BACKGROUND:Neutralizing autoantibodies against interleukin-10 can result in a phenocopy of monogenic defects of interleukin-10 signaling in children and may be associated with inflammatory bowel disease (IBD). The allele HLA-DRB1*01:03 is the strongest genetic risk factor for ulcerative colitis. METHODS:We used a cellular interleukin-10 reporter assay and a confirmatory competitive enzyme-linked immunosorbent assay to assess neutralizing interleukin-10 autoantibodies in serum samples obtained from patients with IBD in the Oxford and U.K. IBD BioResource cohorts and from persons without IBD (controls). An in vitro cytokine-release bioassay was performed in a subgroup of patients to assess interleukin-10, interleukin-23, interleukin-1β, tumor necrosis factor, and interleukin-6. We performed HLA association analysis using imputation and high-resolution sequencing. RESULTS:Interleukin-10-neutralizing autoantibodies were detected in 173 of 4909 patients with IBD (3.5%; 95% confidence interval [CI], 3.0 to 4.1) and in none of 1006 controls (P<0.001). High anti-interleukin-10 activity in serum was associated with a reduction in detectable interleukin-10 and with an exaggerated proinflammatory cytokine response, consistent with functional neutralization of interleukin-10 signaling. Anti-interleukin-10 seropositivity was strongly associated with HLA-DRB1*01:03 on the basis of imputed data from the Oxford cohort (odds ratio, 50.0; 95% CI, 16.4 to 152.3; P = 6.14×10-12) and the U.K. IBD BioResource cohort (odds ratio, 24.7; 95% CI, 14.5 to 42.1; P = 6.20×10-32) and in a high-resolution sequencing analysis of data from the Oxford cohort (odds ratio, 29.5; 95% CI, 12.2 to 71.1; P = 4.85×10-14). CONCLUSIONS:Neutralizing interleukin-10 autoantibodies were present in a subgroup of patients with IBD and were strongly associated with HLA-DRB1*01:03. (Funded by the National Institute for Health and Care Research and others.).

Outcomes following international MDT assessment of adult IEI patients for allogeneic HSCT suggest early referral is vital: patients considered too high risk for transplant have poor outcomes with a 3-year overall survival of 31%.

Background Anti-CD19 CAR T-cell therapies have been practice-changing in the management of refractory and relapsed (r/r) B-cell malignancies with encouraging long-term outcomes. However, 40-60% of patients relapse within 6 months of CAR T-cell infusion. Low or absent CD19 expression on tumour cells is a common cause of treatment failure following CD19-targeting CAR T-cell therapy. ALETA-001 is a first-in-class CAR T-cell engager protein developed as an off-the-shelf solution to address this issue. It contains a CD19 extracellular domain for engaging CD19-targeting CAR T-cells, an anti-CD20 VHH for binding to CD20 antigen on the B-cell surface and an anti-albumin VHH for half-life extension. ALETA-001 is designed to promote anti-tumour efficacy through enhanced antigen availability resulting in reactivation of anti-CD19 CAR T cells, redirecting them to the CD20 antigen on the tumour cell, thus circumventing low or absent CD19 expression and potentially allowing for dual targeting of both CD19 and CD20. Methods ALETA-001 is being evaluated in a multi-centre, open-label Phase I/II trial in patients with B-cell non-Hodgkin lymphoma (NHL) who have received standard of care anti-CD19 CAR T-cell therapy. A safety lead-in will determine safety and tolerability along with a recommended dose, timing and schedule of administration for a subsequent expansion phase (RP2D). The pharmacokinetic (PK) profile, clinical and pharmacodynamic (PD) activity of ALETA-001 are also being evaluated. Two time points are being investigated in the safety lead-in phase for commencement of ALETA-001:Delayed dosing cohort (cohort 1): For patients who are at least 4 weeks post CAR T-cell therapy and are either in less than a complete remission (CR) on PET scan at 4 weeks or have achieved an initial response but subsequently relapse with biopsy proven disease within 9 months.Early dosing cohort (cohort 2): In this cohort, ALETA-001 is administered to patients between 10 to 18 days post CAR T-cell therapy. In both cohorts, ALETA-001 is administered intravenously as a 2-hour infusion fortnightly (doses from 0.4mg/kg to 6mg/kg) until unacceptable toxicity, disease progression or for a total duration varying between 3-12 months depending on the cohort and response. Here we report initial results from our ongoing study in B-cell NHL. Results As of 9th July 2025, 10 patients with r/r large B-cell lymphoma (LBCL) have been enrolled into cohort 1 and received fortnightly infusions of ALETA-001. The interval between CAR T-cell therapy and first dose of ALETA-001 ranged from 46 to 158 days. Median number of infusions given was 3. In total, 57 treatment emergent adverse events have been recorded, 4 of which were considered serious including back pain, jejunal perforation (both CTCAE Grade 2) and clostridium difficile infection (CTCAE Grade 3), all not related to ALETA-001. The only serious adverse event (SAE) considered possibly related to ALETA-001 was cytokine release syndrome (ASTCT Grade 1). No Dose Limiting Toxicities have been observed. The observed PK profile is consistent with a molecule utilising albumin binding for half-life extension and ALETA-001 exposure remained above concentrations expected to have activity. CAR T-cell populations in peripheral blood showed robust expansion in 4/6 patients evaluated to date. Of 10 patients treated, one partial response and two complete responses have been recorded, including one patient who achieved CR from known lymphoma but developed progressive lesions on PET scan, subsequently confirmed to be metastatic prostate cancer on biopsy. The other two responding patients remain on study at the time of data cut off (36 and 12 weeks respectively). Both had biopsy proven r/r LBCL post CAR T-cell therapy at study enrolment. Updated data will be presented at the conference. Conclusions Preliminary data support a highly tolerable safety profile for ALETA-001 at all doses tested, with no ALETA-001-related SAEs greater than Grade 1 observed to date. In keeping with its mechanism of action, robust CAR T-cell expansion was observed in several treated patients. Preliminary efficacy data shows encouraging response in a proportion of patients treated 4 weeks or later after CAR T-cell therapy. ALETA-001 will continue to be evaluated at 10-18 days post CAR-T to explore safety PK, PD and efficacy at this earlier time point.

BACKGROUND:Chronic lymphocytic leukaemia is the commonest leukaemia and is associated with profound immunosuppression. Bruton tyrosine kinase inhibitors (BTKi) have revolutionised chronic lymphocytic leukaemia management; however, therapy impairs vaccine-induced immunity. We evaluated whether a 3-week pause of BTKi treatment improved spike protein receptor binding domain (RBD) immunity to SARS-CoV-2 booster vaccination while maintaining disease control. METHODS:We performed an open-label, two-arm, parallel-group, randomised trial in secondary-care haematology clinics in 11 UK hospitals. Participants aged 18 years or older, diagnosed with chronic lymphocytic leukaemia, and currently taking BTKi therapy (frontline or relapsed setting) for at least 12 months were eligible. Participants were randomly allocated (1:1, by a centralised computer randomisation program, stratified by BTKi therapy line) to pause BTKi for 3 weeks, starting 6 days before their SARS-CoV-2 vaccination booster date, or to continue therapy as usual. Neither participants nor clinical staff were blinded but laboratory staff were. Intramuscular injection of either original BA.1 or original BA.4/5 bivalent mRNA vaccine (50 μg mRNA-1273 or 30 μg BNT162b2), or 5 μg protein-based Vidprevtyn Beta (Sanofi Pasteur, Lyon, France) were received according to the national vaccination programme schedule. The primary outcome measure was anti-spike-RBD-specific antibody titre 3 weeks after vaccination and analysis performed by intention to treat (as randomly allocated, irrespective of compliance) following trial completion. This trial is registered with ISRCTN, 14197181, and has been completed. FINDINGS:Between Oct 10, 2022, and June 8, 2023, 99 individuals (71 [72%] male and 28 [28%] female, with 89 [90%] of White ethnicity) were randomly allocated to groups pausing (n=50 [51%]) or continuing (n=49 [49%]) their BTKi therapy, and followed up for 12 weeks. At 3 weeks after vaccination, the geometric mean anti-spike-RBD-specific antibody titre was 218·8 U/mL (SD 122·9) in the continue group and 153·4 U/mL (103·2) in the pause group, with geometric mean ratio 1·104 (95% CI 0·565-2·158, p=0·77) using a mixed-effects model. The only serious adverse event during the 12-week follow-up was the death of one participant in the pause group due to COVID-19 infection 2 months after randomisation. INTERPRETATION:Although the study was slightly underpowered, the results suggest that pausing BTKi around the time of vaccination is not beneficial for immunity and should not be recommended in clinical practice. FUNDING:National Institute for Health and Care Research.

B-cell maturation antigen (BCMA) is a B cell surface receptor that regulates B cell activation, proliferation and survival. BCMA can be cleaved from the cell surface, producing soluble BCMA (sBCMA), which has been studied as a disease biomarker in systemic lupus erythematosus, multiple sclerosis and multiple myeloma. Reduced sBCMA concentrations have been associated with the severity of different primary antibody deficiencies. We explored the relationship between sBCMA concentrations, humoral immune responses to SARS-CoV-2 vaccination and disease complications in 107 individuals with primary (PAD) and secondary antibody deficiency (SAD) enrolled in the COVID-19 in Antibody Deficiency (COV-AD) study. Serum sBCMA concentrations were significantly reduced in PAD compared to healthy controls and asymptomatic selective IgA deficiency. Individuals with X- linked agammaglobulinemia and common variable immunodeficiency (CVID) demonstrated the lowest serum concentrations of sBCMA. sBCMA concentrations in SAD were highly variable. Amongst individuals with CVID, peripheral blood CD19 count, but not sBCMA concentrations discriminated SARS-CoV-2 vaccine responders. sBCMA was significantly lower in individuals with CVID and bronchiectasis and outperformed serum IgA and IgM concentrations in discriminating this subgroup. sBCMA was not associated with any other complication of CVID. Our data highlights the potential of sBCMA as biomarker to support the assessment of antibody deficiency. In PAD, sBCMA may contribute to the risk stratification of disease severity and identify those at risk of bronchiectasis. In SAD, it may identify subgroups that would benefit from intensive monitoring and therapy.

BACKGROUND:X-linked agammaglobulinemia (XLA), caused by mutations in the Bruton tyrosine kinase (BTK) gene, leads to defective B-cell development and low or absent serum immunoglobulins. Advances in diagnosis and treatment have improved outcomes, allowing some patients to live beyond their sixth decade. OBJECTIVE:To describe the clinical, genetic, treatment, and functional status of XLA patients aged 55 years or older. METHODS:Immunologists provided anonymized, physician-reported clinical and molecular details of XLA patients aged 55 years or older. Patients were categorized as having missense mutations (BTK missense) or non-missense mutations (BTK non-missense). RESULTS:Fifty-seven patients were submitted. Forty-eight were considered for final analysis, including 43 with molecularly confirmed XLA and 5 with a strong clinical history. Persistent respiratory infections were common: 64.6% (upper respiratory tract) and 83.3% (lower respiratory tract). Chronic lung disease (72.9%) and gastrointestinal/hepatic disorders (47.9%) were among the most prevalent complications. Most living patients (80.5%) reported good functional status (Karnofsky scores > 80). Missense variants accounted for 62.8% (n = 27), non-missense variants for 37.2% (n = 16); 5 patients lacked classifiable mutation details. Among 34 patients with BTK expression data, 70.6% had detectable BTK protein, significantly more common in the missense group (83.3% vs 30%; P = .005). The non-missense group had higher mortality, more infections, greater antibiotic use, worse pulmonary function, and lower functional status. CONCLUSIONS:Chronic respiratory complications are common in older XLA patients, although most maintain good functional status. Genetic testing aids prognostication; BTK missense mutations are linked to better outcomes. Further research is needed to address the unique challenges of aging in XLA.

Since its discovery in the late 18th century, the role of vaccination in preventing death and disease has expanded across many infectious diseases and cancer. Key to our understanding of vaccine immunogenicity and efficacy is knowledge of the immune system itself. Inborn errors of immunity (IEI) represent a heterogeneous group of disorders characterized by impaired function of the immune system. Patients with IEI can have variable responses to vaccinations, depending on the nature and extent of the defect. Studies performed during the recent COVID-19 pandemic have brought unique insight into vaccine immunogenicity in individuals with IEI, knowledge that can be extended to the growing number of patients with secondary immunodeficiency arising from malignancy, organ transplantation, autoimmune conditions, and their treatments. In this review, we describe vaccine immunogenicity in IEI alongside their equivalent secondary immunodeficiencies and discuss what lessons can be learned about immunization strategies more broadly.

The relationship between baseline immune status and immune reconstitution post CD19 CAR T-cell therapy with risk of infection, non-relapse mortality (NRM) and survival are matters of much clinical interest. Though immunoglobulin replacement therapy (IGRT) is frequently used in this setting, its effect on infection risk, NRM and survival has not been systematically investigated. We conducted a real world, retrospective, multi-centre study to address this issue. Consecutive patients (n=430) treated between 2019-2024 with CD19 CAR T-cell therapy for large B-cell lymphoma (n=354), mantle cell lymphoma (n=46) or B-acute lymphoblastic leukaemia (n=30) from 4 UK CAR T centres were included. Serum IgG, IgA and IgM levels, numbers of C19+ B-cells, CD3+ T-cells, CD16+56+ NK-cells, CD4+ and CD8+ T-cell subsets were analysed at pre and various time points post CAR T-cell infusion. Detailed data were collected on infections, IGRT and mortality. Early infections up to day 28 post CAR T infusion were analysed separately from delayed infections arising beyond day 28. Infections post progressive disease (PD) were excluded. Median age was 63 years (range: 16-80). CAR-T product was axicabtagene ciloleucel in 326, brexucabtagene autoleucel in 56, and tisagenlecleucel in 48. With a median follow up of 24 months, 2-year overall survival (OS), progression free survival (PFS) and NRM for the cohort were 51.7%, 43.6% and 11.3% respectively. Analysis of immune parameters pre and at 1 and 3 months post infusion showed low IgA was associated with increased NRM at all time points on multivariable analysis (including age, disease, CAR-T product, LDH (pre-lymphodepletion) and CAR Haematotox score). Low IgM at baseline was associated with worse OS and PFS, at 1 month with NRM and at 3 months with worse OS and NRM. Low NK cell count at 3 months was associated with worse OS. None of the immune parameters were associated with outcomes at 6 months post infusion though analysis was limited because fewer samples were available at this timepoint. Early infection data were available for 420 patients with infection reported in 133 (31.7%). Infection was probable in 33 (25.4%) with no pathogen isolated. Of those with a pathogen identified 76.3% were bacterial, 17.5% viral and 6.2% fungal. A large majority were grade ≥3 (93.5%) including 3 (3.3%) grade 5. There was no association between pre-infusion immune parameters and early infection. Delayed infection data were available for 280 patients with 237 infection episodes (in 70 patients) eligible for analysis. Infection was probable in 43 (18.1%). Of episodes with a pathogen identified, 58.3% were viral, 40.7% bacterial, 0.5% fungal and 0.5% other. The primary focus was respiratory in 75%. Infection was grade ≥3 in 44% including grade 5 in 6.8%. There was no significant association between immune parameters at either 1, 3 or 6 months post infusion and delayed infections. Of the 430 patients, 87 (20%) were given IGRT with 3 starting pre-infusion and 10 post-PD. The majority (68%) received IGRT for recurrent infections with IgG<4 g/L. For the 77 given IGRT pre-PD, the median time to initiation was 11 months (IQR: 5.1 – 17.8) post infusion. IGRT was included as a time varying covariate to look at association with NRM; no significant difference was seen (adjusted HR 0.35 (0.04 – 3.12) p=0.35). Effect of IGRT on infection was analysed on 43 patients who started IGRT post infusion and pre-PD with a median follow-up from IGRT initiation of 19 months. Infection rates were significantly lower post IGRT: median incidence (per month) 0.07 (IQR: 0 – 0.18) pre and 0 (IQR: 0 – 0.06) post (p=0.0021).We find low IgA pre and at 1 and 3 months post infusion is consistently associated with increased NRM. Low IgM, but not IgG, is also associated with worse outcomes with some variability in its effect on NRM, OS and PFS at these early timepoints. Both early and delayed infections are frequent with distinct differences in pathogens isolated and no significant correlation between infections and any of the immune parameters either pre or at 1, 3 or 6 months post infusion. Our data suggests IGRT may confer protection from delayed infection, but there is not enough evidence for reduction in NRM. This contrasts with survival benefit of IGRT reported with BCMA-targeting therapies. In the absence of survival benefit, our data would support a selective approach to IGRT, rather than primary prophylaxis, post CD19 CAR T-cell therapy.

Objectives Vitamin D has a role in the innate immunity against pathogens and is also involved in mechanisms for reducing inflammation. VD deficiency (VDD) may increase COVID-19 infection susceptibility, however research is limited on the association between VDD and COVID-19 symptom prevalence and duration. The study aimed to determine whether VDD is a risk factor for the presence and extended duration of COVID-19 symptoms. Methods Data was analyzed from NHS healthcare workers who isolated due to COVID-19 symptoms as a part of the COVID-19 convalescent immunity study between 12th to 22nd May 2020. Participants self-reported the presence and duration of viral symptoms. Anti-SARS-CoV-2 antibodies and vitamin D (25(OH)D3) serum levels were measured on day of recruitment. VDD was defined as 25(OH)D3 levels of < 30 nmol/l. Results Of the 392 participants, 15.6% (n = 61) had VDD. VDD participants had more symptoms overall (p = 0.0030), including body aches (p = 0.0453), and extended duration of body aches (p = 0.0075) and fatigue (p = 0.0127). Binary logistic regression found that both VDD (OR 3.069, 95% CI 1.538-6.124; p = 0.001) and age (OR 1.026, 95% CI 1.003-1.049; p = 0.025) were independently associated with extended durations of body aches. VDD (OR 2.089, 95% CI 1.087-4.011; p = 0.027), age (OR 1.036, 95% CI 1.016-1.057; p < 0.001) and seroconversion (OR 1.917, 95% CI 1.203-3.056; p = 0.006), were independently associated with extended durations of fatigue. Conclusion VDD is a significant independent risk factor for extended durations of body aches and fatigue in healthcare workers who isolated for COVID-19 viral symptoms. Vitamin D supplementation may reduce symptom duration and is thus an area for future research.

IntroductionThis study investigates the frequency of hospital attendances, emergency care attendances and geographical influences on service interaction in cohorts of patients with primary and secondary antibody deficiency, to inform future service planning and delivery.MethodsThe COVID-19 in Antibody Deficiency (COV-AD) study was a United Kingdom study that enrolled 525 participants between April 2021 and September 2022. Data on health care utilisation was extracted from a screening cohort of participants at one participating site (Birmingham, UK). Hospital attendance (i.e. all outpatient and inpatient care episodes, including hospital-based IVIG treatment) and emergency care attendance patterns were analysed. Geographical differences in travel times to hospitals and associated costs were considered for all participants at all recruiting sites.ResultsIndividuals with antibody deficiency had a median of 7 hospital attendances per year. A diagnosis of secondary antibody deficiency, and antibody deficiency severe enough to require treatment with immunoglobulin replacement were associated with an increased frequency of hospital attendance. 12.7% of the cohort attended the Emergency Department at least once in the preceding twelve months. Individuals with secondary antibody deficiency were at greater risk of requiring emergency care over the preceding one-year and five-year periods. Individuals receiving subcutaneous immunoglobulin lived further from their local immunology centre and were more likely to engage with the COV-AD research study remotely, via dried blood spots sampling.ConclusionThis study highlights the utilisation of emergency and secondary care usage amongst patient with immunodeficiency and may inform service adaptation and development to better accommodate patient needs and circumstances.

Neutrophils, pivotal cells of innate and adaptive immune responses, employ reactive oxygen species (ROS) to combat pathogens and control gene expression. Paracetamol (acetaminophen) is widely used as an analgesic and antipyretic medication, yet its precise mechanisms of action are not yet fully understood. Here, we investigate the impact of both ingested and in-vitro paracetamol on neutrophil ROS activity, using flow cytometry and antioxidant assays. Our studies reveal that paracetamol significantly suppresses ROS activity ex-vivo in the short term. Additionally, both paracetamol and its metabolite N-acetyl-p-benzoquinone imine exhibited direct in vitro antioxidant effects, and paracetamol suppressed neutrophil extracellular trap formation ex vivo. These findings suggest a connection between paracetamol use and altered neutrophil responses, with potential implications for use in some patient groups, such as immunocompromised individuals. Further investigation into paracetamol's effects on neutrophil antimicrobial functions is warranted to elucidate possible risks, particularly when taken frequently or in conjunction with other treatments such as vaccinations.

Background: Immunization is recommended internationally to protect against pneumococcal infections in HIV-infected adults. However, vaccination schedule designs are mostly based on studies of initial rather than long-term antibody responses. This UK observational study investigated the short- and long-term antibody responses to polysaccharide and glycoconjugate pneumococcal vaccines in an adult HIV-infected cohort. Methods: We studied a subgroup of 152 of 839 participants from the AIR (Assessment of Immune Responses to Routine Immunisations in HIV-infected Adults, ISRCTN95588307) study, that had received pneumococcal vaccinations, and had blood samples collected pre- and post-vaccination, as well as at least annually for four subsequent calendar years. Patients received either Pneumovax-23 (PPV, N=89) or Prevenar-13 (PCV, N=63) as their primary vaccine, with immunity assessed by measuring IgG antibody concentrations for 12 pneumococcal polysaccharide serotypes (PnPS). The primary outcome was achieving IgG antibody concentrations above the recommended World Health Organisation (WHO) threshold of 0.35 mu g/ml for at least 8/12 of the PnPS assessed (WHO >= 8/12PnPS). Patients who did not achieve WHO >= 8/12PnPS after the primary vaccination were offered further vaccination with PCV; booster vaccinations with PCV were additionally offered to those where antibody levels subsequently fell below the WHO >= 8/12PnPS threshold. Results: Patients receiving PCV as their primary pneumococcal vaccine were significantly more likely to achieve WHO >= 8/12PnPS after a single vaccine dose than those receiving PPV (54% vs. 33%, p=0.012). This difference persisted following booster vaccination with PCV, with cumulative rates of WHO >= 8/12PnPS in those receiving PCV vs. PPV as the primary vaccine of 88% vs. 67% and 100% vs. 85% after receiving up to one and two booster vaccinations, respectively. Where WHO >= 8/12PnPS was achieved, this persisted significantly longer in those receiving PCV as their primary vaccine compared to PPV (median: 23.5 vs. 11.1 months; p=0.010). Conclusions: Immunization with PCV resulted in quantitatively greater antibody responses than immunization with PPV in a cohort of HIV-infected UK adults. Individuals receiving PCV as their primary vaccine required fewer total pneumococcal vaccine doses to achieve WHO >= 8/12PnPS and experienced greater duration of time above this threshold than those with PPV as the primary vaccine. However, the median longevity of both vaccine responses was relatively short, which supports the use of ongoing booster doses using high valency glycoconjugate vaccines to sustain WHO >= 8/12PnPS threshold antibody levels. (c) 2024 The Author(s). Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Viral clearance, antibody response and the mutagenic effect of molnupiravir has not been elucidated in at-risk populations. Non-hospitalised participants within 5 days of SARS-CoV-2 symptoms randomised to receive molnupiravir (n = 253) or Usual Care (n = 324) were recruited to study viral and antibody dynamics and the effect of molnupiravir on viral whole genome sequence from 1437 viral genomes. Molnupiravir accelerates viral load decline, but virus is detectable by Day 5 in most cases. At Day 14 (9 days post-treatment), molnupiravir is associated with significantly higher viral persistence and significantly lower anti-SARS-CoV-2 spike antibody titres compared to Usual Care. Serial sequencing reveals increased mutagenesis with molnupiravir treatment. Persistence of detectable viral RNA at Day 14 in the molnupiravir group is associated with higher transition mutations following treatment cessation. Viral viability at Day 14 is similar in both groups with post-molnupiravir treated samples cultured up to 9 days post cessation of treatment. The current 5-day molnupiravir course is too short. Longer courses should be tested to reduce the risk of potentially transmissible molnupiravir-mutated variants being generated. Trial registration: ISRCTN30448031

Post-acute cardiac sequelae, following SARS-CoV-2 infection, are well recognized as complications of COVID-19. We have previously shown the persistence of autoantibodies against antigens in skin, muscle, and heart in individuals following severe COVID-19; the most common staining on skin tissue displayed an inter-cellular cement pattern consistent with antibodies against desmosomal proteins. Desmosomes play a critical role in maintaining the structural integrity of tissues. For this reason, we analyzed desmosomal protein levels and the presence of anti-desmoglein (DSG) 1, 2, and 3 antibodies in acute and convalescent sera from patients with COVID-19 of differing clinical severity. We find increased levels of DSG2 protein in sera from acute COVID-19 patients. Furthermore, we find that DSG2 autoantibody levels are increased significantly in convalescent sera following severe COVID-19 but not in hospitalized patients recovering from influenza infection or healthy controls. Levels of autoantibody in sera from patients with severe COVID-19 were comparable to levels in patients with non-COVID-19-associated cardiac disease, potentially identifying DSG2 autoantibodies as a novel biomarker for cardiac damage. To determine if there was any association between severe COVID-19 and DSG2, we stained post-mortem cardiac tissue from patients who died from COVID-19 infection. This confirmed DSG2 protein within the intercalated discs and disruption of the intercalated disc between cardiomyocytes in patients who died from COVID-19. Our results reveal the potential for DSG2 protein and autoimmunity to DSG2 to contribute to unexpected pathologies associated with COVID-19 infection.

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