Specific Immunological Functions Research Articles

Potential Oncogenic and Immunosuppressive Roles of Multiple EGF-Like Domains 6 (MEGF6) in Colon Cancer: Insights from Bioinformatic Analysis

Multiple epidermal growth factor-like domains protein 6 (MEGF6) is a high molecular weight protein with several EGF-like domains. Although it has been demonstrated to promote metastasis and chemoresistance in colon cancer cells, its specific oncogenic and immunologic functions remain largely unexplored. This study aims to comprehensively analyze publicly available datasets to define the role of MEGF6 in colon cancer development and immune response modulation. The expression of MEGF6 in colon adenocarcinoma (COAD) and normal tissues at both mRNA and protein levels was assessed using the GEPIA2 and HPA databases, respectively. The UALCAN database was employed to examine the association between MEGF6 expression and clinicopathological outcomes in COAD patients, and survival analysis was conducted using the KM plotter database. Functional enrichment analysis of MEGF6-correlated genes was performed using the ShinyGO online tool. Additionally, the correlation of MEGF6 with immune cell infiltration and immunosuppressive molecules was explored through the TIMER and TISIDB databases. Our analysis revealed significantly higher mRNA and protein expressions of MEGF6 in COAD tissues compared to normal tissues, with associations to cancer stage, nodal metastasis status, and histological subtype. High MEGF6 expression was correlated with poorer survival outcomes, and genes correlated with MEGF6 were enriched in biological processes related to cellular component organization, cell adhesion, and extracellular matrix interaction. Furthermore, MEGF6 expression demonstrated a significant correlation with immune cell infiltration and the expression of immunosuppressive molecules, particularly CTLA-4, PD-1, PD-L1, TGF-β, and IL-10. In conclusion, our findings suggest that MEGF6 may play an oncogenic role by influencing cell and extracellular matrix interactions. Its overexpression may indicate immunosuppressive properties within the cancer microenvironment. Therefore, MEGF6 holds promise as a potential biomarker for predicting both prognosis and therapeutic responses in colon cancer. HIGHLIGHTS MEGF6 has been shown to involve colon cancer growth and chemotherapeutic resistance. Bioinformatics confirmed a prognostic significance of MEGF6 in colon cancer. MEGF6 may exert its oncogenic effects by influencing cell-matrix interactions. MEGF6 expression is correlated with immunosuppressive properties of cancers. GRAPHICAL ABSTRACT

Immune cells in adipose tissue microenvironment under physiological and obese conditions.

This review will focus on the immune cells in adipose tissue microenvironment and their regulatory roles in metabolic homeostasis of adipose tissue and even the whole body under physiological and obese conditions. This review used PubMed searches of current literature to examine adipose tissue immune cells and cytokines, as well as the complex interactions between them. Aside from serving as a passive energy depot, adipose tissue has shown specific immunological function. Adipose tissue microenvironment is enriched with a large number of immune cells and cytokines, whose physiological regulation plays a crucial role for metabolic homeostasis. However, obesity causes pro-inflammatory alterations in these adipose tissue immune cells, which have detrimental effects on metabolism and increase the susceptibility of individuals to the obesity related diseases. Adipose tissue microenvironment is enriched with various immune cells and cytokines, which regulate metabolic homeostasis of adipose tissue and even the whole body, whether under physiological or obese conditions. Targeting key immune cells and cytokines in adipose tissue microenvironment for obesity treatment becomes an attractive research point.

Serum Levels of Selected Cytokines in Male Nigerian Farm Workers Exposed to Dichlorvos Organophosphate Pesticide

Background: Dichlorvos Organophosphate Pesticide (DOP) is an occupational and environmental toxicant which has been classified as highly hazardous and carcinogenic. DOP has been associated with a number of immunocompromised effects as it interferes and interacts with the specific immunological functions. However, there is lack of information on the effects of DOP on serum cytokine levels in DOP users, thus, selected pro- and anti-inflammatory cytokines were therefore measured in adult male farmer workers exposed to DOP. Materials and Methods: One hundred and twenty adult male Farm Workers (FW) consisting of 60 Pesticide Applicators (PA) and 60 farmers exposed to DOP for not less than ten years were randomly enrolled into this study. Sixty apparently healthy adult males without occupational exposure to DOP served as controls. Serum levels of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ)] and anti-inflammatory cytokines [interleukins (IL)-4 and IL-10] were determined using ELISA. Data were analyzed using ANOVA, Post-Hoc and Pearson correlation coefficient. P-values less than 0.05 were considered as statistically significant. Results: The serum levels of IFN-γ and IL-4 were significantly higher in FW compared with the controls while the serum levels of IFN-γ, IL-4 and IL-10 were significantly higher in PA compared with the farmers. IL-4 had significant positive correlation with IFN-ϒ in farm workers, PA and farmers exposed to DOP but IL-4 had significant positive correlation with TNF-α in farmers only. Conclusion: There is a balanced pro and anti-inflammatory cytokine secretion in farm workers with long term exposure to DOP which regulates the pathogenicity of DOP exposure.

Immunological Functions and Evolutionary Emergence of Heavy-Chain Antibodies

Homodimeric antibodies devoid of light chains have evolved multiple times through convergent evolution, yet their specific immunological functions remain poorly understood. We survey the molecular and structural features of these antibodies, their immunological functions in host defense, and reflect on the long-standing question of the evolutionary forces driving their emergence.

Specific β-Turns Precede PPIIL Structures Binding to Allele-Specific HLA-DRβ1* PBRs in Fully-Protective Malaria Vaccine Components.

The 3D structural analysis of 62 peptides derived from highly pathogenic Plasmodium falciparum malaria parasite proteins involved in host cell invasion led to finding a striking association between particular β-turn types located in the N-terminal peripheral flanking residue region (preceding the polyproline II left-handed structures fitting into the HLA-DRβ* allele family) and modified immune protection-inducing protein structure induced long-lasting protective immunity. This is the first time association between two different secondary structures associated with a specific immunological function has been described: full, long-lasting protective immunity.

Th9 lymphocytes: A recent history from IL-9 to its potential role in rheumatic diseases.

Various subtypes of effector T cells have been described up to date, and each one has its specific immunological function and a defined cytokine secretion profile. Th9 lymphocytes, recently described, are characterized by a high IL-9 expression. Their differentiation requires the integration of IL-4 and TGF-β signaling pathways and the coordinated participation of multiple transcription factors. Their role has been mainly found in immunity against parasites and in allergic inflammatory processes. Nevertheless, they have been implicated in processes as autoimmunity, cancer and recently in rheumatic diseases. The objective of this review is to describe the discovery of this cellular subtype, its differentiation, expression regulation and its potential role in rheumatic diseases.

Vitamins mediate immunological homeostasis and diseases at the surface of the body.

The host immune system is regulated not only by endogenous factors, such as cytokines and chemokines, but also by exogenous factors, such as commensal bacteria and dietary materials. Vitamins are vital nutrients that are mainly derived from the diet and commensal bacteria. Accumulating evidence has revealed specific functions of vitamins in the control of host immunity. In agreement with their vital roles in the appropriate maintenance of immunity, excessive or insufficient intake of vitamins leads to the development of immune diseases or susceptibility to infection. In this review, we focus on the diverse but specific immunologic functions of vitamins in regulating host immune responses and their association with immune and infectious diseases.

Shared genetic determinants between eczema and other immune-related diseases

Eczema and other allergic disorders are complex diseases caused by multiple genetic and environmental factors. Here, we review recent success in the identification of novel susceptibility loci for eczema. Genome-wide association studies led to marked progress in unraveling the genetic determinants of allergic disorders. In the past 4 years, a total of 14 new eczema susceptibility loci have been identified and nearly all of them were successfully replicated. Seven additional eczema loci were recently identified by alternative strategies utilizing the remarkable overlap in the genetic cause of diverse immune-related traits. Apart from underlining the importance of the skin barrier in eczema, these studies point to specific immunological functions altered in eczema pathogenesis. The new findings demonstrate that common pathways are involved in the development of eczema and other immune-related traits. Moreover, the genetic determinants shared between eczema, asthma, and allergic rhinitis should aid in resolving the molecular mechanisms triggering disease progression along the atopic march. The identification of the underlying genes and causal variants will be the major challenge for upcoming studies.

Cell therapy as a strategy to minimize maintenance immunosuppression in solid organ transplant recipients

This review presents a clinically focussed introduction to cell-based immunotherapy in solid organ transplantation. The potential benefits and risks of cell-based immunotherapeutics are critically discussed. The use of immunoregulatory cells as medicinal agents is very much in its infancy, but the field is expanding rapidly. In principle, this approach permits manipulation of specific immunological functions, opening new possibilities in the field of tolerance-promoting therapies. Several immunoregulatory cell types have reached the point of preclinical and clinical development that should allow them to be tested in early-phase clinical trials. Solid organ transplantation represents an important potential indication for the use of cell-based immunosuppressive agents because promoting immunological regulation towards allografts remains a promising strategy for preventing chronic rejection. Remarkable progress is being made in the implementation of novel cell-based immunotherapeutics in solid organ transplantation studies. It is hoped that these new immunoregulatory therapies will afford better long-term transplant outcomes by mitigating chronic graft injury.

Effects of Polysaccharide from B.Jiangsiensis to the immune deficit mouse's specific immunological function

目的 研究天螺霜作为免疫增强剂对免疫功能低下模型小鼠特异性免疫功能的影响及其剂量效果关系.方法采用皮下注射环磷酰胺制造小鼠免疫功能低下模型,观察并比较不同剂量天螺霜(400 mg/kg、200 mg/kg、50 mg/kg)与环磷酰胺配合使用对以鸡红细胞为抗原的溶血素生成和二硝基氯苯所致小鼠迟发型超敏反应的影响.结果模型组小鼠溶血素、溶血空斑形成和迟发型超敏反应均明显下降,而阳性药物对照组和高、中剂量天螺霜组该免疫功能均明显增强(P＜0.05或P＜0.01),且其作用强度呈现剂量依赖性,高剂量组作用略强于阳性药.结论天螺霜可明显增强免疫功能低下模型小鼠特异性免疫功能,作用呈剂量依赖性.最高剂量推荐200～400 mg/kg。

Are pANCA, ASCA, or cytokine gene polymorphisms associated with pouchitis? Long-term follow-up in 102 ulcerative colitis patients.

Pouchitis is the most frequent complication after ileal pouch-anal anastomosis for ulcerative colitis. This study aims to analyze the frequency and characteristics of pouchitis in long-term follow-up in a large population, and to determine whether a significant association exists between five immunogenetic markers and pouchitis. From a population of over 500 ulcerative colitis patients who had undergone ileal pouch-anal anastamosis 5-12 yr earlier, 102 subjects participated in the study. Using clinical data obtained from interviews and chart reviews, patients were classified into three groups: no pouchitis; 1-2 episodes per year; and >2 episodes per year. Coded sera from the patients were analyzed for ulcerative colitis-associated perinuclear antineutrophil cytoplasmic antibodies and Crohn's disease-associated anti-saccharomyces cerevesiae antibodies. Interleukin-1 receptor antagonist, tumor necrosis factor (TNF), and lymphotoxin beta (lymphotoxin) polymorphisms were also analyzed. Pouchitis affected 49% of the study population. Antineutrophil cytoplasmic antibodies, anti-saccharomyces cerevesiae antibodies, and lymphotoxin-beta polymorphisms were not associated with pouchitis. Carriage of interleukin-1 receptor antagonist allele 2 was significantly greater among those without pouchitis than those with pouchitis. Patients without pouchitis had a significantly greater carriage rate of TNF allele 2. Perinuclear antineutrophil cytoplasmic antibodies and anti-saccharomyces cerevesiae antibodies are not correlated with pouchitis, but interleukin-1 receptor antagonist and TNF may play a role in its development. Further evaluation of these markers in pouchitis will require larger populations, long-term prospective observation, and studies that correlate polymorphisms with specific immunologic functions.

Cell Adhesion Proteins As Tumor Suppressors

We summarize recent progress on the role of cell adhesion molecules in biology and discuss the potential application of cell adhesion molecules for managing urological cancer. We comprehensively reviewed the literature from 1982 to 2001, including peer reviewed publications and recent abstracts from national meetings, relevant to cell adhesion molecules in urological cancer. A growing body of evidence suggests that alterations in the adhesion properties of neoplastic cells have a pivotal role in the development and progression of cancer. Loss of intercellular adhesion and desquamation of cells from the underlying lamina propria allows malignant cells to escape from their site of origin, degrade the extracellular matrix, acquire a more motile and invasion phenotype, and invade and metastasize. In addition to participating in tumor invasiveness and metastasis, adhesion molecules regulate or significantly contribute to various functions, including signal transduction, cell growth, differentiation, site specific gene expression, morphogenesis, immunological function, cell motility, wound healing and inflammation. To date a diverse system of transmembrane glycoproteins has been identified that mediates cell-cell and cell-extracellular matrix adhesion. The main families of adhesion molecules include members of the Ig superfamily, cadherins, integrins and selectins. Multiple and diverse cell adhesion molecules participate in intercellular and cell-extracellular matrix interactions of cancer. Cancer progression is a multistep process, in which some adhesion molecules have a pivotal role in the development of recurrent, invasive and distant metastasis. Recent data implicate some of these molecules in cell signaling and tumor suppression, which has important consequences for tumor growth.

Effect of adenovirus gene transfer vectors on the immunologic functions of mouse dendritic cells.

To address the effect of adenovirus (Ad) gene transfer vector transduction on the diverse functions of dendritic cells, we used an Ad vector encoding no transgene (AdNull) to transduce mouse bone-marrow-derived dendritic cells (BMDC). Initial experiments using an Ad vector encoding a marker gene (AdGFP, jellyfish green fluorescent protein) showed that the optimal ratio of infectious Ad particles to each cell was 100, when both transgene expression and resultant BMDC viability were taken into account. Exposure to AdNull resulted in upregulation of both surface activation markers (CD40, MHC class II, B7.1, B7.2, ICAM-1) and IL-12 expression by BMDC. AdNull activation of BMDC was observed in multiple strains of mice. Despite this, AdNull-transduced BMDC displayed only modestly impaired antigen uptake ability, as demonstrated in macropinocytosis and phagocytosis assays, in vitro. However, Ad-modified BMDC migrated to regional lymph nodes five times more efficiently than sham-transduced BMDC in vivo. In addition, Ad transduction significantly enhanced the ability of BMDC to present a model peptide antigen to T-lymphocyte hybridoma cells at low BMDC:T cell ratios. We conclude that Ad modification, in and of itself, induces a state of activation in mouse BMDC. This activation, albeit mild compared with that induced by other stimuli, produces measurable effects of the specific immunological functions of these antigen-presenting cells.

The multiple roles of major histocompatibility complex class-I-like molecules in mucosal immune function

The human major histocompatibility complex (MHC) on chromosome 6 encodes three classical class-I genes: human leukocyte antigens (HLA) A, B, and C. These polymorphic genes encode a 43- to 45-kDa cell surface glycoprotein that, in association with the 12-kDa β2-microglobulin molecule, functions in the presentation of nine amino acid peptides to the T-cell receptor of CD8-bearing T lymphocytes and killer inhibitory receptors on natural killer cells. In addition to these ubiquitously expressed, polymorphic proteins, the human genome also encodes several nonclassical MHC class-I-like, or class Ib, genes that, in general, encode nonpolymorphic molecules involved in various specific immunological functions. Many of these genes, including CD1, the neonatal Fc receptor for IgG, HLA-G, HLA-E, the MHC class-I chainrelatedgene A, and Hfe, are prominently displayed on epithelial cells, suggesting an important role in epithelial cell biology.

Re: Procalcitonin: a new parameter for the diagnosis of bacterial infection in the perioperative period. Oczenski et al., Eur J Anaesthesiol 1998; 15

Sir: Major advances in our understanding of sepsis have made it clear that uncontrolled infections are not the only cause of systemic inflammation and that other stimuli, such as pancreatitis, major trauma and thermal injury, can also trigger a systemic inflammatory response and lead to organ failure. Common signs of systemic inflammation such as changes in body temperature, leucocytosis and tachycardia may therefore have an infectious or non-infectious aetiology. Bacteriological evidence of infection, although considered a gold standard, may surprisingly not always be helpful in differentiating between infectious and non-infectious inflammation. Negative blood cultures do not exclude an infection, and multiple samples may be required over extended periods before positive cultures emerge. Because these common clinical and laboratory parameters lack sensitivity and specificity, an early marker of the infectious aetiology of a generalized inflammatory response is needed which would allow early (differential) diagnosis and initiation of specific therapeutic interventions. Furthermore, the disappointing results of immunomodulatory trials in septic patients has raised doubts as to whether conventional clinical and laboratory criteria used for recruiting septic patients may suffice in identifying groups of patients who would most likely benefit from such therapies [1]. New indicators are thus also needed to define the inflammatory response better and help target the populations of septic patients who would benefit from such trials. In recent years, a variety of laboratory and immunological parameters have been proposed as possible indicators of severe inflammatory response to infections. One such parameter, procalcitonin, has emerged as a possible marker of severe generalized infection [2]. Oczenski and co-workers reviewed the current literature concerning procalcitonin [3]. They concluded that procalcitonin is a good indicator of the activity and severity of the inflammatory response and may be used for monitoring severe bacterial infections. However, as we have pointed out elsewhere [2], although procalcitonin offers considerable advantages in comparison with conventionally used laboratory parameters, it does not fulfil all the criteria of an ideal marker for severe microbial infections. Procalcitonin may not or may only slightly increase when infection remains confined to a tissue or organ with no systemic manifestations. For the same reason, although elevated procalcitonin levels during severe infections may decrease to very low levels with appropriate therapy, this does not always indicate complete eradication of the infection, but merely that generalization of the infection is under control. Continuation of antibiotic therapy or surgical measures may be necessary until all clinical signs of infection have disappeared. Furthermore, procalcitonin levels may also be elevated during non-infectious inflammatory states such as after major trauma or surgery and after cardiopulmonary bypass. In addition, patients with C-cell carcinoma of the thyroid gland and small-cell carcinoma of the lung without underlying infection may also have increases in procalcitonin levels [4]. Many other important questions pertaining to procalcitonin remain unanswered. Is procalcitonin release related to bacterial products (alone) or do cytokines also have a role? Which cells produce procalcitonin during severe infections? What specific endocrinological or immunological function does procalcitonin serve during severe infection? Because of these open questions and limitations, more clinical and laboratory studies are needed to uncover the nature and utility of this parameter in inflammatory states. K. REINHART W. KARZAI Department of Anesthesiology and Intensive Care Medicine, University Hospital, Friedrich-Schiller-University Jena, 07740 Jena, Germany

II. One size fits all: nonclassical MHC molecules fulfill multiple roles in epithelial cell function

The human major histocompatibility complex (MHC) on chromosome 6 encodes three classical class I genes: human leukocyte antigen-A (HLA-A), HLA-B, and HLA-C. These polymorphic genes encode a 43- to 45-kDa cell surface glycoprotein that, in association with the 12-kDa beta 2-microglobulin molecule, functions in the presentation of nine amino acid peptides to the T cell receptor of CD8-bearing T lymphocytes and killer inhibitory receptors on natural killer cells. In addition to these ubiquitously expressed polymorphic proteins, the human genome also encodes a number of nonclassical MHC class I-like, or class Ib, genes that in general encode nonpolymorphic molecules involved in a variety of specific immunologic functions. Many of these genes, including CD1, the neonatal Fc receptor for immunoglobulin G, HLA-G, the MHC class I chain-related gene A, and Hfe, are prominently displayed on epithelial cells, suggesting an important role in epithelial cell biology.

50-mile walking race suppresses neutrophil bactericidal function by inducing increases in cortisol and ketone bodies

To examine the effect of intensive aerobic exercise on the interaction between endocrine and immune systems, we studied in ten normal healthy male subjects the effect of a 50-mile walking race on blood concentration of hormones (insulin, GH, ACTH, cortisol, adrenaline, noradrenaline, and dopamine), ketone bodies, specific immunological functions (IgG, IgM, and PHA/Con A-induced lymphocyte blastformation test), and nonspecific immune (CH 50, and neutrophil bactericidal functions). Neutrophil bactericidal activity was measured as chemiluminescences amplified by luciferin analog (CLA-DCL) and luminol (L-DCL). The race increased cortisol and ketone bodies, and decreased insulin, CLA-DCL, and L-DCL (all parameters; P < 0.01). However, other parameters were not significantly changed. There were significant negative correlations between changes of ketone bodies/cortisol and CLA/L-DCL (P < 0.05), however there was no significant correlations between changes of insulin and CLA/L-DCL. These data indicate that extensive aerobic exercise causes impaired neutrophil bactericidal function, probably due to the induced increases in both cortisol and ketone bodies. This impaired neutrophil function may cause the susceptibility to infection after an extensive exercise.

P-170 glycoprotein (P-170) is involved in the impairment of natural killer cell-mediated cytotoxicity in HIV + patients

In the present study we analyze peripheral blood lymphocytes (PBL) from patients with human immunodeficiency virus (HIV) infection for both phenotypic expression and function of P-glycoprotein (P-170). This transmembrane efflux pump is known to be one of the mechanisms responsible for the multidrug resistance (MDR) in cancer therapy and it is also constitutively expressed in normal PBL. P-170 function, evaluated as Rhodamine 123 (Rh123) efflux in flow cytometry, was found to be significantly reduced in CD16 + natural killer (NK) cells from patients with HIV infection. Interestingly, this reduced efflux significantly correlates with the decreased NK cytotoxicity observed in HIV + patients, as evaluated against the NK-specific K562 target cell line. These results support a possible role of the P-170-related pump in specific immunological lymphocyte function such as NK cell-mediated cytotoxicity.

Transmembrane P-glycoprotein (P-gp/P-170) in HIV infection: analysis of lymphocyte surface expression and drug-unrelated function.

P-glycoprotein (P-gp/P-170), a transmembrane efflux pump known to be one of the mechanisms responsible for multidrug resistance in cancer therapy, is constitutively expressed in several solid human tissues as well as in normal peripheral blood lymphocytes and bone marrow cells. In particular, this molecule has been associated with the transport of perforin and other cytolysins in natural killer (NK) and T cytotoxic lymphocytes. In the present study, we analyzed peripheral blood lymphocytes (PBLs) from controls and HIV+ patients for phenotypic expression and function of the P-gp/P-170 molecule. We found that 90% of all PBL subsets (i.e., CD4+, CD8+, CD56+, and CD19+ cells) expressed surface P-gp/P-170 both in controls and HIV+ patients. However, a significant decrease in CD4+/P-170+ and CD19+/P-170+ cells was observed in HIV+ individuals with respect to controls. PHA and IL-2 stimulation of PBLs was unable to increase the expression of P-gp/P-170 both in controls and HIV+ patients, despite the increased detection of the CD25 molecule. On the other hand, stimulation with anti-CD3 determined a significant increase in lymphocyte P-gp/P-170. The function of P-gp/P-170, assessed by a flow cytometric assay for rhodamine-123 (Rh123) efflux, was significantly reduced in CD16+ NK cells and CD19+ B cells from HIV+ patients. The Rh123 efflux by NK cells correlated (p < 0.01) with the NK cytotoxicity against the 51Cr-labeled K562 cell line. Last, the effect of the antiretroviral drugs AZT, ddI, and ddC on P-gp expression and function was evaluated. The dideoxynucleoside compounds did not inhibit P-gp/P-170 function of normal mononuclear cells in vitro, and did not increase P-gp/P-170 expression in vivo, in patients undergoing antiretroviral therapy with AZT. These findings provide further evidence of a possible involvement of the P-gp/P-170 system in specific immunological lymphocyte functions, and especially in cytotoxic-type functions. In addition, it is possible to suggest, on the basis of our experimental data, that the dideoxynucleoside class of antiretroviral agents does not contribute to the phenotypic and functional alterations related to P-glycoprotein during HIV infection.

MHC class I-like, class II-like and CD1 molecules: distinct roles in immunity

Genes encoding MHC class I-like, class II-like and CD1 molecules have evolved to assume specific immunological functions. Some class I-like molecules, including H-2M3 and Qa-2, present formylated bacterial peptides or have distinct peptide-binding motifs. The class II-like DMA and DMB gene products play a role in presentation of peptide antigen by class II molecules. By contrast, CD1 molecules appear to have evolved separately into presenters of nonprotein antigens and into TCR ligands with specialized roles in the immune response. Thus, class I-like, class II-like and CD1 molecules appear either to serve important independent functions or to complement MHC class I and class II. It is expected that future efforts will increasingly reveal the functional ramifications of these molecules.