scholarly journals Progesterone induced blocking factor in health and disease

2021 ◽  
pp. Online First
Author(s):  
Julia Szekeres-Bartho
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Pregnancy Termination ◽  
Serum Levels ◽  
Normal Serum ◽  
Janus Kinase ◽  
Interleukin 4 ◽  
Immune Functions ◽  
Malignant Tumours ◽  
Blocking Factor

The foetus expressing paternal antigens ought to be “rejected” by the maternal immune system. However, the immunological relationship of the mother and the foetus does not follow the rules of transplantation immunology. Maternal immune functions are re-adjusted during pregnancy, to create a tolerant environment for the developing foetus. Progesterone and its downstream mediator; the progesterone induced blocking factor (PIBF) are important in this process. The mRNA transcribed from the PIBF1 gene contains 18 exons, and codes for a 90 kDa protein. The 90 kDa form is associated with the centrosome and plays a role in cell cycle regulation, while smaller isoforms produced by alternative spicing are secreted, and bind to the glycosylphosphatidylinositol (GPI) anchored PIBF receptor. Upon ligation, the former forms a heterodimer with the alpha chain of the interleukin-4 (IL-4) receptor and activates the Janus kinase/signal transducers and activators of transcription (Jak/STAT) pathway, via which, PIBF induces increased production of T helper2 (Th2) cytokines. PIBF regulates natural killer (NK) cytotoxicity, by inhibiting perforin release from the cytoplasmic granules of NK cells. During normal human pregnancy, the serum concentrations of PIBF increase with gestational age, and lower than normal serum levels predict spontaneous pregnancy termination. Depletion of PIBF during the peri-implantation period in mice, results in lower implantation and increased resorption rates, together with increased decidual and peripheral NK activity, downregulation of the genes implicated in T cell activation in CD4+ cells, and Th1 differentiation of the T cells. PIBF is expressed in rapidly proliferating immature cells as well as several tumours, and regulates invasion. The PIBF gene has been identified in the chromosomal region 13q21-q22—which is a common site for somatic deletions in a variety of malignant tumours. These data suggest that PIBF might be involved in tumorigenesis.

scholarly journals Blockade of Costimulation Prevents Infection-Induced Immunopathology in Interleukin-10-Deficient Mice

2000 ◽  
Vol 68 (5) ◽  
pp. 2837-2844 ◽  
Author(s):  
Eric N. Villegas ◽  
Ulrike Wille ◽  
Linden Craig ◽  
Peter S. Linsley ◽  
Donna M. Rennick ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Serum Levels ◽  
Cd40 Ligand ◽  
Interleukin 10 ◽  
Cell Mediated Immunity ◽  
Ifn Γ ◽  
Oxide Synthase

ABSTRACT Interleukin-10 (IL-10) is associated with inhibition of cell-mediated immunity and downregulation of the expression of costimulatory molecules required for T-cell activation. When IL-10-deficient (IL-10KO) mice are infected with Toxoplasma gondii, they succumb to a T-cell-mediated shock-like reaction characterized by the overproduction of IL-12 and gamma interferon (IFN-γ) associated with widespread necrosis of the liver. Since costimulation is critical for T-cell activation, we investigated the role of the CD28-B7 and CD40-CD40 ligand (CD40L) interactions in this infection-induced immunopathology. Our studies show that infection of mice with T. gondii resulted in increased expression of B7 and CD40 that was similar in wild-type and IL-10KO mice. In vivo blockade of the CD28-B7 or CD40-CD40L interactions following infection of IL-10KO mice with T. gondii did not affect serum levels of IFN-γ or IL-12, nor did it prevent death in these mice. However, when both pathways were blocked, the IL-10KO mice survived the acute phase of infection and had reduced serum levels of IFN-γ and alanine transaminase as well as decreased expression of inducible nitric oxide synthase in the liver and spleen. Analysis of parasite-specific recall responses from infected IL-10KO mice revealed that blockade of the CD40-CD40L interaction had minimal effects on cytokine production, whereas blockade of the CD28-B7 interaction resulted in decreased production of IFN-γ but not IL-12. Further reduction of IFN-γ production was observed when both costimulatory pathways were blocked. Together, these results demonstrate that the CD28-B7 and CD40-CD40L interactions are involved in the development of infection-induced immunopathology in the absence of IL-10.

scholarly journals Association of CD28 IVS3 +17T/C Polymorphism with Soluble CD28 in Rheumatoid Arthritis

2011 ◽  
Vol 30 (1) ◽  
pp. 25-29 ◽  
Author(s):  
I. Y. Ledezma-Lozano ◽  
J. J. Padilla-Martínez ◽  
S. D. Leyva-Torres ◽  
I. Parra-Rojas ◽  
M. G. Ramírez-Dueñas ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
T Cell Activation ◽  
Healthy Subjects ◽  
Cell Activation ◽  
Costimulatory Molecule ◽  
Serum Levels ◽  
Unknown Etiology ◽  
Clinical Activity ◽  
Western Mexico

Objective:Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology in which inflammatory pathology involves T cell activation and the CD28 costimulatory molecule involved in T cell presentation. The gene includes the CD28 IVS3 +17T/C polymorphism that could be associated with susceptibility to RA whereas the soluble concentrations of CD28 (sCD28) could be related to clinical activity.Methods:We investigated the CD28 IVS3 +17T/C polymorphism in 200 RA patients and 200 healthy subjects (HS). Furthermore, we quantified the sCD28 concentrations in 77 samples of each group. We applied indexes focused to determine the activity and disability (DAS28 and Spanish HAQ-DI, respectively) in RA patients.Methods:We investigated the CD28 IVS3 +17T/C polymorphism in 200 RA patients and 200 healthy subjects (HS). Furthermore, we quantified the sCD28 concentrations in 77 samples of each group. We applied indexes focused to determine the activity and disability (DAS28 and Spanish HAQ-DI, respectively) in RA patients.Results:RA patients had significantly higher frequencies of the CD28 T allele compared to HS (p= 0.032 OR = 1.59, C.I. 1.02–2.49). In addition, the IVS3 +17 T/T genotype frequency was also increased in RA vs. HS (p= 0.026). The RA patients showed higher sCD28 serum levels than HS (p= 0.001). Carriers of the T/T genotype in RA patients showed higher sCD28 levels than C/C carriers (p= 0.047). In addition, a correlation between sCD28 and Spanish HAQ-DI (correlation, 0.272;p= 0.016), was found.Conclusion:The T allele in CD28 IVS3 +17T/C polymorphism is associated with a susceptibility to RA in Western Mexico. In addition, increased sCD28 levels are related to T/T genotype in RA patients.

scholarly journals Targeted Disruption of the Inosine 5′-Monophosphate Dehydrogenase Type I Gene in Mice

2003 ◽  
Vol 23 (18) ◽  
pp. 6702-6712 ◽  
Author(s):  
Jing Jin Gu ◽  
Amy K. Tolin ◽  
Jugnu Jain ◽  
Hai Huang ◽  
Lalaine Santiago ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
De Novo ◽  
Cytolytic Activity ◽  
Guanine Nucleotides ◽  
Interleukin 4 ◽  
Type I ◽  
Double Knockout ◽  
Inhibition Of Proliferation ◽  
Monophosphate Dehydrogenase

ABSTRACT Inosine 5′-monophosphate dehydrogenase (IMPDH) is the critical, rate-limiting enzyme in the de novo biosynthesis pathway for guanine nucleotides. Two separate isoenzymes, designated IMPDH types I and II, contribute to IMPDH activity. An additional pathway salvages guanine through the activity of hypoxanthine-guanine phosphoribosyltransferase (HPRT) to supply the cell with guanine nucleotides. In order to better understand the relative contributions of IMPDH types I and II and HPRT to normal biological function, a mouse deficient in IMPDH type I was generated by standard gene-targeting techniques and bred to mice deficient in HPRT or heterozygous for IMPDH type II. T-cell activation in response to anti-CD3 plus anti-CD28 antibodies was significantly impaired in both single- and double-knockout mice, whereas a more general inhibition of proliferation in response to other T- and B-cell mitogens was observed only in mice deficient in both enzymes. In addition, IMPDH type I−/− HPRT−/0 splenocytes showed reduced interleukin-4 production and impaired cytolytic activity after antibody activation, indicating an important role for guanine salvage in supplementing the de novo synthesis of guanine nucleotides. We conclude that both IMPDH and HPRT activities contribute to normal T-lymphocyte activation and function.

scholarly journals The role of oxidative stress in the pathogenesis of Graves’ orbitopathy

2021 ◽  
Vol 75 ◽  
pp. 448-455
Author(s):  
Magdalena Londzin-Olesik ◽  
Beata Kos-Kudła ◽  
Aleksandra Nowak ◽  
Mariusz Nowak
Keyword(s):  
Oxidative Stress ◽  
T Cell Activation ◽  
Cell Activation ◽  
Serum Levels ◽  
Thyroid Stimulating Hormone ◽  
Peroxidation Of Lipids ◽  
Hormone Production ◽  
Stress Markers ◽  
Orbital Tissue ◽  
Autoimmune Condition

Graves’ disease (GD) is a chronic autoimmune condition in which the anti-thyroid stimulating hormone receptor antibodies (TRAb) activate the thyrotropin receptor (TSHR) located on thyrocytes, leading to excessive thyroid hormone production. TSHR is also expressed in extrathyroidal tissues, in particular, within the orbit. The serum levels of TRAb correlate with the severity and activity of thyroid orbitopathy (TO). TO is the most common extrathyroidal manifestation of GD. It is an autoimmune inflammation of orbital tissues, that is, extraocular muscles, orbital adipose tissue or a lacrimal gland. Increased orbital fibroblast and adipocyte proliferation, overproduction of glycosaminoglycans, as well as extraocular muscle oedema, result in increased orbital tissue volume and trigger the onset of TO symptoms. The pathophysiology of TO is complex and has not been fully unexplained to date. Orbital fibroblasts show expression of the TSHR, which is the main target of autoimmunity. It has been hypothesised that T-cell activation induced by orbital receptor stimulation by the target antibody results in orbital tissue infiltration, triggering a cascade of events which leads to the production of cytokines, growth factors and reactive oxygen species (ROS). ROS cause damage to many components of the cell: the cell membrane through the peroxidation of lipids and proteins leading to a loss of their function and enzymatic activity. Oxidative stress leads to the activation of the antioxidant system, which operates through two mechanisms: enzymatic and non-enzymatic. Assessment of the concentration of oxidative stress markers and the concentration or activity of anti-oxidative system parameters enables the evaluation of oxidative stress severity, which in the future may be utilized to assess treatment efficacy and prognosis in patients with active OT.

scholarly journals Cellular Factors Targeting APCs to Modulate Adaptive T Cell Immunity

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Anabelle Visperas ◽  
Jeongsu Do ◽  
Booki Min
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Differentiation ◽  
T Cell Immunity ◽  
Immune Functions ◽  
Effector Cells ◽  
Cell Immunity

The fate of adaptive T cell immunity is determined by multiple cellular and molecular factors, among which the cytokine milieu plays the most important role in this process. Depending on the cytokines present during the initial T cell activation, T cells become effector cells that produce different effector molecules and execute adaptive immune functions. Studies thus far have primarily focused on defining how these factors control T cell differentiation by targeting T cells themselves. However, other non-T cells, particularly APCs, also express receptors for the factors and are capable of responding to them. In this review, we will discuss how APCs, by responding to those cytokines, influence T cell differentiation and adaptive immunity.

scholarly journals March1 E3 Ubiquitin Ligase Modulates Features of Allergic Asthma in an Ovalbumin-Induced Mouse Model of Lung Inflammation

2018 ◽  
Vol 2018 ◽  
pp. 1-17 ◽  
Author(s):  
Osama A. Kishta ◽  
Antoine Sabourin ◽  
Leora Simon ◽  
Toby McGovern ◽  
Maxime Raymond ◽  
...  
Keyword(s):  
Allergic Asthma ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Ubiquitin Ligase ◽  
Cell Activation ◽  
E3 Ubiquitin Ligase ◽  
Allergic Inflammation ◽  
Serum Levels ◽  
Specific Ige ◽  
Cell Surface Expression

Membrane-associated RING-CH-1 (March1) is a member of the March family of E3 ubiquitin ligases. March1 downregulates cell surface expression of MHC II and CD86 by targeting them to lysosomal degradation. Given the key roles of MHC class II and CD86 in T cell activation and to get further insights into the development of allergic inflammation, we asked whether March1 deficiency exacerbates or attenuates features of allergic asthma in mice. Herein, we used an acute model of allergy to compare the asthmatic phenotype of March1-deficient and -sufficient mice immunized with ovalbumin (OVA) and later challenged by intranasal instillation of OVA in the lungs. We found that eosinophilic inflammation in airways and lung tissue was similar between WT and March1−/− allergic mice, whereas neutrophilic inflammation was significant only in March1−/− mice. Airway hyperresponsiveness as well as levels of IFN-γ, IL-13, IL-6, and IL-10 was lower in the lungs of asthmatic March1−/− mice compared to WT, whereas lung levels of TNF-α, IL-4, and IL-5 were not significantly different. Interestingly, in the serum, levels of total and ova-specific IgE were reduced in March1-deficient mice as compared to WT mice. Taken together, our results demonstrate a role of March1 E3 ubiquitin ligase in modulating allergic responses.

Effects of combination therapy of beta-interferon 1a and prednisone on serum immunologic markers in patients with multiple sclerosis

2003 ◽  
Vol 9 (1) ◽  
pp. 28-31 ◽  
Author(s):  
Hassan H Salama ◽  
Oldrich J Kolar ◽  
Ying CQ Zang ◽  
Jingwu Zhang
Keyword(s):  
Multiple Sclerosis ◽  
T Cell ◽  
Combination Therapy ◽  
T Cell Activation ◽  
Cell Activation ◽  
Serum Levels ◽  
Inhibitory Effect ◽  
Activation Markers ◽  
Beta Interferon ◽  
Ifn Treatment

Beta-interferon (beta-IFN) has a proven treatment effect on relapsing-remitting multiple sclerosis (MS), presumably through its regulatory properties on T-cell activation and cytokine production. This paper examines whether combination therapy of beta-IFN with prednisone would enhance immunoregulatory effects of beta-IFN by measuring serum levels of selected proinflammatory cytokines and soluble T-cell activation markers associated with MS. The selected markers were analyzed in MS patients treated with beta-IFN alone (n-22) and beta-IFN combined with a low daily dose of prednisone (n-33), as compared with those in 27 healthy controls at baseline and at a three-month interval for one year. The study confirmed that beta-IFN treatment inhibited serum levels of tumor necro sis factor-alpha (TNFa) and intracellular adhesion molecule-1 (IC A M-1) in patients with MS. However, combination therapy did not significantly enhance the inhibitory effect of beta-IFN treatment on the production of TNFa, interleukin (IL)-12, IL-2R, and IC A M-1, while the addition of prednisone antagonized the effect of beta-IFN on up-regulation of IL-10 and soluble C D95. No difference in the occurrence of binding antibodies to beta-IFN was found between the two treatment groups. The findings are important for the understanding of the role of combination therapy in the treatment of MS.

scholarly journals Detection of serum soluble markers of immune activation in rheumatoid arthritis

1996 ◽  
Vol 5 (4) ◽  
pp. 262-265 ◽  
Author(s):  
T. Kogure ◽  
T. Itoh ◽  
Y. Shimada ◽  
T. Shintani ◽  
H. Ochiai ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell Activation ◽  
Immune Activation ◽  
Cell Activation ◽  
Serum Levels ◽  
Serum Markers ◽  
Clinical Aspects ◽  
Mutual Correlation ◽  
One Year ◽  
High Level

The mutual correlation among soluble CD4 (sCD4), soluble CD8 (sCD8), and soluble CD23 (sCD23) has not yet been studied in patients with rheumatoid arthritis (RA), although previous studies have demonstrated that certain soluble markers of immune activation are elevated in RA. Thus, we examined this correlation based on the serum levels of sCD4, sCD8 and sCD23, and that of their levels with other serum markers such as immunoglobulin (Ig) subtypes (IgG, IgM and IgA), IgM-rheumatoid factor (IgM-RF) and C-reactive protein (CRP) in 25 RA patients, sCD4 was not elevated, whereas both sCD8 and sCD23 increased in RA patients compared with the healthy controls; a majority of RA patients, in particular, showed a high sCD23 level. The level of sCD23 showed a correlation with that of IgM-RF, but not with those of IgG, IgM, IgA and CRP. Importantly, a high level of sCD23 was not always accompartied with that of sCD8. The independent change between sCD23 and sCD8 levels was also observed in a one-year follow-up study of the two RA patients. These findings indicate that B cells might be generally activated in RA, whereas T-cell activation in variable in each patient with RA, suggesting that sCD23 is a more indicative marker for the immune status of RA patients than sCD8 from the clinical aspects.

scholarly journals Interaction of CD31 with a heterophilic counterreceptor involved in downregulation of human T cell responses.

1996 ◽  
Vol 184 (1) ◽  
pp. 41-50 ◽  
Author(s):  
E Prager ◽  
R Sunder-Plassmann ◽  
C Hansmann ◽  
C Koch ◽  
W Holter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Types ◽  
Interleukin 4 ◽  
Single Chain ◽  
Necrosis Factor Alpha ◽  
Human T Cell

CD31 is a 130-kD glycoprotein of the immunoglobulin (Ig) superfamily expressed on the surface of endothelial cells, platelets, and several leukocyte subsets. Previous reports indicated that CD31 can mediate intercellular adhesion via both homophilic and heterophilic interaction mechanisms. Using a soluble recombinant CD31-Ig fusion protein (CD31 receptor globulin [Rg]), we demonstrate here that human CD31- T lymphocytes and CD4+CD31- T cell clones express a heterophilic CD31 ligand that is upregulated 18 h after activation. Interaction of CD31Rg with CD31- T helper cell (Th) clones was divalent cation independent but could be blocked by heparin, thus indicating that the CD31 counterreceptor on T cells can be distinguished from the ligands identified on other cell types. Moreover, a single chain protein of 120 kD was precipitated by CD31Rg from the lysates of CD31- Th clones. CD31Rg completely downregulated the proliferative response and cytokine production (interleukin-4, interferon-gamma, and tumor necrosis factor-alpha) of CD31- Th clones when the cells were maximally stimulated via immobilized CD3 monoclonal antibody. These results suggest that interaction of CD31 with a heterophilic counterreceptor on T lymphocytes can interfere with a positive regulatory pathway of T cell activation, or directly signal T cells to downregulate immune function.

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