Clinical and diagnostic features of long-COVID patients presenting with neurologic symptoms in Chicago.

Long COVID, a condition characterized by persistent symptoms after COVID-19 infection, is increasingly being recognized worldwide. Neurologic symptoms are frequently reported in survivors of COVID-19, making it crucial to better understand this phenomenon both on a societal scale and for the quality of life of these patients. Between January 1, 2020, and July 31, 2022, Illinois (IL) had a standardized cumulative death rate that ranked it 24th out of the 51 states in the United States (US). However, the US had one of the highest per capita COVID-19 death rates among large, high-income countries. [Bollyky T. et al. 2023] As a result of the increased number of COVID-19 infections, there was a rise in the number of patients experiencing Long COVID. At our neuro-infectious disease clinic in Chicago (IL), we observed an increasing number of patients presenting with cognitive and other neurologic symptoms after contracting COVID-19. Initially, we needed to provide these individuals with a better understanding of their condition and expected outcomes. We were thus motivated to further evaluate this group of patients for any patterns in presentation, neurologic findings, and diagnostic testing that would help us better understand this phenomenon. We aim to contribute to the growing body of research on Long COVID, including its presentation, diagnostic testing results, and outcomes to enlighten the long COVID syndrome. We hypothesize that the neurological symptoms resulting from long COVID persist for over 12 months. We conducted a retrospective analysis of clinical data from 44 patients with long-COVID. Cognitive symptoms were the most common presenting concern. Abnormalities in Montreal Cognitive Assessment, electroencephalogram, serum autoantibody testing, and cerebrospinal fluid were found in minority subsets of our cohort. At 12 months, most patients continue to experience neurologic symptoms, though more than half reported moderate or marked improvement compared to initial presentation. Although most of the patients in this study did not show a consistent occurrence of symptoms suggesting a cohesive underlying etiology, our clinical data demonstrated some features of Long COVID patients in Chicago (IL) that could lead to new research avenues, helping us better understand this syndrome that affects patients worldwide.

Thyroid autoimmunity in different phenotypes of polycystic ovary syndrome: a single-center experience.

PURPOSE: Polycystic ovary syndrome (PCOS) has been associated with Hashimoto's thyroiditis (HT) and 4 phenotypes have been described in this syndrome. The aim of this work was to investigate the frequency of anti-thyroid antibodies (TAb) and thyroid function in the 4 phenotypes of PCOS. PATIENTS: This study included 448 patients with PCOS: 260 (58.0%) with phenotype A, 119 (26.6%) with phenotype B, 38 (8.5%) with phenotype C and 31 (6.9%) with phenotype D. RESULTS: TAb positivity was detected in 90/448 patients (20.1%) and was statistically significant higher (p = 0.03) in the grouped phenotypes A-B (83/379, 21.9%) than in phenotypes C-D (7/69, 10.1%). Positive anti-thyroglobulin antibodies (TgAb) were detected in 74/448 (16.5%) patients and positive anti-thyroperoxidase antibodies (TPOAb) in 66/448 (14.7%) patients. Both TgAb and TPOAb positivity was higher but not statistically significant in phenotype A-B than phenotype C-D. High titer TgAb (> 100 UI/ml) frequency was significantly higher (p = 0.005) in grouped phenotypes A-B (39/379, 10.3%) than in phenotypes C-D (0/69, 0.0%), while no significant difference was observed for low titer TgAb (≤ 100 UI/ml). According to a binary logistic regression analysis hypothyroidism was significantly associated with TAb positivity (OR 4.19; CI 2.25-7.79; p < 0.01) but not with PCOS phenotype. Androgen profile was not associated with TAb positivity. CONCLUSION: A higher frequency of positive TAb and of high titer TgAb and TPOAb have been detected in PCOS women with phenotypes A and B, probably in relation to the greater imbalances between estrogen and progesterone levels present in these phenotypes.

Autoantigen Exposure in Murine Fetuses Elicited Nonpathogenic Autoimmunity.

BACKGROUND AND AIM: Autoimmunity refers to the presence of autoantibodies and autoreactive lymphocytes against the structural molecules of an individual's cells or tissues, known as self-antigens or autoantigens. It might exist in the absence of autoimmune disease. However, how autoimmunity develops remains a mystery, despite the discovery of autoantibodies in human cord blood. METHODS: Murine fetuses on day 14 of gestation were subjected to intraperitoneal injection of murine thyroid peroxidase (TPO) peptides or collagen type II (CII) at graded doses via transuterine approach. Postnatally, the recipients were examined for autoantibodies by ELISA and autoreactive lymphocytes by in vitro incorporation of tritium and for the development of autoimmune thyroiditis or arthritis. RESULTS: At one month of age, the recipients did not secrete significant levels of anti-TPO or CII IgG2a in sera until a dose of 0.5 µg TPO or 5.0 µg CII was injected in utero. Serum anti-TPO or CII IgG2a persisted for at least two to four months postnatally. In recipients with elevated autoantibodies, their lymphocytes also showed proliferative responses specifically to TPO or CII. However, the development of autoantibodies and autoreactive lymphocytes was not associated with inflammatory cell infiltration of thyroid glands or paw joints even though anti-TPO or CII IgG2a was enhanced by postnatal TPO or CII challenge. CONCLUSION: Fetal exposure to free autoantigens could be immunogenic, shedding new light on the in utero origin of autoantibodies and autoreactive lymphocytes. The development of autoimmunity requires a threshold intensity of autoantigen exposure in the fetus.

Two Decades of Publications in Journals Dedicated to Autoimmunity: A Bibliometric Analysis of the Autoimmunity Field from 2004 to 2023.

To carry out an in-depth analysis of the scientific research on autoimmunity, we performed the first bibliometric analysis focusing on publications in journals dedicated to autoimmunity (JDTA) indexed by science citation index during the period 2004-2023. Using bibliometric analysis, we quantitatively and qualitatively analyzed the country, institution, author, reference and keywords information of publications in JDTA, so as to understand the quantity, publication pattern and publication characteristics of these publications. The co-occurrence networks, clustering map and timeline map were created by CiteSpace and VOSviewer software to visualize the results. The CiteSpace was also used to analyze the strongest citation burst of keywords, which could describe the frequency, intensity and time period of high-frequency keywords, and indicate the research hotspots in the field. A total of 5 710 publications were analyzed, and their annual distribution number was basically stable from 2004 to 2023, fluctuating around 300. The United States and Italy led the way in terms of the number of publications, followed by France and China. For international cooperation, the developed countries represented by the United States cooperate more closely, but the cooperation was localized, reflecting that there was no unified model of autoimmunity among countries. UDICE-French Research Universities had the greatest number of publications. Subsequently, the number of publications decreased slowly with the ranking, and the gradient was not large. Eric Gershwin and Yehuda Shoenfeld stood out among the authors. They had an excellent academic reputation and great influence in the field of autoimmunity. The results of keyword analysis showed that JDTA publications mainly studied a variety of autoimmune diseases, especially SLE and RA. At the same time, JDTA publications also paid special attention to the research of cell function, autoantibody expression, animal experiments, disease activity, pathogenesis and treatment. This study is the first to analyze the publications in JDTA from multiple indicators by bibliometrics, thus providing new insights into the research hotspots and development trends in the field of autoimmunity.

Transcriptomic signatures of classical monocytes reveal pro-inflammatory modules and heterogeneity in polyarticular juvenile idiopathic arthritis.

Introduction: Polyarticular juvenile idiopathic arthritis (pJIA) is a childhood-onset autoimmune disease. Immune cells contribute to persistent inflammation observed in pJIA. Despite the crucial role of monocytes in arthritis, the precise involvement of classical monocytes in the pathogenesis of pJIA remains uncertain. Here, we aimed to uncover the transcriptomic patterns of classical monocytes in pJIA, focusing on their involvement in disease mechanism and heterogeneity. Methods: A total of 17 healthy subjects and 18 premenopausal women with pJIA according to ILAR criteria were included. Classical monocytes were isolated, and RNA sequencing was performed. Differential expression analysis was used to compare pJIA patients and healthy control group. Differentially expressed genes (DEGs) were identified, and gene set enrichment analysis (GSEA) was performed. Using unsupervised learning approach, patients were clustered in two groups based on their similarities at transcriptomic level. Subsequently, these clusters underwent a comparative analysis to reveal differences at the transcriptomic level. Results: We identified 440 DEGs in pJIA patients of which 360 were upregulated and 80 downregulated. GSEA highlighted TNF-α and IFN-γ response. Importantly, this analysis not only detected genes targeted by pJIA therapy but also identified new modulators of immuno-inflammation. PLAUR, IL1B, IL6, CDKN1A, PIM1, and ICAM1 were pointed as drivers of chronic hyperinflammation. Unsupervised learning approach revealed two clusters within pJIA, each exhibiting varying inflammation levels. Conclusion: These findings indicate the pivotal role of immuno-inflammation driven by classical monocytes in pJIA and reveals the existence of two subclusters within pJIA, regardless the positivity of rheumatoid factor and anti-CCP, paving the way to precision medicine.

Elevated serum levels of anti-collagen type I antibodies in patients with spontaneous cervical artery dissection and ischemic stroke: a prospective multicenter study.

Introduction: Spontaneous cervical artery dissection (sCAD) is a rare vasculopathy whose trigger is still unknown. We hypothesized that autoimmunity against components of the vascular wall might play a critical role in sCAD and examined anti-collagen type I antibodies in patients with sCAD, acute ischemic stroke, patients with thromboendarterectomy, and controls. Methods: Fifty-seven patients with sCAD (age 45.7 ± 10.2 years, female 18 (31.6%)) were prospectively enrolled in four German stroke centers. Blood samples were collected at baseline, at day 10 ± 3, and after 6 ± 1 months. Patients with ischemic stroke not related to CAD (n=54, age 56.7 ± 13.7 years, female 15 (27.8%)), healthy probands (n=80, age 57.4 ± 12.9 years, female 56 (70%)), and patients undergoing thromboendarterectomy of the carotid artery (n=9, age 70.7 ± 9.3 years, female 2 (22.2%)) served as controls. Anti-collagen type I antibodies were determined by enzyme-linked immunosorbent assays (ELISAs). Results: Patients with acute sCAD had higher serum levels of anti-collagen type I antibodies (33.9 ± 24.6 µg/ml) than probands (18.5 ± 11.0 µg/ml; p <0.001) but lower levels than patients with ischemic stroke not related to sCAD (47.8 ± 28.4 µg/ml; p=0.003). In patients with sCAD, serum levels of anti-collagen type I antibodies were similar in the acute, subacute, and chronic phase. Levels of anti-collagen type I antibodies significantly correlated with circulating collagen type I (rho=0.207, p=0.003). Conclusion: Anti-collagen type I antibodies seem not to represent a trigger for acute sCAD or ischemic stroke but may rather be linked to the metabolism and turnover of collagen type I.

Altered cytokine and chemokine profile linked to autoantibody and pathogen reactivity in mothers of autistic children.

Maternal autoimmunity, and more specifically, the production of specific maternal autoantibodies, has been associated with altered offspring neurodevelopment. Maternal autoantibody-related (MAR) autism is a subtype of autism that is linked to gestational exposure to certain combinations of autoantibodies to proteins known to be important for fetal neurodevelopment. We wanted to address whether mothers with autism-specific patterns of autoantibodies have a skewed cytokine and chemokine profile during an immune response to infection. To do so, we examined a subset of mothers from the Early Markers for Autism (EMA) study who either produced known patterns of MAR autoantibodies (MAR+) or did not (MAR-). We compared the cytokine/chemokine profiles of MAR+ and MAR- mothers in the context of positive immunoglobulin G (IgG) reactivity to several viral and parasitic agents. We observed that MAR+ mothers have a higher level of proinflammatory cytokine interferon-gamma regardless of IgG status. Additionally, when comparing MAR+ and MAR- mothers in the context of the different pathogens, MAR+ mothers consistently had increases in multiple proinflammatory cytokines and chemokines.

Bilastine in Refractory Chronic Spontaneous Urticaria: Disease Control and Cytokine Modulation in an Open-label Prospective Study.

Introduction: The treatment options for chronic spontaneous urticaria (CSU) primarily include second generation non-sedative antihistamine (SGAHs). Bilastine is a newer, nonsedating SGAH approved for urticaria in February 2019 by the Drugs Controller General of India. Its major advantages are in terms of superior efficacy, lack of drug interactions and adverse effects, including sedation, compared to conventional SGAHs. The role of cytokines in the pathogenesis of CSU is well known. However, there is a shortage of data regarding the change in serum levels of proinflammatory cytokines following H1 antihistamines. We conducted this trial to evaluate the role of bilastine in cytokine modulation and autoimmunity, thereby explaining its role in modifying the disease process in CSU. Materials and Methods: This prospective study was conducted in a tertiary institute in Kolkata on patients aged 12 years and above with a CSU >6 months. These patients had an unsatisfactory response, as per the Urticaria Activity Score 7 (UAS7), to previous antihistamine therapies in standard doses. Treatment effectiveness was determined by comparing the UAS7 at baseline with that at weeks 4, 8 and 12. Also, baseline serum interleukin-6 (IL-6) and IL-17 were compared with those at the end of the study, that is, 12 weeks. Results: Thirty patients who matched the inclusion criteria and signed informed consent were included in the study. At the end of 12 weeks, 10% of patients (n = 3) achieved a complete treatment response (UAS = 0), whereas 43.33% of patients (n = 13) were labelled as having well-controlled urticaria (UAS <6). At 12 weeks, the mean UAS7 score (6.47 ± 4.45) was statistically significant compared to the baseline score (25.47 ± 7.74). The mean values of serum IL-6 (pg/ml) and IL-17 (pg/ml) at baseline were 5.96 ± 5.24 pg/ml and 6.96 ± 5.97 pg/ml, respectively. At the end of treatment, that is, 3 months, the mean values were reduced to 4.61 ± 4.56 pg/ml and 5.08 ± 3.87 pg/ml. The reduction was statistically significant for both serum IL-6 (P < 0.001) and IL-17 (P < 0.0001). Conclusion: We conclude that bilastine at a once-daily continuous dose of 40 mg for 3 months is safe and effective in CSU patients who are refractory to treatment at the standard doses of SGAHs. Improved symptomatic control with bilastine was also associated with better control over the inflammatory process, as suggested by the lowering of mean cytokine levels in our study.

Serum Granulysin as a Possible Key Marker of Vitiligo Activity and Severity.

Background: Vitiligo is an immune-mediated, chronic skin condition that affects both the innate and adaptive immune systems. Antimicrobial peptide overexpression is one of its defining characteristics. Granulysin (GNLY), an antimicrobial peptide, may play a role in the pathogenesis of various autoimmune diseases. Objectives: To estimate the serum GNLY levels in vitiligo patients and to correlate those levels with the severity and activity of the disease. Materials and Methods: This case-control study included 60 non-segmental vitiligo patients (Group A) and a control group of 60 people who were matched for age and sex, appeared to be in good health, and were not suffering from vitiligo (Group B). The serum granulysin levels of all subjects were measured using an enzyme-linked immunosorbent assay. Results: When compared to the control group, vitiligo patients had significantly higher serum GNLY levels (P = 0.001). When compared to patients with stable disease, those with active vitiligo had significantly higher serum GNLY levels (P = 0.008). Additionally, there was a positive correlation between the serum GNLY levels and the vitiligo area severity index and vitiligo disease activity scores (P = 0.004 and <0.001, respectively). Limitations: Study population was relatively small. Evaluation of serum granulysin before and after treatment could have been more beneficial. Conclusions: Blood granulysin levels could contribute to the pathogenesis of vitiligo. A higher serum granulysin level may also be a trustworthy predictor of the severity and progression of a disease.

Factors associated with immune responses to SARS-CoV-2 vaccination in autoimmune disease individuals.

Patients with autoimmune diseases are at higher risk for severe infection due to their underlying disease and immunosuppressive treatments. In this real-world observational study of 463 autoimmune subjects, we examined risk factors for poor B and T cell responses to SARS-CoV-2 vaccination. We show a high frequency of inadequate anti-spike IgG responses to vaccination and boosting in the autoimmune population but minimal suppression of T cell responses. Low IgG responses in B cell-depleted multiple sclerosis (MS) subjects were associated with higher CD8 T cell responses. By contrast, subjects taking mycophenolate mofetil exhibited concordant suppression of B and T cell responses. Treatments with highest risk for low IgG anti-spike response included B cell depletion within the last year, fingolimod, and combination treatment with mycophenolate mofetil (MMF) and belimumab. Our data show that the mRNA-1273 (Moderna) vaccine, is the most effective vaccine in the autoimmune population. There was minimal induction of either disease flares or autoantibodies by vaccination and no significant effect of pre-existing anti-type I interferon antibodies on either vaccine response or breakthrough infections. The low frequency of breakthrough infections and lack of SARS-CoV-2-related deaths suggest that T cell immunity contributes to protection in autoimmune disease.

Exploring the relationship between infectious agents and autoimmune diseases: a review.

The relationship between infectious agents and autoimmune diseases is a complex issue. In recent years, increasing clinical cases have indicated that infectious agents play an important role in the development of autoimmune diseases. Molecular mimicry is currently widely regarded as the primary pathogenic mechanism of various autoimmune diseases in humans. Components of infectious agents can undergo molecular mimicry with components in patients' bodies, leading to the development of various autoimmune diseases. In this article, we provide a brief overview of current research of the current research status on the relationship between infectious agents and autoimmune diseases, and describe our current understanding of their mechanisms of action in order to better understand the pathogenesis, diagnosis, and treatment of autoimmune diseases.

Autoimmune Myocarditis, Old Dogs and New Tricks.

Autoimmunity significantly contributes to the pathogenesis of myocarditis, underscored by its increased frequency in autoimmune diseases such as systemic lupus erythematosus and polymyositis. Even in cases of myocarditis caused by viral infections, dysregulated immune responses contribute to pathogenesis. However, whether triggered by existing autoimmune conditions or viral infections, the precise antigens and immunologic pathways driving myocarditis remain incompletely understood. The emergence of myocarditis associated with immune checkpoint inhibitor therapy, commonly used for treating cancer, has afforded an opportunity to understand autoimmune mechanisms in myocarditis, with autoreactive T cells specific for cardiac myosin playing a pivotal role. Despite their self-antigen recognition, cardiac myosin-specific T cells can be present in healthy individuals due to bypassing the thymic selection stage. In recent studies, novel modalities in suppressing the activity of pathogenic T cells including cardiac myosin-specific T cells have proven effective in treating autoimmune myocarditis. This review offers an overview of the current understanding of heart antigens, autoantibodies, and immune cells as the autoimmune mechanisms underlying various forms of myocarditis, along with the latest updates on clinical management and prospects for future research.

Myasthenia Gravis-Like Syndrome Resulting From Immune Checkpoint Inhibitors in a Patient With Urothelial Carcinoma.

The widespread use of immune checkpoint inhibitors (ICIs) for the treatment of various types of cancer has led to increasing reports of associated adverse effects. The use of the ipilimumab/nivolumab/sacituzumab combination is currently under study in patients with metastatic urothelial carcinoma, given their potential synergism for immunogenic cell death. Information regarding the toxicity spectrum of this combination is lacking. Here, we describe a patient with urothelial carcinoma who had a severe multisystem autoimmune-like toxicity and myasthenia gravis-like syndrome in response to the ipilimumab/nivolumab/sacituzumab combination therapy. We also briefly describe the literature regarding the association between combined immunotherapy use and systemic and neurological autoimmunity.

RGC-32 mediates proinflammatory and profibrotic pathways in immune-mediated kidney disease.

Systemic lupus erythematosus is an autoimmune disease that results in immune-mediated damage to kidneys and other organs. We investigated the role of response gene to complement-32 (RGC-32), a proinflammatory and profibrotic mediator induced by TGFß and C5b-9, in nephrotoxic nephritis (NTN), an experimental model that mimics human lupus nephritis. Proteinuria, loss of renal function and kidney histopathology were attenuated in RGC-32 KO NTN mice. RGC-32 KO NTN mice displayed downregulation of the CCL20/CCR6 and CXCL9/CXCR3 ligand/receptor pairs resulting in decreased renal recruitment of IL-17+ and IFNγ+ cells and subsequent decrease in the influx of innate immune cells. RGC-32 deficiency attenuated renal fibrosis as demonstrated by decreased deposition of collagen I, III and fibronectin. Thus, RGC-32 is a unique mediator shared by the Th17 and Th1 dependent proinflammatory and profibrotic pathways and a potential novel therapeutic target in the treatment of immune complex mediated glomerulonephritis such as lupus nephritis.

IBPA a mutual prodrug of ibuprofen and acetaminophen alleviates inflammation, immune dysregulation and fibrosis in preclinical models of systemic sclerosis.

Systemic sclerosis (SSc) is a devastating autoimmune illness with a wide range of clinical symptoms, including vascular abnormalities, inflammation, and persistent and progressive fibrosis. The disease's complicated pathophysiology makes it difficult to develop effective therapies, necessitating research into novel therapeutic options. Molecular hybridization is a strategy that can be used to develop new drugs that act on two or multiple targets and represents an interesting option to be explored for the treatment of complex diseases. We aimed to evaluate the effects of a hybrid mutual prodrug of ibuprofen and acetaminophen (IBPA) in peripheral blood mononuclear cells (PBMC) isolated from SSc patients, and in an in vivo model of SSc induced in BALB/c mice by intradermal injections of hypochlorous acid (HOCl) for 6 weeks. The mice were treated at the same time with daily intraperitoneal injections of IBPA (40 mg/kg). Pulmonary and skin fibrosis as well as immune responses were evaluated. IBPA significantly decreased the release of cytokines in PBMC culture supernatants from SSc patients after stimulation with phytohemagglutinin-M (IL-2, IL-4, IL-6, IL-10, IL-13, IL-17A, TNF and IFN-γ).In HOCl-induced SSc, IBPA treatment prevented dermal and pulmonary fibrosis, in addition to reducing CD4 + T and B cells activation and reversing the M2 polarization of macrophages in spleen cells, and inhibiting IFN-γ secretion in splenocyte cultures. These results show the anti-inflammatory and antifibrotic effects of IBPA in SSc and highlight the therapeutic potential of this mutual prodrug, providing support for future studies.

Neutrophil glucose flux as a therapeutic target in antiphospholipid syndrome.

Neutrophil hyperactivity and neutrophil extracellular trap release (NETosis) appear to play important roles in the pathogenesis of the thromboinflammatory autoimmune disease known as antiphospholipid syndrome (APS). The understanding of neutrophil metabolism has advanced tremendously in the past decade, and accumulating evidence suggests that a variety of metabolic pathways guide neutrophil activities in health and disease. Our previous work characterizing the transcriptome of APS neutrophils revealed that genes related to glycolysis, glycogenolysis, and the pentose phosphate pathway (PPP) were significantly upregulated. Here, we found that APS patient neutrophils used glycolysis more avidly than healthy control neutrophils, especially when the neutrophils were from APS patients with a history of microvascular disease. In vitro, inhibiting either glycolysis or the PPP tempered phorbol myristate acetate- and APS IgG-induced NETosis, but not NETosis triggered by a calcium ionophore. In mice, inhibiting either glycolysis or the PPP reduced neutrophil reactive oxygen species production and suppressed APS IgG-induced NETosis ex vivo. When APS-associated thrombosis was evaluated in mice, inhibiting either glycolysis or the PPP markedly suppressed thrombosis and circulating NET remnants. In summary, these data identify a potential role for restraining neutrophil glucose flux in the treatment of APS.

Immunotherapy in a case of low titre GAD65 antibody-associated spectrum neurological disorders.

We present a rare case of low titre GAD65 antibody-associated autoimmune encephalitis and status epilepticus in a young woman. She initially presented with left arm dystonic movements, contractures and status epilepticus. Due to the concern of autoimmune encephalitis and seizures, the patient received intravenous immunoglobulin empirically. After the detection of low serum GAD65 antibodies, the patient underwent immunomodulation therapy with significant improvement. This case demonstrated that in autoimmune encephalitis, it is important to monitor serum GAD65 antibodies levels and consider immunotherapy, despite mildly elevated serum levels. The patient's history of left arm dystonic movements without impaired awareness may have been due to limb dystonia, a presenting symptom of stiff person syndrome (SPS), despite SPS more commonly affecting axial muscles. This case further demonstrates that GAD65 antibody-related syndromes can manifest with different neurological phenotypes including co-occurrence of epilepsy with possible focal SPS despite low GAD65 antibodies titres.

Infection episodes and islet autoantibodies in children at increased risk for type 1 diabetes before and during the COVID-19 pandemic.

OBJECTIVES: To determine the impact of the COVID-19 pandemic on the incidence rates of infection and islet autoimmunity in children at risk for type 1 diabetes. METHODS: 1050 children aged 4 to 7 months with an elevated genetic risk for type 1 diabetes were recruited from Germany, Poland, Sweden, Belgium and the UK. Reported infection episodes and islet autoantibody development were monitored until age 40 months from February 2018 to February 2023. RESULTS: The overall infection rate was 311 (95% Confidence Interval [CI], 304-318) per 100 person years. Infection rates differed by age, country, family history of type 1 diabetes, and period relative to the pandemic. Total infection rates were 321 per 100 person-years (95% CI 304-338) in the pre-pandemic period (until February 2020), 160 (95% CI 148-173) per 100 person-years in the first pandemic year (March 2020-February 2021; P < 0.001) and 337 (95% CI 315-363) per 100 person-years in subsequent years. Similar trends were observed for respiratory and gastrointestinal infections. Islet autoantibody incidence rates were 1.6 (95% CI 1.0-2.4) per 100 person-years in the pre-pandemic period, 1.2 (95% CI 0.8-1.9) per 100 person-years in the first pandemic year (P = 0.46), and 3.4 (95% CI 2.3-4.8) per 100 person-years in subsequent years (P = 0.005 vs. pre-pandemic year; P < 0.001 vs. first pandemic year). CONCLUSIONS: The COVID-19 pandemic was associated with significantly altered infection patterns. Islet autoantibody incidence rates increased two-fold when infection rates returned to pre-pandemic levels.

Innate acting memory Th1 cells modulate heterologous diseases.

Through immune memory, infections have a lasting effect on the host. While memory cells enable accelerated and enhanced responses upon rechallenge with the same pathogen, their impact on susceptibility to unrelated diseases is unclear. We identify a subset of memory T helper 1 (Th1) cells termed innate acting memory T (TIA) cells that originate from a viral infection and produce IFN-γ with innate kinetics upon heterologous challenge in vivo. Activation of memory TIA cells is induced in response to IL-12 in combination with IL-18 or IL-33 but is TCR independent. Rapid IFN-γ production by memory TIA cells is protective in subsequent heterologous challenge with the bacterial pathogen Legionella pneumophila. In contrast, antigen-independent reactivation of CD4+ memory TIA cells accelerates disease onset in an autoimmune model of multiple sclerosis. Our findings demonstrate that memory Th1 cells can acquire additional TCR-independent functionality to mount rapid, innate-like responses that modulate susceptibility to heterologous challenges.