SOJ Immunology

2

Authors: Duncan D Adams

The histocompatibility system exists for defence against viruses. It is responsible for the rejection of allograft. The immune system attempts to counter the explosive speed of viral replication by directing the defensive immune attack by cytotoxic T cells on to histocompatibility antigens on the infected cell’s surface. This enables destruction of the virus factories before the cytotoxic T cells are swamped by the myriad numbers of new virions, a thousand coming from each infected cell every 10 hours. The histocompatibility system mistakes alloantigen on grafts for virus-infected host cells that need swift destruction. For surgical transplantation, Henry Kaplan discovered that immune ablation of the recipient followed by inoculation with donor bone marrow prevents rejection of allogeneic grafts. Sykes has improved Kaplan’s technique by adding recipient bone marrow cells to the donor ones injected for reconstitution of the recipient after immune ablation. Kaplan’s technique, used on untreated pigs, should be the standard procedure for transplantation.

6

Authors: Wafa Munir Ansari, Dilshad Ahmad Khan, Omer Jamshed Khan and Farooq Ahmad Khan

Introduction: The objective was to evaluate diagnostic accuracy of high sensitivity C-reactive protein (hS CRP), Interleukin-18 (IL-18), Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin-10 (IL- 10), IL-18/IL- 10 ratio and their serum cut off values for identification of Premature Coronary Artery Disease (PCAD) patients. Method: It was a diagnostic validation case-control study carried out at the Clinical Pathology Laboratories of the Army Medical College, Rawalpindi, Pakistan, from May, 2013 to Jan, 2014. Two hundred and fifty subjects aged < 45 years scheduled to undergo coronary angiography were consecutively screened. Out of these ninetyeight patients with > 70% stenosis, in at least one coronary vessel on angiography, were labeled to have PCAD. An equal number of angio-negative subjects were taken as controls from the study group. Serum IL- 10, IL- 18 and TNF alpha were measured using Enzyme Linked Immuno-sorbent Assay (ELISA), hS CRP on Immulite 1000 and serum cholesterol, Triglycerides and High Density Lipoprotein (HDL) by colorimetric methods. Statistical analysis was done using SPSS-17 and MedCalc software. Results: Total 196 subjects consisting of 98 PCAD patients and 98 angio-negative controls participated in the study. Mean ± SD age of PCAD patients was 40.7 ± 4.23yrs (89 males and 9 females) while in controls it was 35.1 ± 7.55yrs (93 males and 5 females). Serum hS CRP had highest area under curve AUC (95% confidence interval) of 0.936 (0.89- 0.97) while AUC (95% CI) of IL-18, TNF alpha and IL-10 were 0.853 (0.79-0.90), 0.731 (0.659-0.796) and 0.574 (0.497- 0.649) respectively. Sensitivity-specificity of hS CRP and IL-18 at cut off value of 3.18 pg/ml and 200pg/ml were 86%-91% and 77%-81% respectively while that of IL-18/IL-10 ratio and IL-10 at cut off values > 138.9 and > 0.3pg/ml were 68-64% and 20-100% respectively. Significant correlation was observed between hS CRP (p < 0.01), IL- 18 (p < 0.01) and TNF alpha (p < 0.05). Conclusion: hS CRP and IL-18 have the best diagnostic potential among the cytokines for detection of PCAD with high sensitivity and specificity. IL-18/IL-10 ratio had moderate significance in the diagnosis of PCAD although it correlated well with the disease burden. IL-10 had 100% specificity highlighting its role in the diagnosis of the disease but its low sensitivity is a limiting factor. Thus, hS CRP and IL-18 are promising potential biochemical parameters aiding in the clinical diagnosis of Premature Coronary Artery Disease.

10

Authors: Enas A. El-Hussieny, Amira M. Gamal Eldeen, Roba M. Talaat, Ahmed F. Tamara, Mohamed S. Salama and Na dia M. El Beih

Background: CD36 is one of the macrophage scavenger receptor that has been implicated as a key player in the pathogenesis of atherosclerosis. Aim: This study focused on the role of CD36 in coronary artery disease (CAD) and its association with proangiogenic and inflammatory mediators. Patients and Methods: We studied 100 atherosclerotic CAD patients and 100 healthy controls. All patients had angiographic evidence of stenosis ≥ 50% in at least one major coronary artery Soluble CD36 (sCD36), peripheral blood mononuclear cells (PBMCcCD36),vascular endothelial and platelet- derived growth factors (VEGF & PDGF), Tumor necrosis factor (TNF-α) and cycloxygenase-2(COX-2) were measured using enzyme-linked immunosorbent assay (ELISA). CD36 mRNA expression was measured using reverse transcriptase polymerase chain reaction (RT-PCR). Results: A significant reduction in cCD36 expression (protein and mRNA) and plasma levels of sCD36, VEGF, PDGF in CAD patients was demonstrated. In contrast, a marked elevation in the plasma level of TNF-α was observed. There was a strong inverse correlation between severity of CAD and sCD36 (r = -0.413; P < 0.001), cCD36 (r = -0.4663; P < 0.001), CD36 mRNA (r = -0.328; P < 0.01). Furthermore, CD36 was found to be positively correlated with VEGF (r = 0.446; P < 0.001) and PDGF (r = 0.287; P < 0.05), while it was negatively correlated with TNF-α (r= - 0.352; P < 0.01). Conclusion: CD36 deficiency might represent a good expression marker for the development of CAD in Egyptian patients in association with inflammatory and proangiogenic mediators. Targeting the underling mechanism of the direct and inverse association of CD36 with angiogenic and inflammatory mediators could be used in the treatment of athero-inflammatory disorders.

3

Authors: Yalcin AD, Suer K and Yalcin AN

Omalizumab, a humanized mAb that binds to the CH3 domain, near the binding site for the high-affinity type-I IgE Fc receptors of human IgE, can neutralize free IgE and inhibit the IgE allergic pathway without sensitizing mast cell and basophils. The clinical experience during the patient follow-up of an omalizumab treated severe persistent allergic asthma patient with complicated viral infection is introduced. A female patient (aged 58) with severe persistent allergic asthma, on omalizumab therapy had laryngeal oedema during a complicated common cold infection with bacterial sinusitis after omalizumab injection. Systemic steroids, ketotifen fumarate, antibiotic and antihistamines (desloratadine) were given. We did not stop omalizumab therapy. To our knowledge, this is the first time an association between omalizumab use and laryngeal oedema has been documented. In fact we do not know the exact mechanism behind this relationship. In conclusion we do not suggest Omalizumab during the first five days of complicated viral infections such as common cold and bacterial sinus infections.

6

Authors: Gabriela Mellado-Sanchez, Hector Vivanco-Cid, and Adriana Sumoza-Toledo

Dendritic Cells (DCs) are highly potent Antigen-Presenting Cells (APCs) that have a key role in mediating tolerance or immunity to self and non-self antigens. In their immature stage DCs are highly phagocytic and undergo a maturation process after taking up an antigen. DC maturation is characterized by activation of mechanisms of antigen presentation, increased expression of Major Histocompatibility Complex (MHC) class II and co-stimulatory molecules in the plasma membrane, and secretion of cytokines and chemokines. Despite the fact that the role of calcium (Ca2+) in DC function has been clearly established, regulation of Ca2+ signals in these cells is not well known. However, recently it has been demonstrated that functional capacitative Ca2+ release-activated Ca2+ (CRAC), Transient Receptor Potential Melastatin-2(TRPM2) and TRP Vanilloid- 1 (TRPV1) channels are critical for mouse DC maturation and migration. Also, Ryanodine Receptor-1 (RyR1) signaling activated by L-type Ca2+ channel CaV1.2 cause rapid MHC-II expression in the plasma membrane of DCs. The understanding of the regulation of Ca2+ signals in DCs is essential, to potentially modulate DC functions in disease processes. Therefore, in this review, we discuss recent studies on the expression and roles of Ca2+ channels in DC biology and function.

8

Authors: Houda Khatif and Ingo Drexler

Autophagy is a catabolic mechanism developed in eukaryotes in order to maintain cellular homeostasis and development. It is also an essential constituent of the immune system since it is involved in the MHC class I and II antigen generation and exerts an antiviral effect. However many viruses are either able to inhibit or induce autophagy to avoid their own elimination or to favor their replication by interacting with different complexes of the autophagy pathway. This review summarizes the molecular mechanisms of autophagy and its importance in immunity. It describes the different strategies that viruses have adopted to hijack this process.

2

Authors: Young I. Choi

When I was asked to write 2-page editorial for Symbiosis Online Journal Immunology, I contemplated the meaning of symbiosis in immunology. The first thing that came up in my mind was the question how I can connect the symbiosis to drug development. When I started postdoctoral work in the laboratory of Dr. Reinherz at Dana-Farber Cancer Institute, Harvard Medical School, I was fascinated with the beautiful tissue organization of thymus. Thymus is constituted with several irregular roundshape medulla surrounded by outer cortex. The outer cortex is densely packed with CD4+ CD8+ double positive immature thymocytes but the inner medulla is filled with CD4+ or CD8+ single positive mature T cells. Thymic epithelial cells secrete several chemokines such as CXCL12, CCL19 and CCL21. These chemokines control thymocyte migration for the clear separation of developing thymocytes into different thymic compartment. My first question was why each animal has different shape and distribution of medulla. If thymic epithelial cell development is the first step for the construction of thymic architecture, I guessed that all the organisms should have a similar pattern in medulla distribution. The irregularity of medulla distribution suggested that thymic epithelial development is not dependent on epithelial cell alone but on the interaction with other cells such as developing thymocytes. When T cell development was induced with anti CD3ε antibody injection into the TCRβ+ Rag2- /- mice where thymus has only cortex and T cell development was blocked at CD4+ CD8+ double positive stage, T cell development was resumed temporarily and the medulla developed again promptly [1]. This result suggested that the interaction between epithelium and lymphocyte affects the development of both sides

3

Authors: Ian Adcock and Yassine Amrani

Accumulating evidence now shows that low level of vitamin D is associated with the development and/or aggravation of a number of lung diseases in both adults and children [1-3]. Clinically, low levels of vitamin D refers to hormone deficiency which is defined by a serum level <20ng/mL [4]. Vitamin D insufficiency, typically defined by levels ranging from 20-29ng/ mL, has also been regarded as clinically important particularly in children [5]. Despite numerous reports associating vitamin D levels to allergic disorders, the cellular and molecular pathways explaining the protective role of vitamin D in lung diseases have not been fully investigated. The purpose of this short review is to describe the current evidence describing the importance of vitamin D in modulating patient’s response to corticosteroid therapy.

7

Authors: Rakel Carpintero, Karim J. Brandt, Lyssia Gruaz and Danielle Burger

Deregulation of the production of IL-1β and its natural inhibitor, the secreted form of IL-1 receptor antagonist (sIL-1Ra), plays an important role in the pathogenesis of chronic inflammatory diseases such as rheumatoid arthritis and multiple sclerosis. Relevant to the latter conditions direct cellular contact with stimulated T cells potently triggers cytokine production in human monocytes. Identification of signal transduction pathways specific to pathogenic induction of cytokines may lead to new therapeutic approaches. Two different stimuli were compared to investigate the implication of MEK1 and MEK2 in the control of IL-1β and sIL-1Ra production by human monocytes: (i) soluble extracts of plasma membranes from stimulated T cells (CEsHUT), mimicking cellular contact with T cells, i.e., chronic/sterile inflammatory conditions; and (ii) LPS that is relevant to infectious inflammation. The ATP-noncompetitive MEK1/2 (U0126) and MEK1 (PD98059) specific inhibitors diminished the expression (protein and mRNA) of IL-1β in CEsHUT-activated monocytes. In contrast, only the concomitant inhibition of MEK1 and MEK2 inhibited IL-1β production in LPS-activated monocytes, whereas the inhibition of MEK1 only did not affect IL-1β production. In CEsHUT- and LPS-activated monocytes, MEK1 inhibition slightly affected sIL-1Ra production that was significantly inhibited by U0126. These results suggest that MEK1 and MEK2 are differentially involved in the regulation of the IL-1 system upon chronic/sterile and infectious inflammatory conditions. MEK1 which is dispensable to IL-1β production in LPS-activated monocytes represents a potential therapeutic target whose inhibition could participate in the restoration of IL-1β/sIL-1Ra balance in chronic/sterile inflammation without affecting regular responses to pathogens.

1

Authors: Joseph P Chandler

As a new on-line journal, Symbiosis On-line Journal envisions that it will allow its readers to have “access to emerging literature and to promote the knowledge transfer among research communities. “ Without doubt, the rate of communication that occurs on-line is exceptionally rapid and can be, at times, voluminous. As immunologists with monoclonal antibodies as our specialty, we do our best to keep abreast of all things antibody. One arena that has compelled our interest of late has been the numerous blogs and forums devoted to “useless” commercial antibodies. The frustration in these forums is palpable. Many in this industry have written compelling defenses and we will be among those who would like to make a few suggestions to alleviate some of this aggravation. We, too, have been on the receiving end of antibodies that did not perform as we had expected. Potential mismatches and frustration can be avoided through adequate preparation and collaboration.

3

Authors: Philip Hexley and George Babcock

In 1980 Sydney Brenner proclaimed “Progress in science depends on new techniques, new discoveries, and new ideas, probably in that order”, but this was not a novel concept. For decades people have understood the biosciences are not merely hypothesis-led but are driven as much by technological developments. New tools and technologies are essential in advancing modern biology, allowing lines of investigation that otherwise remain inaccessible.

4

Authors: Samuel Antwi-Baffour, Andrew Owusu Boafo, Ransford Kyeremeh and Seidu Abdulai Mahmood

Background: Plasma membrane-derived vesicles (PMVs) are described as sub-cellular vesicles released upon shear stress, cell activation, injury or apoptosis. They are considered as universal biomarkers in a wide range of physiological and pathological processes. Glusoe-6-phosphate dehydrogenase (G6PD) deficiency on the other hand is an x-linked enzymopathy characterized by the inability of red blood cells (RBCs) to withstand oxidative stress. The presence and role of PMVs in G6PD deficiency has not been fully investigated. Objectives: The aim of this study was to quantify and compare the levels of PMVs in G6PD deficient and non-deficient patients. Methods: G6PD deficiency test using the methaemoglobin reduction method was performed on the blood samples. The levels of PMVs in those samples were quantified using quantitative flow cytometry. This was done by centrifuging the blood samples to obtain platelet-free plasma. Annexin V was then added to label the PMVs and quantified by flow cytometry. Results: The mean level of PMVs among G6PD full defects subjects was 26 × 104 PMVs/ml and that among the G6PD normal subjects was 10 × 104 PMVs/ml. Statistically, the difference between the PMV levels of the G6PD normal samples and G6PD deficient samples was significant (p<0.05). Conclusion: There is an increased level of PMVs in the circulating blood of G6PD deficient individuals as compared to G6PD normal individuals.