Epitope Spreading Research Articles

Autoimmunity: A New Focus on Nasal Polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) has long been considered a benign, chronic inflammatory, and hyperplastic disease. Recent studies have shown that autoimmune-related mechanisms are involved in the pathology of nasal polyps. Activated plasma cells, eosinophils, basophils, innate type 2 lymphocytes, mast cells, and proinflammatory cytokine in polyp tissue indicate the mobilization of innate and adaptive immune pathways during polyp formation. The discovery of a series of autoantibodies further supports the autoimmune nature of nasal polyps. Local homeostasis dysregulation, infection, and chronic inflammation may trigger autoimmunity through several mechanisms, including autoantigens overproduction, microbial translocation, molecular mimicry, superantigens, activation or inhibition of receptors, bystander activation, dysregulation of Toll-Like Receptors (TLRs), epitope spreading, autoantigens complementarity. In this paper, we elaborated on the microbiome-mediated mechanism, abnormal host immunity, and genetic changes to update the role of autoimmunity in the pathogenesis of chronic rhinosinusitis with nasal polyps.

Expanded presentation of Lyme autoantigens and identification of a novel immunogenic CD4+ T cell epitope from Borrelia burgdorferiMCP4 in murine Lyme arthritis

Abstract Lyme arthritis (LA), caused by Borrelia burgdorferi (Bb), is often accompanied by autoimmune T and B cell responses, but the mechanisms of infection-induced autoimmunity are unclear. We used an immunopeptidomics approach to identify potential Lyme autoantigens and immunogenic Bb antigens, which were validated by histology and testing of T cell reactivity. C57BL/6 (B6) mice, which develop mild inflammatory LA, and B6 Il10−/− (IL10 KO) mice, which develop severe, persistent LA, were infected with Bb for 4 or 16 weeks, and MHCII-bound peptides from inguinal and popliteal lymph nodes were identified by LC-MS/MS. Joint inflammation, fibrosis, and vascular remodeling were analyzed by H&E, Masson’s trichrome, and anti-CD31 immunohistochemistry, respectively. Six Bb peptides were identified by LC-MS/MS, of which one epitope from methyl-accepting chemotaxis protein 4 (MCP4) was an immunogenic CD4+ T cell antigen. Over 10,000 self peptides, particularly from proteins involved in cholesterol metabolism, tissue damage, and vascular inflammation were identified in infected mice. Presentation of peptides from previously identified human Lyme autoantigens apolipoprotein B-100, fibronectin, and type V collagen were expanded in infected mice, suggestive of epitope spreading. Consistent with immunopeptidomics data, joints showed increased inflammatory infiltrate, fibrosis and neovascularization in infected mice, compared with joints from uninfected mice. In conclusion, this immunopeptidomics approach revealed key insights into potential mechanisms of infection-induced autoimmunity in LA and indentified a novel immunogenic CD4+ T cell antigen from Bb MCP4. Supported by grants from NIAID (R21AI148982)

A Phase I/II Trial of HER2 Vaccine-Primed Autologous T-Cell Infusions in Patients with Treatment Refractory HER2-Overexpressing Breast Cancer.

High levels of type I T cells are needed for tumor eradication. We evaluated whether the HER2-specific vaccine-primed T cells are readily expanded ex vivo to achieve levels needed for therapeutic infusion. Phase I/II nonrandomized trial of escalating doses of ex vivo-expanded HER2-specific T cells after in vivo priming with a multiple peptide-based HER2 intracellular domain (ICD) vaccine. Vaccines were given weekly for a total of three immunizations. Two weeks after the third vaccine, patients underwent leukapheresis for T-cell expansion, then received three escalating cell doses over 7- to 10-day intervals. Booster vaccines were administered after the T-cell infusions. The primary objective was safety. The secondary objectives included extent and persistence of HER2-specific T cells, development of epitope spreading, and clinical response. Patients received a CT scan prior to enrollment and 1 month after the last T-cell infusion. Nineteen patients received T-cell infusions. Treatment was well tolerated. One month after the last T-cell infusion, 82% of patients had significantly augmented T cells to at least one of the immunizing epitopes and 81% of patients demonstrated enhanced intramolecular epitope spreading compared with baseline (P < 0.05). There were no complete responses, one partial response (6%), and eight patients with stable disease (47%), for a disease control rate of 53%. The median survival for those with progressive disease was 20.5 months and for responders (PR+SD) was 45.0 months. Adoptive transfer of HER2 vaccine-primed T cells was feasible, was associated with minimal toxicity, and resulted in an increased overall survival in responding patients. See related commentary by Crosby et al., p. 3256.

Pruritic crusted lesions in an 89‐year‐old woman

Pruritic crusted lesions in an 89‐year‐old woman

New insights of antineutrophil cytoplasmic antibody-associated vasculitis from the perspective of COVID-19 vaccination.

The occurrence of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) has been reported since the coronavirus disease 2019 (COVID-19) vaccination, but whether there is a causal relationship or coincidence remains to be verified. We combined the term COVID-19 vaccination with each word of AAV to search for case reports and case series published in PubMed, EMBASE, and Web of Science databases before 13 March 2023. A total of 56 patients who developed AAV after COVID-19 vaccination were identified from 44 research centers. Of the 56 subjects, 43 (76.7%) were vaccinated with the mRNA vaccine, followed by the adenovirus vaccine (14.3%) and inactivated vaccine (9.0%) (P = 0.015). Compared with relapsed AAV, new-onset AAV patients had at least two other diseases previously (P < 0.001). Twenty-five (44.6%) patients presented symptoms after the first injection, and the medium onset time was 12 (1-77) days, while Twenty-eight (50.0%) patients developed symptoms after the second dose, and their medium period was 14 (1-60) days. Forty-four (78.5%) patients achieved remission after immunosuppressive agents, plasma exchange, and hemodialysis. One (1.8%) patient died from progressive respiratory failure and nine (16.1%) did not recover, leaving five patients permanently dependent on hemodialysis. Pathogenic ANCA may be activated by enhanced immune response and epitope spreading after COVID-19 vaccination and induced the occurrence of AAV, especially in genetically susceptible populations.

ASSOCIATION BETWEEN PEMPHIGUS AND PSORIASIS: A SYSTEMATIC REVIEW

Pemphigus vulgaris, foliaceus, paraneoplastic, IgA, and herpetiformis are autoimmune bullous diseases. Epidemiologically heterogeneous symptoms characterize pemphigus. The first non-HLA genes related with PV have been found, and our knowledge of pemphigus frequency, which varies widely between populations, has increased. Pemphigus causes blisters and lesions. This polymorphism is also linked to many comorbidities, including autoimmune illnesses, hematological malignancies, and psoriasis. Psoriasis is a T cell-mediated papulosquamous skin illness that results from immune system dysregulation. It is characterized by severe inflammatory and hyperproliferative alterations in the affected areas of the skin. Psoriasis has traditionally been linked to bullous pemphigoid, which is a subepidermal autoimmune bullous illness. Pemphigus is a group of IgG-mediated blistering diseases that affect the skin and mucous membranes' squamous epithelium. Pemphigus causes painful intraepidermal blisters and erosions. Pemphigus disease is chronic and autoimmune, which has increased research into its link with other autoimmune and autoinflammatory disorders. Pemphigus and psoriasis have been reported to co-occur, however their relationship is uncertain. Yet, there are also additional biological plausible reasons for this link. The "epitope spreading phenomena" may have caused the disease. This occurs when a primary autoimmune or inflammatory response damages tissue. Hence, the immune system can now detect some protein components, triggering a subsequent autoimmune reaction. Psoriasis patients are three times more likely to develop pemphigus. Psoriasis doctors should know about this epidemiological trend.

Abstract CT207: Phase I trial of vesicular stomatitis virus expressing human interferon beta and tyrosinase related protein 1 (VSV-IFNb-TYRP1) in metastatic ocular melanoma

Abstract Oncologic viruses (OV) can induce tumor death through both direct oncolysis and immune-mediated destruction. Our study investigates the use of a novel OV with a Vesicular Stomatitis Virus (VSV) vector modified to express interferon-beta (IFN-b) and Tyrosinase Related Protein 1 (TYRP1) (VSV-IFNb-TYRP1). VSV is an attractive vector since humans are not naturally infected with VSV; thus, pre-existing immunity is minimal. IFN-b leads to increased T-cell responses and tumor cell apoptosis, while TYRP1, a melanocyte differentiation antigen, increases immunogenicity of the therapy. We conducted a Phase 1 clinical trial with a 3+3 design in patients with metastatic uveal melanoma. VSV-IFNb-TYRP1 was injected into a liver metastasis under image guidance, then administered on the same day as a single intravenous (IV) infusion. IV doses started at dose level (DL) 1 1 × 1010 TCID50, then escalated to DL2 3 × 10 10, DL3 1 × 1011, and DL4 3 × 1011. The dose delivered intratumorally (IT) varied based on the IV dose. The primary endpoints were safety and maximum tolerated dose (MTD). Efficacy was a secondary endpoint. Correlative studies focused on understanding viral pharmacokinetics (PK) and immunological responses induced by VSV-IFNb-TYRP1 therapy. Twelve patients with previously treated metastatic uveal melanoma were enrolled. Median follow up was 19.1 months. Four DLs were evaluated with one patient at DL4 experiencing dose limiting toxicities (DLTs), including decreased platelet count (grade 3), increased aspartate aminotransferase (AST), and cytokine release syndrome (CRS). Non-DLTs at DL4 were fatigue, fever, CRS, hematological toxicities (decreased platelets and lymphocytes), and AST elevation. Four patients had stable disease (SD) and 8 had progressive disease (PD) as their best response. ELIspot data show that three of the four patients with response to TYRP1 also had a response to gp100, suggesting possible epitope spreading. These four patients received immune checkpoint inhibitor treatment as the next line of therapy, which led to clinical benefit for two patients. Our study evaluated VSV-IFNb-TYRP1 administered via IT and IV routes in a previously treated population of metastatic uveal melanoma patients and found no major safety events. Although there were no clear objective responses to VSV-IFNb-TYRP1, dose-dependent immunogenicity to melanoma antigens was seen. While OV response alone is not sufficient for clinical benefit, the evidence of epitope spreading is encouraging. Future studies of VSV-IFNb-TYRP1 will evaluate combinations with other therapies. Citation Format: Katherine E. Smith, Adam Weisbrod, Carrie Strand, Jacob Allerd, Jose S. Pulido, Alysha Newsom, Lianwen Zhang, Nandakumar Packiriswamy, Heather Montane, Lisa Kottschade, Anastasios Dimou, Yiyi Yan, Markovic Svetomir, Kah Whye Peng, Richard G. Vile, Matthew S. Block, Roxana S. Dronca. Phase I trial of vesicular stomatitis virus expressing human interferon beta and tyrosinase related protein 1 (VSV-IFNb-TYRP1) in metastatic ocular melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT207.

Abstract CT241: A phase 1, first-in-human (FIH) study of autologous anti-HER2 chimeric antigen receptor macrophage (CAR-M) in participants (pt) with HER2 overexpressing solid tumors

Abstract Background: Macrophages are abundant in the solid tumor microenvironment (sTME) and can exhibit both pro- and anti-tumor functions. Macrophages can be redirected by CAR expression to phagocytose cancer cells in an antigen-specific manner. CAR-M can reprogram the sTME and present neoantigens to T cells, leading to epitope spreading and anti-tumor immunity. CT-0508 is comprised of autologous monocyte-derived proinflammatory macrophages expressing an anti-HER2 CAR. Pre-clinical studies showed that CT-0508 induced targeted cancer cell phagocytosis while sparing normal cells, decreased tumor burden, prolonged survival, and was safe and effective. Notably, anti-HER2 CAR-M treatment led to activation of the sTME, with infiltration of CD8+ and CD4+ T cells, NK cells, dendritic cells, and increased activated CD8+ tumor infiltrating lymphocytes. In a pre-clinical model of advanced solid tumor resistant to PD1 blockade, mice treated with anti-HER2 CAR-M combined with a PD1 blocking antibody demonstrated improved tumor control, overall survival, and TME activation compared to either treatment alone, indicating synergy and capacity for CAR-M to sensitize solid tumors to checkpoint blockade. Methods: This Phase 1, FIH study is evaluating safety, tolerability, cell manufacturing feasibility, trafficking, TME activation, and preliminary evidence of efficacy of investigational product CT-0508 in 18 pt with locally advanced (unresectable)/metastatic solid tumors overexpressing HER2. Pt previously treated with anti-HER2 therapies are eligible. Filgrastim mobilized autologous CD14+ monocytes are collected by apheresis, followed by manufacturing and cryopreservation. Group 1 pt (n = 9; enrollment complete) received fractionated doses over Days 1, 3, and 5. Group 2 pt (n = 9) receive CT-0508 as a single infusion on D1. Additional cohorts include: CT-0508 co-administered with pembrolizumab and CT-0508 monotherapy administered intraperitoneally in pt with peritoneal predominant disease. Correlative assessments include pre- and post-treatment biopsies and blood samples for safety (immunogenicity), trafficking (qPCR, RNA in situ hybridization), CT-0508 persistence in blood and tumor, target antigen engagement, TME modulation (single cell RNA sequencing), immune response (TCR sequencing) and others. Citation Format: Yara Abdou, E. Claire Dees, Joanne Mortimer, Naoto Ueno, Melissa Johnson, Richard Maziarz, Jennifer Specht, Yuan Yuan, Paula Puhlman, Mathew Angelos, Saar Gill, Amy Ronczka, Thomas Condamine, Daniel J. Cushing, Michael Klichinsky, Debora Barton, Ramona F. Swaby, Kim Reiss Binder. A phase 1, first-in-human (FIH) study of autologous anti-HER2 chimeric antigen receptor macrophage (CAR-M) in participants (pt) with HER2 overexpressing solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT241.

Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy

Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a cell surface antigen for therapeutic targeting in prostate cancer. Here, we report broad expression of STEAP1 relative to prostate-specific membrane antigen (PSMA) in lethal metastatic prostate cancers and the development of a STEAP1-directed chimeric antigen receptor (CAR) T cell therapy. STEAP1 CAR T cells demonstrate reactivity in low antigen density, antitumor activity across metastatic prostate cancer models, and safety in a human STEAP1 knock-in mouse model. STEAP1 antigen escape is a recurrent mechanism of treatment resistance and is associated with diminished tumor antigen processing and presentation. The application of tumor-localized interleukin-12 (IL-12) therapy in the form of a collagen binding domain (CBD)-IL-12 fusion protein combined with STEAP1 CAR T cell therapy enhances antitumor efficacy by remodeling the immunologically cold tumor microenvironment of prostate cancer and combating STEAP1 antigen escape through the engagement of host immunity and epitope spreading.

Abstract 4131: Long-term anti-tumor immunity induced by of HPN328, a DLL3-targeting trispecific, half-life extended T cell engager, in a preclinical immunocompetent mouse model

Abstract Tri-specific T Cell-Activating Constructs (TriTACs) are T-cell engagers that have been developed to redirect T cells to kill tumor cells. HPN328 is a Delta-like ligand 3 (DLL3)-targeting TriTAC currently being evaluated in a Phase 1/2 clinical trial enrolling patients with advanced cancers associated with DLL3 expression, including small cell lung cancer (SCLC) and other neuroendocrine malignancies (NCT04471727). HPN328 consists of three binding domains: a CD3 binder for T cell engagement, an albumin binder for half-life extension, and a DLL3 binder for tumor cell engagement. We have previously reported that HPN328 induces potent dose-dependent killing of DLL3 expressing SCLC cell lines together with dose-dependent T cell activation and cytokine release in T cell co-cultures in vitro. Based on these data and the proposed mechanism of TriTAC induced tumor cell killing we hypothesized that HPN328 could induce epitope spreading and long-term immunogenic effects. To test this hypothesis, we generated an immunocompetent mouse model in which six amino acid residues corresponding to the portion of human CD3ε which TriTAC molecules bind were added to the N terminus of the mouse CD3ε subunit. Homozygous knock-in mice (hCD3ε) were implanted subcutaneously with MC38 murine colon cancer cell line expressing human DLL3 and treated with HPN328 following tumor establishment. HPN328 treatment led to eradication of established tumors in mice. In addition, tumor infiltrating lymphocyte (TIL) analysis was performed on tumors harvested on day 4 post HPN328 treatment. Activation markers CD69 and CD25 were induced on both CD4+ and CD8+ TILs in this model. To evaluate if HPN328 can induce long-term immunity, mice whose tumors were cured by HPN328 were rechallenged on the opposite flank. As expected, tumors grew in treatment naïve mice, but no tumors were detected in mice previously treated with HPN328, demonstrating sustained and durable anti-tumor immunity induced by HPN328 treatment. Anti-tumor immunity is an indicator of T cell memory against tumor antigens. Concomitant with anti-tumor immune response, we detected increases in memory T cells in the spleens of mice previously treated with HPN328. Together these results indicate that HPN328 can induce epitope spreading and prolonged anti-tumor immunity, suggest a novel mechanism for its activity and efficacy in vivo. Citation Format: Mary Ellen Molloy, Laura B. Valenzuela, Chi-Heng Wu, Holger Wesche, Banmeet S. Anand. Long-term anti-tumor immunity induced by of HPN328, a DLL3-targeting trispecific, half-life extended T cell engager, in a preclinical immunocompetent mouse model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4131.

Tumor-targeted superantigens produce curative tumor immunity with induction of memory and demonstrated antigen spreading

BackgroundDespite remarkable progress, the immunotherapies currently used in the clinic, such as immune checkpoint blockade (ICB) therapy, still have limited efficacy against many types of solid tumors. One major barrier to effective treatment is the lack of a durable long-term response. Tumor-targeted superantigen (TTS) therapy may overcome this barrier to enhance therapeutic efficacy. TTS proteins, such as the clinical-stage molecule naptumomab estafenatox (NAP), increase tumor recognition and killing by both coating tumor cells with bacterial-derived superantigens (SAgs) and selectively expanding T-cell lineages that can recognize them. The present study investigated the efficacy and mechanism of action of repeated TTS (C215Fab-SEA) treatments leading to a long-term antitumor immune response as monotherapy or in combination with PD-1/PD-L1 inhibitors in murine tumor models.MethodsWe used syngeneic murine tumor models expressing the human EpCAM target (C215 antigen) to assess the efficacy and mechanism of action of repeated treatment with TTS C215Fab-SEA alone or with anti-PD-1/PD-L1 monoclonal antibodies. Tumor draining lymph nodes (TDLNs) and tumor tissues were processed and analyzed by immunophenotyping and immunohistochemistry. Isolated RNA from tumors was used to analyze gene expression and the TCR repertoire. Tumor rechallenge and T-cell transfer studies were conducted to test the long-term antitumor memory response.ResultsTTS therapy inhibited tumor growth and achieved complete tumor rejection, leading to a T-cell-dependent long-term memory response against the tumor. The antitumor effect was derived from inflammatory responses converting the immunosuppressive TME into a proinflammatory state with an increase in T-cell infiltration, activation and high T-cell diversity. The combination of TTS with ICB therapy was significantly more effective than the monotherapies and resulted in higher tumor-free rates.ConclusionsThese new results indicate that TTSs not only can turn a “cold” tumor into a “hot” tumor but also can enable epitope spreading and memory response, which makes TTSs ideal candidates for combination with ICB agents and other anticancer agents.

COVID-19 as a Trigger for Type 1 Diabetes.

Type 1 diabetes (T1D) is usually caused by immune-mediated destruction of islet β cells, and genetic and environmental factors are thought to trigger autoimmunity. Convincing evidence indicates that viruses are associated with T1D development and progression. During the COVID-19 pandemic, cases of hyperglycemia, diabetic ketoacidosis, and new diabetes increased, suggesting that SARS-CoV-2 may be a trigger for or unmask T1D. Possible mechanisms of β-cell damage include virus-triggered cell death, immune-mediated loss of pancreatic β cells, and damage to β cells because of infection of surrounding cells. This article examines the potential pathways by which SARS-CoV-2 affects islet β cells in these 3 aspects. Specifically, we emphasize that T1D can be triggered by SARS-CoV-2 through several autoimmune mechanisms, including epitope spread, molecular mimicry, and bystander activation. Given that the development of T1D is often a chronic, long-term process, it is difficult to currently draw firm conclusions as to whether SARS-CoV-2 causes T1D. This area needs to be focused on in terms of the long-term outcomes. More in-depth and comprehensive studies with larger cohorts of patients and long-term clinical follow-ups are required.

The Role of Viral Infections in the Onset of Autoimmune Diseases.

Autoimmune diseases (AIDs) are the consequence of a breach in immune tolerance, leading to the inability to sufficiently differentiate between self and non-self. Immune reactions that are targeted towards self-antigens can ultimately lead to the destruction of the host's cells and the development of autoimmune diseases. Although autoimmune disorders are comparatively rare, the worldwide incidence and prevalence is increasing, and they have major adverse implications for mortality and morbidity. Genetic and environmental factors are thought to be the major factors contributing to the development of autoimmunity. Viral infections are one of the environmental triggers that can lead to autoimmunity. Current research suggests that several mechanisms, such as molecular mimicry, epitope spreading, and bystander activation, can cause viral-induced autoimmunity. Here we describe the latest insights into the pathomechanisms of viral-induced autoimmune diseases and discuss recent findings on COVID-19 infections and the development of AIDs.

Mycobacterial Heat Shock Proteins in Sarcoidosis and Tuberculosis.

Pathological similarities between sarcoidosis (SA) and tuberculosis (TB) suggest the role of mycobacterial antigens in the etiopathogenesis of SA. The Dubaniewicz group revealed that not whole mycobacteria, but Mtb-HSP70, Mtb-HSP 65, and Mtb-HSP16 were detected in the lymph nodes, sera, and precipitated immune complexes in patients with SA and TB. In SA, the Mtb-HSP16 concentration was higher than that of Mtb-HSP70 and that of Mtb-HSP65, whereas in TB, the Mtb-HSP16 level was increased vs. Mtb-HSP70. A high Mtb-HSP16 level, induced by low dose-dependent nitrate/nitrite (NOx), may develop a mycobacterial or propionibacterial genetic dormancy program in SA. In contrast to TB, increased peroxynitrite concentration in supernatants of peripheral blood mononuclear cell cultures treated with Mtb-HSP may explain the low level of NOx detected in SA. In contrast to TB, monocytes in SA were resistant to Mtb-HSP-induced apoptosis, and CD4+T cell apoptosis was increased. Mtb-HSP-induced apoptosis of CD8+T cells was reduced in all tested groups. In Mtb-HSP-stimulated T cells, lower CD8+γδ+IL-4+T cell frequency with increased TNF-α,IL-6,IL-10 and decreased INF-γ,IL-2,IL-4 production were present in SA, as opposed to an increased presence of CD4+γδ+TCR cells with increased TNF-α,IL-6 levels in TB, vs. controls. Mtb-HSP modulating the level of co-stimulatory molecules, regulatory cells, apoptosis, clonal deletion, epitope spread, polyclonal activation and molecular mimicry between human and microbial HSPs may also participate in the induction of autoimmunity, considered in SA. In conclusion, in different genetically predisposed hosts, the same antigens, e.g., Mtb-HSP, may induce the development of TB or SA, including an autoimmune response in sarcoidosis.

Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis.

Periodontal disease is more common in individuals with rheumatoid arthritis (RA) who have detectable anti-citrullinated protein antibodies (ACPAs), implicating oral mucosal inflammation in RA pathogenesis. Here, we performed paired analysis of human and bacterial transcriptomics in longitudinal blood samples from RA patients. We found that patients with RA and periodontal disease experienced repeated oral bacteremias associated with transcriptional signatures of ISG15+HLADRhi and CD48highS100A2pos monocytes, recently identified in inflamed RA synovia and blood of those with RA flares. The oral bacteria observed transiently in blood were broadly citrullinated in the mouth, and their in situ citrullinated epitopes were targeted by extensively somatically hypermutated ACPAs encoded by RA blood plasmablasts. Together, these results suggest that (i) periodontal disease results in repeated breaches of the oral mucosa that release citrullinated oral bacteria into circulation, which (ii) activate inflammatory monocyte subsets that are observed in inflamed RA synovia and blood of RA patients with flares and (iii) activate ACPA B cells, thereby promoting affinity maturation and epitope spreading to citrullinated human antigens.

Transverse myelitis following bivalent COVID‐19 booster vaccine and quadrivalent seasonal influenza vaccine

Transverse myelitis following bivalent <scp>COVID</scp>‐19 booster vaccine and quadrivalent seasonal influenza vaccine

The Intriguing Links between Psoriasis and Bullous Pemphigoid.

The coexistence of psoriasis with autoimmune bullous diseases (AIBDs), particularly bullous pemphigoid (BP), has been documented in case reports and series, as well as in epidemiological studies. The onset of psoriasis precedes that of BP in the majority of cases. Patients with concomitant BP and psoriasis are generally younger at the onset of BP and present with fewer erosions and blisters as compared with patients suffering from isolated BP. Intriguingly, it has been speculated that some BP cases with comorbid psoriasis can actually correspond to anti-laminin gamma-1 pemphigoid, a rare form that was recently recognized as a distinct entity and which can mimic BP and/or other subepidermal AIBDs. The pathomechanisms underlying the BP-psoriasis association have not yet been identified, although several hypotheses have been proposed. The most credited among such hypotheses involves the so-called "epitope spreading" phenomenon, with tissue injury secondary to a primary inflammatory process (i.e., psoriasis) leading to the exposure of sequestered antigens evoking a secondary autoimmune disease (i.e., bullous pemphigoid). This narrative review aims to give a brief overview of the association between psoriasis and BP, examining epidemiological, clinical, and immunopathological features, the pathomechanisms underlying this association, the treatments for psoriasis incriminated as potential triggers of BP, and the therapeutic management of patients with psoriasis and BP.

Unmasking of a Relapsing Encephalomyelitis After SARS-CoV-2 Infection and COVID-19 Vaccination

Objective NA. Background Prior case studies suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its vaccines may unmask neuroinflammatory conditions. We present a case of relapsing steroid-responsive encephalomyelitis after SARS-CoV-2 infection and subsequent COVID-19 vaccination. Design/Methods NA. Results A 47-year-old man with a history COVID-19 presented with subacute lower extremity weakness, erectile dysfunction, and gait instability with falls. His symptoms started several weeks after COVID-19 vaccination which he underwent 3 months after COVID-19 infection. His initial exam demonstrated weakness at the knees and ankles and extensor plantar responses. MRI demonstrated innumerable enhancing lesions involving the subcortical white matter, basal ganglia, thalami, brainstem, cerebellum, and the entire spinal cord parenchyma. CSF testing revealed a lymphocytic pleocytosis (10 WBC, 88% lymphocytes), and transient matched serum and CSF oligoclonal bands. Testing was unremarkable for infections, malignancies, primary demyelinating conditions, etc. He responded dramatically to five days of high dose methylprednisolone but had recurrence of symptoms with weaning of oral prednisone, requiring another pulse of IV steroids. After 2 months, his steroids were weaned again, with clinical and radiographic recurrence, requiring another course of IV steroids. He was subsequently transitioned to mycophenolate as a steroid-sparing agent. Literature review identified 20 additional cases of CNS neuroinflammatory disease after either SARS-CoV-2 infection or vaccination (11 transverse myelitis, 6 optic neuritis, 3 encephalomyelitis). Conclusions Our patient's steroid-dependency and relapsing course suggests unmasking of an underlying CNS neuroinflammatory condition. Temporal associations of neurological conditions with vaccinations or infections do not prove causality despite previous reports of such sequelae. Vaccines containing SARS-CoV-2 antigens may enhance autoimmunity by mechanisms including polyclonal activation, epitope spreading, or molecular mimicry. This case highlights that the resulting inflammation may be insidious and extensive, though treatable. As COVID-19 constitutes a life-threatening infection in some patients, the benefits of vaccination outweigh the smaller risk of unmasking an immune-related condition.

Infectious diseases, autoantibodies, and autoimmunity

Infections are known to trigger flares of autoimmune diseases in humans and serve as an inciting cause of autoimmunity in animals. Evidence suggests a causative role of infections in triggering antigen-specific autoimmunity, previous thought mainly through antigen mimicry. However, an infection can induce bystander autoreactive T and B cell polyclonal activation, believed to result in non-pathogenic and pathogenic autoimmune responses. Lastly, epitope spreading in autoimmunity is a mechanism of epitope changes of autoreactive cells induced by infection, promoting the targeting of additional self-epitopes. This review highlights recent research findings, emphasizes infection-mediated autoimmune responses, and discusses the possible mechanisms involved.

LBA6 UCPVax therapeutic vaccination promotes cytotoxic and Th1 polarized antitumor CD4 T cells and epitope spreading in patients with advanced non-small cell lung cancer

The stimulation of antitumor CD4 T helper response represents a critical requirement for therapeutic cancer vaccine effectiveness. In this context, we developed a Th1-inducer anticancer peptide vaccine derived from telomerase called UCPVax (Dosset et al. Clin Can Res 2012). The safety and efficacy of UCPVax therapeutic vaccination were recently reported in metastatic non-small cell lung cancer (NSCLC) phase I/II trial (Adotévi et al., J Clin Oncol 2022, NCT02818426). Here, we described the immunological responses promoted by UCPVax.