SOJ Immunology

3

Authors: Marta Navratil

Abstract Burkholderia gladioli (B. gladioli) is an environmental pathogen which causes disease in both humans and plants. B. gladioli infections in immunocompetent individuals are rare. The following text presents two cases of nosocomial B. gladioli bacteremia in children without documented cystic fibrosis or immunedeficiency. The source of infection and route of entry are also discussed. Keywords: Bacteremia; Burkholderia gladioli; Nosocomial; RSV

4

Authors: Fereshteh Alsahebfosoul

Abstract Background: Multiple Sclerosis (MS) is an autoimmune disease of Central Nervous System (CNS) which is supposed the interaction of genetic and environmental factors have a role in its pathogenesis. Previous studies have described association between some single nucleotide polymorphisms of IL7Ra gene and risk of MS. Rs6897932 SNP is located in coding region of this gene is associated with increased level of soluble form of IL7Ra and so may be correlated with development of MS. Methods: In this case-control study, DNA from peripheral blood of 200 Relapsing Remitting Multiple Sclerosis (RRMS) patient of Isfahan Multiple Sclerosis Society (IMSS) is extracted and then allele frequencies and genotyping were performed using HRM-PCR method. Results: Our results showed that there is no significant difference between RRMS patients and controls with respect to the distribution of IL7Ra gene polymorphism (P = 0.57, OR = 1.16). Further analysis after adjusting for age and sex has displayed similar results. Conclusion: We could not find association between CD127 gene polymorphism and risk of MS; however, more studies with larger sample sizes in different ethnical populations are needed to demonstrate role of this SNP in pathogenesis of MS. Keywords: Multiple sclerosis; CD127; rs6897932; IL7Ra

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Authors: Tatsuaki Tsuruyama

Small bowel transplantation is one of the standard therapies for short-bowel syndrome. Nevertheless, histological rejection is still a main cause for failure of intestinal transplants. The present review aims to elucidate the histologic findings for diagnosis of acute cellular rejection (ACR). We review immunohistologic findings along with assessment of patients’ clinical courses. In addition to crypt apoptosis, which is considered as a sensitive histologic finding in ACR, T-lymphocyte apoptosis and phagocytosis of apoptotic bodies in the lamina propria of villi were common findings of ACR. Recent research in variable T cell populations may contribute to the immunological understanding of ACR. Therefore, in the future, earlier diagnosis of ACR may be achievable.

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Authors: Asal Gharib and Sudhir Gupta

Primary Immunodeficiencies (PIDs) occur due to inherited disorders in the innate or adaptive immune systems, or combinations of disorders in both. The underlying disorder may be attributed to decreased levels, decreased function, or complete nonfiction of immune components. There are 200 different PIDs and more than 270 genes have been described that are associated with or cause PIDs. These PIDs have recently been re-classified into nine different categories using the International Union of Immunological Societies (IUIS) classification of Primary Immunodeficiencies. This review highlights the different manifestations, including infectious as well as noninfectious etiologies that may occur in the skeletal system of patients with primary Immunodeficiencies.

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Authors: Carlos Alberto ParraLópez

Abstract Background: Optimize the generation of clinical-grade monocyte-derived dendritic cells (DC) suitable for cancer immunotherapy affordable to cancer patients worldwide remains a formidable challenge. Although vaccination with DC pulsed with tumor-associated antigens (TAA) has been thoroughly evaluated in Caucasian individuals, the immunogenicity of DCs in Colombian individuals is yet to be explored. Methodology: Mononuclear cells obtained from buffy coats of healthy Colombian volunteers were used to compare the phenotype and proficiency as Antigen Presenting Cells (APC) of matured DCs obtained in two vs. seven days from monocytes purified either by adherence to plastic or by negative selection used fresh or after cryopreservation. Furthermore, the functional capacity of two types of 2d-DCs maturated with two different cytokine-cocktails: Standard (2d-stDCs) or Type I Alpha (2d-aDCs), to prime or boost TAA specific CD8+ T cells and to stimulate Th1 stem cells and follicular T helper CD4+ T-cells (TFH), was examined. Results: Both 2d-stDCs and 2d-aDCs exhibited a maturation profile similar to standard DCs obtained in seven days. Despite both types of DCs were efficient in stimulating antigen specific CD4+ and CD8+ T cells, only 2d-aDCs secreted high amounts of IL-12p70 and fostered more efficiently than 2d-stDCs the expansion of stem memory Th1, TFH cells and effector TAA specific CD8+ T cells. Conclusions: Two-day derived DCs are phenotypically and functionally equivalent to seven day derived DCs and are suitable for cancer immunotherapy in Colombian individuals. Key Words: Dendritic cells; T Lymphocytes; Flow Cytometry; Immunotherapy; HLA-A*0201-restricted Tumor-Associated Antigen.

4

Authors: Hirota Fujiki, Masami Suganuma, Tatsuro Watanabe, Eisaburo Sueoka

In 2013, we published a review article entitled “Tumor promoters: from chemicals to inflammatory proteins”, describing that pro-inflammatory cytokines and chemokines in the cancer microenvironment induce tumor-promoting inflammation in human cancer development. We present here some significant topics based on our experiments: (i) The okadaic acid class of compounds, which are potent inhibitors of Protein Phosphatases 1 (PP1) and 2A (PP2A), showed a common mechanism of tumor promotion on mouse skin, in rat glandular stomach and in rat liver, (ii) Both 12-O-tetradecanoylphorbol-13-acetate (TPA) and okadaic acid commonly induced gene expressions of TNF-α, IL-1α and IL-1β on TNF+/+ mouse skin, and these pro-inflammatory cytokines induced clonal growth of v-Ha-ras-transfected BALB/3T3 cells (Bhas 42), (iii) H. pylori genome contained a new TNF-α-inducing protein (Tipα) gene, and Tipα protein induced the Epithelial-Mesenchymal Transition (EMT) in human gastric cancer cells and (iv) Nucleolin on cell surface was identified as a receptor for Tipα, emphasizing gastric tumor promotion and progression of H. pylori. Finally we discussed the broad roles of pro-inflammatory cytokines in tumor progression in relation to inflammasomes reported by other investigators. Keywords: Cytokine; Okadaic acid; Inflammasome; Nucleoli

9

Authors: Junchao Cai, Xin Qing, Guosheng Wu, Matthew Everly, Elaine Cheng, Paul Terasaki

ABO-compatible intestinal transplants have been more frequently performed in the US in recent years (from 4% to 16%). However, they have not been clearly shown to have comparable short- and long-term graft outcome compared to ABO-identical transplants. The US national registry database was analyzed to show the current status of ABO-compatible intestinal transplantation and to determine its effect on acute rejection and long-term graft survival. Blood type A, B, and AB patients received 11%, 26%, and 62% of ABO-compatible intestinal transplants, respectively. ABO-compatible transplant recipients experienced a higher rate of acute rejection than ABO-identical patients (77% vs. 64%, p < 0.0001). In addition, they had a significantly lower 10-year graft survival rate than ABO-identical transplant recipients (27% vs. 35%, p = 0.020). Acute rejection was the cause of graft failure in 42% of ABO-compatible and 25% of ABOidentical patients who lost intestinal transplants (p = 0.041). Since ABO-compatible transplants were associated with high rates of acute rejection and graft failure, intense induction/maintenance immunosuppressive therapies are recommended for ABO-compatible transplant recipients. In addition, packed red blood cells of donor type and plasma of recipient type, if needed, should be considered as a safer transfusion strategy for ABO-compatible transplant patients to avoid intensification of allograft injury by GVH immunity.

5

Authors: Matthew J. Everly

Despite significant efforts, long-term outcomes in transplantation have not substantially improved over the past few decades. Nonetheless, innovations in immunosuppression have led to the control or a better understanding of T-cell mediated responses. By improving control of the T-cell immune response with immunosuppression, acute cellular rejections have substantially decreased while long-term outcomes remain the same. Transplant researchers have now shifted their focus to the humoral arm of the immune system. It is thought that a significant proportion of transplants experience failure as a result of human leukocyte antigen antibody-mediated injury. Recent studies of the natural history, mechanisms, and pathologic signatures for antibody-mediated injury have led to advancements. This review outlines these advancements and the current understanding of the model of chronic alloantibodymediated injury and describes a path to improve outcomes as they relate to alloantibodies in transplantation.

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Authors: Vadim Jucaud, Mepur H. Ravindranath, Paul I. Terasaki

The objective of this review is to elucidate the role of HLA-Ib molecules in transplantation after elucidating their immunobiological potential. Structurally, the non-classical HLA-Ib molecules (HLA-E, HLA-F and HLA-G) are less polymorphic than HLA-Ia molecules. In transplantation, HLA-Ib molecules are emerging as immune regulators, functioning as ligands for immunomodulatory cell surface receptors expressed by the subsets of NK and CD8+ T cells-the major players in allograft rejection. HLA-E is the most pleiotropic molecule in an allograft setting; it can interact with both inhibitory (CD94/NKG2A) and activating (CD94/NKG2C) receptors expressed by NK and CD8+ T cells. This interaction is dependent on the nature and source of peptides presented by HLA-E. When HLA-Ia-derived peptides are presented, HLA-E interacts with CD94/NKG2A, inhibiting the cytotoxic cell functions that promote graft survival. When the HLA-G leader sequence is presented, it interacts mainly with CD94/NKG2C to activate the cytotoxic cells, leading to graft rejection. In addition, HLA-E can present viral and bacterial peptides that can bind to both CD94/NKG2 receptors, and also can interact with the other receptors of CD8+ cells, enhancing the risk of allograft rejection. HLA-G and HLA-F can promote graft acceptance by binding to another family of receptors: the Ig-like transcripts (ILT2/ ILT4) expressed by NK cells. Consequently, higher levels of HLA-G on the cell surface and in circulation promote graft acceptance, survival, and immunosuppression-free status for graft recipients. In contradistinction, overexpression of HLA-Ib results in higher risk of developing Graft-versus-Host Disease (GvHD) in cell transplantation. Soluble HLA-Ib (sHLA-Ib) molecules are augmented in circulation during injury, inflammation and transplantation. The sHLA-Ib can be free or associated with β2-microglobulin. In addition, sHLA-Ib molecules occur in a variety of conformations (isoform); as a result, HLA-Ib exposes epitopes to different immune components, contributing to antibody production. These antibodies can be monospecific or polyreactive. Binding of the monospecific antibodies can block the interaction of HLA-Ib with inhibitory receptors on cytotoxic cells, affecting graft survival. Polyreactive antibodies that bind to both cryptic and non-cryptic domains can affect routine HLAIa antibody screening and organ allocation. The antibodies binding to a cryptic domain are capable of suppressing blastogenesis and proliferation of CD4+ T cells as well as secretion of HLA antibodies by B cells; both could prolong graft survival.

6

Authors: Markus Gabel, Ayeda AlMahri, Lennart Rydberg, Jan Holgersson, and Michael E. Breimer

A flow cytometric crossmatch test detecting antibodies specific for donor Endothelial Precursor Cells (EPC) was evaluated in a multicenter study in 2005-06. A Positive Pre-Transplant EPC Crossmatch (EPCXM) was associated with a higher frequency of early rejections and reduced renal function at three and six months. The long-term follow-up of all patients (n = 53/147) recruited at our center is reported. Patients were retrospectively evaluated regarding rejections, patient/ graft survival and renal function over a four-year follow-up. As for the whole multicenter study patient population, significantly more early rejections occurred in EPCXM positive compared to EPCXM negative patients (5/7 vs. 5/46, p = 0.002). The EPCXM positive group had higher SCr at three (183 vs. 118 μmol/l,p = 0.01) and six (172 vs. 124 μmol/l, p = 0.02) months compared to the EPCXM negative group, and measured Glomerular Filtration Rate (mGFR) was decreased in the EPCXM positive group at 6 months(50 vs. 29 ml/min, p = 0.01). SCr decreased and mGFR increased over time in the EPCXM positive group, while SCr increased slightly and mGFR decreased slightly in the EPCXM negative group eliminating the difference in renal function between the groups.A positive EPCXM pre-transplantation is associated with higher frequency of early graft rejections, but does not influence long (4 year) term renal function.

6

Authors: Kalyan Srivastava, Kamna Srivastava

Platelets play an important role in the pathogenesis of malaria infection. Platelets’ action is mostly considered to be mediated by their immune effects. Platelets release thrombo-inflammatory agents such as chemokines, cytokines and coagulatory agents that may contribute to the pathogenesis of the disease. They can also participate in cytoadherence to the micro vessels of organs such as brain, lungs and spleen. Both immune response and cytoadherence can act in tandem to cause blood organ (e.g. brain) barrier breakdown causing damage. Circulating infected red blood cells interact with platelets in a receptor-mediated process that results in platelet activation and chemokines and inflammatory cytokines release. In this review, we intend to provide evidence that indicate the platelets’ role in cytoadherence and immune response. We have mostly used the example of cerebral malaria; however, a similar mechanism involving platelets might contribute, to understand the pathogenesis in other cases of severe malaria.

5

Authors: Jianwei Zhou

Eighteen reports related to Variable region of Beta Chain (Vβ) of T cell Receptors (TCR) of the patients with leukemia were reanalyzed. In the results, Vβ3 and Vβ9 were the usually predominantly used genes in all the diseases, which including infectious disease, cancers and leukemia. There were common characteristic of TCR Vβ usage in the same kind of disease; while there were specific characters in the different individuals with the same disease. This finding indicated that it may be helpful for the mechanism study or diagnosis of the diseases according to the specific or common features of TCR Vβ usage.

8

Authors: Ganka Bekyarova, Maria Tzaneva

Severe thermal injury is a common traumatic injury that results in local tissue damage and systemic response and represents a serious clinical problem. A skin burn leads to dysfunction of organs distant from the original burn skin injury, including the liver. The pathophysiology of burn-induced liver injury is very complicated and remains unclear. Increasing evidence implicate activation of the inflammatory response along with the oxidative stress as the main mechanisms of hepatic injury in burns. Melatonin is a multifunctional molecule that might counteract all pathophysiologic steps and displays beneficial effects against cellular damage, induced by thermal injury. This review summarises protective effect of melatonin on hepatic injury related with suppression of oxidative stress, inflammatory response and apoptosis induced by thermal skin injury. Special emphasis is focused on modulating effect of melatonin on Nuclear Erythroid 2-related factor 2 (Nrf2) and Nuclear Factor-kappa B (NFkB) signaling pathways, related with activation of cellular defense against oxidative stress and reduction of proinflammatory mediator production. The overall findings suggest that melatonin should be exploited as a therapeutic tool to prevent or reverse the harmful effects of thermal trauma