ABSTRACT Upon activation, B cells undergo either the germinal center (GC) or extrafollicular (EF) response. While GC are known to generate high‐affinity memory B cells and long‐lived plasma cells, the role of the EF response is less well understood. Initially, it was thought to be limited to that of a source of fast but lower‐quality antibodies until the GC can form. However, recent evidence strongly supports the EF response as an important component of the humoral response to infection. EF responses are now also recognized as a source of pathogenic B cells in autoimmune diseases. The EF response itself is dynamic and regulated by pathways that are only recently being uncovered. We have identified that the cytokine IL‐12 acts as a molecular switch, enhancing the EF response and suppressing GC through multiple mechanisms. These include direct effects on both B cells themselves and the coordinated differentiation of helper CD4 T cells. Here, we explore this pathway in relation to other recent advancements in our understanding of the EF response's role and highlight areas for future research. A better understanding of how the EF response forms and is regulated is essential for advancing treatments for many disease states.
Amie J. Eisfeld, Lindsey N. Anderson, Shufang Fan
et al.
AbstractHuman infections caused by viral pathogens trigger a complex gamut of host responses that limit disease, resolve infection, generate immunity, and contribute to severe disease or death. Here, we present experimental methods and multi-omics data capture approaches representing the global host response to infection generated from 45 individual experiments involving human viruses from the Orthomyxoviridae, Filoviridae, Flaviviridae, and Coronaviridae families. Analogous experimental designs were implemented across human or mouse host model systems, longitudinal samples were collected over defined time courses, and global multi-omics data (transcriptomics, proteomics, metabolomics, and lipidomics) were acquired by microarray, RNA sequencing, or mass spectrometry analyses. For comparison, we have included transcriptomics datasets from cells treated with type I and type II human interferon. Raw multi-omics data and metadata were deposited in public repositories, and we provide a central location linking the raw data with experimental metadata and ready-to-use, quality-controlled, statistically processed multi-omics datasets not previously available in any public repository. This compendium of infection-induced host response data for reuse will be useful for those endeavouring to understand viral disease pathophysiology and network biology.
ContextMa Xing Shi Gan Decoction (MXSGD) is a traditional remedy for treating lung injuries that was developed by the Typhoid and Fever School of Pharmaceutical Biology. It has antitussive and expectorant effects, anti-inflammatory, antiviral, regulates the body’s immunity, etc.AimThe aim of this study is to investigate whether MXSGD can ameliorate cyclosporine A (CsA)-induced hypoimmunity lung injury by regulating microflora metabolism. Methods: Establishment of a model for CsA-induced hypoimmunity lung injury. Using 16S rRNA high-throughput sequencing and LC-MS, the effects of MXSGD on gut flora and lung tissue microecology of mice with CsA-induced hypoimmunity were investigated.ResultsMXSGD was able to preserve lung tissue morphology and structure, reduce serum inflammatory marker expression and protect against CsA-induced lung tissue damage. Compared to the model, MXSGD increased beneficial gut bacteria: Eubacterium ventriosum group and Eubacterium nodatum group; decreased intestinal pathogens: Rikenellaceae RC9 intestinal group; reduced the abundance of Chryseobacterium and Acinetobacter, promoted the production of Lactobacillus and Streptococcus, and then promoted the lung flora to produce short-chain fatty acids. MXSGD was able to enhance the expression of serum metabolites such as Americine, 2-hydroxyhexadecanoylcarnitine, Emetine, All-trans-decaprenyl diphosphate, Biliverdin-IX-alpha, Hordatin A and N-demethyl mifepristone in the CsA-induced hypoimmunity lung injury model.ConclusionMXSGD can restore gut and lung microbiota diversity and serum metabolite changes to inhibit inflammation, ameliorate CsA-induced hypoimmunity lung injury.
Background: Cardiovascular and cerebrovascular outcomes in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) remain elusive, especially for some specific cardiovascular and cerebrovascular disease (CCVD). We aimed to quantify the magnitude of the risk of total and type-specific CCVD in AAV population. Method: Electronic database searches of PubMed, EMBASE and Cochrane Library plus a hand search of conference proceedings were performed. Observational studies reporting data on CCVD in AAV patients were eligible. Pooled risk ratios (RR) with 95% confidence intervals were calculated. The primary outcome was the risk of CCVD, CAD and CVA in AAV population. The secondary outcomes were the risk of cause-specific CCVD, including myocardial infraction, angina pectoris, heart failure, stroke, ischemic stroke. Results: Fourteen studies met the inclusion criteria, comprising 20,096 AAV patients (over 46,495 person-years) with 5,757 CCVD events. Compared with non-vasculitis population, AAV patients showed an 83% increased risk of incident CCVD (1.83 [1.37-2.45]; n=10), 48% for coronary artery disease (1.48 [1.26-1.75]; n=9), and 56% for cerebrovascular accident (1.56 [1.22-1.99]; n=9). For type-specific CCVD, the risks of myocardial infarction, stroke, heart failure were increased by 67% (1.67 [1.29-2.15]; n=6), 97% (1.97 [1.19-3.25]; n=8) and 72% (1.72 [1.28-2.32]; n=4), whereas there was only a trend toward a higher risk of angina pectoris (1.46 [0.90-2.39]; n=2), and ischemic stroke (1.88 [0.86-4.12]; n=4). Subgroup analyses by AAV type found significantly increased CCVD risk in both granulomatosis with polyangiitis (1.87 [1.29-2.73]; n=7) and microscopic polyangiitis (2.93 [1.58-5.43]; n=3). In three studies reporting impact of follow-up period after AAV diagnosis, the CCVD risk was significantly higher in the first two years after diagnosis than the subsequent follow-up (2.23 [2.00-2.48] vs. 1.48 [1.40-1.56]; p < 0.01). Significant heterogeneity existed in the main analyses. Conclusions: This meta-analysis demonstrates that AAV is associated with increased risks of overall and type-specific CCVD, especially within two years after AAV diagnosis.
V. Schichter-Konfino, R. Mubariki, E. Toubi
et al.
BackgroundOmalizumab (OMA) was the first FDA-approved biological drug for severe chronic spontaneous urticaria (CSU), and until today is the only beneficial and truly safe one. The objectives were: To assess the prevalence of CSU patients in whom OMA cannot be stopped over time. We also asked if biomarkers (e.g., anti-TPO antibodies and total IgE) could assist in anticipating this issue.MethodsWe used our prospective registry of 93 patients, which included CSU disease duration, the onset of OMA treatment, Urticaria Activity Score (UAS7) during follow-up, co-morbidities, serum IgE levels and the presence of anti-TPO antibodies. Finally, we assessed the response to OMA during a period of six years.ResultsOut of the 93 treated CSU patients, OMA was stopped in ten patients after six months being defined as failures. In another ten patients, OMA was discontinued after 2–4 years of therapy, achieving a remission. Seventy-three patients are still treated between 2 and 6 years, having different degrees of response. Of these, in thirty-eight (52%) patients, we could not stop OMA even after six years due to CSU relapses. The prevalence of lower serum IgE levels and anti-TPO antibody positivity was significantly higher in CSU patients in whom OMA could not be stopped.ConclusionThis is the first study where OMA-treated CSU patients were followed up to six years. In half of them, long-term therapy of six years is still required.
Acinetobacter baumanniiis a highly antibiotic-resistant bacterial pathogen for which novel therapeutic approaches are needed. Unfortunately, the drivers of virulence inA.baumanniiremain uncertain. By comparing genomes among a panel ofA.baumanniistrains we identified a specific gene variation in the capsule locus that correlated with altered virulence. While less virulent strains possessed the intact genegtr6, a hypervirulent clinical isolate contained a spontaneous transposon insertion in the same gene, resulting in the loss of a branchpoint in capsular carbohydrate structure. By constructing isogenicgtr6mutants, we confirmed thatgtr6-disrupted strains were protected from phagocytosisin vitroand displayed higher bacterial burden and lethalityin vivo.Gtr6+ strains were phagocytized more readily and caused lower bacterial burden and no clinical illnessin vivo. We found that the CR3 receptor mediated phagocytosis ofgtr6+, but notgtr6-, strains in a complement-dependent manner. Furthermore, hypovirulentgtr6+strains demonstrated increased virulencein vivowhen CR3 function was abrogated. In summary, loss-of-function in a single capsule assembly gene dramatically altered virulence by inhibiting complement deposition and recognition by phagocytes across multipleA.baumanniistrains. Thus, capsular structure can determine virulence amongA.baumanniistrains by altering bacterial interactions with host complement-mediated opsonophagocytosis.
María Eugenia Cortina, R. Clayton Bishop, Brittany A. DeVasure
et al.
All Chlamydia species are obligate intracellular bacteria that undergo a unique biphasic developmental cycle strictly in the lumen of a membrane bound compartment, the inclusion. Chlamydia specific Type III secreted effectors, known as inclusion membrane proteins (Inc), are embedded into the inclusion membrane. Progression through the developmental cycle, in particular early events of conversion from infectious (EB) to replicative (RB) bacteria, is important for intracellular replication, but poorly understood. Here, we identified the inclusion membrane protein IncS as a critical factor for Chlamydia development. We show that a C . trachomatis conditional mutant is impaired in transition from EB to RB in human cells, and C . muridarum mutant bacteria fail to develop in a mouse model of Chlamydia infection. Thus, IncS represents a promising target for therapeutic intervention of the leading cause of sexually transmitted infections of bacterial origin.
Jenna J. Guthmiller, Henry A. Utset, Patrick C. Wilson
Antibodies are critical for providing protection against influenza virus infections. However, protective humoral immunity against influenza viruses is limited by the antigenic drift and shift of the major surface glycoproteins, hemagglutinin and neuraminidase. Importantly, people are exposed to influenza viruses throughout their life and tend to reuse memory B cells from prior exposure to generate antibodies against new variants. Despite this, people tend to recall memory B cells against constantly evolving variable epitopes or non-protective antigens, as opposed to recalling them against broadly neutralizing epitopes of hemagglutinin. In this review, we discuss the factors that impact the generation and recall of memory B cells against distinct viral antigens, as well as the immunological limitations preventing broadly neutralizing antibody responses. Lastly, we discuss how next-generation vaccine platforms can potentially overcome these obstacles to generate robust and long-lived protection against influenza A viruses.
Natural killer T cells (NKTs) are an important part of the immune system. Since their discovery in the 1990s, researchers have gained deeper insights into the physiology and functions of these cells in many liver diseases. NKT cells are divided into two subsets, type I and type II. Type I NKT cells are also named iNKT cells as they express a semi-invariant T cell-receptor (TCR) α chain. As part of the innate immune system, hepatic iNKT cells interact with hepatocytes, macrophages (Kupffer cells), T cells, and dendritic cells through direct cell-to-cell contact and cytokine secretion, bridging the innate and adaptive immune systems. A better understanding of hepatic iNKT cells is necessary for finding new methods of treating liver disease including autoimmune liver diseases, alcoholic liver diseases (ALDs), non-alcoholic fatty liver diseases (NAFLDs), and liver tumors. Here we summarize how iNKT cells are activated, how they interact with other cells, and how they function in the presence of liver disease.
Khaled Atmar, Claudia A. L. Ruivenkamp, Louise Hooimeijer
et al.
BackgroundSevere multilineage cytopenia in childhood caused by bone marrow failure (BMF) often represents a serious condition requiring specific management. Patients are at risk for invasive infections and bleeding complications. Previous studies report low rates of identifiable causes of pediatric BMF, rendering most patients with a descriptive diagnosis such as aplastic anemia (AA).MethodsWe conducted a multi-center prospective cohort study in which an extensive diagnostic approach for pediatric patients with suspected BMF was implemented. After exclusion of malignant and transient causes of BMF, patients entered thorough diagnostic evaluation including bone marrow analysis, whole exome sequencing (WES) including copy number variation (CNV) analysis and/or single nucleotide polymorphisms (SNP) array analysis. In addition, functional and immunological evaluation were performed. Here we report the outcomes of the first 50 patients (2017-2021) evaluated by this approach.ResultsIn 20 patients (40%) a causative diagnosis was made. In this group, 18 diagnoses were established by genetic analysis, including 14 mutations and 4 chromosomal deletions. The 2 remaining patients had short telomeres while no causative genetic defect was found. Of the remaining 30 patients (60%), 21 were diagnosed with severe aplastic anemia (SAA) based on peripheral multi-lineage cytopenia and hypoplastic bone marrow, and 9 were classified as unexplained cytopenia without bone marrow hypoplasia. In total 28 patients had undergone hematopoietic stem cell transplantation (HSCT) of which 22 patients with an unknown cause and 6 patients with an identified cause for BMF.ConclusionWe conclude that a standardized in-depth diagnostic protocol as presented here, can increase the frequency of identifiable causes within the heterogeneous group of pediatric BMF. We underline the importance of full genetic analysis complemented by functional tests of all patients as genetic causes are not limited to patients with typical (syndromal) clinical characteristics beyond cytopenia. In addition, it is of importance to apply genome wide genetic analysis, since defects in novel genes are frequently discovered in this group. Identification of a causal abnormality consequently has implications for the choice of treatment and in some cases prevention of invasive therapies.
Henry A. Utset, Jenna J. Guthmiller, Patrick C. Wilson
The generation of high affinity antibodies is a crucial aspect of immunity induced by vaccination or infection. Investigation into the B cells that produce these antibodies grants key insights into the effectiveness of novel immunogens to induce a lasting protective response against endemic or pandemic pathogens, such as influenza viruses, human immunodeficiency virus, or severe acute respiratory syndrome coronavirus-2. However, humoral immunity has largely been studied at the serological level, limiting our knowledge on the specificity and function of B cells recruited to respond to pathogens. In this review, we cover a number of recent innovations in the field that have increased our ability to connect B cell function to the B cell repertoire and antigen specificity. Moreover, we will highlight recent advances in the development of both ex vivo and in vivo models to study human B cell responses. Together, the technologies highlighted in this review can be used to help design and validate new vaccine designs and platforms.
Rebecca L. Brocato, Steven A. Kwilas, Robert K. Kim
et al.
Abstract A worldwide effort to counter the COVID-19 pandemic has resulted in hundreds of candidate vaccines moving through various stages of research and development, including several vaccines in phase 1, 2 and 3 clinical trials. A relatively small number of these vaccines have been evaluated in SARS-CoV-2 disease models, and fewer in a severe disease model. Here, a SARS-CoV-2 DNA targeting the spike protein and delivered by jet injection, nCoV-S(JET), elicited neutralizing antibodies in hamsters and was protective in both wild-type and transiently immunosuppressed hamster models. This study highlights the DNA vaccine, nCoV-S(JET), we developed has a great potential to move to next stage of preclinical studies, and it also demonstrates that the transiently-immunosuppressed Syrian hamsters, which recapitulate severe and prolonged COVID-19 disease, can be used for preclinical evaluation of the protective efficacy of spike-based COVID-19 vaccines.
Immunologic diseases. Allergy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Kelly E. Seaton, Rachel L. Spreng, Milite Abraha
et al.
Abstract RTS,S/AS01 is an advanced pre-erythrocytic malaria vaccine candidate with demonstrated vaccine efficacy up to 86.7% in controlled human malaria infection (CHMI) studies; however, reproducible immune correlates of protection (CoP) are elusive. To identify candidates of humoral correlates of vaccine mediated protection, we measured antibody magnitude, subclass, and avidity for Plasmodium falciparum (Pf) circumsporozoite protein (CSP) by multiplex assays in two CHMI studies with varying RTS,S/AS01B vaccine dose and timing regimens. Central repeat (NANP6) IgG1 magnitude correlated best with protection status in univariate analyses and was the most predictive for protection in a multivariate model. NANP6 IgG3 magnitude, CSP IgG1 magnitude, and total serum antibody dissociation phase area-under-the-curve for NANP6, CSP, NPNA3, and N-interface binding were also associated with protection status in the regimen adjusted univariate analysis. Identification of multiple immune response features that associate with protection status, such as antibody subclasses, fine specificity and avidity reported here may accelerate development of highly efficacious vaccines against P. falciparum.
Immunologic diseases. Allergy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Background: Lincang City in Yunnan Province on the China-Myanmar border, has reached the World Health Organization recommended coverage (95%) for measles-containing vaccine (MCV), but measles outbreaks still occur. We conducted a survey in Lincang City to determine the measles vaccination status of children on the China–Myanmar border. Methods: We used multistage sampling among children aged 8–83 months. Information on measles vaccination status was obtained from the child’s vaccination certificate, and serum samples were tested using commercially available ELISA kits. Results: A total of 938 children were surveyed. The vaccination coverage rate was 98.9% (95% CI: 98.2–99.6%) for measles–containing vaccine dose 1 (MCV1), and 95.8% (95% CI:94.9–96.7%) for measles–containing vaccine dose 2 (MCV2). The timely vaccination coverage rate was 52.0% (95% CI:48.8–55.2%) for MCV1, and 74.1% (95% CI: 82.9–89.0%) for MCV2. The timely-and–complete vaccination coverage rate was 41.0% (95% CI: 36.7–45.3%). The median delay period was 33 (95% CI: 27–39) days for MCV1, and 196 (95% CI: 146–246) days for MCV2. The seropositivity rate in children aged less than 7 years was 94.0% (95% CI: 92.5–95.5%) with a geometric mean titer of 1210.1 mIU/mL. Conclusions: The MCV coverage was high, but timely and timely-and-complete vaccination coverage were low and insufficient to prevent measles outbreaks. It is necessary to add the timely and timely-and-complete vaccination coverage as indicators of vaccination to provide a more complete picture of measles immunization status.