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Systemic lupus erythematosus (SLE or lupus for short) is an autoimmune disease in which the immune system attacks healthy tissue in organs across the body. The cause is unknown, but people with the illness make antibodies that stick to proteins that are normally found inside the cell nucleus, where DNA is stored. To make these antibodies, the immune system must first ‘see’ these proteins and mistakenly recognise them as a threat. But how does the immune system recognise proteins that are normally hidden inside cells? During infection, a type of immune cell called a neutrophil releases DNA from its nucleus to form structures called neutrophil extracellular traps, or NETs for short. The role of these NETs is to capture and kill pathogens, but they also expose the neutrophil’s DNA and the proteins attached to it to other immune cells. It is therefore possible that other immune cells interacting with NETs during infection may contribute to the development of lupus. Two proteins of interest are AIM2 and IFI16. These proteins form large, shield-like structures around strands of DNA, and previous work has shown that some people with lupus make antibodies against IFI16. Antiochos et al. wondered whether IFI16 and AIM2 might stick to NETs, exposing themselves to the immune system. Examining the blood of people with lupus revealed that one in three of them made antibodies that could stick to AIM2. Those people were also more likely to have antibodies that could stick to IFI16 and to strands of DNA. Using microscopy, Antiochos et al. also found AIM2 and IFI16 on NETs in the kidneys of some people with lupus. Further investigation showed that the presence of AIM2 and IFI16 prevents NETs from breaking down. If proteins like AIM2 and IFI16 can stop NETs from breaking down, they could allow the immune system more time to develop antibodies against them. Further investigation could reveal whether this is one of the causes of lupus. A clearer understanding of the antibodies could also boost research into diagnosis and treatment.

Objective Antibodies against the small ubiquitin‐like modifier (SUMO) activating enzyme (SAE) are one of the rarer specificities associated with dermatomyositis (DM). The purpose of this study is to describe the clinical characteristics of patients with anti‐SAE autoantibodies in a North American cohort and to ascertain cancer prevalence. We also describe the performance characteristics of the line blotting (Euroimmun) method for antibody detection compared with an immunoprecipitation‐based assay. Methods Sera from 2127 patients suspected of having myositis were assayed for myositis‐specific autoantibodies using the Euroimmun platform. Those positive for SAE autoantibodies were assayed by a second method (immunoprecipitation) for confirmation. Only those cases positive by both methods were taken as definite cases of anti‐SAE–positive DM. Chart reviews of these patients were completed to obtain information on clinical characteristics, cancer history, and treatment. Results Forty‐three of 2127 sera were anti‐SAE autoantibody positive by Euroimmun (≥15 units, +); of these, only 19 were confirmed positive by immunoprecipitation. All 19 cases had skin involvement and varying presentations of muscle, lung, and joint disease. Cancer occurred coincident with DM in two patients, and cancers were detected more than 5 years from symptom onset in three patients. In a population of suspected inflammatory myositis, a higher cutoff on line blot testing (≥36 units, ++) yielded better agreement with immunoprecipitation methods. Conclusion SAE autoantibodies associate with a clinical phenotype of DM, which most commonly presents with a rash first, followed by muscle involvement and varying extramuscular involvement. As coincident cancer was seen in anti‐SAE–positive DM, judicious malignancy screening may be warranted.

Background Tumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken to investigate the functional relationship between anti-tumor and anti-self immunity, to facilitate irAE management while promoting anti-tumor immunity. Methods Multiple biopsies from tumor and inflamed tissues were collected from a patient with melanoma experiencing both tumor regression and irAEs on ICB, who underwent rapid autopsy. Immune cells infiltrating melanoma lesions and inflamed normal tissues were subjected to gene expression profiling with multiplex qRT-PCR for 122 candidate genes. Subsequently, immunohistochemistry was conducted to assess the expression of 14 candidate markers of immune cell subsets and checkpoints. TCR-beta sequencing was used to explore T cell clonal repertoires across specimens. Results While genes involved in MHC I/II antigen presentation, IFN signaling, innate immunity and immunosuppression were abundantly expressed across specimens, irAE tissues over-expressed certain genes associated with immunosuppression ( CSF1R, IL10RA, IL27/EBI3, FOXP3, KLRG1, SOCS1, TGFB1 ), including those in the COX-2/PGE2 pathway ( IL1B, PTGER1/EP1 and PTGER4/EP4 ). Immunohistochemistry revealed similar proportions of immunosuppressive cell subsets and checkpoint molecules across samples. TCRseq did not indicate common TCR repertoires across tumor and inflammation sites, arguing against shared antigen recognition between anti-tumor and anti-self immunity in this patient. Conclusions This comprehensive study of a single patient with melanoma experiencing both tumor regression and irAEs on ICB explores the immune landscape across these tissues, revealing similarities between anti-tumor and anti-self immunity. Further, it highlights expression of the COX-2/PGE2 pathway, which is known to be immunosuppressive and potentially mediates ICB resistance. Ongoing clinical trials of COX-2/PGE2 pathway inhibitors targeting the major COX-2 inducer IL-1B, COX-2 itself, or the PGE2 receptors EP2 and EP4 present new opportunities to promote anti-tumor activity, but may also have the potential to enhance the severity of ICB-induced irAEs.

Objective Adaptive immunity mediates psoriatic disease pathogenesis. We aimed to identify novel psoriatic autoantigens and their phenotypic associations in deeply characterized patient cohorts. Methods Sera from psoriatic arthritis (PsA) patients were used for autoantibody discovery. Immunoprecipitations performed with cell lysates were on‐bead digested, and autoantigens were identified by mass spectrometry. Prevalence and clinical features associated with anti–SRY‐Box transcription factor‐D (SOX‐D) antibodies were determined by screening discovery cohorts of patients with PsA (n = 135), patients with psoriasis without PsA (n = 24), and healthy controls (n = 41). A PsA validation cohort (n = 325) and disease control samples of individuals with rheumatoid arthritis (RA; n = 66) and systemic lupus erythematosus (SLE, n = 66) were assayed for anti‐SOX5 antibodies. Disease characteristics were compared by antibody status. Longitudinal data were analyzed using linear mixed‐effects models with patient‐specific intercept to ascertain associations. We also tested PsA sera for the recently described anti–ADAMTS‐L5 autoantibody in PsA. Results The novel autoantigens identified were SOX‐D transcription factors, with SOX‐5 being the focus of this analysis. Anti‐SOX5 antibodies were present in 8.9% (12 of 135) and 4.3% (14 of 323) of patients in the PsA discovery and validation cohorts, respectively, 12.5% of patients (3 of 24) in the psoriasis group, 2.4% (1 of 41) of healthy controls, and 7.6% (5 of 66) each of patients in the RA and SLE groups. Anti‐SOX5 were associated with female sex in both PsA cohorts (discovery: 15.7% women, 2.6% men, P = 0.006; validation: 6.3% women, 1.4% men, P = 0.049). In a longitudinal analysis adjusted for sex, anti‐SOX5 associated with biologic disease‐modifying antirheumatic drug treatment (95% vs 61%; P = 0.001; n = 96) and with differences in estimated treatment effects by mechanism of action. Anti–ADAMTS‐L5 autoantibodies were identified in 8 of 124 patients (6.5%) in the PsA group. Conclusion SOX‐D transcription factors are novel psoriatic autoantigens. Anti‐SOX5 antibodies were preferentially found in women with PsA and associated with specific clinical and treatment characteristics, suggesting that anti‐SOX5 antibodies may identify mechanistic subgroups. We independently validated anti–ADAMTS‐L5 autoantibodies in PsA.

Objective The objective of this study was to describe the frequency, co‐occurrence, and cancer association of anti–cell division cycle and apoptosis regulator 1 (anti‐CCAR1) and anti‐Sp4 in two large independent adult dermatomyositis (DM) cohorts. Methods Anti–transcription intermediary factor 1γ (anti‐TIF1γ)–positive patients with DM from two independent cohorts were studied to determine the serologic overlap of anti‐CCAR1 and anti‐Sp4 autoantibodies measured by enzyme‐linked immunosorbent assay. Associations between cancer‐associated myositis (CAM) and antibody‐defined subgroups within anti‐TIF1γ–positive patients with DM were determined. Results A total of 305 anti‐TIF1γ–positive patients with DM were studied: 169 patients from Johns Hopkins and 136 patients from Stanford. In each cohort, approximately one‐third of anti‐TIF1γ–positive patients with DM were anti‐Sp4 positive, one‐third were anti‐CCAR1 positive, 20% were positive for both, and half of patients were negative for both. There was a strong association with CAM in patients lacking both these antibodies (Johns Hopkins, odds ratio [OR] 12.9 [95% confidence interval (CI) 3.6–89.5]; Stanford, OR 4.5 [95% CI 1.8–13.2]). The strongest negative association with CAM was found in patients with anti‐Sp4 or anti‐CCAR1 (Johns Hopkins, OR 0.07 [95% CI 0.01–0.27]; Stanford, OR 0.22 [95% CI 0.07–0.55]). Conclusion Both anti‐Sp4 and anti‐CCAR1 autoantibody subgroups are negatively associated with CAM. Although the magnitude of this association is substantial, cancer occasionally occurs in patients positive for either specificity. Conversely, approximately half of anti‐TIF1γ–positive patients with DM are negative for both antibodies (anti‐Sp4/anti‐CCAR1 negative), and thus this subgroup may warrant more intensive cancer surveillance.

Several rheumatic diseases have a perplexing association with cancer. Unraveling this mysterious connection is likely to provide deeper understanding regarding mechanisms governing the onset of both autoimmunity and cancer immunity, in addition to providing clinicians much needed guidance around whom and when to screen for occult malignancy. Systemic sclerosis (scleroderma) and dermatomyositis are two diseases in which the association with internal malignancy is well-described and can be considered as models from which to gain important insights that likely have broader applicability. The past 15 years have witnessed a striking acceleration in understanding how these two diseases are related to cancer emergence–an important crack in this inscrutable armor has been the discovery and characterization of disease-specific autoantigens that are closely tied with risk of cancer emergence. The best-described examples of this are antibodies against anti-RNA polymerase III (anti-POL3) and transcription intermediary factor 1-gamma (anti-TIF1γ). Patients with systemic sclerosis and cancer that are diagnosed within a short time interval of each other frequently have anti-POL3 antibodies. Antibodies against the minor spliceosome protein RNA-Binding Region Containing 3 (RNPC3) are also associated with increased cancer incidence in systemic sclerosis. Similarly, in the dermatomyositis spectrum, the majority of anti-TIF1γ-associated cancers are detected around the time of DM onset (most often within 1 year). Antibodies against Nuclear Matrix Protein 2 are also potentially associated with increased cancer emergence in dermatomyositis. The systemic sclerosis/anti-POL3 connection with close cancer onset led to the first experiments directly supporting the concept that rheumatic disease may in fact be a manifestation of cancer. It is now clear that studying these diseases through the lens of autoantibodies can reveal relationships and insights that would otherwise remain obscured. Extending these studies, new findings show that antibodies against RNA polymerase I large subunit are associated with protection against short interval cancers in anti-POL3-positive systemic sclerosis patients. These insights highlight the fact that autoantigen discovery related to cancer emergence remains an important priority; such new tools will enable the testing of specific hypotheses regarding mechanisms governing disease emergence and development of effective anti-tumor responses. Autoantibody phenotype will likely play an important role in the development of cancer screening guidelines that are critically needed by clinicians taking care of these patients. In this review, we will summarize the current state of knowledge regarding the different ways in which autoantibodies are connected with systemic sclerosis/dermatomyositis and malignancy and highlight potential paths forward.

Objective Patients with anti‐melanoma‐differentiation‐associated 5 (anti‐MDA5)‐positive dermatomyositis (DM) share several striking similarities to patients with SARS‐CoV‐2. Our objective was to assess the prevalence of anti‐angiotensin converting enzyme‐2 (ACE2) immunoglobulin M (IgM) antibodies, found in patients with severe SARS‐CoV‐2, in two independent anti‐MDA5‐positive DM cohorts. Methods Anti‐ACE2 IgM antibodies were assayed by enzyme‐linked immunosorbent assay (ELISA) in two anti‐MDA5‐positive DM cohorts: a predominantly outpatient North American cohort (n = 52) and a Japanese cohort enriched for new‐onset disease (n = 32). Additionally, 118 patients with SARS‐CoV‐2 with a spectrum of clinical severity were tested for anti‐MDA5 antibodies by ELISA. Results Five of fifty‐two (9.6%) North American patients and five of thirty‐two (15%) Japanese patients were positive for anti‐ACE2 IgM. In the North American cohort, all five patients with anti‐ACE2 IgM antibodies had proximal muscle weakness, had interstitial lung disease, were significantly more likely to receive pulse dose methylprednisolone (80% vs 30%, P = 0.043), and had worse forced vital capacity (median 59% predicted vs 78%, P = 0.056) compared with the anti‐ACE2‐IgM‐negative group. In the Japanese cohort, all five anti‐ACE2‐IgM‐positive patients also required pulse dose methylprednisolone, and three of five (60%) patients died. Japanese patients with anti‐ACE2 IgM had significantly worse oxygenation, as defined by a lower partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio (233 vs 390, P = 0.021), and a higher alveolar‐arterial oxygenation gradient (91 vs 23 mm Hg, P = 0.024) than the IgM‐negative group. Conclusion We describe anti‐ACE2 IgM autoantibodies in two independent cohorts with anti‐MDA5‐positive DM. These autoantibodies may be biomarkers for severe disease and provide insight into disease pathogenesis.

Autoimmune diseases are thought to be initiated by exposures to foreign antigens that cross-react with endogenous molecules. Scleroderma is an autoimmune connective tissue disease in which patients make antibodies to a limited group of autoantigens, including RPC1, encoded by the POLR3A gene. As patients with scleroderma and antibodies against RPC1 are at increased risk for cancer, we hypothesized that the \"foreign\" antigens in this autoimmune disease are encoded by somatically mutated genes in the patients' incipient cancers. Studying cancers from scleroderma patients, we found genetic alterations of the POLR3A locus in six of eight patients with antibodies to RPC1 but not in eight patients without antibodies to RPC1. Analyses of peripheral blood lymphocytes and serum suggested that POLR3A mutations triggered cellular immunity and cross-reactive humoral immune responses. These results offer insight into the pathogenesis of scleroderma and provide support for the idea that acquired immunity helps to control naturally occurring cancers.

BACKGROUNDThe temporal clustering of a cancer diagnosis with dermatomyositis (DM) onset is strikingly associated with autoantibodies against transcriptional intermediary factor 1-γ (TIF1-γ). Nevertheless, many patients with anti-TIF1-γ antibodies never develop cancer. We investigated whether additional autoantibodies are found in anti-TIF1-γ-positive patients without cancer.METHODSUsing a proteomic approach, we defined 10 previously undescribed autoantibody specificities in 5 index anti-TIF1-γ-positive DM patients without cancer. These were subsequently examined in discovery (n = 110) and validation (n = 142) cohorts of DM patients with anti-TIF1-γ autoantibodies.RESULTSWe identified 10 potentially novel autoantibodies in anti-TIF1-γ-positive DM patients, 6 with frequencies ranging from 3% to 32% in 2 independent DM cohorts. Autoantibodies recognizing cell division cycle and apoptosis regulator protein 1 (CCAR1) were the most frequent, and were significantly negatively associated with contemporaneous cancer (discovery cohort OR 0.27 [95% CI 0.7-1.00], P = 0.050; validation cohort OR 0.13 [95% CI 0.03-0.59], P = 0.008). When cancer did emerge, it occurred significantly later in anti-CCAR1-positive compared with anti-CCAR1-negative patients (median time from DM onset 4.3 vs. 0.85 years, respectively; P = 0.006). Cancers that emerged were more likely to be localized (89% of anti-CCAR1-positive cancers presenting at stage 0 or 1 compared with 42% of patients without anti-CCAR1 antibodies, P = 0.02). As the number of additional autoantibody specificities increased in anti-TIF1-γ-positive DM patients, the frequency of cancer decreased (P < 0.001).CONCLUSIONAs the diversity of immune responses in anti-TIF1-γ DM patients increases, the likelihood of cancer emerging decreases. Our findings have important relevance for cancer risk stratification in DM patients and for understanding natural immune regulation of cancer in humans.TRIAL REGISTRATIONNot applicable.FUNDING SOURCESThe NIH, the Donald B. and Dorothy L. Stabler Foundation, and the Huayi and Siuling Zhang Discovery Fund.

CD209L and its homologous protein CD209 act as alternative entry receptors for the SARS-CoV-2 virus and are highly expressed in the virally targeted tissues. We tested for the presence and clinical features of autoantibodies targeting these receptors and compared these with autoantibodies known to be associated with COVID-19. Using banked samples (  = 118) from Johns Hopkins patients hospitalised with COVID-19, we defined autoantibodies against CD209 and CD209L by enzyme-linked immunosorbent assay (ELISA). Clinical associations of these antibodies were compared with those of patients with anti-interferon (IFN) and anti-angiotensin-converting enzyme-2 (ACE2) autoantibodies. Amongst patients hospitalised with COVID-19, 19.5% (23/118) had IgM autoantibodies against CD209L and were more likely to have coronary artery disease (44% vs 19%,  = 0.03). Antibodies against CD209 were present in 5.9% (7/118); interestingly, all 7 were male (  = 0.02). In our study, the presence of either antibody was positively associated with disease severity [OR 95% confidence interval (95% CI): 1.80 (0.69-5.03)], but the association did not reach statistical significance. In contrast, 10/118 (8.5%) had IgG autoantibodies against IFNα, and 21 (17.8%) had IgM antibodies against ACE2. These patients had significantly worse prognosis (intubation or death) and prolonged hospital stays. However, when adjusting for patient characteristics on admission, only the presence of anti-ACE2 IgM remained significant [pooled common OR (95% CI), 4.14 (1.37, 12.54)]. We describe IgM autoantibodies against CD209 and CD209L amongst patients hospitalised with COVID-19. These were not associated with disease severity. Conversely, patients with either anti-ACE2 IgM or anti-IFNα IgG antibodies had worse outcomes. Due to the small size of the study cohort, conclusions drawn should be considered cautiously.