ISRN Immunology

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.

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.

CD200:CD200R-Mediated Regulation of Immunity

Reginald M. Gorczynski — 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.

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

W. van Eden — 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.

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.

An Emerging Role for Serine Protease Inhibitors in T Lymphocyte Immunity and Beyond

Philip G. Ashton-Rickardt — 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.

Host Defence against Bacterial Biofilms: “Mission Impossible”?

Gertrud Maria Hänsch — 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.

What Have We Learned about the Pathogenesis of Rheumatoid Arthritis from TNF-Targeted Therapy?

Richard O. Williams — 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.

Role of Natural Killer Cells in Multiple Sclerosis

A. A. Maghazachi — 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.

An Overview of the Immunological Defenses in Fish Skin

María Ángeles Esteban — 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.

C3b-Independent Complement Activation in Ischemia/Reperfusion Mesenteric Tissue Injury in Autoimmune Prone (B6.MRL/lpr) Mice

J. Tofferi, S. Peng, and C. M. Moratz — 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.

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.

Overview of Achievements and Challenges of the Fight against AIDS in China

Laiyi Kang — 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”.

New Aspects in Immunopathology of Mycobacterium tuberculosis

E. Mortaz, M. Varahram, P. Farnia, M. Bahadori, and MR Masjedi — 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.

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.

Resection and Immunotherapy for Recurrent Grade III Glioma

Iris Elens, Steven De Vleeschouwer, Femke Pauwels, and Stefaan Van Gool — 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.

Course of Antibody Response in Lyme Borreliosis Patients before and after Therapy

Elisabeth Aberer and Gerold Schwantzer — 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.

HIV and AIDS Programmes in Zimbabwe: Implications for the Health System

Tafadzwa Chevo and Sandra Bhatasara — 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.

The Role of Granulysin in Cancer Immunology

Satoshi Okada and Tetsuo Morishita — Wed, 18 Jan 2012 10:24:21 +0000

Granulysin is a cytotoxic granule expressed in cytotoxic T cells and natural killer cells. Although its cytotoxic effect against a number of tumor cell lines has been demonstrated in vitro, recent studies with transgenic mice, and a number of clinical studies, have further established its significance in cancer immunology. Furthermore, granulysin-induced in vitro chemotaxis and activation of both human and mouse dendritic cells have been reported. Given the results in recent clinical studies, granulysin may offer a useful indicator in the prognosis of cancer. Taken together, an understanding of the mechanism by which granulysin destroys target cells would provide vital information in the development of new therapies for the treatment of this disease.

Evaluation of the Immune Response of Individuals Infected with Mycobacterium tuberculosis and Patients with Active Tuberculosis

Wed, 11 Jan 2012 14:06:11 +0000

This study reports the association between Mycobacterium tuberculosis and the immune response to pulmonary tuberculosis (TB). Three groups were analyzed: (a) symptomatic patients with pulmonary tuberculosis (PTB), HIV-negative; (b) healthy individuals, tuberculin skin test reactive (TST+); (c) asymptomatic individuals, TST nonreactive (TST−). Groups B and C presented a negative bacilloscopic smear, normal chest radiographs, and negative HIV. The ELISA was used for IFN-γ, IL-10, TNF-α, and IgG quantification and lymph proliferative assay (LPA) to evaluate the cellular immune response. IgG and LPA increased in all study groups as well as IFN-γ and TNF-α, but IL-10 remained low in all study groups. There was an association between LPA and IFN-γ in group B. It was demonstrated an association between IgG and IL-10 and between IFN-γ and IL-10 in group A. There were direct and significant correlations between LPA and IgG, TNF-α and IFN-γ, IL-10 and IgG, and between IL-10 and IFN-γ, but an inverse relationship was observed between IFN-γ and LPA.

“Abscopal” Effect of Radiation Therapy Combined with Immune-Therapy Using IFN-γ Gene Transfected Syngeneic Tumor Cells, in Rats with Bilateral Implanted N29 Tumors

Wed, 14 Dec 2011 13:44:46 +0000

The tumor growth rate response was studied on N29 rat glioma tumor cells subcutaneously implanted on both hind legs of Fischer-344 rats. At around 30 days after inoculation, RT was given with 60Co gamma radiation with 4 daily fractions of 5 Gy only to the right-lateral tumors. At days 26, 42, and 54 after inoculation, immunization was performed with irradiated syngeneic IFNγ-gene transfected cells. Tumor growth rate (TGR % per day) of the right-lateral irradiated tumor was significantly decreased (𝑃<0.01) after RT alone and with the combination of RT and immunization. But immunization alone gave no significant decrease of the TGR but significantly increased time of survival. The TGR of the unirradiated left-lateral tumors was significantly decreased (𝑃<0.02) only in the group of rats treated with RT alone. It is apparent that tumor cells killed by the radiation mediate suppression of tumor cells outside the target area. This effect is called the abscopal effect.

Consumption of Galactooligosaccharides together with Probiotics Stimulates the In Vitro Peripheral Blood Mononuclear Cell Proliferation and IFNγ Production in Healthy Men

Wed, 30 Nov 2011 16:24:01 +0000

Probiotics and prebiotics modify the intestinal environment and could have immunomodulatory effects. The proliferation of spontaneous and phytohemagglutinin-stimulated peripheral blood mononuclear cells (PBMCs) and their production of interleukin-4, interleukin-5, transforming growth factor-β1, and interferon-γ (IFNγ) were determined in eighteen men at the baseline and during a 2-week period of probiotics (mixture of Lactobacillus rhamnosus GG, Lactobacillus rhamnosus LC705, Propionibacterium freudenreichii ssp. shermanii JS, and Bifidobacterium breve Bb99) and galactooligosaccharides (GOSs) (3.8 g/day). The spontaneous and stimulated proliferation of PBMC increased from the baseline during probiotics+GOS (𝑃<0.001). The secretion of IFNγ, but not other cytokines, by stimulated PBMC increased during the same period (𝑃<0.05). In conclusion, the consumption of this probiotic mixture including GOS appears to increase the capacity of PBMC to proliferate and release IFNγ selectively in healthy men.

Circulating Anti-PLAC1 Antibodies during Pregnancy and in Women with Reproductive Failure: A Preliminary Analysis

Tue, 29 Nov 2011 11:02:57 +0000

The aims of this study were to determine the prevalence of anti-PLAC1 antibodies in normal pregnant women and in women with infertility or recurrent pregnancy loss (RPL). Secondary outcomes were the development of complications associated with anti-PLAC1 seropositivity and the rate of seroconversion during pregnancy. Sera from 103 healthy pregnant women and 45 women with unexplained infertility or RPL were analyzed by ELISA. The prevalence of anti-PLAC1 antibodies was 2% in healthy pregnant women and 4.5% in women with unexplained infertility or RPL (𝑃=0.355). There was no detectable association of seropositivity with increased risk of pregnancy complications. Finally, 2% of women seroconverted during pregnancy. The prevalence of anti-PLAC1 antibodies in women with unexplained infertility or RPL is not significantly higher than the prevalence in normal pregnant women. However, the sample size in this study was too small. The exposure to the PLAC1 antigen during pregnancy can lead to the spontaneous development of antibodies.

Immunosuppressive Factor MNSFβ Regulates Cytokine Secretion by Mouse Lymphocytes and Is Involved in Interactions between the Mouse Embryo and Endometrial Cells In Vitro

Thu, 24 Nov 2011 14:32:13 +0000

Immune tolerance at the fetomaternal interface must be established during the processes of implantation and pregnancy. Monoclonal nonspecific suppressor factor beta (MNSFβ) is a secreted protein that possesses antigen-nonspecific immune-suppressive function. It was previously reported that intrauterine immunoneutralization of MNSFβ significantly inhibited embryo implantation in mice. In the present study, MNSFβ protein expression was up- or downregulated by overexpression or RNA interference, respectively, in HCC-94 cells and the culture supernatants used to determine effects of MNSFβ on the secretion of IL-4 and TNFα from mouse lymphocytes as detected by ELISA. A coculture model of mouse embryos and endometrial stromal cells was also utilized to determine the effects of a specific anti-MNSFβ antibody on hatching and growth of embryos in vitro. The results show that MNSFβ induced secretion of IL-4 and inhibited secretion of TNFα from mouse lymphocytes. Following immunoneutralization of MNSFβ protein in the HCC-94 supernatant, the stimulatory effect of MNSFβ on IL-4 secretion from mouse lymphocytes was reduced, while the inhibitory effect on secretion of TNFα was abrogated. Expression of MNSFβ was detected in both embryonic and endometrial stromal cells, and its immunoneutralization inhibited the hatching and spreading of embryos in an in vitro coculture model. These results indicated that MNSFβ may play critical roles during the peri-implantation process by regulating cytokine secretion of lymphocytes and by mediating the crosstalk between embryonic cells and endometrial stromal cells.

Mucosal Immunity and the Intestinal Microbiome in the Development of Critical Illness

Thu, 24 Nov 2011 10:21:41 +0000

The intestinal community, including the commensal microbial flora as well as the host tissues, represents a functional whole in vivo. Under physiological circumstances, this symbiosis brings great benefit for the host; however, critical illness induces profound disturbances in the intestinal ecosystem affecting both procaryotic and eucaryotic members. Today, 25 years after the gut was first described as a motor of multiple organ dysfunction syndrome, the role of the injured splanchnic compartment in the pathomechanism and development of critical illness is still in the first line of research. Multiple mechanisms have been identified by which the stressed gut may affect host homeostasis, and how external intervention might help to rebalance physiology. This paper provides a brief overview of the present of this field.

The Roles of CD4+ T Cells in Tumor Immunity

Yo-Ping Lai, Chung-Jiuan Jeng, and Shu-Ching Chen — Wed, 09 Nov 2011 09:31:39 +0000

Activation of CD8+ cytotoxic T cells has long been regarded as a major antitumor mechanism of the immune system. Emerging evidence suggests that CD4+ T cells are required for the generation and maintenance of effective CD8+ cytotoxic and memory T cells, a phenomenon known as CD4+ T-cell help. CD4+ T-cell help facilitates the optimal expansion, trafficking, and effector function of CD8+ T cells, thereby enhancing tumor destruction. In addition, a specialized subset of CD4+ T cells, CD4+CD25+ regulatory T cells (TRegs), effectively hampers anti-tumor immune responses, which has been proposed to be one of the major tumor immune evasion mechanisms. Here, we review recent advances in deciphering how anti-tumor immune responses are orchestrated by CD4+ T cells. We will also discuss the immunotherapeutic potential of CD4+ T-cell manipulation in anti-tumor immune response.

Systemic Lupus Erythematosus: Recent Concepts in Genomics, Pathogenetic Mechanisms, and Therapies

Sriram Krishnamurthy and Subramanian Mahadevan — Mon, 24 Oct 2011 14:02:28 +0000

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disorder associated with multiple immunological abnormalities and a wide range of clinical manifestations. Recent progress in genetics has expanded the number of the genes associated with SLE to more than 20 in number and has contributed to improvement of understanding of the pathogenesis of the disease. This has enhanced the development of novel therapeutic targets and biomarkers for individualized and tailor-made clinical management of lupus patients. Despite this knowledge, however, it is a challenge to fully understand the genetic pathogenesis of the disease. The present paper describes the current concepts in the mechanisms, genomics, and pathogenesis of SLE and their implications for management of the disorder. The potential role of gene therapy, biological agents, intravenous immunoglobulin, anti-inflammatory cytokines, and cytokine inhibitors is discussed.

PICOT: A Multidomain Protein with Multiple Functions

Anna Keselman, Ranjan Nath Pulak, Keren Moyal, and Noah Isakov — Wed, 19 Oct 2011 14:56:47 +0000

The PICOT protein possesses three highly conserved regions that include an aminoterminal thioredoxin-like homology domain and a tandem repeat of a carboxyterminal PICOT homology domain with an overall conformation that resembles a glutaredoxin homology domain. In contrast to the classical dithiol thioredoxins and glutaredoxins, PICOT possesses a single cysteine residue in each of its three domains and is therefore distinct from the classical thioredoxin and glutaredoxin redox enzymes. Recent studies demonstrated that PICOT is a prerequisite for mouse embryogenesis and participates in several independent biological systems in the adult. This paper examines advances made over the past few years in understanding the role of PICOT in various biological systems.

Umbilical Serum sHLA-G Levels in Preeclamptic Pregnancies with and without Intrauterine Fetal Growth Restriction: A Comparison with Normotensive Pregnancies with Isolated IUGR and Healthy Controls

Marzena Laskowska, Katarzyna Laskowska, and Jan Oleszczuk — Sun, 18 Sep 2011 14:25:43 +0000

The aim of this study was the analysis of the umbilical cord serum sHLA-G levels in pregnancies complicated by severe preeclampsia and/or IUGR. Patients and Methods. The study was carried out on 12 preeclamptic patients with appropriate-for-gestational-age weight infants, 14 pregnant patients with severe preeclampsia complicated by IUGR, 7 normotensive patients with isolated IUGR, and 22 healthy controls with uncomplicated pregnancies. Results. Our study revealed higher umbilical serum levels of sHLA-G in preeclamptic pregnancies complicated by IUGR and decreased in the preeclamptic women with the normal fetal growth. The pregnant normotensive patients with isolated IUGR revealed the same levels of sHLA-G as observed in healthy pregnant controls. Conclusions. Lower levels of sHLA-G observed in preeclamptic pregnancies without IUGR may lead to excessive maternal immune reaction against the fetus. Higher levels of sHLA-G in preeclamptic pregnancies with IUGR may reflect the excessive releasing of this molecule to protect fetus, but it may be insufficient to balance disturbed fetomaternal immune relationship. The lack of association with normotensive pregnancies complicated by isolated IUGR may suggest that a different pathomechanism is involved in the impairment of intrauterine fetal growth in both patient groups with pregnancies complicated by isolated IUGR and in the course of preeclampsia.

Modification of a Popular Syngeneic Murine Mammary Tumor Model for Immunotherapy Studies

Armando Rivera, Xinping Fu, Lihua Tao, and Xiaoliu Zhang — Sun, 18 Sep 2011 08:44:42 +0000

To facilitate the evaluation of immunotherapeutic intervention against malignant diseases, it is desirable to have a syngeneic tumor model that closely resembles the growth pattern of human tumors. Murine 4T1 breast cancer model is known for its metastatic properties that mimic its human counterpart. However, a drawback of this model is the lack of an identified tumor antigen to function as a therapeutic target for immunologic intervention. We used the piggyBac transposon system to stably transduce a tumor antigen, the human epidermal growth factor receptor 2 gene (HER2), into this tumor cell. In vitro characterization shows that the newly established cells have a similar growth pattern as the parental line. In vivo evaluation shows that host immune response was generated against the HER2 tumor antigen, despite the high homology between HER2 and its murine counterpart (neu gene). When implanted into immune-deficient mice, the HER2-expressing 4T1 cells readily formed sizable tumors, indicating that these cells are useful for evaluating the therapeutic effect of adoptively transferred cytotoxic T cells that are specifically raised or modified to target the HER2 tumor antigen.