bluuebunny/crossref_metadata_2025 huggingface dataset:
IL-7-Adjuvanted Vaginal Vaccine Elicits Strong Mucosal Immune Responses in Non-Human Primates
Authors: Logerot Sandrine , Figueiredo-Morgado Suzanne , Charmeteau-de-Muylder Bénédicte , Sandouk Abdelkader , Drillet-Dangeard Anne-Sophie , Bomsel Morgane , Bourgault-Villada Isabelle , Couëdel-Courteille Anne , Cheynier Rémi , Rancez Magali
Published: February 2021

Mucosal immune responses are crucial in protecting against pathogens entering through mucosal surfaces. However, due to poor T-cell responsiveness upon mucosal antigenic stimulation, mucosal immunity remains difficult to obtain through vaccines and requires appropriate adjuvants. We previously demonstrated that administered systemically to healthy macaques or locally expressed in the intestinal mucosa of acutely SIV-infected macaques, interleukin-7 (IL-7) triggers chemokine expression and immune cell homing into mucosae, suggesting its important role in the development of mucosal immune responses. We therefore examined whether local delivery of recombinant glycosylated simian IL-7 (rs-IL-7gly) to the vaginal mucosa of rhesus macaques could prepare the lower female genital tract (FGT) for subsequent immunization and act as an efficient mucosal adjuvant. First, we showed that local administration of rs-IL-7gly triggers vaginal overexpression of chemokines and infiltration of mDCs, macrophages, NKs, B- and T-cells in the lamina propria while MamuLa-DR+APCs accumulated in the epithelium. Subsequent mucosal anti-DT immunization in macaques resulted in a faster, stronger, and more persistent mucosal antibody response compared to DT-immunization alone. Indeed, we detected robust productions of DT-specific IgAs and IgGs in their vaginal secretions and identified cells secreting DT-specific IgAs in their vaginal mucosa and IgGs in draining lymph nodes. Finally, the expression of chemokines involved in the organization of tertiary lymphoid structures (TLS) was only increased in the vaginal mucosa of IL-7-adjuvanted immunized macaques. Interestingly, TLSs developed around PNAd+high endothelial venules in their lower FGT sampled 2 weeks after the last immunization. Non-traumatic vaginal administration of rs-IL-7gly prepares the mucosa to respond to subsequent local immunization and allows the development of a strong mucosal immune response in macaques, through the chemokine-dependent recruitment of immune cells, the activation of mDCs and the formation of TLSs. The localization of DT-specific IgA+plasma cells in the upper vaginal mucosa argues for their contribution to the production of specific immunoglobulins in the vaginal secretions. Our results highlight the potential of IL-7 as a potent mucosal adjuvant to stimulate the FGT immune system and elicit vaginal antibody responses to local immunization, which is the most promising way to confer protection against many sexually transmitted diseases.
Clonorchis sinensis-Derived Protein Attenuates Inflammation and New Bone Formation in Ankylosing Spondylitis
Authors: Lee Yu Jeong , Kim Moon-Ju , Jo Sungsin , Jin So-Hee , Park Pu-Reum , Park Kijeong , Song Ho-Chun , Kim Jahae , Kim Ji-Young , Shim Seung Cheol , Kim Tae-Hwan , Hong Sung-Jong , Kang Hyundeok , Kim Tae-Jong , Won Eun Jeong
Published: February 2021

Helminth infections and their components have been shown to have the potential to modulate and attenuate immune responses. The objective of this study was to evaluate the potential protective effects of Clonorchis sinensis-derived protein (CSp) on ankylosing spondylitis (AS). Cytotoxicity of CSp at different doses was assessed by MTS and flow cytometry before performing experiments. Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) were obtained from AS patients. Inflammatory cytokine-producing cells were analyzed using flow cytometry. The levels of INF-γ, IL-17A, TNF-α, and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA). SKG mice were treated with CSp or vehicles. Inflammation and new bone formation were evaluated using immunohistochemistry, positron emission tomography (PET), and micro-computed tomography (CT). Treatment with CSp resulted in no reduced cell viability of PBMCs or SFMCs until 24 h. In experiments culturing PBMCs and SFMCs, the frequencies of IFN-γ and IL-17A producing cells were significantly reduced after CSp treatment. In the SKG mouse model, CSp treatment significantly suppressed arthritis, enthesitis, and enteritis. Micro-CT analysis of hind paw revealed reduced new bone formation in CSp-treated mice than in vehicle-treated mice. We provide the first evidence demonstrating that CSp can ameliorate clinical signs and cytokine derangements in AS. In addition, such CSp treatment could reduce the new bone formation of AS.
Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces
Authors: Dopler Arthur , Stibitzky Selina , Hevey Rachel , Mannes Marco , Guariento Mara , Höchsmann Britta , Schrezenmeier Hubert , Ricklin Daniel , Schmidt Christoph Q.
Published: February 2021

To discriminate between self and non-self surfaces and facilitate immune surveillance, the complement system relies on the interplay between surface-directed activators and regulators. The dimeric modulator FHR-1 is hypothesized to competitively remove the complement regulator FH from surfaces that strongly fix opsonic C3b molecules—a process known as “deregulation.” The C-terminal regions of FH and FHR-1 provide the basis of this competition. They contain binding sites for C3b and host surface markers and are identical except for two substitutions: S1191L and V1197A (i.e., FH “SV”; FHR-1 “LA”). Intriguingly, an FHR-1 variant featuring the “SV” combination of FH predisposes to atypical hemolytic uremic syndrome (aHUS). The functional impact of these mutations on complement (de)regulation, and their pathophysiological consequences, have largely remained elusive. We have addressed these questions using recombinantly expressed wildtype, mutated, and truncated versions of FHR-1 and FH. The “SV” to “LA” substitutions did not affect glycosaminoglycan recognition and had only a small effect on C3b binding. In contrast, the two amino acids substantially affected the binding of FH and FHR-1 to α2,3-linked sialic acids as host surfaces markers, with the S-to-L substitution causing an almost complete loss of recognition. Even with sialic acid-binding constructs, notable deregulation was only detected on host and not foreign cells. The aHUS-associated “SV” mutation converts FHR-1 into a sialic acid binder which, supported by its dimeric nature, enables excessive FH deregulation and, thus, complement activation on host surfaces. While we also observed inhibitory activities of FHR-1 on C3 and C5 convertases, the high concentrations required render the physiological impact uncertain. In conclusion, the SV-to-LA substitution in the C-terminal regions of FH and FHR-1 diminishes its sialic acid-binding ability and results in an FHR-1 molecule that only moderately deregulates FH. Such FH deregulation by FHR-1 only occurs on host/host-like surfaces that recruit FH. Conversion of FHR-1 into a sialic acid binder potentiates the deregulatory capacity of FHR-1 and thus explains the pathophysiology of the aHUS-associated FHR-1 “SV” variant.
Exposure to Dengue Envelope Protein Domain III Induces Nlrp3 Inflammasome-Dependent Endothelial Dysfunction and Hemorrhage in Mice
Authors: Lien Te-Sheng , Sun Der-Shan , Wu Cheng-Yeu , Chang Hsin-Hou
Published: February 2021

Typically occurring during secondary dengue virus (DENV) infections, dengue hemorrhagic fever (DHF) causes abnormal immune responses, as well as endothelial vascular dysfunction, for which the responsible viral factor remains unclear. During peak viremia, the plasma levels of virion-associated envelope protein domain III (EIII) increases to a point at which cell death is sufficiently induced in megakaryocytesin vitro. Thus, EIII may constitute a virulence factor for endothelial damage. In this study, we examined endothelial cell death induced by treatment with DENV and EIIIin vitro. Notably, pyroptosis, the major type of endothelial cell death observed, was attenuated through treatment with Nlrp3 inflammasome inhibitors. EIII injection effectively induced endothelial abnormalities, and sequential injection of EIII and DENV-NS1 autoantibodies induced further vascular damage, liver dysfunction, thrombocytopenia, and hemorrhage, which are typical manifestations in DHF. Under the same treatments, pathophysiological changes in the Nlrp3 inflammasome–deficient mice were notably reduced compared with those in the wild-type mice. These results suggest that the Nlrp3 inflammasome constitutes a potential therapeutic target for treating DENV-induced hemorrhage in DHF.
Hepatitis B Surface Antigen Suppresses the Activation of Nuclear Factor Kappa B Pathway via Interaction With the TAK1-TAB2 Complex
Authors: Deng Feiyan , Xu Gang , Cheng Zhikui , Huang Yu , Ma Caijiao , Luo Chuanjin , Yu Chen , Wang Jun , Xu Xiupeng , Liu Shi , Zhu Ying
Published: February 2021

Chronic hepatitis B is a major health problem worldwide, with more than 250 million chronic carriers. Hepatitis B virus interferes with the host innate immune system so as to evade elimination via almost all of its constituent proteins; nevertheless, the function of HBsAg with respect to immune escape remains unclear. This study aimed to determine the role HBsAg plays in assisting HBV to escape from immune responses. We found that HBsAg suppressed the activation of the nuclear factor kappa B (NF-кB) pathway, leading to downregulation of innate immune responses. HBsAg interacted with TAK1 and TAB2 specifically, inhibiting the phosphorylation and polyubiquitination of TAK1 and the K63-linked polyubiquitination of TAB2. Autophagy is a major catabolic process participating in many cellular processes, including the life cycle of HBV. We found that HBsAg promoted the autophagic degradation of TAK1 and TAB2 via the formation of complexes with TAK1 and TAB2, resulting in suppression of the NF-κB pathway. The expression of TAK1, TAB2, and the translocation of NF-κB inversely correlated with HBsAg levels in clinical liver tissues. Taken together, our findings suggest a novel mechanism by which HBsAg interacts with TAK1-TAB2 complex and suppresses the activation of NF-κB signaling pathway via reduction of the post-translational modifications and autophagic degradation.
Case Report: Epstein–Barr Virus Encephalitis Complicated With Brain Stem Hemorrhage in an Immune-Competent Adult
Authors: Huang Lingtong , Zhang Xuan , Fang Xueling
Published: February 2021

Encephalitis caused by Epstein-Barr virus infection is uncommon, but most patients have a good outcome after symptomatic treatment. The infiltration of mononuclear cells in blood vessels and necrosis resulting from the immune response to Epstein-Barr virus infection in a very small number of patients seem to be the main cause of death. We describe a fatal case of Epstein-Barr virus encephalitis diagnosed by next-generation sequencing in an immune-competent adult but progressed to brainstem hemorrhage.
The Impact of Oral-Gut Inflammation in Cerebral Palsy
Authors: Ferreira Ana Cristina Fernandes Maria , Eveloff Ryan J. , Freire Marcelo , Santos Maria Teresa Botti Rodrigues
Published: February 2021

Background: Oral-gut inflammation has an impact on overall health, placing subjects at risk to acquire chronic conditions and infections. Due to neuromotor disturbances, and medication intake, cerebral palsy (CP) subjects present intestinal constipation, impacting their quality of life (QOL). We aimed to investigate how oral inflammatory levels predicted gut phenotypes and response to therapy.

Methods: A total of 93 subjects aging from 5 to 17 years were included in the study, and assigned into one of the 4 groups: CP with constipation (G1, n = 30), CP without constipation (G2, n = 33), and controls without CP with constipation (G3, n = 07) and without CP and without constipation (G4, n = 23). In addition to characterizing subjects' clinical demographics, medication intake, disease severity levels, salivary cytokine levels [TNF-α, interleukin (IL)-1β, IL-6, IL-8, IL-10], and Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD). Statistical significance was evaluated by Shapiro-Wilks, Student's T-Test, ANOVA, and ANCOVA analysis.

Results: Salivary proinflammatory cytokines were highly correlated with the severe form of gut constipation in G1 (P < 0.001), and out of all cytokines IL-1β levels demonstrated highest correlation with all gut constipation (P < 0.05). A significant relationship was found between the type of medication, in which subjects taking Gamma-Aminobutyric Acid (GABA) and GABA+ (GABA in association with other medication) were more likely to be constipated than the other groups (P < 0.01). Cleary salivary inflammatory levels and gut constipation were correlated, and impacted QOL of CP subjects. G1 presented a lower QOL mean score of CPCHILD (49.0 ± 13.1) compared to G2 (71.5 ± 16.7), when compared to G3 (88.9 ± 7.5), and G4 (95.5 ± 5.0) (P < 0.01). We accounted for gingival bleeding as a cofounder of oral inflammation, and here were no differences among groups regarding gender (P = 0.332) and age (P = 0.292).

Conclusions: Collectively, the results suggest that saliva inflammatory levels were linked to gut constipation, and that the clinical impact of medications that controlled gut was reliably monitored via oral cytokine levels, providing reliable and non-invasive information in precision diagnostics.
In Pursuit of Adult Progenitors of Thymic Epithelial Cells
Authors: Ishikawa Tatsuya , Akiyama Nobuko , Akiyama Taishin
Published: February 2021

Peripheral T cells capable of discriminating between self and non-self antigens are major components of a robust adaptive immune system. The development of self-tolerant T cells is orchestrated by thymic epithelial cells (TECs), which are localized in the thymic cortex (cortical TECs, cTECs) and medulla (medullary TECs, mTECs). cTECs and mTECs are essential for differentiation, proliferation, and positive and negative selection of thymocytes. Recent advances in single-cell RNA-sequencing technology have revealed a previously unknown degree of TEC heterogeneity, but we still lack a clear picture of the identity of TEC progenitors in the adult thymus. In this review, we describe both earlier and recent findings that shed light on features of these elusive adult progenitors in the context of tissue homeostasis, as well as recovery from stress-induced thymic atrophy.
The Role of Natural Killer Cells in Autoimmune Diseases
Authors: Kucuksezer Umut Can , Aktas Cetin Esin , Esen Fehim , Tahrali Ilhan , Akdeniz Nilgun , Gelmez Metin Yusuf , Deniz Gunnur
Published: February 2021

Natural killer (NK) cells, the large granular lymphocytes differentiated from the common lymphoid progenitors, were discovered in early 1970’s. They are members of innate immunity and were initially defined by their strong cytotoxicity against virus-infected cells and by their important effector functions in anti-tumoral immune responses. Nowadays, NK cells are classified among the recently discovered innate lymphoid cell subsets and have capacity to influence both innate and adaptive immune responses. Therefore, they can be considered as innate immune cells that stands between the innate and adaptive arms of immunity. NK cells don’t express T or B cell receptors and are recognized by absence of CD3. There are two major subgroups of NK cells according to their differential expression of CD16 and CD56. While CD16+CD56dimsubset is best-known by their cytotoxic functions, CD16-CD56brightNK cell subset produces a bunch of cytokines comparable to CD4+T helper cell subsets. Another subset of NK cells with production of interleukin (IL)-10 was named as NK regulatory cells, which has suppressive properties and could take part in immune-regulatory responses. Activation of NK cells is determined by a delicate balance of cell-surface receptors that have either activating or inhibitory properties. On the other hand, a variety of cytokines including IL-2, IL-12, IL-15, and IL-18 influence NK cell activity. NK-derived cytokines and their cytotoxic functions through induction of apoptosis take part in regulation of the immune responses and could contribute to the pathogenesis of many immune mediated diseases including ankylosing spondylitis, Behçet’s disease, multiple sclerosis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus and type-1 diabetes. Dysregulation of NK cells in autoimmune disorders may occur through multiple mechanisms. Thanks to the rapid developments in biotechnology, progressive research in immunology enables better characterization of cells and their delicate roles in the complex network of immunity. As NK cells stand in between innate and adaptive arms of immunity and “bridge” them, their contribution in inflammation and immune regulation deserves intense investigations. Better understanding of NK-cell biology and their contribution in both exacerbation and regulation of inflammatory disorders is a requisite for possible utilization of these multi-faceted cells in novel therapeutic interventions.
Potential Targets to Mitigate Trauma- or Sepsis-Induced Immune Suppression
Authors: Bergmann Christian B. , Beckmann Nadine , Salyer Christen E. , Hanschen Marc , Crisologo Peter A. , Caldwell Charles C.
Published: February 2021

In sepsis and trauma, pathogens and injured tissue provoke a systemic inflammatory reaction which can lead to overwhelming inflammation. Concurrent with the innate hyperinflammatory response is adaptive immune suppression that can become chronic. A current key issue today is that patients who undergo intensive medical care after sepsis or trauma have a high mortality rate after being discharged. This high mortality is thought to be associated with persistent immunosuppression. Knowledge about the pathophysiology leading to this state remains fragmented. Immunosuppressive cytokines play an essential role in mediating and upholding immunosuppression in these patients. Specifically, the cytokines Interleukin-10 (IL-10), Transforming Growth Factor-β (TGF-β) and Thymic stromal lymphopoietin (TSLP) are reported to have potent immunosuppressive capacities. Here, we review their ability to suppress inflammation, their dynamics in sepsis and trauma and what drives the pathologic release of these cytokines. They do exert paradoxical effects under certain conditions, which makes it necessary to evaluate their functions in the context of dynamic changes post-sepsis and trauma. Several drugs modulating their functions are currently in clinical trials in the treatment of other pathologies. We provide an overview of the current literature on the effects of IL-10, TGF-β and TSLP in sepsis and trauma and suggest therapeutic approaches for their modulation.
Case Report: Rapidly Progressive Interstitial Lung Disease in A Pregnant Patient With Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis
Authors: Chen Cuihong , Chen Yulan , Huang Qin , Hu Qiu , Hong Xiaoping
Published: February 2021

Dermatomyositis occurs extremely rarely during pregnancy. A number of studies in the published literature have documented how the outcome of pregnancy is poor for both mother and fetus. The present case study reports on a patient who was diagnosed with clinically amyopathic dermatomyositis complicated by interstitial lung disease during pregnancy, and was successfully treated with a combined immunosuppressant regimen. To the best of the authors’ knowledge, this is the first case study detailing how a pregnant woman with clinically amyopathic dermatomyositis with positive anti-melanoma differentiation-associated gene 5 antibody achieved complete remission after early intervention of combined immunosuppressive therapy without residual pulmonary interstitial changes.
Gamma Delta T Cells and Their Pathogenic Role in Psoriasis
Authors: Qi Cong , Wang Yazhuo , Li Ping , Zhao Jingxia
Published: February 2021

γδT cells are an unconventional population of T lymphocytes that play an indispensable role in host defense, immune surveillance, and homeostasis of the immune system. They display unique developmental, distributional, and functional patterns and rapidly respond to various insults and contribute to diverse diseases. Although γδT cells make up only a small portion of the total T cell pool, emerging evidence suggest that aberrantly activated γδT cells may play a role in the pathogenesis of psoriasis. Dermal γδT cells are the major IL-17-producing cells in the skin that respond to IL-23 stimulation. Furthermore, γδT cells exhibit memory-cell-like characteristics that mediate repeated episodes of psoriatic inflammation. This review discusses the differentiation, development, distribution, and biological function of γδT cells and the mechanisms by which they contribute to psoriasis. Potential therapeutic approaches targeting these cells in psoriasis have also been detailed.
HLA RNA Sequencing With Unique Molecular Identifiers Reveals High Allele-Specific Variability in mRNA Expression
Authors: Johansson Tiira , Yohannes Dawit A. , Koskela Satu , Partanen Jukka , Saavalainen Päivi
Published: February 2021

The HLA gene complex is the most important single genetic factor in susceptibility to most diseases with autoimmune or autoinflammatory origin and in transplantation matching. Most studies have focused on the vast allelic variation in these genes; only a few studies have explored differences in the expression levels of HLA alleles. In this study, we quantified mRNA expression levels of HLA class I and II genes from peripheral blood samples of 50 healthy individuals. The gene- and allele-specific mRNA expression was assessed using unique molecular identifiers, which enabled PCR bias removal and calculation of the number of original mRNA transcripts. We identified differences in mRNA expression between different HLA genes and alleles. Our results suggest that HLA alleles are differentially expressed and these differences in expression levels are quantifiable using RNA sequencing technology. Our method provides novel insights into HLA research, and it can be applied to quantify expression differences of HLA alleles in various tissues and to evaluate the role of this type of variation in transplantation matching and susceptibility to autoimmune diseases.
Complement Has Brains—Do Intracellular Complement and Immunometabolism Cooperate in Tissue Homeostasis and Behavior?
Authors: Kunz Natalia , Kemper Claudia
Published: February 2021

The classical liver-derived and serum-effective complement system is well appreciated as a key mediator of host protectionviainstruction of innate and adaptive immunity. However, recent studies have discovered an intracellularly active complement system, the complosome, which has emerged as a central regulator of the core metabolic pathways fueling human immune cell activity. Induction of expression of components of the complosome, particularly complement component C3, during transmigration from the circulation into peripheral tissues is a defining characteristic of monocytes and T cells in tissues. Intracellular complement activity is required to induce metabolic reprogramming of immune cells, including increased glycolytic flux and OXPHOS, which drive the production of the pro-inflammatory cytokine IFN-γ. Consequently, reduced complosome activity translates into defects in normal monocyte activation, faulty Th1 and cytotoxic T lymphocyte responses and loss of protective tissue immunity. Intriguingly, neurological research has identified an unexpected connection between the physiological presence of innate and adaptive immune cells and certain cytokines, including IFN-γ, in and around the brain and normal brain function. In this opinion piece, we will first review the current state of research regarding complement driven metabolic reprogramming in the context of immune cell tissue entry and residency. We will then discuss how published work on the role of IFN-γ and T cells in the brain support a hypothesis that an evolutionarily conserved cooperation between the complosome, cell metabolism and IFN-γ regulates organismal behavior, as well as immunity.
Comprehensive Genomic Profiling of Rare Tumors in China: Routes to Immunotherapy
Authors: Wang Shuhang , Fang Yuan , Jiang Ning , Xing Shujun , Li Qin , Chen Rongrong , Yi Xin , Zhang Zhiqian , Li Ning
Published: February 2021

Treatment options for rare tumors are limited, and comprehensive genomic profiling may provide useful information for novel treatment strategies and improving outcomes. The aim of this study is to explore the treatment opportunities of patients with rare tumors using immune checkpoint inhibitors (ICIs) that have already been approved for routine treatment of common tumors. We collected immunotherapy-related indicators data from a total of 852 rare tumor patients from across China, including 136 programmed cell death ligand-1 (PD-L1) expression, 821 tumors mutational burden (TMB), 705 microsatellite instability (MSI) and 355 human leukocyte antigen class I (HLA-I) heterozygosity reports. We calculated the positive rates of these indicators and analyzed the consistency relationship between TMB and PD-L1, TMB and MSI, and HLA-I and PD-L1. The prevalence of PD-L1 positive, TMB-H, MSI-, and HLA-I -heterozygous was 47.8%, 15.5%, 7.4%, and 78.9%, respectively. The consistency ratio of TMB and PD-L1, TMB and MSI, and HLA-I and PD-L1 was 54.8% (78/135), 87.3% (598/685), and 47.4% (54/114), respectively. The prevalence of the four indicators varied widely across tumors systems and subtypes. The probability that neuroendocrine tumors (NETs) and biliary tumors may benefit from immunotherapy is high, since the proportion of TMB-H is as high as 50% and 25.4% respectively. The rates of PD-L1 positivity, TMB-H and MSI-H in carcinoma of unknown primary (CUP) were relatively high, while the rates of TMB-H and MSI-H in soft tissue tumors were both relatively low. Our study revealed the distribution of immunotherapeutic indicators in patients with rare tumors in China. Comprehensive genomic profiling may offer novel therapeutic modalities for patients with rare tumors to solve the dilemma of limited treatment options.
ERAP2 Increases the Abundance of a Peptide Submotif Highly Selective for the Birdshot Uveitis-Associated HLA-A29
Authors: Venema Wouter J. , Hiddingh Sanne , de Boer Joke H. , Claas Frans H. J. , Mulder Arend , den Hollander Anneke I. , Stratikos Efstratios , Sarkizova Siranush , van der Veken Lars T. , Janssen George M. C. , van Veelen Peter A. , Kuiper Jonas J. W.
Published: February 2021

Birdshot Uveitis (BU) is a blinding inflammatory eye condition that only affects HLA-A29-positive individuals. Genetic association studies linked ERAP2 with BU, an aminopeptidase which trims peptides before their presentation by HLA class I at the cell surface, which suggests that ERAP2-dependent peptide presentation by HLA-A29 drives the pathogenesis of BU. However, it remains poorly understood whether the effects of ERAP2 on the HLA-A29 peptidome are distinct from its effect on other HLA allotypes. To address this, we focused on the effects of ERAP2 on the immunopeptidome in patient-derived antigen presenting cells. Using complementary HLA-A29-based and pan-class I immunopurifications, isotope-labeled naturally processed and presented HLA-bound peptides were sequenced by mass spectrometry. We show that the effects of ERAP2 on the N-terminus of ligands of HLA-A29 are shared across endogenous HLA allotypes, but discover and replicate that one peptide motif generated in the presence of ERAP2 is specifically bound by HLA-A29. This motif can be found in the amino acid sequence of putative autoantigens. We further show evidence for internal sequence specificity for ERAP2 imprinted in the immunopeptidome. These results reveal that ERAP2 can generate an HLA-A29-specific antigen repertoire, which supports that antigen presentation is a key disease pathway in BU.
Persistent T Cell Repertoire Perturbation and T Cell Activation in HIV After Long Term Treatment
Authors: Turner Carolin T. , Brown James , Shaw Emily , Uddin Imran , Tsaliki Evdokia , Roe Jennifer K. , Pollara Gabriele , Sun Yuxin , Heather James M. , Lipman Marc , Chain Benny , Noursadeghi Mahdad
Published: February 2021

Objective

In people living with HIV (PLHIV), we sought to test the hypothesis that long term anti-retroviral therapy restores the normal T cell repertoire, and investigate the functional relationship of residual repertoire abnormalities to persistent immune system dysregulation.

Methods

We conducted a case-control study in PLHIV and HIV-negative volunteers, of circulating T cell receptor repertoires and whole blood transcriptomes by RNA sequencing, complemented by metadata from routinely collected health care records.

Results

T cell receptor sequencing revealed persistent abnormalities in the clonal T cell repertoire of PLHIV, characterized by reduced repertoire diversity and oligoclonal T cell expansion correlated with elevated CD8 T cell counts. We found no evidence that these expansions were driven by cytomegalovirus or another common antigen. Increased frequency of long CDR3 sequences and reduced frequency of public sequences among the expanded clones implicated abnormal thymic selection as a contributing factor. These abnormalities in the repertoire correlated with systems level evidence of persistent T cell activation in genome-wide blood transcriptomes.

Conclusions

The diversity of T cell receptor repertoires in PLHIV on long term anti-retroviral therapy remains significantly depleted, and skewed by idiosyncratic clones, partly attributable to altered thymic output and associated with T cell mediated chronic immune activation. Further investigation of thymic function and the antigenic drivers of T cell clonal selection in PLHIV are critical to efforts to fully re-establish normal immune function.
Dietary Lysine Levels Improved Antioxidant Capacity and Immunity via the TOR and p38 MAPK Signaling Pathways in Grass Carp, Ctenopharyngodon idellus Fry
Authors: Huang Dongyu , Maulu Sahya , Ren Mingchun , Liang Hualiang , Ge Xianping , Ji Ke , Yu Heng
Published: February 2021

An 8-week rearing trial was designed to appraise the dietary lysine levels on intestinal antioxidant capacity and immunity of grass carp fry. Six practical diets were prepared with graded levels of lysine (1.44, 1.79, 1.97, 2.44, 2.56 and 2.87% dry matter), and these diets were fed to grass carp fry. The results showed that the activities of intestinal antioxidant factors including catalase and glutathione peroxidase were markedly improved by the 2.44% dietary lysine compared with the control diet (1.44% dietary lysine) (P < 0.05). In terms of antioxidants, compared with the control diet, the 2.44% diet markedly upregulated the mRNA expression levels of target of rapamycin, S6 kinase1 and nuclear factor erythroid 2-related factor 2 pathway-related antioxidant genes, containing catalase and glutathione peroxidase 1α (P < 0.05) and downregulated the mRNA levels of Kelch-like ECH-associated protein 1 (P > 0.05). The mRNA levels of 4E-binding protein 2 showed the opposite trend compared with those of target of rapamycin, and the minimum value was observed in the group of 1.97% dietary lysine (P < 0.05). In terms of immunity, compared with the 1.44% diet, the 2.44% diet markedly suppressed the intestinal p38 mitogen-activated protein kinase and interferon γ2 mRNA levels (P < 0.05). Moreover, nuclear factor-kappa B p65, tumor necrosis factor α, interleukin 6, interleukin 8, and interleukin 15 mRNA levels all exhibited the same trend as p38 mitogen-activated protein kinase and interferon γ2; however, the difference among all the lysine treatments groups was not significant (P > 0.05). The anti-inflammatory cytokines transforming growth factor β2 and interleukin 4/13B mRNA levels in the intestine were remarkably upregulated by high dietary lysine levels (2.56 and 2.87%) (P < 0.05), and when the dietary lysine level reached 2.44%, the interleukin 4/13A mRNA levels were strikingly increased (P < 0.05). Overall, the data suggested that 2.44% dietary lysine could strengthen the immune and antioxidant capacities of grass carp fry via activating the target of rapamycin (TOR) signaling pathway, and suppressing the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway, which then improve the survival rate.
Influence of PTPN22 Allotypes on Innate and Adaptive Immune Function in Health and Disease
Authors: Armitage Lucas H. , Wallet Mark A. , Mathews Clayton E.
Published: February 2021

Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) regulates a panoply of leukocyte signaling pathways. A single nucleotide polymorphism (SNP) inPTPN22,rs2476601, is associated with increased risk of Type 1 Diabetes (T1D) and other autoimmune diseases. Over the past decade PTPN22 has been studied intensely in T cell receptor (TCR) and B cell receptor (BCR) signaling. However, the effect of the minor allele on PTPN22 function in TCR signaling is controversial with some reports concluding it has enhanced function and blunts TCR signaling and others reporting it has reduced function and increases TCR signaling. More recently, the core function of PTPN22 as well as functional derangements imparted by the autoimmunity-associated variant allele of PTPN22 have been examined in monocytes, macrophages, dendritic cells, and neutrophils. In this review we will discuss the known functions of PTPN22 in human cells, and we will elaborate on how autoimmunity-associated variants influence these functions across the panoply of immune cells that express PTPN22. Further, we consider currently unresolved questions that require clarification on the role of PTPN22 in immune cell function.
GIPR Signaling in Immune Cells Maintains Metabolically Beneficial Type 2 Immune Responses in the White Fat From Obese Mice
Authors: Efimova Irina , Steinberg Inbar , Zvibel Isabel , Neumann Anat , Mantelmacher Dana Fernanda , Drucker Daniel J. , Fishman Sigal , Varol Chen
Published: February 2021

Glucose-dependent insulinotropic polypeptide (GIP) communicates information on energy availability from the gut to peripheral tissues. Disruption of its signaling in myeloid immune cells during high-fat diet (HFD)-induced obesity impairs energy homeostasis due to the unrestrained metabolically deleterious actions of S100A8/A9 alarmin. White adipose tissue (WAT) type 2 immune cell networks are important for maintaining metabolic and energy homeostasis and limiting obesity-induced inflammation. Nevertheless, the consequences of losing immune cell GIP receptor (GIPR) signaling on type 2 immunity in WAT remains unknown. Bone marrow (BM) chimerism was used to generate mice with GIPR (Gipr-/- BM) and GIPR/S100A8/A9 (Gipr-/-/S100a9-/- BM) deletion in immune cells. These mice were subjected to short (5 weeks) and progressive (14 weeks) HFD regimens. GIPR-deficiency was also targeted to myeloid cells by crossing Giprfl/fl mice and Lyz2cre/+ mice (LysMΔGipr). Under both short and progressive HFD regimens, Gipr-/- BM mice exhibited altered expression of key type 2 immune cytokines in the epididymal visceral WAT (epiWAT), but not in subcutaneous inguinal WAT. This was further linked to declined representation of type 2 immune cells in epiWAT, such as group 2 innate lymphoid cells (ILC2), eosinophils, and FOXP3+ regulatory T cells (Tregs). Co-deletion of S100A8/A9 in Gipr-/- immune cells reversed the impairment of type 2 cytokine expression in epiWAT, suggesting a mechanistic role for this alarmin in type 2 immune suppression. LysMΔGipr mice on HFD also displayed altered expression of type 2 immune mediators, highlighting that GIPR-deficiency in myeloid immune cells is responsible for the impairment of type 2 immune networks. Finally, abrogated GIPR signaling in immune cells also affected adipocyte fraction cells, inducing their increased production of the beiging interfering cytokine IL-10 and stress- related type 2 cytokine IL-13. Collectively, these findings attribute an important role for GIPR in myeloid immune cells in supporting WAT type 2 immunity.
Gene Therapies for Primary Immune Deficiencies
Authors: Kohn Lisa A. , Kohn Donald B.
Published: February 2021

Gene therapy is an innovative treatment for Primary Immune Deficiencies (PIDs) that uses autologous hematopoietic stem cell transplantation to deliver stem cells with added or edited versions of the missing or malfunctioning gene that causes the PID. Initial studies of gene therapy for PIDs in the 1990–2000's used integrating murine gamma-retroviral vectors. While these studies showed clinical efficacy in many cases, especially with the administration of marrow cytoreductive conditioning before cell re-infusion, these vectors caused genotoxicity and development of leukoproliferative disorders in several patients. More recent studies used lentiviral vectors in which the enhancer elements of the long terminal repeats self-inactivate during reverse transcription (“SIN” vectors). These SIN vectors have excellent safety profiles and have not been reported to cause any clinically significant genotoxicity. Gene therapy has successfully treated several PIDs including Adenosine Deaminase Severe Combined Immunodeficiency (SCID), X-linked SCID, Artemis SCID, Wiskott-Aldrich Syndrome, X-linked Chronic Granulomatous Disease and Leukocyte Adhesion Deficiency-I. In all, gene therapy for PIDs has progressed over the recent decades to be equal or better than allogeneic HSCT in terms of efficacy and safety. Further improvements in methods should lead to more consistent and reliable efficacy from gene therapy for a growing list of PIDs.
Climate-Driven Range Shifts Are Rapid Yet Variable Among Recreationally Important Coastal-Pelagic Fishes
Authors: Champion Curtis , Brodie Stephanie , Coleman Melinda A.
Published: February 2021

Shifts in species distributions are occurring globally in response to climate change, but robust comparisons of redistribution rates among species are often prevented by methodological inconsistencies, challenging the identification of species that are most rapidly undergoing range shifts. In particular, comparable assessments of redistributions among harvested species are essential for identifying climate-driven changes in fishing opportunities and prioritising the development of management strategies. Here we utilise consistent datasets and methodologies to comparably analyse rates of climate-driven range shifts over 21 years for four recreationally important coastal-pelagic fishes (Australian bonito, Australian spotted mackerel, narrow-barred Spanish mackerel, and common dolphinfish) from the eastern Australian ocean warming hotspot. Latitudinal values corresponding to the poleward edge of species’ core oceanographic habitats were extracted from species distribution models (SDMs). Rates of poleward shifts in core oceanographic habitats ranged between 148.7 (i.e., common dolphinfish) and 278.6 (i.e., narrow-barred Spanish mackerel) km per decade over the study period. However, rates of redistribution varied by approximately 130 km per decade among species, demonstrating that subtle differences in species’ environmental responses can manifest in highly variable rates of climate-driven range shifts. These findings highlight the capacity for coastal-pelagic species to undergo rapid, yet variable, poleward range shifts, which have implications for ecosystem structure and the changing availability of key resources to fisheries.
Approaches and Challenges in the Management of Multiple Myeloma in the Very Old: Future Treatment Prospects
Authors: Kaweme Natasha Mupeta , Changwe Geoffrey Joseph , Zhou Fuling
Published: February 2021

The increasing incidence of geriatric patients with multiple myeloma has elevated concerns in clinical practice. While the introduction of novel therapeutic agents has substantially improved outcomes in younger patients with myeloma, poorer outcomes remain in older patients. Managing older patients requires a multidisciplinary team approach to consider factors that may influence both treatment selection and outcomes. Aging is associated with remodeling of vital organs, physiological downregulations of basal metabolism, susceptibility to multiple comorbidities with ultimate frailty, thereby contributing to the underrepresentation and exclusion of very old patients from clinical trials. Therefore, timely confirmation of a precise diagnosis is crucial for prompt initiation of treatment if the desired outcome is to be achieved. Adequate and judicious assessment using comprehensive geriatric assessment tools minimizes toxicities and treatment discontinuation. Initiating treatment with combinational therapy requires knowledge of indications and anticipated outcomes, as well as individualized therapy with appropriate dose-adjustment. Individualized therapy based on good clinical acumen and best practices obverts unwanted polypharmacy, preventing iatrogenic harm. This review will therefore address the approaches and challenges faced in managing myeloma in geriatric patients aged 80 years and older, highlighting recommended therapeutic strategies and future prospective regimens.
Sensing, Uptake and Catabolism of L-Phenylalanine During 2-Phenylethanol Biosynthesis via the Ehrlich Pathway in Saccharomyces cerevisiae
Authors: Dai Jun , Xia Huili , Yang Chunlei , Chen Xiong
Published: February 2021

2-Phenylethanol (2-PE) is an important flavouring ingredient with a persistent rose-like odour, and it has been widely utilized in food, perfume, beverages, and medicine. Due to the potential existence of toxic byproducts in 2-PE resulting from chemical synthesis, the demand for “natural” 2-PE through biotransformation is increasing. L-Phenylalanine (L-Phe) is used as the precursor for the biosynthesis of 2-PE through the Ehrlich pathway by Saccharomyces cerevisiae. The regulation of L-Phe metabolism in S. cerevisiae is complicated and elaborate. We reviewed current progress on the signal transduction pathways of L-Phe sensing, uptake of extracellular L-Phe and 2-PE synthesis from L-Phe through the Ehrlich pathway. Moreover, the anticipated bottlenecks and future research directions for S. cerevisiae biosynthesis of 2-PE are discussed.
The CD147 Protein Complex Is Involved in Entry of Chikungunya Virus and Related Alphaviruses in Human Cells
Authors: De Caluwé Lien , Coppens Sandra , Vereecken Katleen , Daled Simon , Dhaenens Maarten , Van Ostade Xaveer , Deforce Dieter , Ariën Kevin K. , Bartholomeeusen Koen
Published: February 2021

Chikungunya virus (CHIKV) is an arbovirus with a global spread and significant public health impact. It is a positive stranded RNA alphavirus belonging to the Togaviridae family. However, many questions about the replication cycle of CHIKV remain unanswered. The entry process of CHIKV is not completely understood nor are the associated virus-receptor interactions fully identified. Here, we designed an affinity purification mass spectrometry coupled approach that allowed the identification of factors that facilitate entry of CHIKV in human cells. The identified entry factors were further validated using CRISPR/Cas9. In HEK293T cells we identified the CD147 protein complex as an entry factor for CHIKV. We further showed the involvement of the CD147 protein complex in the replication cycle of related alphaviruses. Interestingly, CD147 contains similar protein domains as the previously identified alphavirus entry factor MXRA8.
Metagenome Sequencing Reveals the Midgut Microbiota Makeup of Culex pipiens quinquefasciatus and Its Possible Relationship With Insecticide Resistance
Authors: Wang Yi-ting , Shen Rui-xin , Xing Dan , Zhao Chen-pei , Gao He-ting , Wu Jia-hong , Zhang Ning , Zhang Heng-duan , Chen Yan , Zhao Tong-yan , Li Chun-xiao
Published: February 2021

Midgut microbiota can participate in the detoxification and metabolism processes in insects, but there are few reports on the relationship between midgut microbiota and insecticide resistance in mosquitoes. In this study, we performed metagenomic sequencing on a susceptible strain (SS), a field-collected Hainan strain (HN), and a deltamethrin-resistant strain (RR) of Culex pipiens quinquefasciatus to understand the diversity and functions of their midgut microbiota. The results revealed differences in midgut microbiota among the three strains of Cx. pipiens quinquefasciatus. At the phylum level, Proteobacteria was the most prominent, accounting for nearly 70% of their midgut microbes. At the genus level, Aeromonas made up the highest proportion. In addition, Aeromonas, Morganella, Elizabethkingia, Enterobacter, Cedecea, and Thorsellia showed significant differences between strains. At the species level, Bacillus cereus, Enterobacter cloacae complex sp. 4DZ3-17B2, Streptomyces sp. CNQ329, and some species of Pseudomonas and Wolbachia were more abundant in the two resistant strains. Principal component analysis (PCA) showed that the SS strain had significantly different metagenomic functions than the two deltamethrin-resistant strains (HN and RR strain). The HN and RR strains differed from the SS strain in more than 10 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The analysis of species abundance and functional diversity can provide directions for future studies.
Studying the Ability of Thymol to Improve Fungicidal Effects of Tebuconazole and Difenoconazole Against Some Plant Pathogenic Fungi in Seed or Foliar Treatments
Authors: Shcherbakova Larisa , Mikityuk Oleg , Arslanova Lenara , Stakheev Alexander , Erokhin Denis , Zavriev Sergey , Dzhavakhiya Vitaly
Published: February 2021

Thymol, a secondary plant metabolite possessing antifungal and chemosensitizing activities, disrupts cell wall or membrane integrity and interferes with ergosterol biosynthesis. Thymol also functions as a redox-active compound inducing generation of reactive oxygen species and lipid peroxidation in fungal cells. Previously, we showed thymol significantly enhanced the in vitro growth inhibitory effect of difenoconazole against Bipolaris sorokiniana and Parastagonospora nodorum. More recently, we demonstrated a possibility to use thymol to overcome the resistance of a P. nodorum strain able to grow on difenoconazole-containing media. However, potential for thymol to serve as a chemosensitizing agent in seed or plant treatments, to provide an effective suppression of the above-mentioned plant pathogens by triazole fungicides applied in lowered dosages, had yet to be tested. In the work presented here, we showed combined treatments of naturally infected barley seeds with thymol and difenoconazole (Dividend® 030 FS) synergistically exacerbated the protective effect against common root rot agent, B. sorokiniana, and other fungi (Fusarium spp. and Alternaria spp.). Similarly, co-applied treatment of wheat seeds, artificially inoculated with Fusarium culmorum, resulted in equivalent reduction of disease incidence on barley seedlings as application of Dividend®, alone, at a ten-fold higher dosage. In foliar treatments of wheat seedlings, thymol combined with Folicur® 250 EC (a.i. tebuconazole) enhanced sensitivity of P. nodorum, a glume/leaf blotch pathogen, to the fungicide and provided a significant mitigation of disease severity on treated seedlings, compared to controls, without increasing Folicur® dosages. Folicur® co-applied with thymol was also significantly more effective against a strain of P. nodorum tolerant to Folicur® alone. No additional deoxynivalenol or zearalenone production was found when a toxigenic F. culmorum was cultured in a nutrient medium containing thymol at a concentration used for chemosensitization of root rot agents. Accordingly, F. culmorum exposure to thymol at the sensitizing concentration did not up-regulate key genes associated with the biosynthesis of trichothecene or polyketide mycotoxins in this pathogen. Further studies using field trials are necessary to determine if thymol-triazole co-applications result in sensitization of seed- and foliar-associated plant pathogenic fungi, and if thymol affects production of fusarial toxins under field conditions.