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PubMed1982

Immunological profile of amyotrophic lateral sclerosis patients and their cell-mediated immune responses to viral and CNS antigens.

The 'immunological profile' of amyotrophic lateral sclerosis (ALS) patients was established from standard tests for B- and T-cell function. This showed no significant difference from age and sex-matched other neurological (CNS) disease controls and normal subjects. Immune complex (IC) levels in ALS serum differed significantly from normal controls but not from CNS controls. There was no relation between the various indices of immune activity of IC levels and the clinical disability of the ALS patient or progression of the disease. Distribution of complement-fixing antibodies to poliovirus was similar to sera of ALS and control groups. The in vitro cell-mediated immune responses to poliovirus, however, were significantly greater in ALS patients than in CNS controls and were inversely related to the ALS disability score. Poliovirus has not been demonstrated in the CNS or extra-CNS tissues of ALS patients by conventional means but, if latent or defective poliovirus or related virus were present, this could account for sensitization and a possible autoimmune mechanism. ALS patients exhibited in vitro cellular immunity to ALS and normal CNS subfractions. These responses were not related to the ALS disability score or progression of the disease and probably represent epiphenomena.

Adenoviridae↗

PubMed2026

Multi-level aggregation analysis of microbiome composition and host gene expression reveals associations with systemic and local immunity.

The human gut microbiome plays a critical role in immune regulation, yet the molecular links between microbiome composition and host gene expression remain incompletely understood. We analyzed associations between host gene expression and microbiome composition in a cohort of 315 healthy individuals, integrating microarray-based gene expression data from three intestinal sites (ileum, transverse colon, and rectum) and six immune cell types with microbiome sequencing data. Using a hierarchical feature aggregation strategy combining principal component analysis, clustering, and covariate correction, we discovered significant associations primarily related to immunity. While microbial profiles were similar across the three intestinal sites, the transverse colon yielded the most "microbiome-host gene expression" associations. Among the immune cell types, CD8+ cells showed the highest number of associations. The first principal component of microbiome composition, reflecting a gradient from commensals (e.g., Ruminococcaceae and Christensenellaceae) to proinflammatory taxa ([Ruminococcus] gnavus and Lachnoclostridium), correlated with the expression of TNF-α-linked genes (HMOX1, CPI17, HSD3B2, and SLC5A1). Among individual genera, Catenibacterium abundance was associated with gene expression in both intestinal and immune cells, including negative associations with MRPS21 (related to mitochondrial function) in the transverse colon and with CD8+ gene programs related to T cell differentiation. These findings align with emerging evidence implicating mitochondrial dysfunction in intestinal inflammation. Our results identify multi-level associations between the gut microbiome and host gene expression, suggesting potential mechanisms by which microbiota shape local and systemic immunity and vice versa. The implicated genes and taxa represent candidates for experimental validation to improve understanding of host-microbiome homeostasis and its disruption in disease.IMPORTANCEThe gut microbiome and immune system are engaged in a complex interplay throughout human life. While most associative studies focus on case-control comparisons-typically examining patients with conditions such as inflammatory bowel disease or metabolic diseases-less is known about the molecular links between the microbiome and immune system in healthy individuals. In this study of a large cohort of healthy individuals, we addressed this gap by applying multiscale modeling to tackle the high dimensionality of host-microbiome data. We identified multi-level associations between microbiome composition and host gene expression in both intestinal tissues and immune cells. These findings offer a valuable reference for understanding baseline host-microbiome communication and highlight molecular candidates-such as TNF-α-related genes and mitochondrial pathways-for future experimental validation.

Humans↗

PubMed2003

Tumor-associated antigen profiling in breast and ovarian cancer: mRNA, protein or T cell recognition?

PURPOSE: The absence of tumor-associated antigens (TAA) which might elicit an immune response is one reason for the disappointing results of therapeutical vaccines in cancer patients. Moreover, impaired expression of MHC class-I and components involved in antigen processing, such as TAP-1, -2, LMP-2, -7, and MECL-1, may lead to tumor escape from immune recognition. Expression profiling of TAA is one approach towards the design of well-defined and individualized anti-tumor vaccines. METHODS: Quantitative polymerase chain reaction (qRT-PCR) is the method of choice to characterize immunologically relevant properties of individual tumors. However, the application of qRT-PCR as a surrogate parameter for the expression of TAAs depends upon the assumption that the level of an mRNA species correlates with the cellular level of the protein it encodes. Therefore, we additionally analyzed TAA expression by immunofluorescence and T cell recognition. RESULTS: In the present study we were unable to confirm that impaired TAP-1 or -2 (transporter associated with antigen processing) expression characterized at the mRNA level is an appropriate surrogate parameter for down-regulated MHC class-I expression in breast cancer. In addition, we analyzed the expression pattern of TAAs in breast and ovarian cancer cell lines. Besides the well-known over-expression of HER-2/neu, CEA, and MUC-1, multiple antigens of the MAGE-family were frequently co-expressed. We investigated whether detection of TAAs by qRT-PCR correlates with monoclonal antibody staining, and which method could predict T cell recognition. We demonstrated a correlation between tumor cell lysis by HLA-A*0201-restricted, MUC-1-specific CTL and threshold levels of MUC-1-specific mRNA. CONCLUSION: MUC-1 is an example that TAA profiling by RT-PCR and flow cytometry can fail to correlate with each other and are of limited value in the prediction of T cell recognition.

ATP-Binding Cassette Transporters↗

PubMed2002

Prospective molecular profiling of melanoma metastases suggests classifiers of immune responsiveness.

We amplified RNAs from 63 fine needle aspiration (FNA) samples from 37 s.c. melanoma metastases from 25 patients undergoing immunotherapy for hybridization to a 6108-gene human cDNA chip. By prospectively following the history of the lesions, we could correlate transcript patterns with clinical outcome. Cluster analysis revealed a tight relationship among autologous synchronously sampled tumors compared with unrelated lesions (average Pearson's r = 0.83 and 0.7, respectively, P < 0.0003). As reported previously, two subgroups of metastatic melanoma lesions were identified that, however, had no predictive correlation with clinical outcome. Ranking of gene expression data from pretreatment samples identified approximately 30 genes predictive of clinical response (P < 0.001). Analysis of their annotations denoted that approximately half of them were related to T-cell regulation, suggesting that immune responsiveness might be predetermined by a tumor microenvironment conducive to immune recognition.

Adult↗

PubMedDate not supplied

Gene expression profiling of peripheral blood mononuclear leukocytes from psoriasis patients identifies new immune regulatory molecules.

In the present report gene expression profiling of peripheral blood mononuclear cells (PBMC) from psoriasis patients suffering from severe generalized disease was performed comparing diseased stage with cured stage. By this means, 18 genes were identified which showed differential expression. The most significant differences were found for IL-8, annexin A3, cycloxygenase-2 (COX-2), cell cycle regulator G0S2, and pre-B cell enhancing factor (PBEF), all of which showed upregulation in the diseased stage. Microarray data were confirmed by real-time RT-PCR. Further analyses using support vector machines identified three pairs of genes (IL-8 - CDKN1C/p57, cyclooxygenase-2 - NR1D2, and desmocollin-2 - CDKN1C/p57) which allowed an accuracy of disease stage prediction of 86%, based on gene expression patterns. Taken together, this is the first large-scale gene expression study of psoriasis PBMC identifying candidate genes that might contribute to psoriasis immunopathogenesis. The genes identified in the present report and the molecular mechanisms underlying their regulation might serve as future targets for therapeutic intervention in psoriasis.

Gene Expression Profiling↗

PubMed1997

Bordetella pertussis-specific Th1/Th2 cells generated following respiratory infection or immunization with an acellular vaccine: comparison of the T cell cytokine profiles in infants and mice.

In an investigation of cell-mediated immunity against Bordetella pertussis, we found that B. pertussis infection in infants and in mice was associated with the induction of antigen-specific T cells that secrete IFN-g and IL-2, but not IL-4 or IL-5. This cytokine profile is characteristic of Th1 cells that mediate cellular immune responses against a range of intracellular pathogens. An examination of cytokine production following immunization with a three-component acellular vaccine, comprising inactive PT, FHA and pertactin adsorbed to alum, demonstrated that spleen cells from vaccinated mice produced high levels of IL-5, but no detectable IFN-g and low levels of IL-2. In contrast, peripheral blood mononuclear cells from vaccinated infants produced IL-2, IL-5 and IFN-g. These findings highlight significant differences in the immune responses generated by vaccination and natural infection with B. pertussis and demonstrate that the T-cell response induced with an acellular vaccine, although dominated by type 2 cytokines in mice, is more heterogeneous in infants with a Th0 or mixed Th1/Th2 cytokine profile.

Adult↗

PubMed2005

Johne's disease in cattle is associated with enhanced expression of genes encoding IL-5, GATA-3, tissue inhibitors of matrix metalloproteinases 1 and 2, and factors promoting apoptosis in peripheral blood mononuclear cells.

Infection of ruminants with Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis) leads to a chronic and often fatal granulomatous enteritis known as Johne's disease. Most infections with M. paratuberculosis occur during the first 6 months of life, and there is some evidence for transmission in utero. Once established, infections typically exist in a subclinical state for several years. Recent gene-expression profiling studies suggested the hypothesis that inherent gene-expression profiles in peripheral blood mononuclear cells (PBMCs) from M. paratuberculosis-infected cattle may be different than expression profiles in PBMCs from uninfected controls. If true, this would suggest that it is possible to identify an M. paratuberculosis infection "signature" through transcriptional profiling of peripheral immune cells. In addition, identification of groups or classes of genes showing inherently different expression in PBMCs from M. paratuberculosis-infected cattle relative to PBMCs from uninfected controls might highlight important interactions between this pathogen and the host immune system. In this report, we describe studies aimed at testing this hypothesis. Our novel results indicate that, indeed expression profiles of at least 42 genes are inherently different in freshly isolated PBMCs from M. paratuberculosis-infected cattle when compared to similar cells from uninfected controls. Gene-expression differences observed following microarray analysis were verified and expanded upon by quantitative real-time PCR (Q-RT-PCR). Our results indicate that T cells within PBMCs from M. paratuberculosis-infected cows have adopted a predominant Th 2-like phenotype (enhanced expression of IL-5, GATA 3, and possibly IL-4 mRNA), that cells within infected cow PBMCs may exhibit tissue remodeling deficiencies through higher expression of tissue inhibitor of matrix metalloproteinase (TIMP) 1 and TIMP2 RNA and lower expression of matrix metalloproteinase (MMP) 14 RNA than similar cells from healthy controls, and that cells within the PBMC population of M. paratuberculosis-infected cows are likely poised for rapid apoptosis (upregulation of CIDE-A, Bad, TNFRI, and Fas).

Animals↗

PubMed2003

Specific history of heterologous virus infections determines anti-viral immunity and immunopathology in the lung.

Having previously shown that previous immunity to one virus can influence the host response to a subsequent unrelated virus, we questioned whether the outcome to a given virus infection would be altered in similar or different ways by previous immunity to different viruses, and whether immunity to a given virus would have similar effects on all subsequent infections. In mouse models of respiratory viral infections, immunity to lymphocytic choriomeningitis virus (LCMV), murine cytomegalovirus (MCMV), or influenza A virus enhanced both Th1-type cytokine responses and viral clearance in the lung on vaccinia virus infection. A common pathological feature was the presence of chronic mononuclear infiltrates instead of the acute polymorphonuclear response seen in the infected nonimmune mice, but some pathologies such as enhanced bronchus-associated lymphoid tissue and bronchiolitis obliterans were unique for the immunizing virus, LCMV. Immunity to influenza virus influenced subsequent infections diversely, inhibiting vaccinia virus but enhancing LCMV and MCMV titers and completely altering cytokine profiles. Influenza virus immunity enhanced the mild mononuclear responses usually observed during acute infections with MCMV or LCMV in nonimmune mice, but unique features such as enhanced bronchiolization and mononuclear consolidation occurred during MCMV infection of influenza virus-immune mice. Heterologous immunity induced two patterns of disease outcome dependent on the specific virus infection sequence: improved, if the acute response switched from a neutrophilic to a lymphocytic response or worsened, if it switched from a mild to a severe lymphocytic response. Heterologous immunity thus occurs between many viruses, resulting in altered protective immunity and lung immunopathology, and this is influenced by the specific virus infection sequence.

Animals↗

PubMed2026

Proteomic analysis identifies pathways related to immune dysregulation in patients with hematologic malignancies after COVID-19 infection.

Patients with hematologic malignancies (HMs) are particularly vulnerable to coronavirus disease 2019 (COVID-19) because of underlying immune dysfunction and treatment-related immunosuppression. However, proteomic features associated with different clinical trajectories in this population remain insufficiently characterized. We performed serum proteomic analysis in 40 HM patients with COVID-19 and 15 healthy controls. Compared with controls, HM patients showed impaired immune-related responses during the acute phase of COVID-19. Acute-phase proteomic patterns differed across outcome groups; however, because outcome groups were closely intertwined with initial COVID-19 severity, ICU admission, and systemic illness, and because multivariable adjustment was not performed due to the limited sample size, these patterns should be interpreted as severity- and outcome-associated profiles rather than independent trajectory-specific markers. Fatal cases showed evidence of dysregulated immune activation, whereas patients later classified as having long COVID exhibited broader suppression of immune-related pathways. In addition to immune alterations, pathways related to platelet activation and cardiac-related dysfunction were associated with adverse clinical trajectories. Enzyme-linked immunosorbent assay validation supported the association of selected proteins with outcome groups during acute infection. These findings provide a proteomic overview of COVID-19 in HM patients and offer a basis for future mechanistic studies and larger external validation cohorts.IMPORTANCEPatients with hematologic malignancies are highly vulnerable to severe coronavirus disease 2019 (COVID-19), acute death, and long COVID due to preexisting immune dysfunction. However, the proteomic signatures linked to adverse clinical trajectories remain poorly understood. Our serum proteomic study identifies distinct acute-phase immune profiles associated with different outcomes: broad immune suppression characterizes long COVID, while dysregulated immune activation is associated with fatal cases. Platelet activation and cardiac-related pathways are also linked to poor outcomes. These findings provide key molecular insights for this high-risk population, supporting future biomarker development, risk stratification, and targeted clinical management.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT05683353.

Humans↗

PubMed1994

Lymphokine production by human T cells in disease states.

A large body of evidence suggests the existence of polarized human T cell responses, reminiscent of Th1 and Th2 subsets described for mouse T cells. Human Th1-like cells preferentially develop during infections by intracellular bacteria, protozoa, and viruses, whereas Th2-like cells predominate during helminthic infestations and in response to common environmental allergens. The cytokine profile of "natural immunity" evoked by different offending agents in the context of different host genetic backgrounds appears to be a critical factor in determining the phenotype of the subsequent specific response. Strongly polarized human Th1-type and Th2-type responses not only play different roles in protection, they can also promote different immunopathological reactions. Th1-type responses appear to be involved in organ specific autoimmunity, in contact dermatitis, and in some chronic inflammatory disorders of unknown etiology. In contrast, in genetically predisposed hosts, Th2-type responses against common environmental allergens are responsible for triggering of allergic atopic disorders. Altered profiles of lymphokine production may account for immune dysfunctions in some primary or acquired immunodeficiency syndromes. The role of lymphokines produced by T cells in the pathogenesis of systemic autoimmune disorders is less clear. Further work is also required to better clarify the role of T cell-derived lymphokines in protecting against tumors or in favoring their development.

Autoimmune Diseases↗

PubMed2006

Patterns of immune response to a vaccine or virus as measured by intracellular cytokine staining in flow cytometry: hypothesis generation and comparison of groups.

Candidate HIV vaccines must show an immune response in order to be considered for further testing and development. What constitutes a "response," however, is still not clear. While the hunt for a protective vaccine continues, hypotheses are being formed by studying the immune responses across cohorts of people with differing responses to the infection, as well as the immune responses formed by healthy people to other viruses, ones that are generally common and well controlled. Here we examine the functional profile of the immune responses of a group of HIV+ long-term non-progressors as measured by intracellular cytokine staining using polychromatic flow cytometry, and compare these responses to those of a larger group of other HIV+ people. We describe some of the types of patterns in immune response that are of interest to vaccine researchers, and compare several statistical tests appropriate for this type of data.

AIDS Vaccines↗

PubMed2006

B cell targeted therapies: safety considerations.

Reported data from recent clinical trials have contributed substantially to our growing understanding of the potential effectiveness and safety of B cell targeted therapy in the treatment of rheumatic diseases. Trials with rituximab, an anti-CD20 monoclonal antibody that depletes mature B cells, have amassed the most data of any B cell targeted therapy to date. A number of other B cell directed therapies are under investigation. Interestingly, although they may share a common target, the different agents have quite distinct mechanisms of action, and therefore their efficacy and safety profiles may differ. A common concern with all B cell directed therapies is the potential effect these agents may have on humoral immunity. The safety profile of rituximab in the oncology setting is well known, based on a database of well over 370,000 patients. Phase II trials of rituximab in rheumatoid arthritis (RA) have begun to examine safety issues specifically in the RA population, including issues surrounding longterm and repeated treatment safety profiles. Questions about the longterm safety of B cell therapy remain to be clarified: What will be the safety profile for repeated treatment courses? What will be the safety profile when B cell targeted therapies are used in sequence or in conjunction with other agents? Answers to these important questions are likely to come from careful observations by treating clinicians, data from registries, and longterm followup of patients enrolled in clinical trials.

Antibodies, Monoclonal↗

PubMed2000

Effects of active and passive gonadotrophin-releasing hormone immunization on recognition and establishment of pregnancy in pigs.

This study investigated the effects of a reduction in gonadotrophins, by means of differently timed active and passive gonadotrophin-releasing hormone (GnRH) immunization at various stages, on the maintenance of early pregnancy in pigs. In the first experiment crossbred sows (n = 11) were immunized against GnRH using a commercial vaccine on the day of farrowing, mated at the first oestrus, and a booster immunization was administered 10 days (n = 7) or 20 days (n = 4) after mating. Plasma samples were collected every second day and assayed for GnRH antibodies and progesterone. Pregnancy testing was carried out by real time ultrasound. None of the sows receiving the booster immunization 10 days after mating were pregnant on Day 18 after mating. All sows receiving the booster on Day 20 after mating aborted, with a mean vaccination-to-abortion interval of 10.0 +/- 1.5 days. In the second experiment, crossbred gilts (n = 6) were passively immunized by infusing (i.v.) GnRH immune pig serum on Day 12 after mating. Luteinizing hormone profiles were determined on the day before immunization and one day afterwards. Daily plasma samples were assayed for GnRH antibodies and progesterone. None of the gilts were pregnant 18 days after mating, compared with 5 of 6 non-immunized controls. Booster immunization 10 days after mating resulted in failure of embryonic development and establishment of pregnancy before the corpora lutea (CL) regressed, according to progesterone profiles, whereas immunization 20 days after mating resulted in regression of CL followed by abortion. Passive immunization 12 days after mating had a similar effect to the active immunization 10 days after mating. These results demonstrate two different outcomes of active GnRH immunization depending on the timing of immunization, and indicate that loss of pregnancy between Days 12 and 18 may occur due a reduction in progesterone rather than complete failure of the CL, as occurs at later stages. The findings may provide an explanation for the reduced fertility of pigs in the summer-autumn period.

Animals↗

PubMed2001

Somebody else's antibodies: the characteristics and roles of immune globulins.

UNLABELLED: CREDIT: This lesson is good for 0.2 CE units, with a passing grade of 70%. OBJECTIVES: After completing this continuing education article, the pharmacist will be able to: 1. Compare and contrast active vs. passive immunity and homologous vs. heterogenous antibodies. 2. Describe the historical development and modern manufacture of immune globulins. 3. Identify the wide range of uses and effects of modern immune globulin products. 4. Discuss the adverse effect profiles of currently available immune globulins.

Antibodies, Monoclonal↗

PubMed2001

Survey of standards and guidelines for immunization delivery.

Data Collection↗

PubMed2002

Cutting edge: molecular portrait of human autoimmune disease.

Autoimmune diseases affect 3-5% of the population, are mediated by the immune response to self-Ags, and are characterized by the site of tissue destruction. We compared expression levels of >4,000 genes in PBMC of control individuals before and after immunization to those of individuals with four distinct autoimmune diseases. The gene expression profile of the normal immune response exhibits coordinate changes in expression of genes with related functions over time. In contrast, each individual from all autoimmune diseases displays a similar gene expression profile unrelated to the pattern of the immunized group. To our surprise, genes with a distinct expression pattern in autoimmunity are not necessarily "immune response" genes, but are genes that encode proteins involved in apoptosis, cell cycle progression, cell differentiation, and cell migration.

Adult↗

PubMed2000

DNA-Based immunization with Trypanosoma cruzi complement regulatory protein elicits complement lytic antibodies and confers protection against Trypanosoma cruzi infection.

A complement regulatory protein (CRP) of Trypanosoma cruzi was evaluated as a vaccine candidate in a murine model of experimental T. cruzi infection. Recombinant CRP derived from an Escherichia coli expression system and a plasmid encoding the full-length crp structural gene under the control of a eukaryotic promoter were used to immunize BALB/c mice. Immunization with both protein and DNA vaccines resulted in a Th1-type T-cell response, comparable antibody titers, and similar immunoglobulin G isotype profiles. Only mice immunized with the crp DNA plasmid produced antibodies capable of lysing the parasites in the presence of complement and were protected against a lethal challenge with T. cruzi trypomastigotes. These results demonstrate the superiority of DNA immunization over protein immunization with the recombinant CRP. The work also supports the further investigation of CRP as a component of a multigene, anti-T. cruzi DNA vaccine.

Animals↗

PubMed1996

Immune regulation by cannabinoid compounds through the inhibition of the cyclic AMP signaling cascade and altered gene expression.

Immune modulation by cannabinoid compounds, although established for several decades, has remained up until recently mechanistically obscure. The identification of a novel class of G-protein coupled receptors that negatively regulate the cyclic adenosine 3':5'-monophosphate (cAMP) cascade, bind cannabinoids, and are expressed on cells within the immune system has provided new insights into the mechanism for their biologic activity. Although the role of the cAMP cascade in the regulation of immune responses is itself highly controversial, a number of laboratories recently demonstrated that aberrant regulation of this signaling pathway leads to alterations in the expression of critical immunoregulatory genes, cell cycle arrest, and decreased immune function. This profile of effects is strikingly similar to that which is induced in leukocytes in the presence of cannabinoid compounds. In the present commentary, a putative mechanism of immune regulation by cannabinoids is proposed. This mechanism is discussed in the context of decreased cAMP signaling, the transcription factors that are consequently adversely regulated, and immunologically relevant genes that ultimately exhibit altered expression.

Adjuvants, Immunologic↗