of AAB reactivity was more prominent in men following at least mildly symptomatic infection. Notably, the observed reactivity included distinct antigens with molecular homology with SARS-CoV-2. CONCLUSION: Our results reveal that prior SARS-CoV-2 infection, even in the absence of severe clinical disease, can lead to a broad AAB response that exhibits sex-specific patterns of prevalence and antigen selectivity. Further understanding of the nature of triggered AAB activation among men and women exposed to SARS-CoV-2 will be essential for developing effective interventions against immune-mediated sequelae of COVID-19.

Enhanced Expression of Autoantigens During SARS-CoV-2 Viral Infection.

Immune homeostasis is disturbed during severe viral infections, which can lead to loss of tolerance to self-peptides and result in short- or long-term autoimmunity. Using publicly available transcriptomic datasets, we conducted an in-silico analyses to evaluate the expression levels of 52 autoantigens, known to be associated with 24 autoimmune diseases, during SAR-CoV-2 infection. Seven autoantigens (MPO, PRTN3, PADI4, IFIH1, TRIM21, PTPRN2, and TSHR) were upregulated in whole blood samples. MPO and TSHR were overexpressed in both lung autopsies and whole blood tissue and were associated with more severe COVID-19. Neutrophil activation derived autoantigens (MPO, PRTN3, and PADI4) were prominently increased in blood of both SARS-CoV-1 and SARS-CoV-2 viral infections, while TSHR and PTPRN2 autoantigens were specifically increased in SARS-CoV-2. Using single-cell dataset from peripheral blood mononuclear cells (PBMCs), we observed an upregulation of MPO, PRTN3, and PADI4 autoantigens within the low-density neutrophil subset. To validate our in-silico analysis, we measured plasma protein levels of two autoantigens, MPO and PRTN3, in severe and asymptomatic COVID-19. The protein levels of these two autoantigens were significantly upregulated in more severe COVID-19 infections. In conclusion, the immunopathology and severity of COVID-19 could result in transient autoimmune activation. Longitudinal follow-up studies of confirmed cases of COVID-19 could determine the enduring effects of viral infection including development of autoimmune disease.