Cladribine Alters Immune Cell Surface Molecules for Adhesion and Costimulation: Further Insights to the Mode of Action in Multiple Sclerosis

Cladribine (CLAD) is a deoxyadenosine analogue prodrug which is given in multiple sclerosis (MS) as two short oral treatment courses 12 months apart. Reconstitution of adaptive immune function following selective immune cell depletion is the presumed mode of action. In this exploratory study, we investigated the impact of CLAD tablets on immune cell surface molecules for adhesion (CAMs) and costimulation (CoSs) in people with MS (pwMS). We studied 18 pwMS who started treatment with CLAD and 10 healthy controls (HCs). Peripheral blood mononuclear cells were collected at baseline and every 3 months throughout a 24-month period. We analysed ICAM-1, LFA-1, CD28, HLADR, CD154, CD44, VLA-4 (CD49d/CD29), PSGL-1 and PD-1 with regard to their expression on B and T cells (T helper (Th) and cytotoxic T cells (cT)) and surface density (mean fluorescence intensity, MFI) by flow cytometry. The targeted analysis of CAM and CoS on the surface of immune cells in pwMS revealed a higher percentage of ICAM-1 (B cells, Th, cT), LFA-1 (B cells, cT), HLADR (B cells, cT), CD28 (cT) and CD154 (Th). In pwMS, we found lower frequencies of Th and cT cells expressing PSGL-1 and B cells for the inhibitory signal PD-1, whereas the surface expression of LFA-1 on cT and of HLADR on B cells was denser. Twenty-four months after the first CLAD cycle, the frequencies of B cells expressing CD44, CD29 and CD49d were lower compared with the baseline, together with decreased densities of ICAM-1, CD44 and HLADR. The rate of CD154 expressing Th cells dropped at 12 months. For cT, no changes were seen for frequency or density. Immune reconstitution by oral CLAD was associated with modification of the pro-migratory and -inflammatory surface patterns of CAMs and CoSs in immune cell subsets. This observation pertains primarily to B cells, which are key cells underlying MS pathogenesis.

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Potential Impact of B Cells on T Cell Function in Multiple Sclerosis

Multiple Sclerosis International ◽

10.1155/2011/423971 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 7

Author(s):

Sara Ireland ◽

Nancy Monson

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

T Cell ◽

B Cells ◽

Cell Function ◽

The Central Nervous System ◽

Potential Impact ◽

Anti Cd20 ◽

The Impact ◽

Ms Pathogenesis

Multiple sclerosis is a chronic debilitating autoimmune disease of the central nervous system. The contribution of B cells in the pathoetiology of MS has recently been highlighted by the emergence of rituximab, an anti-CD20 monoclonal antibody that specifically depletes B cells, as a potent immunomodulatory therapy for the treatment of MS. However, a clearer understanding of the impact B cells have on the neuro-inflammatory component of MS pathogenesis is needed in order to develop novel therapeutics whose affects on B cells would be beneficial and not harmful. Since T cells are known mediators of the pathology of MS, the goal of this review is to summarize what is known about the interactions between B cells and T cells, and how current and emerging immunotherapies may impact B-T cell interactions in MS.

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Antibodies as antigens. The use of mouse monoclonal antibodies to focus human T cells against selected targets.

Journal of Experimental Medicine ◽

10.1084/jem.167.2.345 ◽

1988 ◽

Vol 167 (2) ◽

pp. 345-352 ◽

Cited By ~ 72

Author(s):

A Lanzavecchia ◽

S Abrignani ◽

D Scheidegger ◽

R Obrist ◽

B Dörken ◽

...

Keyword(s):

T Cells ◽

Monoclonal Antibodies ◽

Cell Surface ◽

Mhc Class Ii ◽

Class Ii ◽

Cell Surface Molecules ◽

Tumor Patients ◽

Surface Molecules ◽

Human T Cells ◽

Positive Target

We found that three tumor patients treated with mouse mAbs have T cells that recognize processed mouse Ig on autologous APC in a class II-restricted fashion, and we have shown that mouse mAbs directed against various cell surface molecules can be used as antigens to focus these T cells on an MHC class II-positive target of choice.

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Immunophenotypic Analysis of B Lymphocytes in Patients with Common Variable Immunodeficiency: Identification of CD23 as a Useful Marker in the Definition of the Disease

ISRN Immunology ◽

10.1155/2013/512527 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Giuseppe Patuzzo ◽

Filippo Mazzi ◽

Antonio Vella ◽

Riccardo Ortolani ◽

Alessandro Barbieri ◽

...

Keyword(s):

B Cells ◽

Cell Surface ◽

B Lymphocytes ◽

Clinical Features ◽

Common Variable Immunodeficiency ◽

The Novel ◽

Cell Surface Molecules ◽

Surface Molecules ◽

Definition Of ◽

Common Variable

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by the failure of B lymphocytes differentiation leading to deficient immunoglobulins secretion. The identified genetic defects account only for a minority of cases. The importance of B cells immunophenotyping in the classification of CVID is known. This procedure can identify alterations on the cell surface molecules expression that could explain some immunological disorders characteristic of CVID. Moreover, some immunophenotypical aspects can correlate with clinical features of the disease. We used this procedure to analyze a cohort of 23 patients affected by CVID, in order to identify the novel alterations of B cells and to find the possible correlations with clinical features. Circulating B cells were studied by flow cytometry incubating whole blood with specific antibodies for B cell surface molecules including CD27, IgM, IgD, CD21, and CD23. We compared the population of “switched memory” IgD− CD27+ B lymphocytes with the population of “switched memory” IgM− IgD− CD23− CD27+ B cells. These last B cells were reduced in patients compared to healthy controls; moreover, IgM− IgD− CD23− CD27+ B cells were lower than IgD− CD27+ B cells in patients with CVID. The reduction of this subset of B lymphocytes correlates more tightly than IgD− CD27+ B cells with lymphadenopathy and airways infections. In conclusion, our findings may help in better identifying patients with CVID.

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Depression, Anxiety, and Social Environmental Adversity as Potential Modulators of the Immune Tumor Microenvironment in Breast Cancer Patients

Medical Sciences ◽

10.3390/medsci9020046 ◽

2021 ◽

Vol 9 (2) ◽

pp. 46

Author(s):

Eida M. Castro-Figueroa ◽

Karina I. Acevedo ◽

Cristina I. Peña-Vargas ◽

Normarie Torres-Blasco ◽

Idhaliz Flores ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

B Cells ◽

Tumor Microenvironment ◽

Immune Cell ◽

Depressive Symptomatology ◽

Anxiety Symptoms ◽

Trauma History ◽

Social Environmental ◽

The Impact

Background: Mounting data suggest that exposure to chronic stress is associated with worse breast cancer outcomes. This study aimed to explore the impact of social environmental adversity (SEA, e.g., child abuse, crime, sexual, and physical violence), depressive symptomatology, and anxiety on immune cell infiltration into the breast tumor microenvironment. Methods: Participants (n = 33) completed a series of surveys assessing depression and anxiety symptoms, adverse childhood events (ACE), and trauma history. Tumor-associated macrophages (CD68+), B cells (CD19+), and T cells (CD3+) were identified by immunohistochemical analyses of formalin-fixed paraffin-embedded tumor samples and quantified. Spearman rank tests were used to explore the relationships between the variables studied. Results: Exposure to SEA was high (ACE = 72%, exposure to crime = 47%, and exposure to physical/sexual assault = 73%) among participants. Moreover, 30% reported a comorbid history of depression and ACE; 39% reported one or more traumatic events, and clinically significant depression symptomatology, while 21% reported trauma history and significant anxiety symptomatology. Increased tumor-infiltrating B cells were significantly correlated with exposure to crime, anxiety symptoms, and exposure to an ACE. The ACE plus anxiety group presented the highest infiltration of B cells, T cells, and macrophages. Conclusion: These findings support a role for SEA, anxiety symptoms, and depression as potential modulators of the immune tumor microenvironment in breast cancer.

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Single-cell RNA-Seq reveals transcriptional heterogeneity and immune subtypes associated with disease activity in human myasthenia gravis

Cell Discovery ◽

10.1038/s41421-021-00314-w ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Wanlin Jin ◽

Qi Yang ◽

Yuyao Peng ◽

Chengkai Yan ◽

Yi Li ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Myasthenia Gravis ◽

Disease Activity ◽

Single Cell ◽

Immune Cell ◽

Large Cell ◽

Cellular Heterogeneity ◽

T Cell Subsets ◽

The Impact

AbstractMyasthenia gravis (MG) is a rare autoimmune disease. Although the impact of immune cell disorder in MG has been extensively studied, little is known about the transcriptomes of individual cells. Here, we assessed the transcriptional profiles of 39,243 cells by single-cell sequencing and identified 13 major cell clusters, along with 39 subgroups of cells derived from patients with new-onset myasthenia gravis and healthy controls. We found that B cells, CD4+ T cells, and monocytes exhibited more heterogeneity in MG patients. CD4+ T cells were expanded in MG patients. We reclustered B cells and CD4+ T cells, and predict their essential regulators. Further analyses demonstrated that B cells in MG exhibited higher transcriptional activity towards plasma cell differentiation, CD4+ T cell subsets were unbalanced, and inflammatory pathways of monocytes were highly activated. Notably, we discovered a disease-relevant subgroup, CD180− B cells. Increased CD180− B cells in MG are indicative of a high IgG composition and were associated with disease activity and the anti-AChR antibody. Together, our data further the understanding of the cellular heterogeneity involved in the pathogenesis of MG and provide large cell-type-specific markers for subsequent research.

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SAT-669 CD40 Ligand Gene Mutation in Type 1 Diabetes Mellitus in a Saudi Consanguineous Family

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1692 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Naweed Alzaman ◽

Monis Bilal Shamsi ◽

Firoz abdul Samad ◽

Syed Nazar Imam ◽

Ghadeer Alharbi ◽

...

Keyword(s):

T Cells ◽

Cell Surface ◽

Immune Cells ◽

Genetic Factors ◽

Cd40 Ligand ◽

Genetic Change ◽

Autoimmune Response ◽

Cell Surface Molecules ◽

Surface Molecules

Abstract Introduction: Type 1 Diabetes Mellitus (T1D) is a common autoimmune disorder. Investigating genetic factors that could turn the immune cells to auto-reactive are critical to our understanding of T1D. In this study genetic factors and the affected autoimmunity related molecular mechanisms in familial T1D with parental consanguinity were studied. Materials and Method: Whole Exome Sequencing (WES) was performed in a family with familial T1D. Sanger Sequencing was done to analyze segregation in affected and non-affected. Clinical and molecular aspects were also evaluated. Protein modeling and other in silico tools were used to identify probable impact of genetic abnormalities on the structure and function of protein. Result: We identified a novel homozygous substitution mutation at “c.379A>T:p.Iso127Val” in CD40 Ligand (CD40LG) gene in diabetic siblings by WES. This change was found to be segregating in the affected and non-affected individuals by Sanger sequencing. Parents and non-diabetic siblings were found to be heterozygous carriers of the nucleotide change. The c.379A>T is located within evolutionarily conserved locus of human genome. Functional prediction by Gene Ontology term analysis suggested that immune functions of CD40LG are compromised by this genetic change. Further, by protein-modeling analysis we identified that structure of ligand-binding domain of CD40LG protein, with which it interacts with other immune cells, may also be affected. In silico analysis revealed significantly reduced spatial inter amino acid distance between the site of genetic change and the ligand binding domain in mutant CD40LG. Discussion: Apoptotic elimination of developing auto-reactive T-cells, having the potential to generate an autoimmune response against pancreatic cells, is critical to prevent T1D. This apoptotic removal mechanisms, occurs in thymus and is dependent on highly specific interaction of cell surface molecules as CD40LG on developing T-cells, and the corresponding cell surface molecules on Antigen Presenting Cells (APC). In the diabetic individuals investigated in our study, the mutation in CD40LG gene, caused significant structural damage to its protein, due to which these interactions between mutant CD40LG (present on T-cells) and the corresponding CD40 (present on APC) were probably affected. This loss of interaction between CD40LG bearing T-cells and APC, probably led to escape of auto-reactive T-cells in to immune system, which further generated autoimmune response against the pancreatic tissue, precipitating to T1D among these individuals. Conclusion Genetic investigation of cell surface proteins in autoimmune cells and understanding their mechanism for development of autoimmunity offers prospects for the development of new therapeutic strategies in the approach to probable early diagnosis of T1D.

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Mitogen-induced genes are subject to multiple pathways of regulation in the initial stages of T-cell activation

Molecular and Cellular Biology ◽

10.1128/mcb.9.3.1034-1040.1989 ◽

1989 ◽

Vol 9 (3) ◽

pp. 1034-1040

Author(s):

S G Irving ◽

C H June ◽

P F Zipfel ◽

U Siebenlist ◽

K Kelly

Keyword(s):

Gene Expression ◽

T Cells ◽

T Cell ◽

Cell Surface ◽

Interleukin 2 ◽

Cell Surface Molecules ◽

Surface Binding ◽

Surface Molecules ◽

Induced Genes ◽

Mitogenic Signal

The delivery of a mitogenic signal to T cells via any one of several cell surface molecules elicits a variety of intracellular responses, some or all of which regulate subsequent gene expression events. The expression of nine novel mitogen-induced genes in response to various T-cell-activating agents was examined to evaluate the diversity of pathways which regulate such genes. The relative contribution of distinct secondary signals, individually or together, to mitogen-stimulated gene induction and the capability of individual genes to respond to the sometimes divergent signals generated from different cell surface structures is addressed. The activation of T cells with mitogenic monoclonal antibodies directed against the CD2 or CD3 cell surface molecules, or with phytohemagglutinin, induced all nine genes. Thus, stimulation by fully mitogenic agents regardless of cell surface-binding specificity correlated with the expression of all of the genes studied. However, heterogeneous patterns of gene expression, encompassing five regulatory classes, were revealed by the use of phorbol 12-myristate 13-acetate, calcium ionophore, and anti-CD28 monoclonal antibody, agents which mediated only a subset of intracellular events and thus an incomplete mitogenic signal. Interleukin-2 and two novel lymphokines represented one regulatory class that appeared to require unique transcriptional activation signals relative to the other mitogen-induced genes. As demonstrated in the accompanying paper (P. F. Zipfel, S. G. Irving, K. Kelly, and U. Siebenlist, Mol. Cell. Biol. 9:1041-1048, 1989), the immediate transcriptional response of T cells to mitogenic stimulation is quite complex, involving numerous genes beyond those which have been previously described. Furthermore, the discrimination of several regulatory phenotypes among these nine genes suggests that a multiplicity of signaling pathways extends from the cell surface to the level of transcription.

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Genetic control of immunoregulatory circuits. Genes linked to the Ig locus govern communication between regulatory T-cell sets.

Journal of Experimental Medicine ◽

10.1084/jem.150.1.44 ◽

1979 ◽

Vol 150 (1) ◽

pp. 44-50 ◽

Cited By ~ 58

Author(s):

D D Eardley ◽

F W Shen ◽

H Cantor ◽

R K Gershon

Keyword(s):

T Cells ◽

T Cell ◽

Cell Surface ◽

Regulatory T Cell ◽

Cell Surface Molecules ◽

Suppressive Activity ◽

T Helper ◽

Surface Molecules ◽

Helper Activity ◽

Per Se

Antigen-stimulated Ly1:Qa1+ cells induce a nonimmune set of T-acceptor cells (surface phenotype Ly123+Qa1+) to participate in the generation of specific suppressive activity. The experiments reported here were designed to test the possibility that the interaction between T-inducer and T-acceptor cells might be governed by genes linked to the Ig locus. We find that inducer:acceptor interactions occur only if the inducer and acceptor T-cell sets are obtained from donor that are identical at the Ig locus and are independent of the Ig locus expressed on the B cells used for assay of T-helper activity. In addition, experiments using inducer and acceptor T cells from the congenic recombinant BAB. 14 strain show that T-T interactions are not governed by Ig-CH genes, per se. These data indicate that T-inducer: T-acceptor interactions are governed by Ig-linked genes that may control expression of VH-like structures on T cells, or control expression of as yet unidentified cell-surface molecules.

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Impact of Cell Surface Molecules on Conjugative Transfer of the Integrative and Conjugative Element ICESt3ofStreptococcus thermophilus

Applied and Environmental Microbiology ◽

10.1128/aem.02109-17 ◽

2017 ◽

Vol 84 (5) ◽

Cited By ~ 4

Author(s):

Narimane Dahmane ◽

Emilie Robert ◽

Julien Deschamps ◽

Thierry Meylheuc ◽

Christine Delorme ◽

...

Keyword(s):

Gene Transfer ◽

Cell Surface ◽

Bacterial Genome ◽

Conjugative Transfer ◽

Cell Surface Molecules ◽

Content Type ◽

Teichoic Acids ◽

Surface Molecules ◽

Donor Cells ◽

The Impact

ABSTRACTIntegrative conjugative elements (ICEs) are chromosomal elements that are widely distributed in bacterial genomes, hence contributing to genome plasticity, adaptation, and evolution of bacteria. Conjugation requires a contact between both the donor and the recipient cells and thus likely depends on the composition of the cell surface envelope. In this work, we investigated the impact of different cell surface molecules, including cell surface proteins, wall teichoic acids, lipoteichoic acids, and exopolysaccharides, on the transfer and acquisition of ICESt3fromStreptococcus thermophilus. The transfer of ICESt3from wild-type (WT) donor cells to mutated recipient cells increased 5- to 400-fold when recipient cells were affected in lipoproteins, teichoic acids, or exopolysaccharides compared to when the recipient cells were WT. These mutants displayed an increased biofilm-forming ability compared to the WT, suggesting better cell interactions that could contribute to the increase of ICESt3acquisition. Microscopic observations ofS. thermophiluscell surface mutants showed different phenotypes (aggregation in particular) that can also have an impact on conjugation. In contrast, the same mutations did not have the same impact when the donor cells, instead of recipient cells, were mutated. In that case, the transfer frequency of ICESt3decreased compared to that with the WT. The same observation was made when both donor and recipient cells were mutated. The dominant effect of mutations in donor cells suggests that modifications of the cell envelope could impair the establishment or activity of the conjugation machinery required for DNA transport.IMPORTANCEICEs contribute to horizontal gene transfer of adaptive traits (for example, virulence, antibiotic resistance, or biofilm formation) and play a considerable role in bacterial genome evolution, thus underlining the need of a better understanding of their conjugative mechanism of transfer. While most studies focus on the different functions encoded by ICEs, little is known about the effect of host factors on their conjugative transfer. Using ICESt3ofS. thermophilusas a model, we demonstrated the impact of lipoproteins, teichoic acids, and exopolysaccharides on ICE transfer and acquisition. This opens up new avenues to control gene transfer mediated by ICEs.

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