Assessment of serological Plasmodium falciparum–specific antibodies in highly endemic areas provides valuable information about malaria status and parasite exposure in the population. Although serological evidence of Plasmodium exposure is commonly determined by Plasmodium-specific immunoglobulin G (IgG) levels; IgM and IgA are likely markers of malaria status that remain relatively unexplored. Previous studies on IgM and IgA responses have been based on their affinity for single antigens with shortage of immune responses analysis against the whole Plasmodium proteome. Here, we provide evidence of how P. falciparum infection triggers the production of specific IgM and IgA in plasma and its relationship with parasite density and changes in hematological parameters. A total of 201 individuals attending a hospital in Breman Asikuma, Ghana, were recruited into this study. Total and P. falciparum–specific IgM, IgA, and IgG were assessed by ELISA and examined in relation to age (0–5, 14–49, and ≥50 age ranges); infection (submicroscopic vs. microscopic malaria); pregnancy and hematological parameters. Well-known IgG response was used as baseline control. P. falciparum–specific IgM and IgA levels increased in the population with the age, similarly to IgG. These data confirm that acquired humoral immunity develops by repeated infections through the years endorsing IgM and IgA as exposure markers in endemic malaria regions. High levels of specific IgA and IgM in children were associated with microscopic malaria and worse prognosis, because most of them showed severe anemia. This new finding shows that IgM and IgA may be used as diagnostic markers in this age group. We also found an extremely high prevalence of submicroscopic malaria (46.27% on average) accompanied by IgM and IgA levels indistinguishable from those of uninfected individuals. These data, together with the observed lack of sensitivity of rapid diagnostic tests (RDTs) compared to PCR, invoke the urgent need to implement diagnostic markers for submicroscopic malaria. Overall, this study opens the potential use of P. falciparum–specific IgM and IgA as new serological markers to predict malaria status in children and parasite exposure in endemic populations. The difficulties in finding markers of submicroscopic malaria are highlighted, emphasizing the need to explore this field in depth.

• Antibodies, Protozoan
• Biomarkers
• Child
• Humans
• Immunoglobulin A
• Immunoglobulin G
• Immunoglobulin M
• Malaria
• Malaria, Falciparum/diagnosis
• Plasmodium
• Plasmodium falciparum
• Proteome

• Ministerio de Economía y Competitividad
• Comunidad de Madrid
• Universidad Complutense de Madrid

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States and globally. The currently understood model of pathogenesis consists of a ‘multiple hit’ hypothesis in which environmental and genetic factors contribute to hepatic inflammation and injury.

To examine the genetic expression of NAFLD and non-alcoholic steatohepatitis (NASH) tissue samples to identify common pathways that contribute to NAFLD and NASH pathogenesis.

We employed the Search Tag Analyze Resource for Gene Expression Omnibus platform to search the The National Center for Biotechnology Information Gene Expression Omnibus to elucidate NAFLD and NASH pathology. For NAFLD, we conducted meta-analysis of data from 58 NAFLD liver biopsies and 60 healthy liver biopsies; for NASH, we analyzed 187 NASH liver biopsies and 154 healthy liver biopsies.

Our results from the NAFLD analysis reinforce the role of altered metabolism, inflammation, and cell survival in pathogenesis and support recently described contributors to disease activity, such as altered androgen and long non-coding RNA activity. The top upstream regulator was found to be sterol regulatory element binding transcription factor 1 (SREBF1), a transcription factor involved in lipid homeostasis. Downstream of SREBF1, we observed upregulation in CXCL10, HMGCR, HMGCS1, fatty acid binding protein 5, paternally expressed imprinted gene 10, and downregulation of sex hormone-binding globulin and insulin-like growth factor 1. These molecular changes reflect low-grade inflammation secondary to accumulation of fatty acids in the liver. Our results from the NASH analysis emphasized the role of cholesterol in pathogenesis. Top canonical pathways, disease networks, and disease functions were related to cholesterol synthesis, lipid metabolism, adipogenesis, and metabolic disease. Top upstream regulators included pro-inflammatory cytokines tumor necrosis factor and IL1B, PDGF BB, and beta-estradiol. Inhibition of beta-estradiol was shown to be related to derangement of several cellular downstream processes including metabolism, extracellular matrix deposition, and tumor suppression. Lastly, we found riciribine (an AKT inhibitor) and ZSTK-474 (a PI3K inhibitor) as potential drugs that targeted the differential gene expression in our dataset.

In this study we describe several molecular processes that may correlate with NAFLD disease and progression. We also identified ricirbine and ZSTK-474 as potential therapy.

• Non-alcoholic fatty liver disease
• Non-alcoholic steatohepatitis
• Bioinformatics
• AKT inhibitor
• Therapy

• U01 LM012675 NLM NIH HHS
• UH2 CA203792 NCI NIH HHS

Accumulating evidence indicates that immunotherapy helped to improve the survival and quality-of-life of patients with lung adenocarcinoma (LUAD) or lung squamous cell carcinoma (LUSC) besides chemotherapy and gene targeting treatment. This study aimed to develop immune-related gene signatures in LUAD and LUSC subtypes, respectively. LUAD and LUSC samples were divided into high- and low-abundance groups of immune cell infiltration (Immunity_H and Immunity_L) based on the abundance of immune cell infiltrations. The distribution of immune cells was significantly different between the high- and low-immunity subtypes in LUAD and LUSC samples. The differentially expressed genes (DEGs) between those two groups in LUAD and LUSC contain some key immune-related genes, such as PDL1, PD1, CTLA-4, and HLA families. The DEGs were enriched in multiple immune-related pathways. Furthermore, the seven-immune-related-gene-signature (CD1B, CHRNA6, CLEC12B, CLEC17A, CLNK, INHA, and SLC14A2) prognostic model-based high- and low-risk groups were significantly associated with LUAD overall survival and clinical characteristics. The eight-immune-related-gene-signature (C4BPB, FCAMR, GRAPL, MAP1LC3C, MGC2889, TRIM55, UGT1A1, and VIPR2) prognostic model-based high- and low-risk groups were significantly associated with LUSC overall survival and clinical characteristics. The prognostic models were tested as good ones by receiver operating characteristic, principal component analysis, univariate and multivariate analysis, and nomogram. The verifications of these two immune-related-gene-signature prognostic models showed consistency in the train and test cohorts of LUAD and LUSC. In addition, patients with LUAD in the low-risk group responded better to immunotherapy than those in the high-risk group. This study revealed two reliable immune-related-gene-signature models that were significantly associated with prognosis and tumor microenvironment cell infiltration in LUAD and LUSC, respectively. Evaluation of the integrated characterization of multiple immune-related genes and pathways could help to predict the response to immunotherapy and monitor immunotherapy strategies.

• clinical characteristics
• immune-related gene signature
• lung cancer
• tumor microenvironment
• tumor mutation burden

• Ig multimerization
• Xenopus
• ddIgSF
• evolution
• pIgR

Glycoprotein D (gD) of Herpes Simplex Virus-2 is used as an antigen in various anti-herpes subunit vaccines owing to its involvement in binding the host cell receptors for host infectivity. However, most of these monomeric protein based candidates have shown low immunogenicity in animal models. To enhance the immunogenicity of gD, a fresh approach of fusing its ectodomain with the Fc domain(s) of IgM has been adopted to oligomerize the viral antigen and to exploite the immune-modulating potential of IgM Fc. Six vaccine constructs, generated by fusing three gD-ectodomain-length-variants with the Ig µ-chain domain 4 (µCH4) and µCH3-CH4 fragment, were cloned in Escherichia coli using pET28b( +) vector. The vaccine proteins were expressed in the form of inclusion bodies (IBs) and were in vitro refolded into protein oligomers of high stoichiometries of ~ 15–24, with 70–80% refolding yields. The conformations of gD and Fc components of the refolded oligomers were analyzed by ELISA and CD spectroscopy and were found to be native-like. The sizes and profiles of the size-distribution of oligomers were determined by dynamic light scattering (DLS). The candidate C2 (gD-μCH3-CH4), showing the most compact oligomer size and uniform distribution of its particles was chosen as the suitable candidate for mice immunization studies to assess the immunogenicity of the antigen gD. The C2 oligomer stimulated a strong anti-gD humoral response with an antibody titer of 102,400 and a strong, biased Th1 immune response in C57BL/6 mice, indicating its potential as a strong immunogen which may serve as an effective vaccine candidate.

• Fusion protein
• Glycoprotein D
• Herpes simplex virus-2
• In vitro refolding
• Vaccine

• Science and Engineering Research Board

• Animals
• Antibodies, Bacterial/immunology
• Bacteria/classification
• Bacteria/immunology
• Humans
• Immunity, Mucosal/immunology
• Immunoglobulin A/immunology
• Immunoglobulin D/immunology
• Immunoglobulin G/immunology
• Immunoglobulin M/immunology
• Intestinal Mucosa/immunology
• Intestinal Mucosa/microbiology

• R01 DK123749 NIDDK NIH HHS
• R21 AI138089 NIAID NIH HHS
• R21 AI122256 NIAID NIH HHS
• P01 AI061093 NIAID NIH HHS
• P30 CA022453 NCI NIH HHS

• Antibody response
• B cells
• Immunological memory
• Mycobacterium bovis
• Mycobacterium tuberculosis
• Tuberculosis

• IgM
• autoimmunity
• microbiota
• mucosal immunity
• secretory
• tolerance

• IgG antibody(s)
• antibody drug conjugate(s) (ADC)
• antibody drug(s)
• antibody(s)
• developability
• drug design
• immunotherapy
• monoclonal antibody(s)
• pharmacokinetics
• physicochemical properties

• Animals
• Antibodies, Monoclonal/administration & dosage
• Antibodies, Monoclonal/chemistry
• Antibodies, Monoclonal/immunology
• Communicable Diseases/drug therapy
• Communicable Diseases/immunology
• Drug Design
• Humans
• Immunity, Humoral/drug effects
• Immunity, Humoral/immunology
• Immunoconjugates/administration & dosage
• Immunoconjugates/chemistry
• Immunoconjugates/immunology
• Immunoglobulin G/immunology
• Neoplasms/drug therapy
• Neoplasms/immunology
• Protein Engineering/methods
• Receptors, Fc/immunology

• T32 GM007750 NIGMS NIH HHS

Immunoglobulin (Ig) M is the first antibody isotype to appear during evolution, ontogeny and immune responses. IgM not only serves as the first line of host defense against infections but also plays an important role in immune regulation and immunological tolerance. For many years, IgM is thought to function by binding to antigen and activating complement system. With the discovery of the IgM Fc receptor (FcμR), it is now clear that IgM can also elicit its function through FcμR. In this review, we will describe the molecular characteristics of FcμR, its role in B cell development, maturation and activation, humoral immune responses, host defense, and immunological tolerance. We will also discuss the functional relationship between IgM-complement and IgM-FcμR pathways in regulating immunity and tolerance. Finally, we will discuss the potential involvement of FcμR in human diseases.

• BCR signal
• FcμR
• IgM
• complement
• humoral immune response