ISRN Immunology The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Effects of Atorvastatin on Atherosclerosis and Atherogenesis in Systemic Lupus Erythematosus: A Pilot Study Wed, 19 Mar 2014 14:42:55 +0000 Objective. The effect of statins on atherogenesis in systemic lupus erythematosus (SLE) is poorly known. To inform a wider trial we performed a pilot study evaluating the intima-media thickness of the common carotid artery (CIMT) and some oxidative [beta-2-glycoprotein-1 complexed with oxidised low density lipoprotein (2GPIoxLDL)], metabolic [paraoxonase (PON), nitrate (), nitrite () and nitrotyrosine (NT)], inflammatory [C-reactive protein (CRP) and serum amyloid A (SAA)], and lipid markers before and after 1 year of treatment with 40 mg of oral atorvastatin (AT). Methods. Randomised, double blind, placebo controlled pilot study on consecutive SLE patients: 17 SLE patients were randomised into the AT arm and 20 into the placebo arm. CIMT was measured by high-resolution sonography, PONa by a spectrophotometric method, and by a colorimetric assay and oxLDL-2GPI, NT, CRP, and SAA by Elisa. Results. After correction for age and disease duration oxLDL-2GPI decreased by 27% () and PON/HDL ratio increased by 12% () but CIMT did not change. Conclusion. This pilot study revealed a decrease of oxLDL-2GPI (oxidant marker) and an increase of PON/HDL ratio (antioxidant activity) after AT indicating a favourable effect of the drug on atherogenic pathways that should be explored on larger trials. Katharina Benita Sokoll, Joana Batuca, Luis Romulo Lopez, Elizabeth Hensor, Paul Emery, José Delgado Alves, and Paul Richard Julian Ames Copyright © 2014 Katharina Benita Sokoll et al. All rights reserved. Comparative Analysis of the Informative Value of Radioimmunoassay and Laser Correlation Spectroscopy in Myasthenia Gravis Wed, 12 Mar 2014 11:01:58 +0000 The objective of this study was to compare informative value of traditional approach (anti-AChR antibody radioimmunoassay) and evaluation of metabolic shifts by laser correlation spectroscopy in myasthenia gravis. The method based on changes in spectral characteristics of laser radiation caused by scattering in a disperse system yields a histogram reflecting particle contribution into light scatter as a function of particle radius in nanometers. The spectrum of anti-AChR-positive serum is characterized by appreciably increased contribution of particles with a radius 4.6–6.2 nm. Binding of serum components with solubilized AChR confirms that this peak is determined by elevated concentration of antibodies to this receptor. The search for the relationship between the disease severity and the distribution pattern of subfraction serum components revealed three informative zones: 6–15, 27–67, and 127–223 nm. In patients without disturbances of vital functions, the contribution of the first zone particles into light scatter increases and that of the third zone particles decreases. Considerable differences attaining the level of statistical significance in zones 4–6 and 20 nm were revealed in the spectra of serum from patients with myasthenia gravis of the same severity with and without thymoma. This opens prospects for dynamic monitoring of the efficiency of therapy. Irina Alchinova, Elena Arkhipova, Dmitry Sidnev, Alexandr Sanadze, Sergey Dedaev, and Mikhail Karganov Copyright © 2014 Irina Alchinova et al. All rights reserved. Effect of Analgesics on Monoclonal Antibody Ascites Production in Mice Administered Upon Recognition of Pain Tue, 11 Mar 2014 09:46:07 +0000 Monoclonal antibody (mAb) ascites fluid production in mice is a well described method of antibody production, although ethical questions regarding the pain and distress of the animals utilized in this process have been raised. In this study, mice were injected with pristane to initiate granuloma formation, followed by an injection of murine hybridoma PA 2II 2F9-1-1 (2F9) to produce IgG1 subclass mAb directed against protective antigen (PA) protein of Bacillus anthracis. Upon the recognition of pain or distress, characterized by well accepted clinical signs, analgesics were administered by treatment group. The control group (A) received saline, group (B) received meloxicam, group (C) received buprenorphine, and group (D) received both meloxicam and buprenorphine. Analgesics were administered by group for a total of 36–48 hours prior to the second ascites fluid collection. There was no statistical difference in the antibody titer or functionality between treatment groups at the first or the second collection time points. As reported here, analgesics may be administered upon recognition of pain in mice used for mAb ascites fluid production without affecting antibody concentration or quality and may warrant further evaluation as a refinement in other hybridoma cell lines. Shannon T. Marko, Stephen F. Little, Carrie G. Benton, Richard Kelly III, Amy E. Field, and Rachel S. Laufer Copyright © 2014 Shannon T. Marko et al. All rights reserved. Molecular and Cellular Pathways of Immunoglobulin G Activity In Vivo Wed, 05 Mar 2014 14:03:14 +0000 In retrospect, the therapeutic potential of immunoglobulins was first demonstrated by von Behring and Kitasato in the late nineteenth century by protecting mice from the lethal effects caused by tetanus and diphtheria toxin via injection of a hyperimmune serum generated in rabbits. Even today, hyperimmune sera generated from human donors with high serum titers against a certain pathogen are still in use as a means of providing passive protection. More importantly, therapeutic antibodies specific for malignant or autoreactive cells have become included in the standard of care in diseases such as breast cancer and malignant lymphoma. Despite this clinical success, we are only at the beginning of understanding the precise molecular and cellular pathways responsible for immunoglobulin G (IgG) activity in vivo. Since then, an enormous amount of information about the mechanism of IgG activity has been obtained in various model systems. The aim of this review is to provide a comprehensive overview of our current understanding of how IgG antibodies mediate their activity in vivo and how we can use this knowledge to enhance the activity of therapeutic antibodies or block the proinflammatory and tissue pathology inducing activity of autoantibodies. Falk Nimmerjahn Copyright © 2014 Falk Nimmerjahn. All rights reserved. Coevolution of Mucosal Immunoglobulins and the Polymeric Immunoglobulin Receptor: Evidence That the Commensal Microbiota Provided the Driving Force Tue, 04 Mar 2014 07:53:54 +0000 Immunoglobulins (Igs) in mucosal secretions contribute to immune homeostasis by limiting access of microbial and environmental antigens to the body proper, maintaining the integrity of the epithelial barrier and shaping the composition of the commensal microbiota. The emergence of IgM in cartilaginous fish represented the primordial mucosal Ig, which is expressed in all higher vertebrates. Expansion and diversification of the mucosal Ig repertoire led to the emergence of IgT in bony fishes, IgX in amphibians, and IgA in reptiles, birds, and mammals. Parallel evolution of cellular receptors for the constant (Fc) regions of Igs provided mechanisms for their transport and immune effector functions. The most ancient of these Fc receptors is the polymeric Ig receptor (pIgR), which first appeared in an ancestor of bony fishes. The pIgR transports polymeric IgM, IgT, IgX, and IgA across epithelial cells into external secretions. Diversification and refinement of the structure of mucosal Igs during tetrapod evolution were paralleled by structural changes in pIgR, culminating in the multifunctional secretory IgA complex in mammals. In this paper, evidence is presented that the mutualistic relationship between the commensal microbiota and the vertebrate host provided the driving force for coevolution of mucosal Igs and pIgR. Charlotte S. Kaetzel Copyright © 2014 Charlotte S. Kaetzel. All rights reserved. Cytomorphological and Cytochemical Identification of Microglia Tue, 27 Aug 2013 13:25:25 +0000 Microglia is one of the major resident immune cells in the central nervous system and is considered to be the key cellular mediator of neuroinflammatory processes. Identification of different Microglial states of activation by morphologic means has been one of the major challenges in the field of neurobiology of diseases. Therefore, microglial biology demands techniques to identify differing stages of microglia in different neuroanatomic locations as well as understanding the role of Microglia in different Neurological diseases. This present study is aimed towards summarizing the literature and for understanding the progress made in different Cytomorphological and Cytochemical techniques of identifying Microglia. This study also review recently used Immunohistochemistry techniques, along with Ultrastructural studies determining different morphological features of resting to activated phagocytic Microglia in a viral induced experimental animal model of neuroinflammation. Results revealed that chronic Microglial activation is considered to be an important component of neuronal dysfunction, injury, and loss (and hence to disease progression). Thus, Microglial research with special emphasis on identification of different activation states of Microglia has gradually become significant. Subhajit Das Sarma, Koushik Chatterjee, Himadri Dinda, Dhriti Chatterjee, and Jayasri Das Sarma Copyright © 2013 Subhajit Das Sarma et al. All rights reserved. Increased Frequency of Antigen-Specific Polyfunctional T Cells in Tuberculosis Patients Thu, 22 Aug 2013 11:38:50 +0000 This study assessed the polyfunctional T cells in healthy household contacts (HHCs) and TB patients. This study also assessed the memory subsets responsible for the secretion of IFN-γ during the short-term culture with Mycobacterium tuberculosis antigens. Frequencies of CD4+IFN-γ+TNF-α+ T cells and CD8+IFN-γ+TNF-α+ T cells specific to M. tuberculosis antigens were significantly higher in TB patients compared to HHC. IFN-γ-secreting T cells, during overnight stimulation with M. tuberculosis antigens, belonged to effector memory subset with a CD45RA−CD27− phenotype. However, the number of IFN-γ-secreting effector memory cells did not differ between HHC and TB patients. Basirudeen Syed Ahamed Kabeer, Anbalagan Selvaraj, and Alamelu Raja Copyright © 2013 Basirudeen Syed Ahamed Kabeer et al. All rights reserved. Retrospective Analysis of Efficacy and Safety of Tocilizumab Treatment in Patients with Severe Systemic-Onset Juvenile Idiopathic Arthritis Followed for 12 Months Thu, 22 Aug 2013 09:28:24 +0000 The results of the retrospective study evaluating efficacy and safety of tocilizumab treatment in 75 patients with severe systemic-onset juvenile idiopathic arthritis refractory to standard immunosuppressive therapy are presented in the paper. Inactive disease was documented in 64% of patients after 6 months of treatment and in 73% of patients after 12 months. Adverse events manifested as mild and moderate infections as well as laboratory abnormalities: leukopenia, neutropenia, and elevated aminotransferase levels. E. I. Alexeeva, A. A. Baranov, R. V. Denisova, S. I. Valieva, T. M. Bzarova, K. B. Isaeva, T. V. Sleptsova, E. V. Mitenko, N. I. Taybulatov, E. G. Chistyakova, and A. N. Fetisova Copyright © 2013 E. I. Alexeeva et al. All rights reserved. Partial Characterization of Immunoglobulin C Gene of Water Buffalo (Bubalus bubalis) Predicts Distinct Structural Features of C1q-Binding Site in C3 Domain Mon, 01 Jul 2013 12:02:58 +0000 Partial characterization of immunoglobulin C gene of water buffalo (Bubalus bubalis) revealed high amino acid sequence identity with C of cattle (94.28%) and sheep (91.71%). Four amino acid replacements (Met-301, Val-310, Asn-331, and Thr-432) in C2, C3, and C4 of buffalo IgM are distinct, however. Unlike cattle, a codon deletion (GTG encoding valine at position 507 in cattle) and an insertion (GGC encoding glycine at position 532) occur in buffalo C4. Three N-linked glycosylation (Asn-X-Thr/Ser) sites (one at position 325–327 in C2; two at positions 372–374 and 394–396 in C3) differentiate buffalo IgM from cattle and sheep. Similar to cattle, buffalo IgM has fewer prolines in C2, which acts as hinge, which restricts Fab arm flexibility. Increased structural flexibility of the C1q-binding site in C3 compensates for the rigid buffalo C2 domain. Secondary structure of C1q-binding site is distinct in buffalo and cattle IgM where long alpha-helical structure is predominant that may be relevant to complement fixation function. Conserved protein motif “Thr-Cys-Thr-Val-Ala-His” provides protein signatures of C1q-binding region of ruminant species. The distinct structural features of C1q-binding site of buffalo and cattle IgM seem to be of functional significance and, therefore, useful in designing antibody based therapeutics. Surinder S. Saini, N. K. Maiti, and Azad K. Kaushik Copyright © 2013 Surinder S. Saini et al. All rights reserved. Synergy in B-Cell Activation between Toll-Like Receptor 9 and Transmembrane Activator and Calcium-Modulating Cyclophilin Ligand Interactor (TACI) in A181E/C104R Compound Heterozygous Siblings Mon, 17 Jun 2013 11:33:11 +0000 Purpose. Approximately 9% of common variable immunodeficiency (CVID) patients harbor variants in the transmembrane activator and CAML interactor gene, TACI, which contribute to CVID development. We found identical compound heterozygous TACI variants (C104R and A181E) in kindred of which one sibling had severe CVID with refractory auto immunity, and a second sibling remained asymptomatic. This study investigated possible differences in B-cell phenotype and function that could explain this divergent clinical expression. Methods. C104R and A181E TACI variants were identified through Sanger sequencing. Phenotypic evaluation of the lymphocyte compartment was performed by flow cytometry analyses. Lymphoblastoid cell lines (LCL) from the index patient, asymptomatic sibling, and controls were generated. Intracellular TACI expression was determined, and activation-associated calcium flux capacity was measured. In vitro stimulation assays and RT PCR were performed. Results. Both intracellular levels and surface expressed TACI protein were higher in the asymptomatic sibling than the CVID patient as were TACI-triggering-induced mRNA expression AID and production of Ig class-switched antibodies. In analogy, the asymptomatic sibling displayed enhanced Toll-like receptor 9 expression and signaling, suggesting a compensatory immune mechanism. Conclusions. Posttranscriptional regulation of TACI protein and cross-talk with TLR9 signaling may contribute to phenotypic diversity between individuals with TACI variants. Annick A. J. M. van de Ven, Willemijn J. M. Janssen, Lisette van de Corput, Andries C. Bloem, Joris M. van Montfrans, and Marianne Boes Copyright © 2013 Annick A. J. M. van de Ven et al. All rights reserved. Local and Systemic Immune Responses to Salmonella in Genetically Susceptible I/St Mice after Mucosal Challenge Sun, 02 Jun 2013 09:07:51 +0000 It was previously demonstrated that mice of I/StSnEgYCit (I/St) strain are more susceptible to tuberculosis infection than A/SnYCit (A/Sn) mice, and this susceptibility was controlled by a few interacting QTLs mapped to chromosomes 3, 9, 17. It was also shown, that I/St mice displayed higher susceptibility to acute salmonella disease after intraperitoneal challenge with S. enterica serovar Typhimurium. Genetic mapping showed the involvement of Tbs2 (D9Mit89) loci in control of both salmonella and tuberculosis infections. In this study we define the immunological correlates of susceptibility in I/St mice after oral administration of S. enterica serovar Typhimurium. We found that resistance/susceptibility in I/St and A/Sn mice in our experiments correlated with differential pattern of early local and systemic responses of innate cells and specifically with higher involvement of Gr-1+ cells in local responses of resistant mice. This correlated with higher mucosal antibody production in A/Sn mice compared to I/St. I/St mice had predominant local involvement of CD11c+ cells and lack of mucosal antibodies. CD11c+ cells were the major type of cells that facilitated dissemination of salmonella to the target organs, while Gr-1+ cells contributed to exaggerated systemic inflammatory responses later in the course of infection. Our observations regarding the role of different cell populations in local and systemic immunity in susceptible and resistant mice are of importance for understanding of salmonella-induced cellular pathology and development of the strategy of its control. N. V. Kobets, L. N. Nesterenko, and D. V. Balunets Copyright © 2013 N. V. Kobets et al. All rights reserved. Circulating CCL5 Levels in Patients with Breast Cancer: Is There a Correlation with Lymph Node Metastasis? Wed, 29 May 2013 10:58:20 +0000 CC-chemokine ligand 5 (CCL5) was measured in plasma of 238 patients with breast cancer and in serum of 149 of these patients. Mean circulating CCL5 levels tended to be higher in patients with lymph-node-positive breast cancer, larger tumour sizes, the presence of lymphovascular invasion, and multifocal tumours. Additionally, circulating CCL5 levels were higher in the order of stages III, II, and I. The addition of circulating CCL5 concentration to known clinicopathological predictors for lymph node involvement did not allow more precise prediction of the lymph node status. These results suggest that CCL5 is a biomarker for tumour load rather than for lymph node involvement. As such, it might be helpful to identify patients with escape from immunosurveillance who will benefit from therapies to restore immune function. Ann Smeets, Barbara Brouwers, Sigrid Hatse, Annouschka Laenen, Robert Paridaens, Giuseppe Floris, Hans Wildiers, and Marie-Rose Christiaens Copyright © 2013 Ann Smeets et al. All rights reserved. Immunophenotypic Analysis of B Lymphocytes in Patients with Common Variable Immunodeficiency: Identification of CD23 as a Useful Marker in the Definition of the Disease Thu, 04 Apr 2013 08:17:46 +0000 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. Giuseppe Patuzzo, Filippo Mazzi, Antonio Vella, Riccardo Ortolani, Alessandro Barbieri, Elisa Tinazzi, Giacomo Marchi, Orazio Codella, Ruggero Beri, Antonio Puccetti, and Claudio Lunardi Copyright © 2013 Giuseppe Patuzzo et al. All rights reserved. Immune Escape Mechanisms in Diffuse Large B-Cell Lymphoma Sun, 23 Dec 2012 14:40:08 +0000 Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of non-Hodgkin lymphomas in Western countries. Implementation of immunotherapy using monoclonal antibodies to therapeutic protocols has led to dramatic improvements in overall survival. DLBCL became a model of a successful immunochemotherapy concept. Despite this fact, there is still a proportion of patients who do not respond to or relapse early after treatment. Growing evidence suggests that host antitumor immunity is suppressed by lymphoma cells in many ways. First, host cytotoxic T cells are directly suppressed by interaction with programmed cell death (PD) ligand on lymphoma cell surface and a similar mechanism enhances the activity of suppressive regulatory T cells (Tregs). Second, tumor cells escape host cytotoxic cells due to lower immunogenicity caused by reduced expression of HLA antigens. Both mechanisms have an origin in primary genetic events in lymphomagenesis. Rearrangement of MHC class II transcriptional activator (CIITA) gene and amplification of Janus kinase (JAK2) gene lead to enhanced expression of PD ligands 1 and 2, higher proliferation activity, and lower expression of HLA. This paper summarizes current knowledge about clinically relevant immune escape mechanisms in DLBCL. V. Procházka, M. Jarošová, Z. Prouzová, R. Nedomová, T. Papajík, and K. Indrák Copyright © 2012 V. Procházka et al. All rights reserved. CD200:CD200R-Mediated Regulation of Immunity Wed, 12 Dec 2012 15:12:47 +0000 The type 1 membrane glycoprotein CD200, widely expressed on multiple cells/tissues, uses a structurally similar receptor (CD200R1), whose expression is more restricted to cells of the myeloid and lymphoid lineages, to transmit signals affecting responses in multiple physiological systems. Thus CD200 expression is reported to exert effects on cancer growth, autoimmune and allergic disorders, infection, transplantation, bone development and homeostasis, and reproductive biology. It was initially thought, based on the idea that CD200R1 was mostly expressed on cells of myeloid origin, that CD200:CD200R1 interactions were primarily dedicated to controlling myeloid cell function. However additional members of the CD200R family have now also been identified, although their function(s) remain unclear, and CD200R1 itself is now known to be expressed by subsets of T cells and other cells. Together these observations add layers of complexity to our understanding of CD200-related regulation. In common with a number of physiological systems, the mechanism(s) of CD200-induced signaling seem to fit within a similar framework of opposing actions of kinases and phosphatases. This paper highlights the advances in our knowledge of immunoregulation achieved following CD200:CD200R interaction and the potential clinical applicability of that information. Reginald M. Gorczynski Copyright © 2012 Reginald M. Gorczynski. All rights reserved. Immune Recognition of Heat Shock Proteins Provides a Molecular Basis for the “Hygiene Hypothesis” Linking High Prevalence of Immune Disorders to Lack of Cell Stress Eliciting Events Thu, 29 Nov 2012 10:52:12 +0000 A modern interpretation of the hygiene hypothesis proposes the so-called “old friends” to trigger tolerogenic responses through innate receptors of dendritic cells (DC). Tolerogenic DCs would drive regulatory T-cell polarization through induction of old-friend-specific Treg. In the tissues of the gut that are besieged by our old friends, these cells are held to produce a continuous bystander regulation. However, such local bystander regulation in the gut may be difficult to reconcile with suppression of responses to airway allergens or autoimmune antigens present in distant body tissues. Alternatively, the regulatory Tregs may be triggered through recognition of stress proteins or heat shock proteins (HSP). Microbial HSP are immunodominant and evolutionary conserved with homologs present in mammalian cells. Microbial HSP are now known to induce Tregs that cross-recognize mammalian HSP. In addition, microbial exposures, both friendly and nonfriendly, cause cell stress and, consequently, HSP upregulation in host cells. Also such upregulated HSP can activate HSP-specific Tregs that target the upregulated HSP at sites of inflammatory stress wherever in our body. Under inflammatory conditions, cell stress-associated HSP are abundant and therefore easy targets for cognate T-cell interactions. Herewith, they provide a molecular basis for the hygiene hypothesis. W. van Eden Copyright © 2012 W. van Eden. All rights reserved. Analysis of LAM and 38 kDa Antibody Levels for Diagnosis of TB in a Case-Control Study in West Africa Mon, 26 Nov 2012 08:56:55 +0000 CD4+ T cells are required for protection against tuberculosis (TB) disease progression, but interest in the role of antibodies in early protection, as biomarkers for disease status, and use in diagnostic tests has recently increased. In this study we analyzed plasma antibody levels in TB cases before and after treatment in both HIV-positive and -negative individuals and compared them with tuberculin skin test (TST+) (latently infected) household contacts (HHC). We also analyzed HHC that subsequently progressed to active disease within 2 years in order to see if antibodies play a role in protection against disease progression. We used a commercially available kit to 38 kDa antigen and lipoarabinomannan (LAM) and found that immunoglobulin (Ig) G levels were 4-fold higher in subjects with disease compared to latently infected controls () and were 2-fold higher than pretreatment levels following successful TB treatment ( compared to both pretreated cases and latently infected controls). HIV infection resulted in low antibody levels regardless of disease status or treatment outcome. Furthermore, levels in disease progressors (incident cases) were similar to nonprogressors and were not elevated until just prior to disease progression confirming previous reports that IgG antibodies, at least in the periphery, do not confer protection against TB disease progression. Marie P. Gomez, Simon Donkor, Ifedayo M. Adetifa, Martin O. C. Ota, and Jayne S. Sutherland Copyright © 2012 Marie P. Gomez et al. All rights reserved. An Emerging Role for Serine Protease Inhibitors in T Lymphocyte Immunity and Beyond Mon, 19 Nov 2012 12:41:41 +0000 The serine proteases of T lymphocytes provide immunity to infection. Serine Proteases Inhibitors (serpins) control the recognition of antigen, effector function, and homeostatic control of T lymphocytes through the inhibition of serine protease targets. Serpins are important promoters of cellular viability through their inhibition of executioner proteases, which affects the survival and development of long-lived memory T cells. The potent antiapoptotic properties of serpins can also work against cellular immunity by protecting viruses and tumors from eradication by T lymphocytes. Recent insights from knockout mouse models demonstrate that serpins also are required for hematological progenitor cells and so are critical for the development of lineages other than T lymphocytes. Given the emerging role of serpins in multiple aspects of lymphocyte immunity and blood development, there is much potential for new therapeutic approaches based directly on serpins or knowledge gained from identifying their physiologically relevant protease targets. Philip G. Ashton-Rickardt Copyright © 2012 Philip G. Ashton-Rickardt. All rights reserved. Host Defence against Bacterial Biofilms: “Mission Impossible”? Mon, 05 Nov 2012 10:27:06 +0000 Bacteria living as biofilms have been recognised as the ultimate cause of persistent and destructive inflammatory processes. Biofilm formation is a well-organised, genetically-driven process, which is well characterised for numerous bacteria species. In contrast, the host response to bacterial biofilms is less well analysed, and there is the general believe that bacteria in biofilms escape recognition or eradication by the immune defence. In this review the host response to bacterial biofilms is discussed with particular focus on the role of neutrophils because these phagocytic cells are the first to infiltrate areas of bacterial infection, and because neutrophils are equipped with a wide arsenal of bactericidal and toxic entities. I come to the conclusion that bacterial biofilms are not inherently protected against the attack by neutrophils, but that control of biofilm formation is possible depending on a timely and sufficient host response. Gertrud Maria Hänsch Copyright © 2012 Gertrud Maria Hänsch. All rights reserved. What Have We Learned about the Pathogenesis of Rheumatoid Arthritis from TNF-Targeted Therapy? Tue, 16 Oct 2012 09:59:41 +0000 Studies of cytokine regulation in rheumatoid arthritis led to the development of TNFα inhibitors which are now used for a number of indications, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, and ankylosing spondylitis. The widespread use of biologics in the clinic offers unique opportunities for probing disease pathogenesis and this paper provides an overview of rheumatoid arthritis, with a particular emphasis on the impact of anti-TNFα therapy on pathogenetic mechanisms. An overview is also provided on the most commonly used animal models that mimic RA, including adjuvant-induced arthritis, collagen-induced arthritis, TNFα-transgenic mice, and the K/BxN and SKG models. These models have led to significant discoveries relating to the importance of pro-inflammatory cytokines in the pathogenesis of rheumatoid arthritis, resulting from disregulation of the normally finely tuned balance of pro- and anti-inflammatory cytokine signalling. In addition, experimental evidence is discussed suggesting how genetic and environmental factors can contribute to disease susceptibility. The role of effector and regulatory T cells is discussed in the light of the relatively disappointing therapeutic effects of T cell modifying agents such as anti-CD4 antibody and cyclosporin. It is concluded that comprehensive analyses of mechanisms of action of biologics and other drugs entering the clinic will be essential to optimise therapy, with the ultimate aim of providing a cure. Richard O. Williams Copyright © 2012 Richard O. Williams. All rights reserved. Role of Natural Killer Cells in Multiple Sclerosis Sun, 14 Oct 2012 15:14:19 +0000 Although the etiology of multiple sclerosis (MS) is not known, the consensus is that Th1 cells sensitized to myelin proteins in the periphery are recruited into the CNS and damage the myelin sheath. Natural killers (NK) are cells that spontaneously lyse tumor target cells and have immunoregulatory activity secreting multiple cytokines and chemokines, as well as interacting with cells of innate and adaptive immune systems. A great discovery in the field is the cloning of several inhibitory and activating receptors. Another important contribution is the discovery that these cells express many seven-transmembrane-spanning domain receptors which aid them in extravasations into injured tissues. Despite all this progress, the role of NK cells in autoimmune diseases including MS is still not quite clear. In this paper, I will summarize recent findings related to the effects of these cells in both MS and the animal model of experimental autoimmune encephalomyelitis (EAE). Hence, I will discuss the effects of drugs used to treat MS/EAE and then explain their effects on NK cells. These include anti-CD25 or daclizumab, interferon-β (IFN-β), natalizumab, glatiramer acetate (GA), and fingolimod (FTY720). Finally, I will explain the contribution of the recently discovered NK17/NK1 cells in MS disease. A. A. Maghazachi Copyright © 2012 A. A. Maghazachi. All rights reserved. An Overview of the Immunological Defenses in Fish Skin Sun, 14 Oct 2012 15:05:39 +0000 The vertebrate immune system is comprised of numerous distinct and interdependent components. Every component has its own inherent protective value, and the final combination of them is likely to be related to an animal’s immunological history and evolutionary development. Vertebrate immune system consists of both systemic and mucosal immune compartments, but it is the mucosal immune system which protects the body from the first encounter of pathogens. According to anatomical location, the mucosa-associated lymphoid tissue, in teleost fish is subdivided into gut-, skin-, and gill-associated lymphoid tissue and most available studies focus on gut. The purpose of this paper is to summarise the current knowledge of the immunological defences present in skin mucosa as a very important part of the fish immune system, serving as an anatomical and physiological barrier against external hazards. Interest in defence mechanism of fish arises from a need to develop health management tools to support a growing finfish aquaculture industry, while at the same time addressing questions concerning origins and evolution of immunity in vertebrates. Increased knowledge of fish mucosal immune system will facilitate the development of novel vaccination strategies in fish. María Ángeles Esteban Copyright © 2012 María Ángeles Esteban. All rights reserved. C3b-Independent Complement Activation in Ischemia/Reperfusion Mesenteric Tissue Injury in Autoimmune Prone (B6.MRL/lpr) Mice Sun, 16 Sep 2012 11:42:02 +0000 Complement plays a critical role in the development of tissue injury in systemic lupus erythematosus. The B6.MRL/lpr mouse, an autoimmune prone mouse, exhibits accelerated and intensified tissue injury in the ischemia/reperfusion (IR) model. It has been demonstrated in nonautoimmune mice that inhibition of complement attenuates inflammatory tissue injury in IR models. The role of complement is not as clear in the B6.MRL/lpr strain. B6.MRL/lpr-C3 deficient animals are susceptible to injury, but long-term use of C3 inhibitors in B6.MRL/lpr-C3 competent animals restrained the development of nephritis. To clarify the role of complement in the B6.MRL/lpr strain, initial and midpathway inhibitors were evaluated. C1 inhibition attenuated tissue injury, thrombin deposition, and C5a generation in the B6.MRL/lpr strain. Downstream of C1 inhibition of C3 activation by administration of cobra venom factor suppressed IR injury in immune competent mice, but was not as effective in B6.MRL/lpr mice. C3 levels in both strains were decreased after cobra venom factor treatment; however, C5a generation, thrombin deposition, and tissue injury were observed in the B6.MRL/lpr strain. These studies suggest that in the B6.MRL/lpr autoimmune prone strain C1 activation leads to C3-dependent and C3-independent pathways of complement activation. J. Tofferi, S. Peng, and C. M. Moratz Copyright © 2012 J. Tofferi et al. All rights reserved. Intratumoral TLR-4 Agonist Injection Is Critical for Modulation of Tumor Microenvironment and Tumor Rejection Wed, 25 Jul 2012 13:35:07 +0000 The tumor microenvironment shelters a complex network of mechanisms that enables local Immunosuppression to support tumor growth. In this study we found that, B16F10 melanoma growth is inversely correlated with peritumoral infiltrate cell number and with cell numbers in draining lymph nodes. Tumor growth ensued even when a foreign antigen was expressed by B16F10 cells in the presence of naïve specific CD8+ T cells. Treatment with TLR agonists has shown to sometimes result in tumor regression, however, not always with long-lasting effects. We compared the relevance of different injection regimens of lipopolysaccharide (LPS). Tumor growth was arrested only by intratumoral LPS injection after the tumor was already established. This result was accompanied by a dramatic change in DC activation inside the tumor. Intratumoral LPS also enhanced antigen presentation and tumor-specific CD4+ T cell production of IFN-γ. Injection of LPS before tumor challenge or codelivery of tumor cells and LPS did not have any effect on tumor progression. Our results suggest that an efficient antitumor immune response leading to tumor regression can be achieved with proper TLR4 activation inside the tumor tissue, impacting the tumor microenvironment. These findings are relevant for the design of treatment for patients with malignant melanomas. Fabio Luiz Dal Moro Maito, Ana Paula Duarte de Souza, Luciana Pereira, Megan Smithey, David Hinrichs, Archie Bouwer, and Cristina Bonorino Copyright © 2012 Fabio Luiz Dal Moro Maito et al. All rights reserved. Overview of Achievements and Challenges of the Fight against AIDS in China Thu, 17 May 2012 09:13:33 +0000 The epidemic of HIV/AIDS exists in China from more than 26 years and is still at a low prevalence (<0.06%) on the global level. The purpose of this paper is to disclose the rational of how to keep the low rate through strenthening key strategies and comprehensive measures for prevention and control of the disease using collecting, reviewing, and analyzing surveillance data, special materials from publications, national meetings, symposiums, and forums, major research results as well as the personal experiences within the period of 1985–2011. In the meantime, the paper mentions that currently China is facing challenges and also going to carry out its actions concerning how to deal with the problems in order to respond to the UN CALL on “Getting to Zero”. Laiyi Kang Copyright © 2012 Laiyi Kang. All rights reserved. New Aspects in Immunopathology of Mycobacterium tuberculosis Wed, 28 Mar 2012 16:04:09 +0000 Our understanding of tuberculosis (TB) pathology and immunology has become extensively deeper and more refined since the identification of Mycobacterium tuberculosis (MTB) as the etiologic agent of disease by Dr. Robert Koch in 1882. A great challenge in chronic disease is to understand the complexities, mechanisms, and consequences of host interactions with pathogens. TB, caused by MTB, is a major health problem in world, with 10 million new cases diagnosed each year. Innate immunity is shown playing an important role in the host defense against the MTB, and the first step in this process is recognition of MTB by cells of the innate immune system. Several classes of pattern recognition receptors (PPRs) are involved in the recognition of MTB, including toll-like receptors (TLRs), C-type lectin receptors (CLRs), and nod-like receptors (NLRs). Among the TLR family, TLR1, TLR2, TLR4, and TLR9 and their down streams, proteins play the most prominent roles in the initiation of the immune response against MTB. Beside of TLRs signaling, recently the activation of inflammasome pathway in the pathogenesis of TB much appreciated. Knowledge about these signaling pathways is crucial for understanding the pathophysiology of TB, on one hand, and for the development of novel strategies of vaccination and treatment such as immunotherapy on the other. Given the critical role of TLRs/inflammasome signaling in innate immunity and initiation of the appropriate adaptive response, the regulation of these pathways is likely to be an important determinant of the clinical outcome of MTB infection. In this review paper we focused on the immune response, which is the recognition of MTB by inflammatory innate immune cells following infection. E. Mortaz, M. Varahram, P. Farnia, M. Bahadori, and MR Masjedi Copyright © 2012 E. Mortaz et al. All rights reserved. The Florida Melanoma Trial I: A Prospective Multicenter Phase I/II Trial of Postoperative Hypofractionated Adjuvant Radiotherapy with Concurrent Interferon-Alfa-2b in the Treatment of Advanced Stage III Melanoma with Long-Term Toxicity Follow-Up Sun, 19 Feb 2012 11:19:04 +0000 Radiotherapy (RT) and interferon-alfa-2b (IFN α-2b) have individually been used for adjuvant therapy stage III melanoma with high-risk pathologic features. We hypothesized that concurrent adjuvant RT and IFN α-2b may decrease the risk of regional recurrence following surgery with acceptable toxicity. A prospective multicenter phase I/II study was conducted to evaluate hypofractionated RT with concurrent IFN. Induction IFN α-2b, 20 MU/m2/d, was administered IV ×5 consecutive days every week for 4 weeks. Next, RT 30 Gy in 5 fractions was given with concurrent IFN α-2b, 10 MU/m2 SQ 3 times per week on days alternating with RT. Subsequent maintenance therapy consisted of adjuvant IFN α-2b, 10 MU/m2 SQ 3 times per week to a total of 1 year. To fully evaluate patterns of failure, long-term follow-up was conducted for up to 10 years. A total of 29 consenting patients were enrolled between August 1997 and March 2000. The maximum (worst) grade of acute nonhematologic toxicity during concurrent RT/IFN α-2b (and up to 2 weeks post RT) was grade 3 skin toxicity noted in 2 patients (9%). Late effects were limited. Probability of regional control was 78% (95% CI: 55%–90%) at 12 months. The median follow-up (range) was 80 (51–106) months among ten survivors (43%). The median overall survival was 34.5 months while the median failure-free survival was 19.9 months. Postoperative concurrent hypofractionated RT with IFN α-2b for advanced stage III melanoma appears to be associated with acceptable toxicity and may provide reasonable in-field control in patients at high risk of regional failure. Steven E. Finkelstein, Andy Trotti, Nikhil Rao, Douglas Reintgen, Wayne Cruse, Lynn Feun, Vernon Sondak, Daohai Yu, Weiwei Zhu, Clement Gwede, and Ronald DeConti Copyright © 2012 Steven E. Finkelstein et al. All rights reserved. Resection and Immunotherapy for Recurrent Grade III Glioma Thu, 09 Feb 2012 16:20:34 +0000 Background. Despite surgery, radiotherapy, and chemotherapy, the prognosis of relapsed grade III gliomas remains poor. After promising results of immunotherapy in grade IV gliomas, we investigated its safety and efficacy in recurrent grade III gliomas. Methods. Thirty-nine patients received vaccines containing dendritic cells loaded with autologous tumor lysate after tumor resection. Progression-free survival (PFS) and overall survival (OS) were compared with those obtained after temozolomide (TMZ) treatment as found in the literature. Results. Median PFS and OS were 4.6 and 20.5, 3.4 and 18.8, 7.8 and 13.3 months in recurrent grade III astrocytoma, oligodendroglioma, and oligoastrocytoma, respectively. Compared with TMZ, no grade III/IV toxicity was reported and median OS tended to be higher although there was no difference in median PFS. The perceived benefit of immunotherapy was more pronounced in astrocytic tumors. Conclusions. We provide the first description of immunotherapy in recurrent grade III glioma as safe, promising, and feasible. Iris Elens, Steven De Vleeschouwer, Femke Pauwels, and Stefaan Van Gool Copyright © 2012 Iris Elens et al. All rights reserved. Course of Antibody Response in Lyme Borreliosis Patients before and after Therapy Thu, 26 Jan 2012 13:41:09 +0000 The early immune response (IR) in European Lyme borreliosis patients has not yet been studied in detail. The aim of the study was to analyse retrospectively the antibody development in 61 erythema migrans (EMs) patients depending on the duration of infection from tick bite by using a whole-cell lysate B. garinii immunoblot. The evolution of antibodies proved to be undulatory in untreated patients with two peaks for IgM at weeks 5 and 9 and for IgG at weeks 4 and 8. The analysis of IR courses after therapy identified patients constantly seropositive or seronegative and patients with repeated seroconversions with a switch, disappearance, or reappearance of anti-23 kD or anti-39 kD antibodies during the one-year period. We suggest that the antibody production in EM patients may be missed due to an undulatory IR. This phenomenon might be an as yet insufficiently researched aspect in Lyme borreliosis. Elisabeth Aberer and Gerold Schwantzer Copyright © 2012 Elisabeth Aberer and Gerold Schwantzer. All rights reserved. HIV and AIDS Programmes in Zimbabwe: Implications for the Health System Thu, 26 Jan 2012 11:22:08 +0000 This paper analyzes the implications of HIV and AIDS prevention, treatment, and care programmes on the health system in Zimbabwe. The programmes have been spearheaded by various stakeholders that include the public and private sectors, nongovernmental organizations, formal and informal institutions, and intergovernmental organizations. There has been a tremendous increase of the programmes as they adapt to local contexts, accommodate new funders, and changes in population attitudes, and expectations in the country. Through a comprehensive literature review, this paper focuses on Behaviour Change, the Antiretroviral Therapy, Home-Based Care, Prevention to Mother To Child Transmission and Voluntary Counselling and Testing programmes and services in relation to the components of the health system that include health service delivery, human resources, finance, leadership and governance, and the medical products and technologies. Thus far, the implications are uneven throughout the health system and there is need to integrate the HIV and AIDS programmes within the health system in order to achieve positive heath outcomes. Tafadzwa Chevo and Sandra Bhatasara Copyright © 2012 Tafadzwa Chevo and Sandra Bhatasara. All rights reserved.