Infections by varicella zoster virus in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)

Rationale: APECED is a life-threatening monogenic disorder characterized by multiorgan autoimmunity. Most patients harbor autoantibodies (auto-abs) to type-1 interferons (IFNs), which are important mediators of viral defense. Auto-abs to type-1 IFNs are associated with severe COVID-19 and may play a role in other viral infections including by varicella zoster virus (VZV). A recent study of 44 European APECED patients reported increased susceptibility to VZV, and a correlation between VZV recurrence and auto-abs to IFN-α. The clinical, immunophenotypic, and auto-ab characteristics of APECED patients in the USA with VZV are described. Methods: Data was obtained from 103 participants on a prospective, natural history study after informed consent. Auto-abs to IFN-α, IFN-β or IFN-ω were measured using a multiplex particle-based assay. Unpaired t tests or U Mann Whitney tests were used, with Holm correction for multiple comparisons, where appropriate. Results: Twenty-six patients reported childhood chickenpox (mean onset 5.6 years) and 2 (7.7%) required hospitalization for severe disease. Nineteen patients (18%) had at least one episode of shingles (median onset 13 years;range, 4-55 years) and 4 had >1 episode. Fifteen of the 19 patients with shingles (79%) were not receiving immunosuppressive medications during their first infection. VZV IgG levels;total and percent CD3, CD8, CD4, CD19, NK cells;and auto-abs to IFN-α, IFN-β and IFN-ω did not significantly differ between patients with or without recurrent shingles. Conclusions: A subset of APECED patients develop early-onset, recurrent VZV infections even in the absence of immunosuppression. The mechanisms underlying susceptibility to VZV in APECED require further study.

The biology of symptom-based disorders - time to act.

Symptom-based disorders are conditions that are characterised mostly by somatic symptoms rather than objectively identifiable signs. They are very common, including pain and fatigue disorders, functional gastrointestinal and respiratory disorders, and others, and they cause far greater disability than diseases where signs are prominent. Such conditions may sometimes be triggered by infection, as in Post Covid Syndrome (Cabral-Marques et al., 2022; Baiocchi et al., 2022) or physical or psychological trauma. By employing passive immunoglobulin transfer experimental approaches, recent research in several 'unexplained' chronic pain conditions has demonstrated that pathogenic IgG autoantibodies can explain several of these conditions' core symptoms and are ubiquitous in patients with severe phenotypes. The promise from placing positive resources into exploring the role of 'invisible', functional, non-inflammatory autoantibodies in symptom-based disorders across additional areas of Medicine includes patient empowerment and the development of new diagnostic tests and therapies.

A case of post coronavirus disease 2019 (COVID-19) multisystem inflammatory syndrome in adults (MIS-A) presenting as fever and seizures

Background/Purpose: The coronavirus disease 2019 (COVID-19) pandemic has led to the emergence of a severe associated condition, multisystem inflammatory syndrome in adults (MIS-A). Initially identified in children as MIS-C, literature regarding the clinical manifestations, illness progression, and treatment of MIS-A are limited. Method(s): This study describes a case of MIS-A presenting as fever and seizures. She was initially given steroids and IVIG, and due to recurrence of fever, she was later treated with tocilizumab. Result(s): The patient was a 55-year- old Filipino female presenting to the emergency department with five days of fever, headache, and disorientation. Lumbar tap was done, which showed elevated opening pressure, normal leukocyte count, normal glucose, slightly elevated protein, and no microorganisms. She was admitted and managed as a case of viral encephalitis. On hospital day 6, she had sudden onset of head-jerking and further decrease in sensorium, hence she was transferred to the intensive care unit. Brain MRI was unremarkable, and subsequent immune-mediated encephalitis was considered. The patient underwent methylprednisolone pulse therapy and IVIG infusion, which provided immediate improvement of sensorium and resolution of fever episodes. Her condition stabilized, and she was transferred out of intensive care. She underwent physical and occupational rehabilitation as preparation for discharge. Two weeks after infusion therapy, on hospital day 26, patient had recurrence of fever episodes and persistence of elevated inflammatory markers. The patient had reported a previous COVID-19 infection 10 weeks prior to admission and received a booster dose of Moderna (Spikevax) COVID-19 vaccine three weeks prior. She tested positive for ANA (1:640, nuclear speckled), while the rest of the autoimmune antibody tests were negative. She was diagnosed as MIS-A based on the following: documented fever (>=38 degrees centigrade) for >=24 hours prior to hospitalization;new-onset neurologic signs and symptoms including seizures and encephalopathy in a patient without prior cognitive impairment;elevated CRP, ferritin, IL-6, and ESR;and a positive SARS-CoV- 2 test for recent infection by RT-PCR. Patient was treated with a locally available monoclonal antibody, tocilizumab, which was given on hospital day 43. Following infusion, she had lysis of fever and marked decrease in CRP, ferritin, IL-6, and ESR. Patient was discharged improved and without end-stage organ damage. Conclusion(s): Immunomodulators target hyperinflammation seen in MIS-A. There may be a role for the use of tocilizumab via blockage of IL-6. MIS-A remains a topic for research, particularly its disease characteristics, management, and relation to a dysregulated immune system.

EFFECT OF COVID-19 VACCINATION ON THE IMMUNE STATUS AND AUTOANTIBODY PROFILE IN WOMEN OF REPRODUCTIVE AGE.

In the context of the COVID-19 pandemic, scientific interest is growing in studying the impact of the proposed vaccination on women's reproductive health. As is known, alterations in the state of the immune system and activation of an autoimmune response can lead to reproductive failure in women and potential complications of subsequent pregnancy. Objective(s): to evaluate the effect of the "Gam-COVID-Vac" on the immune status parameters, the relationship of their changes and the specific immune response to vaccination with the dynamics of the level of autoantibodies in women of reproductive age. The prospective study included 120 women who were vaccinated against COVID-19 with the "Gam-COVID-Vac". The criteria for inclusion in the study were: the age from 18 to 49 years, the absence of COVID-19 in the anamnesis, a negative result of a study on SARS-CoV-2 by PCR and negative results of tests for antibodies of classes G and M to SARS-CoV-2 before vaccination, the absence of pregnancy and serious somatic diseases. The patients were examined twice: immediately before vaccination and 90-100 days after the introduction of the 1st component of the vaccine. The level of IgG antibodies to SARS-CoV-2 after vaccination was assessed using ELISA. Before and after vaccination, the levels of antiphospholipid, anti-nuclear, organ-specific and antihormonal autoantibodies were determined, peripheral blood lymphocytes were immunophenotyped to determine the main subpopulations (CD3, CD4, CD8, CD19, CD5, CD16, CD56), as well as the expression of activation markers of lymphocytes (HLA-DR, CD25, CD147) using monoclonal antibodies. The effectiveness and safety of the combined vector vaccine against COVID-19 were high. Specific IgG antibodies to SARS-CoV-2 were produced in 98.3% of vaccinated women, no serious adverse reactions were observed. After vaccination, there was an increase in the level of some autoantibodies within the reference ranges, only IgM antibodies to phosphatidylethanolamine (PE) and IgG antibodies to DNA increased above the reference values. However, this increase was transient. After vaccination, the following changes in the parameters of the immunogram were observed: an increase in the content of cells with CD3+CD25+, CD19+ phenotype in peripheral blood and a decrease in the content of cells with CD56+CD16+ phenotype within the reference ranges, a decrease in CD147+/CD3+. Weak correlations were noted between these changes in immunogram parameters and the levels of some autoantibodies. The specific antiviral immune response to vaccination did not correlate with the autoimmune response. Vaccination with "Gam-COVID-Vac" is effective and safe and does not lead to disorders in the immune system. The observed increase in the level of autoantibodies to PE and DNA is transient. Changes in the parameters of the immune status within the reference ranges may be due to vaccination and the development of a specific antiviral immune response. Copyright © 2022, SPb RAACI.

Age-related changes in the immune system and the consequences of immunosenescence

The cellular and molecular hallmarks of aging include genomic instability, telomere attrition, epigenetic alterations, changes in intracellular signaling, cellular senescence, and mitochondrial dysfunction. These lead to complex remodeling and changes involving both the innate and adaptive immune systems. Besides age related changes in immune cells, the microenvironment in the lymphoid and non-lymphoid organs, as well as circulating factors interacting with the immune system also contribute to immunosenescence. Overall, immunosenescence is characterized by reduction of immune response, an increase in inflammatory and oxidation background (inflamm-aging), and production of autoantibodies. One of the most prominent age-related changes in the adaptive immune system is the decline in regenerative thymic capacity. Similar aging related defects have also been observed in stroma of the bone marrow. While lymphocytes in infants show a naive phenotype, memory phenotype predominates after midlife. Though immune responses against recall antigens may still be conserved, the ability to mount primary response against novel antigens declines with age. As a result, increased susceptibility to infections, and suboptimal vaccine response is observed in the elderly. Apart from functional alternation in immune cells, there is a low-grade persistent elevation in inflammatory molecules. Inflamm-aging may result from the accumulation of misfold proteins, compromised gut barrier function, chronic infection, obesity, etc. Furthermore, aging is associated with immune dysregulation, with defective resolution of immune response after activation, and impaired clearance of dead cells with sustained inflammation. Excessive inflammation not only impairs antigen specific immunity, but also leads to tissue damage. In fact, this may partly account for the increased mortality of COVID infection in the elderly. Apart from vulnerability to infection and weakened vaccine response, immunosenescence also plays an important role in cancer and autoimmunity in the elderly. Because of increased tissue damage and apoptosis, coupled with inflamm-aging, increased autoantibodies production is observed in the elderly. Nevertheless, there is an age-related increase in peripheral regulatory T cells. While there is an increase in autoimmunity with aging, this does not always translate into an increase in autoimmune disease. On the other hand, the increase in regulatory T cells, along with other immunosuppressive cells and the senescence associated proinflammatory environment, promotes tumor development and progression in the elderly. As immunosenescence has a significant impact on health and disease, better understanding on this process is crucial for research and development in the future geriatric health care.

Dermatomyositis: severe acute respiratory syndrome coronavirus 2, an initiator or a trigger?

Dermatomyositis is an immune-mediated inflammatory myopathy. In adults, the common triggering factors for its onset include viral infections, malignancy, and drugs. The clinical manifestation of these group of disorders may be cutaneous, neurological, pulmonary, or a combination of all. The cutaneous manifestations are helpful in the early clinical diagnosis. The detection of myositis-specific autoantibodies serves as specific biomarkers for the diagnosis and helps in predicting the prognosis. We are presenting two cases of dermatomyositis, temporally related to the severe acute respiratory syndrome coronavirus 2 infection and vaccination. Copyright © 2022 Journal of the Egyptian Women's Dermatologic Society.

Adult onset refractory nxp2 dermatomyositis following covid 19 infection

Background: Dermatomyositis is a type of systemic inflammatory autoimmune disorder characterised by muscle inflammation and skin rashes. We present a rare adult onset refractory Nxp2 dermatomyositis following COVID 19 infection Methods: 36-year- old male came with the complaints of: Redness of right eye, Easy fatgiuability ,dysphagia of 3 months duration * Patient had uncomplicated COVID-19 1 month prior to onset of present complaints * On examination he had anasarca proximal muscle weakness and muscle tenderness and had neck and pharyngeal muscle weakness dysphagia and nasal regurgitation.He also had malar rash and periribital rash and swelling (Figure 1) * Investigations revealed biochemical radiological and Electrophysiological evidence of myositis (Table 1) * He was managed with pulse sterids ivig rituximab and tacrolimus with gradual but definite resolution Conclusion(s): Auto-antibodies against NXP2 are detected in 15% to 25% cases of Juvenile dermatomyositis and in only 1% of adult cases. This form of DM is characterized by accompanying calcinosis and severe and chronic disease course and is often carcinoma-associated (breast, uterine or pancreatic carcinoma). Post COVID NXP2 DM has not yet been reported. (Figure Presented).

An unusual presentation of malignant Invasive Mucinous Adenocarcinoma of Lung mimicking Pulmonary Renal syndrome

Background: A 54-year- old male presented to our centre with a chronic non-productive cough and breathlessness. Recent history of COVID treated and resolved few months back. He had a history of brain surgery performed five years back but details not known. Physical examination revealed no oedema and bilateral coarse creps with bronchiolar breathing. Laboratory findings indicated neutrophilic leucocytosis, elevated inflammatory markers, with elevated troponin I and D dimers. Urine analysis suggested microscopic haematuria with sediments. While 24 hour quantification revealed sub nephrotic proteinuria. As auto immune workup and vasculitis profile was negative and patient has not improved in spite of standard of therapy hence we went ahead with CT-Chest indicating ground-glass opacities in bilateral lung parenchyma and prominent interlobular/intralobular septal thickening. Then Bronchoscopy done which revealed the blood-stained secretions in the main stem bronchi and diffuse alveolar haemorrhage in bilateral bronchial segments indicating an inflammatory study, while tuberculosis diagnostic panel and infective bio fire panel in BAL was negative. Meanwhile, his repeat BAL culture suggested Carbapenem resistant Acinetobacter baumannii complex infection. As the patient did not respond to the standard of care for vasculitis. Probability considered was a small vessel vasculitis (namely Granulomatous polyangiitis) was considered due to lung manifestation involving upper respiratory tract with epistaxis, neutrophilic leucocytosis, elevated acute reactive protein, and renal manifestation including microscopic haematuria and proteinuria. However he responded poorly to conventional standard of treatment including pulse steroids and IVIG. Hence after MDT discussion we proceeded with lung biopsy which showed linear cores of lung tissue infiltrated by a malignant neoplasm and acinar pattern suggesting Invasive mucinous adenocarcinoma. Hence we went ahead with the biopsy diagnosis for the treatment plan. As he was to be started on chemotherapy, but he suddenly collapsed and went into hypotension, bradycardia, and cardiac arrest. In spite of high supports and post 4 cycles of CPR, was unable to revive and sadly succumbed to his illness. Discussion(s): In this rare case, the original diagnosis pointed to the pulmonary-renal syndrome, an autoimmune disease characterized by diffuse pulmonary haemorrhage and glomerulonephritis. However, negative autoimmune antibodies and vasculitis profile along with lung biopsy results indicated an unusual case of malignant lung adenocarcinoma presented with pulmonary renal syndrome. Conclusion(s): In cases suggesting pulmonary-renal syndromes, if autoimmune work up is negative and response is suboptimal relook the diagnosis.

A Series of Catastrophic Events

Case report - Introduction: Catastrophic antiphospholipid syndrome (CAPS) is a rare, life-threatening disease occurring in up to 1% of antiphospholipid syndrome (APS) cases. It was first defined in 1992 and remains a difficult to treat entity with a mortality rate of 37%. We describe a patient with systemic lupus erythematosus (SLE) and CAPS presenting with simultaneous multi-organ injuries who was successfully managed with 'triple' therapy including cyclophosphamide. Case report - Case description: A 42-year-old female presented to her local hospital with chest pain and worsening vision. She had a background of SLE, triple antibody-positive APS (previous DVT, pregnancy loss and strokes), hypertension, a metallic mitral valve, a previous myocardial infarction and pre-existing visual impairment due to a prior intra-cerebral bleed related to anticoagulation. Examination revealed a faint malar rash, cortical blindness and long tract neurological signs. Her ECG showed ischaemic changes and the admission troponin was significantly raised (3773ng/L). An echocardiogram showed new left ventricular dysfunction and a subsequent cardiac MRI was in keeping with coronary artery disease. Investigations showed an acute kidney injury, newly deranged liver function tests and a raised INR (>11, with no bleeding). Complement was normal with a low dsDNA titre. Urinalysis revealed proteinuria and a protein creatinine ratio measured 176mg/mmol. MRI diffusion weighted brain imaging showed acute bilateral occipital and left fronto-parietal infarcts. She had symptoms of a lupus flare with arthralgia and a butterfly facial rash. COVID-19 PCR tests were negative and she had not been recently vaccinated. She was diagnosed with CAPS and transferred to St Thomas' hospital intensive care. On arrival, she received 1mg intravenous vitamin K followed by triple therapy for CAPS: an unfractionated heparin infusion, oral prednisolone 40mg daily, 5 days of plasma exchange and, given her background of SLE, she was treated with intravenous cyclophosphamide (according to the EUROLUPUS regimen). Intravenous methylprednisolone was avoided due to a previous hypertensive encephalopathy reaction. She responded rapidly. Her troponin fell from a peak of 5054 to 294ng/ L, her creatinine settled at a new baseline (232umol/L) and her liver function normalised. She was switched back to warfarin due to her metallic valve and started on aspirin for cardiovascular secondary prevention. She required physical and occupational therapy due to her strokes but recovered well. Case report - Discussion: According to the 2003 criteria, CAPS can be classified as definite when there is evidence of: -3 organs involved, development of manifestations simultaneously or within a week, confirmation by imaging and/or histopathology of small vessel occlusion and positive antiphospholipid antibodies. Probable CAPS is when 3 out of the 4 criteria are present. In this case, three organs were confirmed to be involved with imaging showing cerebral and cardiac ischaemia. Her creatinine rose from a base of 190 to 289umol/L coupled with a high protein creatinine ratio confirming renal involvement. A Budd-Chiari syndrome was also suspected due to deranged liver function tests and INR, though imaging performed after therapy did not confirm this. A biopsy of any of these four organs was not feasible given the severity of her presentation and coagulopathy. There are no randomised controlled trials but data from the CAPS registry guides treatment and management follows a logical approach: anticoagulation to treat thrombosis, glucocorticoids for inflammation and plasma exchange (or IVIG) to remove the circulating autoantibodies. Triple therapy was associated with a reduced mortality compared to no treatment (28.6% versus 75%, respectively). Following analyses from the CAPS registry we also chose to treat with cyclophosphamide, which is associated with improved survival in patients with SLE. This decision was based on the clinical features of an SLE flare as opposed to serological grounds. There have b en reports of rituximab and eculizumab being used successfully in CAPS, though generally as a last resort. As complement activation is seen in animal models of antiphospholipid syndrome thrombosis and rituximab is often used in refractory SLE, they may prove to be promising agents for refractory CAPS. Case report - Key learning points: 1. Prompt recognition and early treatment is vital in managing CAPS 2. Triple therapy with anticoagulation, glucocorticoids and plasma exchange / IVIG is associated with better survival in CAPS 3. Cyclophosphamide is associated with better survival in patients with CAPS and concomitant SLE.

Finding an Answer for an Adolescent with Back Pain

Case report - Introduction: This is the case of an adolescent referred to rheumatology following 5 years of back pain. After years of trying a number of treatments without much success, the cause was found to be a previously undiagnosed urological pathology. The case highlights awareness of non-rheumatological causes and incidental findings which can redirect a patient towards more appropriate treatment and reduce the potential for long-term adverse health issues and anxiety. Case report - Case description: B was referred age 16 to rheumatology with a 5-year history of lower back pain. She had previously seen paediatricians with symptoms initially attributed to constipation due to intermittent straining and hard stool. However, constipation remedies had not relieved the pain which progressed gradually to a more persistent dull ache with impact on daily activities. Various analgesics (including paracetamol and non-steroidal anti-inflammatories), exercises and acupuncture had not helped. There was no history of recurrent urinary tract infections or symptom correlation with fluid intake, menstruation or bowel habit. No inflammatory features or connective tissue disease symptoms were noted and family history was unremarkable Clinical examination was normal apart from mild tenderness in the lumbar region. Rheumatoid factor was borderline positive (15 iu/mL) with the rest of blood tests normal including renal function, inflammatory markers (CRP, ESR), anti CCP and ANA. She had minimal microscopic haematuria without proteinuria. MRI spine in 2015 was normal. In view of her young age and symptoms affecting daily activities, STIR sequence spinal MRI was requested. This excluded any new or old inflammatory changes but incidentally identified a dilated left pelvi-calyceal system. Renal ultrasound confirmed a grossly hydronephrotic left kidney with hydroureter and minimal renal tissue suggesting longstanding obstruction. No calculi were seen. The patient was referred to urologists. Further investigations (including MRI abdomen) confirmed similar findings and a distal ureteric stricture. A MAG 3 renogram showed a normal right kidney but only 12% functioning of the left kidney. Urologists have advised surgery (removal of left kidney and ureter) which may relieve symptoms or a conservative non-surgical approach (continue analgesia, physiotherapy and monitoring). The patient and her family are relieved to have a possible cause identified and are considering the surgical option due to ongoing flank discomfort. Case report - Discussion: This was an interesting finding of hydroureter and hydronephrosis causing longstanding back pain presenting to rheumatologists. Until completion of the spondyloarthropathy protocol MRI (STIR images), aetiology had been unclear. Hydronephrosis and hydroureter has no specific age or racial predilection. Signs and symptoms may depend on whether obstruction is acute/chronic. Chronic cases may be asymptomatic or present as a dull discomfort (like this case). Some cases may only present in adulthood with pain precipitated by fluid intake. Blood tests may show impaired kidney function. Post-mortem studies suggest 50% of people have at least one renal abnormality (e.g., renal cysts, duplex ureters) with autopsy series incidence of hydronephrosis reported as 3.1%. Causes include anatomical abnormalities such as vesico-ureteric reflux, urethral strictures (usually present in childhood), calculi, benign prostatic hyperplasia, or intrapelvic neoplasms, pregnancy and infections (e.g., TB). Sudden onset unilateral renomegaly was reported in one case of primary Sjogren's with lymphocytic interstitial nephritis and positive Sjogren's autoantibodies. Our patient has no clinical or serological evidence of connective tissue disease. Minor pelvi-calyceal distension can occur as a normal finding in wellhydrated patients and pregnancy. However, significant hydronephrosis requires assessment to determine cause as it may affect long term renal function. Imaging via computed tomography, ultrasound and urograms can help guide further management. In this case the preceding cause and duration of pathology is unknown. Sterile, giant hydronephrosis treatment options include observation and ureteric stent or nephrostomy in patients unfit for surgery. Nephrectomy is advised for pain and recurrent infection in a non-functioning kidney. Complications may include bowel perforation, vascular injury and urine leakage. Both open and minimally invasive procedures have good reported outcomes. The COVID-19 pandemic and exams have affected timing of any elective procedures and the patient understands surgery may or may not offer complete symptom resolution. Case report - Key learning points: . Non-inflammatory causes of back pain should always be considered in cases of persistent back pain, particularly in young people to ascertain if there is a treatable cause . Hydronephrosis cases can be asymptomatic or present with vague, intermittent, non-specific abdominal symptoms with normal physical examination with or without haematuria. This can cause diagnostic uncertainty and delay referral to urology and appropriate renal investigations . Assessment of renal function (including MAG 3 renogram) is important to guide further management . Surgical interventions (pyeloplasty/nephrectomy) may ease symptoms long term but there is no guarantee of a successful outcome and operative risks need to be considered too . Left undiagnosed, potentially this patient could have had further disruption to daily activities and both physical and mental well being.

IgG autoantibodies against ACE2 in SARS-CoV-2 infected patients.

How frequently autoantibodies against angiotensin-converting enzyme 2 (ACE2) occur in patients infected by SARS-CoV-2 is understudied and limited to investigations on a small sample size. The presence of these antibodies may contribute to the long-lasting effects of COVID-19 observed in some individuals, particularly if IgG-class antibodies would emerge in patients. This study assessed the prevalence of IgG autoantibodies against ACE2 in 1139 patients infected with SARS-CoV-2 and examined their relationship with severity, demographic characteristics, and status of vaccination against influenza. The overall prevalence of anti-ACE IgG antibodies in our cohort was 1.5%. Most of these individuals were men (76.5%) and underwent mild COVID-19, but some severe and asymptomatic cases were also observed. Patients with severe infection had twofold higher titers than mild and asymptomatic cases. Age, comorbidities, and influenza vaccination status were not related to antibody prevalence. The prevalence of IgG anti-SARS-CoV-2 antibodies (against nucleocapsid protein and S2 subunit, but not against receptor-binding domain) was higher in the subset with ACE2 autoantibodies. Further research is required to understand the potential spectrum and duration of effects of IgG autoantibodies against ACE2 in patients after SARS-CoV-2 infection, particularly concerning long COVID-19.

COVID-19: A trigger of autoimmune diseases.

The SARS-coronavirus-2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19), has spread worldwide and caused a global health emergency. SARS-CoV-2 is a coronaviridae virus that infects target cells by interacting with the plasma membrane-expressed angiotensin-converting enzyme 2 (ACE2) via the S1 component of the S protein. Effective host immune response to SARS-CoV-2 infection, which includes both innate and adaptive immunity, is critical for virus management and elimination. The intensity and outcome of COVID-19 may be related to an overabundance of pro-inflammatory cytokines, which results in a "cytokine storm" and acute respiratory distress syndrome. After SARS-CoV-2 infection, the immune system's hyperactivity and production of autoantibodies may result in autoimmune diseases such as autoimmune hemolytic anemia, autoimmune thrombocytopenia, Guillain-Barré syndrome, vasculitis, multiple sclerosis, pro-thrombotic state, and diffuse coagulopathy, as well as certain autoinflammatory conditions such as Kawasaki disease in children. We have reviewed the association between COVID-19 and autoimmune disorders in this article.

Is COVID-19 severity unrelated to antinuclear antibodies?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces an overreaction of the immune system, resulting in the production of auto-antibodies. Several studies have reported that autoantibodies are prevalent in COVID-19 patients. In our study, antinuclear antibodies were evaluated in patients with COVID-19. We examined 131 sera from patients (>17-year-old) with confirmed COVID-19. Samples were collected prior to receiving any medication and antinuclear antibodies (ANA) levels were measured by the indirect immunofluorescence (IIF) method. Furthermore, the immunoblotting test was used to determine the presence of anti-nuclear antigen antibodies. The IIF-ANA test was positive in 36.4% (48/131) of patients. Overall, non-ICU patients had higher IIF-ANA titers than ICU patients. In particular, ICU patients had fewer nuclear, cytoplasmic, and mitotic IIF-ANA antibodies than non-ICU patients. In conclusion, COVID-19 patients frequently have ANA possibly reflecting the immune dysregulation due to several damaged cells by SARS-CoV-2 virus.

EFFECT OF COVID-19 VACCINATION ON THE IMMUNE STATUS AND AUTOANTIBODY PROFILE IN WOMEN OF REPRODUCTIVE AGE

In the context of the COVID-19 pandemic, scientific interest is growing in studying the impact of the proposed vaccination on women's reproductive health. As is known, alterations in the state of the immune system and activation of an autoimmune response can lead to reproductive failure in women and potential complications of subsequent pregnancy. Objective: to evaluate the effect of the "Gam-COVID-Vac” on the immune status parameters, the relationship of their changes and the specific immune response to vaccination with the dynamics of the level of autoantibodies in women of reproductive age. The prospective study included 120 women who were vaccinated against COVID-19 with the "Gam-COVID-Vac”. The criteria for inclusion in the study were: the age from 18 to 49 years, the absence of COVID-19 in the anamnesis, a negative result of a study on SARS-CoV-2 by PCR and negative results of tests for antibodies of classes G and M to SARS-CoV-2 before vaccination, the absence of pregnancy and serious somatic diseases. The patients were examined twice: immediately before vaccination and 90-100 days after the introduction of the 1st component of the vaccine. The level of IgG antibodies to SARS-CoV-2 after vaccination was assessed using ELISA. Before and after vaccination, the levels of antiphospholipid, anti-nuclear, organ-specific and antihormonal autoantibodies were determined, peripheral blood lymphocytes were immunophenotyped to determine the main subpopulations (CD3, CD4, CD8, CD19, CD5, CD16, CD56), as well as the expression of activation markers of lymphocytes (HLA-DR, CD25, CD147) using monoclonal antibodies. The effectiveness and safety of the combined vector vaccine against COVID-19 were high. Specific IgG antibodies to SARS-CoV-2 were produced in 98.3% of vaccinated women, no serious adverse reactions were observed. After vaccination, there was an increase in the level of some autoantibodies within the reference ranges, only IgM antibodies to phosphatidylethanolamine (PE) and IgG antibodies to DNA increased above the reference values. However, this increase was transient. After vaccination, the following changes in the parameters of the immunogram were observed: an increase in the content of cells with CD3+CD25+, CD19+ phenotype in peripheral blood and a decrease in the content of cells with CD56+CD16+ phenotype within the reference ranges, a decrease in CD147+/CD3+. Weak correlations were noted between these changes in immunogram parameters and the levels of some autoantibodies. The specific antiviral immune response to vaccination did not correlate with the autoimmune response. Vaccination with "Gam-COVID-Vac” is effective and safe and does not lead to disorders in the immune system. The observed increase in the level of autoantibodies to PE and DNA is transient. Changes in the parameters of the immune status within the reference ranges may be due to vaccination and the development of a specific antiviral immune response. © 2022, SPb RAACI.

Association of cerebrospinal fluid brain-binding autoantibodies with cognitive impairment in post-COVID-19 syndrome.

BACKGROUND: Neurological symptoms, in particular cognitive deficits, are common in post-COVID-19 syndrome (PCS). There is no approved therapy available, and the underlying disease mechanisms are largely unknown. Besides others, autoimmune processes may play a key role. DESIGN: We here present data of a prospective study conducted between September 2020 and December 2021 and performed at two German University hospitals with specialized Neurology outpatient clinics. Fifty patients with self-reported cognitive deficits as main complaint of PCS and available serum and CSF samples were included. Cell-based assays and indirect immunofluorescence on murine brain sections were used to detect autoantibodies against intracellular and surface antigens in serum and CSF and analyzed for associations with cognitive screening assessment. RESULTS: Clearly abnormal cognitive status (MoCA ≤ 25/30 points) was only seen in 18/50 patients with self-reported cognitive deficits. Most patients (46/50) had normal routine CSF parameters. anti-neuronal autoantibodies were found in 52 % of all patients: n = 9 in serum only, n = 3 in CSF only and n = 14 in both, including those against myelin, Yo, Ma2/Ta, GAD65 and NMDA receptor, but also a variety of undetermined epitopes on brain sections. These included cerebral vessel endothelium, Purkinje neurons, granule cells, axon initial segments, astrocytic proteins and neuropil of basal ganglia or hippocampus as well as a formerly unknown perinuclear rim pattern. Pathological MoCA results were associated with the presence of anti-neuronal antibodies in CSF (p = 0.0004). CONCLUSIONS: Autoantibodies targeting brain epitopes are common in PCS patients and strongly associate with pathological cognitive screening tests, in particular when found in CSF. Several underlying autoantigens still await experimental identification. Further research is needed to inform on the clinical relevance of these autoantibodies, including controlled studies that explore the potential efficacy of antibody-depleting immunotherapy in PCS.

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.

Partners in crime: Autoantibodies complicit in COVID-19 pathogenesis.

Autoantibodies (AABs) play a critical role in the pathogenesis of autoimmune diseases (AIDs) and serve as a diagnostic and prognostic tool in assessing these complex disorders. Viral infections have long been recognized as a principal environmental factor affecting the production of AABs and the development of autoimmunity. COVID-19 has primarily been considered a hyperinflammatory syndrome triggered by a cytokine storm. In the following, the role of maladaptive B cell response and AABs became more apparent in COVID-19 pathogenesis. The current review will primarily focus on the role of extrafollicular B cell response, Toll-like receptor-7 (TLR-7) activation, and neutrophil extracellular traps (NETs) formation in the development of AABs following SARS-CoV-2 infection. In the following, this review will clarify how these AABs dysregulate immune response to SARS-CoV-2 by disrupting cytokine function and triggering neutrophil hyper-reactivity. Finally, the pathologic effects of these AABs will be further described in COVID-19 associate clinical manifestations, including venous and arterial thrombosis, a multisystem inflammatory syndrome in children (MIS-C), acute respiratory distress syndrome (ARDS), and recently described post-acute sequelae of COVID-19 (PASC) or long-COVID.

NFKB2 haploinsufficiency identified via screening for IFN-α2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2-related complications.

BACKGROUND: Autoantibodies against type I IFNs occur in approximately 10% of adults with life-threatening coronavirus disease 2019 (COVID-19). The frequency of anti-IFN autoantibodies in children with severe sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is unknown. OBJECTIVE: We quantified anti-type I IFN autoantibodies in a multicenter cohort of children with severe COVID-19, multisystem inflammatory syndrome in children (MIS-C), and mild SARS-CoV-2 infections. METHODS: Circulating anti-IFN-α2 antibodies were measured by a radioligand binding assay. Whole-exome sequencing, RNA sequencing, and functional studies of peripheral blood mononuclear cells were used to study any patients with levels of anti-IFN-α2 autoantibodies exceeding the assay's positive control. RESULTS: Among 168 patients with severe COVID-19, 199 with MIS-C, and 45 with mild SARS-CoV-2 infections, only 1 had high levels of anti-IFN-α2 antibodies. Anti-IFN-α2 autoantibodies were not detected in patients treated with intravenous immunoglobulin before sample collection. Whole-exome sequencing identified a missense variant in the ankyrin domain of NFKB2, encoding the p100 subunit of nuclear factor kappa-light-chain enhancer of activated B cells, aka NF-κB, essential for noncanonical NF-κB signaling. The patient's peripheral blood mononuclear cells exhibited impaired cleavage of p100 characteristic of NFKB2 haploinsufficiency, an inborn error of immunity with a high prevalence of autoimmunity. CONCLUSIONS: High levels of anti-IFN-α2 autoantibodies in children and adolescents with MIS-C, severe COVID-19, and mild SARS-CoV-2 infections are rare but can occur in patients with inborn errors of immunity.