Humoral Adaptive Immune Responses Research Articles

Translocating gut pathobiont Enterococcus gallinarum induces T H 17 and IgG3 anti-RNA–directed autoimmunity in mouse and human

Chronic autoimmune diseases often lead to long-term sequelae and require lifelong immunosuppression because of an incomplete understanding of the triggers and drivers in genetically predisposed patients. Gut bacteria that escape the gut barrier, known as translocating gut pathobionts, have been implicated as instigators and perpetuators of extraintestinal autoimmune diseases in mice. The gut microbial contributions to autoimmunity in humans remain largely unclear, including whether specific pathological human adaptive immune responses are triggered by such pathobionts. Here, we show that the translocating pathobiont Enterococcus gallinarum can induce both human and mouse interferon-γ + T helper 17 (T H 17) differentiation and immunoglobulin G3 (IgG3) subclass switch of anti– E. gallinarum RNA antibodies, which correlated with anti-human RNA autoantibody responses in patients with systemic lupus erythematosus (SLE) and autoimmune hepatitis, two extraintestinal autoimmune diseases. E. gallinarum RNA, but not human RNA, triggered Toll-like receptor 8 (TLR8), and TLR8-mediated human monocyte activation promoted human T H 17 induction by E. gallinarum . Translocation of the pathobiont triggered increased anti-RNA autoantibody titers that correlated with renal autoimmune pathophysiology in murine gnotobiotic lupus models and with disease activity in patients with SLE. These studies elucidate cellular mechanisms of how a translocating gut pathobiont induces systemic human T cell– and B cell–dependent autoimmune responses and provide a framework for developing host- and microbiota-derived biomarkers and targeted therapies in autoimmune diseases.

Temporal profiling of human lymphoid tissues reveals coordinated defense against viral challenge

Adaptive immunity is generated in lymphoid organs, but how these structures defend themselves during infection in humans is unknown. The nasal epithelium is a major site of viral entry, with adenoid nasal-associated lymphoid tissue (NALT) generating early adaptive responses. In the present study, using a nasopharyngeal biopsy technique, we investigated longitudinal immune responses in NALT after a viral challenge, using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as a natural experimental model. In acute infection, infiltrating monocytes formed a subepithelial and perifollicular shield, recruiting neutrophil extracellular trap-forming neutrophils, whereas tissue macrophages expressed pro-repair molecules during convalescence to promote the restoration of tissue integrity. Germinal center B cells expressed antiviral transcripts that inversely correlated with fate-defining transcription factors. Among T cells, tissue-resident memory CD8 T cells alone showed clonal expansion and maintained cytotoxic transcriptional programs into convalescence. Together, our study provides unique insights into how human nasal adaptive immune responses are generated and sustained in the face of viral challenge.

Differential Immune Responses of Th1 Stimulatory Chimeric Antigens of Leishmania donovani in BALB/c Mice.

Visceral leishmaniasis (VL) is the third most severe infectious parasitic disease and is caused by the protozoan parasite Leishmania. To control the spread of the disease in endemic areas where the asymptomatic patients act as reservoirs as well as in nonendemic areas, an effective vaccine is indispensable. In this direction, we have developed three chimeric proteins by the combination of three already known Th1 stimulatory leishmanial antigens, i.e., enolase, aldolase, and triose phosphate isomerase (TPI). The newly developed chimeric proteins, i.e., enolase-aldolase, TPI-enolase, and aldolase-TPI along with BCG as an adjuvant were assessed and compared, examining humoral and cellular adaptive immune responses elicited in BALB/c mice. The three chimeric antigens exhibited differential immune responses shown by differences in Th1 and Th2 cytokine production in ex vivo stimulated splenocytes of immunized mice. It was observed that all three chimeric proteins are more immunogenic than their component proteins. However, while comparing the immune response of the three chimeric proteins, aldolase-TPI exhibited a better immunogenic (Th1-type) response, as evidenced by the highest IFN-γ production, a high IgG2a antibody isotype switching, a high % population of CD8+ and CD4+ T-cells, and a significantly high expression of iNOS2. Thus, the results suggest the potential of these chimeric antigens as strong immunogens that can be harnessed in vaccine development against VL.

Human dendritic cell differentiation in hematopoietic stem cell-transplanted NOG hFLT3L Tg/mFlt3 KO humanized mice

Human immune system-reconstituted humanized mice are useful animal models to study human immunology in vivo. Human hematopoietic stem cell-transferred NOG mice are well recognized as humanized immune system models with reconstitution of mature lymphoid lineage cells such as T and B cells. However, human myeloid lineage cells including dendritic cells (DCs) do not fully differentiate in conventional NOG mice. DCs play a crucial role in adaptive immunity through antigen presentation to T cells to acquire antigen specificity. In this study, we established a novel humanized mouse with human DC differentiation. To induce DCs, we generated human Fms-like tyrosine kinase 3 ligand (hFLT3L) transgenic NOG (hFLT3L-Tg) mice and transferred human CD34+ hematopoietic stem cells (HSC) into them. Unexpectedly, low frequency of human cell engraftment was observed in the hFLT3L-Tg mice after HPC reconstitution. In the Tg mice, mouse CD11b+Gr1− myeloid cells were markedly expanded in the bone marrow due to the cross-reaction between hFLT3L and mouse Flt3 receptor, and these myeloid leukemia-like cells interfered with the engraftment of human hematopoietic cells in hFLT3L-Tg mice. To avoid this cross-reaction, we further generated NOG FLT3 receptor KO (mFlt3 KO) mice by CRISPR/Cas9 technique, and the KO mice combined with hFLT3L Tg mice to create hFLT3L Tg/mFlt3 KO (FL Tg/KO) mice. Mouse CD11b+Gr1− leukemia-like cells did not proliferate in FL Tg/KO mice due to blockade of the FLT3 signals in mouse leukocytes. After human HSC transplantation, human CD45+ cells were successfully engrafted in FL Tg/KO mice. Furthermore, major subsets of human DC populations, cDC1, cDC2, and pDC, and skin Langerhans cells were significantly differentiated in FL Tg/KO mice. Therefore, these humanized mouse models are potentially valuable in the investigation of DC-mediated human adaptive immune responses in vivo.

Induction of an 11 KDA Protein Epitope For Reducing Mrsa Bacterial Colony Counts Via Cellular and Humoral Adaptive Immune Responses In Postpartum MUS Musculus Infected With MRSA: A Strategy for Enhancing Public Health and Combating Antibiotic Resistance

Objective: This study investigates how the 11 kDa protein epitope, from the cross-reaction between MRSA bacteria and L. reuteri, reduces MRSA colonies through adaptive immune responses (Th17, Th2), cytokines (IL-4, IL-22), and innate immunity (IgG antibodies) in postpartum Mus musculus. Method: A true experimental design was applied using Balb/c mice divided into seven groups, including controls and those treated with different combinations of L. reuteri, MRSA proteins, and peptides. Cellular immunity (Th17, Th2), cytokines (IL-4, IL-22), IgG antibodies, and MRSA colonies were measured post-treatment. Results & Discussion: The candidate vaccine enhanced cellular adaptive immunity (Th2, Th17), cytokine responses (IL-4, IL-22), and reduced MRSA colonies. IgG levels were notably higher in Groups K3 and K6 compared to K1. Conclusion: The 11 kDa protein epitope, from the MRSA-L. reuteri cross-reaction, effectively modulates adaptive immunity, reducing MRSA colonies in postpartum Mus musculus.

Immunogenicity to Herpes Zoster recombinant subunit vaccine in immune-mediated rheumatic patients under treatment with JAK inhibitors.

Patients with immune-mediated rheumatic diseases (IMRDs) face an elevated risk of varicella-zoster virus infection (VZV), and herpes zoster (HZ). Treatment with immunosuppressors further increases the risk. A new recently approved adjuvant recombinant inactive vaccine, offers safe protection against HZ. However, limited data exist on the efficacy of this new vaccine in patients with IMRDs treated with JAK inhibitors. We aimed to characterize B cell and T cell immune responses elicited by the HZ recombinant subunit vaccine in patients with IMRDs under treatment with JAK inhibitors, and to identify factors that might be associated with reduced immunogenicity, and therefore reduced protection. We investigated humoral, and cellular CD4 and CD8 immune responses following a two-dose regimen of the recombinant inactive vaccine in 43 patients with rheumatic diseases treated with different JAK inhibitors. The responses were compared with age, gender and disease-matched healthy controls. Patients with IMRDs treated with JAK inhibitors showed reduced seroconversion rate (63% vs 100% and lower VZV IgG titers (1222 ± 411 vs 3048 ± 556, p< 0.0001) as compared with healthy controls. Functional T CD4 (IL-2 plus IFN-γ secretion) and T CD8 (Granzyme A and/or Granzyme B secretion) immune responses were also significantly diminished in IMRDs patients. Negative correlation was found between VZV antibody titers and age, specific treatments (baricitinib, tofacitinib, upadacitinib), cumulative methotrexate and glucocorticoid doses, history of multiple DMARDs, and treatment duration with JAK inhibitors. Functional T-CD4 responses but not functional T-CD8 responses also showed similar negative correlations. Positive associations were observed between functional T-CD4 and T-CD8 responses. Our study provides valuable insights into the immune responses elicited by the recombinant inactive vaccine in patients with IMRDs treated with JAK inhibitors. In these patients we have observed a broad impact on the adaptive humoral and cellular immune responses, suggesting a potential reduction in protection against herpes zoster infection and VHZ reactivation.

Dinámica de los receptores de quimioquinas en la membrana celular

Chemokines are chemotactic cytokines that control the migratory patterns and positioning of many cells, including immune cells. Although chemokines were initially considered to be important mediators of acute inflammation, we now know that this complex system of ligands and receptors is essential for the generation of primary and secondary adaptive cellular and humoral immune responses. In addition, they also trigger other biological responses ranging from cell polarization or movement or the prevention of HIV-1 infection. Chemokine-mediated cell activation was believed to be due to the binding of a monomeric chemokine to its monomeric receptor. However, the biology of these mediators is more complex than initially anticipated, as several studies indicate that chemokines dimerize. In addition, the use of new advanced optical imaging techniques have made possible to determine that the receptors also form dimers, homo- and heterodimers, as well as higher order oligomers at the cell surface. These are very dynamic and plastic structures/conformations, influenced by the presence of ligands, the co-expression of other receptors and proteins, the lipid composition of the cell membrane or the environment where cells perform their function. Keywords: Chemokines; Chemokine receptors; Receptor conformation; Molecular dynamics; Signaling

Comprehensive Analysis of Characteristics of Cuproptosis-Related LncRNAs Associated with Prognosis of Lung Adenocarcinoma and Tumor Immune Microenvironment.

As a novel discovered mechanism of cell death, cuproptosis is copper-dependent and induces protein toxicity related to advanced tumors, disease prognosis, and human innate and adaptive immune response. However, it has not yet been fully established how the prognosis of lung adenocarcinoma (LUAD) is related to the immune microenvironment of cuproptosis-related lncRNAs using several bioinformatic techniques. In the study, 19 genes related to cuproptosis were collected. Subsequently, 783 lncRNAs related to the co-expression of cuproptosis were obtained. Moreover, the Cox model revealed and constructed four lncRNA (AC012020.1, AC114763.1, AL161431.1, AC010260.1) prognostic markers related to cuproptosis. Based on the median risk score (RS) values, patients were categorized into two groups: high risk and low risk. The Kaplan-Meier (KM) survival curve depicted a statistically significant overall survival (OS) rate among two groups. Principal component analysis (PCA) and receiver operator characteristic curve (ROC) proved that the model had promising ability in prognosis. The analysis of univariate and multivariate Cox regression revealed that RS served as an independent prognostic factor. Moreover, multivariate Cox regression was employed for the establishment of a nomogram of prognostic indicators. The tumor mutational burden (TMB) depicted a considerable difference between the two risk groups. The immunotherapy response of LUAD patients with high risk was improved compared to low risk patients. The study also revealed that drug sensitivity associated with LUAD was significantly linked to RS. The findings could be helpful to establish a good diagnosis, prognosis, and management regime for patients with LUAD.

Unraveling spontaneous humoral immune responses against human cancer: a road to novel immunotherapies.

In immuno-oncology, the focus has traditionally been on αβ T cells, and immune checkpoint inhibitors that primarily target PD-1 or CTLA4 in these lymphocytes have revolutionized the management of multiple human malignancies. However, recent research highlights the crucial role of B cells and the antibodies they produce in antagonizing malignant progression, offering new avenues for immunotherapy. Our group has demonstrated that dimeric Immunoglobulin A can penetrate tumor cells, neutralize oncogenic drivers in endosomes, and expel them from the cytosol. This mechanistic insight suggests that engineered antibodies targeting this pathway may effectively reach previously inaccessible targets. Investigating antibody production within intratumoral germinal centers and understanding the impact of different immunoglobulins on malignant progression could furnish new tools for the therapeutic arsenal, including the development of tumor-penetrating antibodies. This review aims to elucidate the nature of humoral adaptive immune responses in human cancer and explore how they could herald a new era of immunotherapeutic modalities. By expanding the scope of antitumor immunotherapies, these approaches have the potential to benefit a broader range of cancer patients, particularly through the utilization of tumor cell-penetrating antibodies.

Severe acute respiratory syndrome coronavirus-2 seroprevalence in non-vaccinated people living with HIV in Uganda during 2022

A cross-sectional study on severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) seroprevalence among unvaccinated people living with HIV (PLWH) was conducted in Kampala, Uganda, in 2022. Data collection was done using a structured questionnaire. SARS-CoV-2 serologies were done using the Roche Elecsys Anti-SARS-CoV-2 S immunoassay, which assesses the adaptive humoral immune response to the SARS-CoV-2 Spike protein. A total of 575 PLWH (female n=355, 61.7%) with a median age of 49 years (IQR 39-55) were included. SARS-CoV-2 seroprevalence was 93%. The majority had antibody concentration levels ≥ 250 U/ml (n=383, 66.6%). Participants aged &amp;gt;55 years were significantly more likely to have lower antibody concentrations compared to younger participants (p-value &amp;lt; 0.001). A high BMI (≥ 30 kg/m2) was significantly associated with higher antibody concentrations (p-value 0.001). Concerning COVID-19 history, a small proportion of participants (n=79, 13.6%) reported contact with a known COVID-19 patient. Only 8.1% (n=47) had ever had a nasopharyngeal swab for SARS-CoV-2 RT-PCR done, and 3.1% (n=18) actually had a laboratory-confirmed SARS-CoV-2 infection in the past. SARS-CoV-2 seroprevalence was high among our study population, which may be attributed to the fact that the study took place right after all restrictions were lifted and the population was exposed to the dominant Omicron variant. Interestingly, only a small proportion of infections had been laboratory-confirmed.

Immune Response to Respiratory Viral Infections.

The respiratory system is constantly exposed to viral infections that are responsible for mild to severe diseases. In this narrative review, we focalized the attention on respiratory syncytial virus (RSV), influenza virus, and severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infections, responsible for high morbidity and mortality in the last decades. We reviewed the human innate and adaptive immune responses in the airways following infection, focusing on a particular population: newborns and pregnant women. The recent Coronavirus disease-2019 (COVID-19) pandemic has highlighted how our interest in viral pathologies must not decrease. Furthermore, we must increase our knowledge of infection mechanisms to improve our future defense strategies.

Impaired immune responses in the airways are associated with poor outcome in critically ill COVID-19 patients.

Mounting evidence indicates that an individual's humoral adaptive immune response plays a critical role in the setting of SARS-CoV-2 infection, and that the efficiency of the response correlates with disease severity. The relationship between the adaptive immune dynamics in the lower airways with those in the systemic circulation, and how these relate to an individual's clinical response to SARS-CoV-2 infection, are less understood and are the focus of this study. We investigated the adaptive immune response to SARS-CoV-2 in paired samples from the lower airways and blood from 27 critically ill patients during the first wave of the pandemic (median time from symptom onset to intubation 11 days). Measurements included clinical outcomes (mortality), bronchoalveolar lavage fluid (BALF) and blood specimen antibody levels, and BALF viral load. While there was heterogeneity in the levels of the SARS-CoV-2-specific antibodies, we unexpectedly found that some BALF specimens displayed higher levels than the paired concurrent plasma samples, despite the known dilutional effects common in BALF samples. We found that survivors had higher levels of anti-spike, anti-spike-N-terminal domain and anti-spike-receptor-binding domain IgG antibodies in their BALF (p<0.05), while there was no such association with antibody levels in the systemic circulation. Our data highlight the critical role of local adaptive immunity in the airways as a key defence mechanism against primary SARS-CoV-2 infection.

D-galacto-D-mannan-mediated Dectin-2 activation orchestrates potent cellular and humoral immunity as a viral vaccine adjuvant.

Conventional foot-and-mouth disease (FMD) vaccines have been developed to enhance their effectiveness; however, several drawbacks remain, such as slow induction of antibody titers, short-lived immune response, and local side effects at the vaccination site. Therefore, we created a novel FMD vaccine that simultaneously induces cellular and humoral immune responses using the Dectin-2 agonist, D-galacto-D-mannan, as an adjuvant. We evaluated the innate and adaptive (cellular and humoral) immune responses elicited by the novel FMD vaccine and elucidated the signaling pathway involved both in vitro and in vivo using mice and pigs, as well as immune cells derived from these animals. D-galacto-D-mannan elicited early, mid-, and long-term immunity via simultaneous induction of cellular and humoral immune responses by promoting the expression of immunoregulatory molecules. D-galacto-D-mannan also enhanced the immune response and coordinated vaccine-mediated immune response by suppressing genes associated with excessive inflammatory responses, such as nuclear factor kappa B, via Sirtuin 1 expression. Our findings elucidated the immunological mechanisms induced by D-galacto-D-mannan, suggesting a background for the robust cellular and humoral immune responses induced by FMD vaccines containing D-galacto-D-mannan. Our study will help to facilitate the improvement of conventional FMD vaccines and the design of next-generation FMD vaccines.

Quantifying how much host, pathogen, and other factors affect human protective adaptive immune responses.

Recognizing the "essential" factors that contribute to a clinical outcome is critical for designing appropriate therapies and prioritizing limited medical resources. Demonstrating a high correlation between a factor and an outcome does not necessarily imply an essential role of the factor to the outcome. Human protective adaptive immune responses to pathogens vary among (and perhaps within) pathogenic strains, human individual hosts, and in response to other factors. Which of these has an "essential" role? We offer three statistical approaches that predict the presence of newly contributing factor(s) and then quantify the influence of host, pathogen, and the new factors on immune responses. We illustrate these approaches using previous data from the protective adaptive immune response (cellular and humoral) by human hosts to various strains of the same pathogenic bacterial species. Taylor's law predicts the existence of other factors potentially contributing to the human protective adaptive immune response in addition to inter-individual host and intra-bacterial species inter-strain variability. A mixed linear model measures the relative contribution of the known variables, individual human hosts and bacterial strains, and estimates the summed contributions of the newly predicted but unknown factors to the combined adaptive immune response. A principal component analysis predicts the presence of sub-variables (currently not defined) within bacterial strains and individuals that may contribute to the combined immune response. These observations have statistical, biological, clinical, and therapeutic implications.

Choice of adjuvant and antigen composition alters the immunogenic profile of a SARS-CoV-2 subunit vaccine

Introduction: Since their introduction, adjuvanted recombinant subunit vaccines against COVID-19 have played a pivotal role in protecting global populations. Optimizing the immune response’s quality, amplitude, and durability to these vaccines depends on the appropriate adjuvant choice and dose in combination with the selected antigen.Methods: Here, we employed a preclinical mouse model to study the adaptive humoral and cellular immune responses to a SARS-CoV-2 receptor binding domain (RBD) antigen formulated with one of four different immune agonists [GLA, 3M-052, CpG-1826 (CpG), and dmLT], in combination with one of two different immune-stimulating formulations, a stabilized squalene emulsion (SE) or aluminum hydroxide (Alum). Using a weighted desirability index, we established an immunogenicity ranking for each adjuvant in combination with the RBD antigen.Results: We found that formulations of the RBD with Alum in combination with either 3M-052 or CpG led to at least a 2-log increase in serum IgG production and a 1.3- to 2.2-log increase in the number of bone marrow-derived antibody-secreting cells compared to the RBD formulated with Alum without an additional agonist. In contrast, the RBD formulated with SE in combination with 3M-052 or CpG did not elicit an IgG response greater than the unadjuvanted control. Additionally, RBD formulated with 3M-052 or CpG on Alum generated a 0.8- or 1.6-log lower splenocyte IL-5 response (a pro-Th2 marker), respectively, than Alum without an additional agonist. When formulated with 3M-052-Alum, a bivalent vaccine containing the original lineage (Wuhan-Hu-1) and the Delta variant (B.1.617.2) RBD antigens led to a more than 2-log increase in neutralizing antibodies against an Omicron variant (B.1.1.529) pseudovirus in vaccinated animals compared to animals that received the monovalent RBD antigen.Discussion: Our results suggest that optimal immune responses to subunit antigens may be achieved through an orthogonal approach that applies adjuvant formulation, antigen combination, and advances in rational vaccine development techniques.

A multiscale spatial modeling framework for the germinal center response.

The germinal center response or reaction (GCR) is a hallmark event of adaptive humoral immunity. Unfolding in the B cell follicles of the secondary lymphoid organs, a GC culminates in the production of high-affinity antibody-secreting plasma cells along with memory B cells. By interacting with follicular dendritic cells (FDC) and T follicular helper (Tfh) cells, GC B cells exhibit complex spatiotemporal dynamics. Driving the B cell dynamics are the intracellular signal transduction and gene regulatory network that responds to cell surface signaling molecules, cytokines, and chemokines. As our knowledge of the GC continues to expand in depth and in scope, mathematical modeling has become an important tool to help disentangle the intricacy of the GCR and inform novel mechanistic and clinical insights. While the GC has been modeled at different granularities, a multiscale spatial simulation framework - integrating molecular, cellular, and tissue-level responses - is still rare. Here, we report our recent progress toward this end with a hybrid stochastic GC framework developed on the Cellular Potts Model-based CompuCell3D platform. Tellurium is used to simulate the B cell intracellular molecular network comprising NF-κB, FOXO1, MYC, AP4, CXCR4, and BLIMP1 that responds to B cell receptor (BCR) and CD40-mediated signaling. The molecular outputs of the network drive the spatiotemporal behaviors of B cells, including cyclic migration between the dark zone (DZ) and light zone (LZ) via chemotaxis; clonal proliferative bursts, somatic hypermutation, and DNA damage-induced apoptosis in the DZ; and positive selection, apoptosis via a death timer, and emergence of plasma cells in the LZ. Our simulations are able to recapitulate key molecular, cellular, and morphological GC events, including B cell population growth, affinity maturation, and clonal dominance. This novel modeling framework provides an open-source, customizable, and multiscale virtual GC simulation platform that enables qualitative and quantitative in silico investigations of a range of mechanistic and applied research questions on the adaptive humoral immune response in the future.

Trichostatin A-modified vaccine provides superior protection against ovarian cancer formation and development.

More attention has been paid to immunotherapy for ovarian cancer and the development of tumor vaccines. We developed a trichostatin A (TSA)-modified tumor vaccine with potent immunomodulating activities that can inhibit the growth of ovarian cancer in rats and stimulate immune cell response in vivo. TSA-treated Nutu-19 cells inactivated by X-ray radiation were used as a tumor vaccine in rat ovarian cancer models. Prophylactic and therapeutic experiments were performed with TSA-modified tumor vaccine in rats. Flow cytometry and ELISpot assays were conducted to assess immune response. Immune cell expression in the spleen and thymus were detected by immunohistochemical staining. GM-CSF, IL-7, IL-17, LIF, LIX, KC, MCP-1, MIP-2, M-CSF, IP-10/CXCL10, MIG/CXCL9, RANTES, IL-4, IFN-γ, and VEGF expressions were detected with Milliplex Map Magnetic Bead Panel immunoassay. TSA vaccination in therapeutic and prophylactic models could effectively stimulate innate immunity and boost the adaptive humoral and cell-mediated immune responses to inhibit the growth and tumorigenesis of ovarian cancer. This vaccine stimulated the thymus into reactivating status and enhanced infiltrating lymphocytes in tumor-bearing rats. The expression of key immunoregulatory factors were upregulated in the vaccine group. The intensities of infiltrating CD4+ and CD8+ T cells and NK cells were significantly increased in the vaccine group compared to the control group (P<0.05). This protection was mainly dependent on the IFN-γ pathway and, to a much lesser extent, by the IL-4 pathway. The tumor cells only irradiated by X-ray as the control group still showed a slight immune effect, indicating that irradiated cells may also cause certain immune antigen exposure, but the efficacy was not as significant as that of the TSA-modified tumor vaccine. Our study revealed the potential application of the TSA-modified tumor vaccine as a novel tumor vaccine against tumor refractoriness and growth. These findings offer a better understanding of the immunomodulatory effects of the vaccine against latent tumorigenesis and progression. This tumor vaccine therapy may increase antigen exposure, synergistically activate the immune system, and ultimately improve remission rates. A vaccine strategy designed to induce effective tumor immune response is being considered for cancer immunotherapy.

Characterization of the adaptive cellular and humoral immune responses to persistent colonization of Brucella abortus strain RB51 in a Jersey cow.

Brucella abortus strain RB51 is the commercial cattle vaccine used in the United States (US) and many parts of the world against bovine brucellosis. RB51 was licensed for use in 1996, and it has been shown to be safe and efficacious in cattle, eliciting humoral and cellular responses in calves and adult animals. In 2017, an epidemiological trace-back investigation performed by the Centers for Disease Control and Prevention (CDC) identified human cases of brucellosis caused by infection with RB51. These infections resulted from the consumption of unpasteurized dairy products, which were traced back to otherwise healthy animals that were shedding RB51 in their milk. At the current time, six adult Jersey cows have been identified in the U.S. that are shedding RB51 in milk. One of the RB51 shedding cattle was obtained and housed at the National Animal Disease Center (NADC) for further study. Improved understanding of host cellular and humoral immune responses to RB51 in persistently colonized cattle may be achieved by the characterization of responses in shedding animals. We hypothesized, based on the lack of RB51 clearance, that the RB51 shedder animal has a diminished adaptive cellular immune response to RB51. Our data demonstrate that in the presence of persistent RB51 infection, there is a lack of peripheral anti-RB51 CD4+ T cell responses and a concurrently high anti-RB51 IgG humoral response. By understanding the mechanisms that result in RB51 persistence, the development of improved interventions or vaccinations for brucellosis may be facilitated, which would provide public health benefits, including reducing the risks associated with the consumption of non-pasteurized milk products.

Sarcoidosis-related autoimmune inflammation in COVID-19 convalescent patients.

Currently, there are a large number of reports about the development of autoimmune conditions after COVID-19. Also, there have been cases of sarcoid-like granulomas in convalescents as a part of the post-COVID-19 syndrome. Since one of the etiological theories of sarcoidosis considers it to be an autoimmune disease, we decided to study changes in the adaptive humoral immune response in sarcoidosis and SARS-CoV-2 infection and to find out whether COVID-19 can provoke the development of sarcoidosis. This review discusses histological changes in lymphoid organs in sarcoidosis and COVID-19, changes in B cell subpopulations, T-follicular helper cells (Tfh), and T-follicular regulatory cells (Tfr), and analyzes various autoantibodies detected in these pathologies. Based on the data studied, we concluded that SARS-CoV-2 infection may cause the development of autoimmune pathologies, in particular contributing to the onset of sarcoidosis in convalescents.

Contribution of SARS-CoV-2 infection preceding COVID-19 mRNA vaccination to generation of cellular and humoral immune responses in children.

Primary COVID-19 vaccination for children, 5-17 years of age, was offered in the Netherlands at a time when a substantial part of this population had already experienced a SARS-CoV-2 infection. While vaccination has been shown effective, underlying immune responses have not been extensively studied. We studied immune responsiveness to one and/or two doses of primary BNT162b2 mRNA vaccination and compared the humoral and cellular immune response in children with and without a preceding infection. Antibodies targeting the original SARS-CoV-2 Spike or Omicron Spike were measured by multiplex immunoassay. B-cell and T-cell responses were investigated using enzyme-linked immunosorbent spot (ELISpot) assays. The activation of CD4+ and CD8+ T cells was studied by flowcytometry. Primary vaccination induced both a humoral and cellular adaptive response in naive children. These responses were stronger in those with a history of infection prior to vaccination. A second vaccine dose did not further boost antibody levels in those who previously experienced an infection. Infection-induced responsiveness prior to vaccination was mainly detected in CD8+ T cells, while vaccine-induced T-cell responses were mostly by CD4+ T cells. Thus, SARS-CoV-2 infection prior to vaccination enhances adaptive cellular and humoral immune responses to primary COVID-19 vaccination in children. As most children are now expected to contract infection before the age of five, the impact of infection-induced immunity in children is of high relevance. Therefore, considering natural infection as a priming immunogen that enhances subsequent vaccine-responsiveness may help decision-making on the number and timing of vaccine doses.