Journal of Immunology Research The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Activation-Inactivation Cycling of Rab35 and ARF6 Is Required for Phagocytosis of Zymosan in RAW264 Macrophages Wed, 01 Jul 2015 06:00:39 +0000 Phagocytosis of zymosan by phagocytes is a widely used model of microbial recognition by the innate immune system. Live-cell imaging showed that fluorescent protein-fused Rab35 accumulated in the membranes of phagocytic cups and then dissociated from the membranes of newly formed phagosomes. By our novel pull-down assay for Rab35 activity, we found that Rab35 is deactivated immediately after zymosan internalization into the cells. Phagosome formation was inhibited in cells expressing the GDP- or GTP-locked Rab35 mutant. Moreover, the simultaneous expression of ACAP2—a Rab35 effector protein—with GTP-locked Rab35 or the expression of plasma membrane-targeted ACAP2 showed a marked inhibitory effect on phagocytosis through ARF6 inactivation by the GAP activity of ACAP2. ARF6, a substrate for ACAP2, was also localized on the phagocytic cups and dissociated from the membranes of internalized phagosomes. In support of the microscopic observations, ARF6-GTP pull-down experiments showed that ARF6 is transiently activated during phagosome formation. Furthermore, the expression of GDP- or GTP-locked ARF6 mutants also suppresses the uptake of zymosan. These data suggest that the activation-inactivation cycles of Rab35 and ARF6 are required for the uptake of zymosan and that ACAP2 is an important component that links Rab35/ARF6 signaling during phagocytosis of zymosan. Youhei Egami, Makoto Fujii, Katsuhisa Kawai, Yurie Ishikawa, Mitsunori Fukuda, and Nobukazu Araki Copyright © 2015 Youhei Egami et al. All rights reserved. DC-Based Immunotherapy Combined with Low-Dose Methotrexate Effective in the Treatment of Advanced CIA in Mice Sun, 28 Jun 2015 09:06:10 +0000 We have previously demonstrated that semimature dendritic cell- (smDC-) based immunotherapy is effective for the treatment of collagen-induced arthritis (CIA) prior to disease onset. In the present study, we examined the efficacy of combination therapy with smDCs and methotrexate (MTX) in advanced CIA with a score of 2-3. Combination therapy with low-dose MTX and type II collagen- (CII-) pulsed smDCs (CII-smDCs) was more effective in inhibiting disease progression than high or low-dose MTX alone or a combination of high dose MTX and CII-smDCs. The effect of CII-smDCs alone was also comparable to the combination therapy. CD4+Foxp3+ Treg populations and IL-10 secretion markedly increased, and CII-specific autoreactive T cells decreased in mice treated with CII-smDCs alone or in combination with MTX. Combination therapy reduced the secretion of interferon-γ (IFN-γ) and IL-17 with little influence on the IL-4 secretion in the mixed leukocyte reaction. These results imply that the combination therapy with low-dose MTX and smDCs is effective in controlling advanced CIA by enhancing Treg population and suppresses antigen-specific Th1/Th17 immunity, rather than initiating Th1 to Th2 immune deviation. Our findings provide a better understanding of the DC therapy in combination with MTX for the treatment of patients with rheumatoid arthritis (RA). Jun-Eui Park, Jinah Jang, Ji-Hye Choi, Mi-sun Kang, Yun-Ju Woo, Young-Rim Seong, Chan-Bum Choi, Hye-Soon Lee, Sang-Cheol Bae, and Yong-Soo Bae Copyright © 2015 Jun-Eui Park et al. All rights reserved. Branched Polyethylenimine-Superparamagnetic Iron Oxide Nanoparticles (bPEI-SPIONs) Improve the Immunogenicity of Tumor Antigens and Enhance Th1 Polarization of Dendritic Cells Sun, 28 Jun 2015 09:01:58 +0000 Nanoparticles in the field of dendritic cell (DC) research are emerging as a promising method of enhancing the efficacy of cancer immunotherapy. We investigated the effect of branched polyethylenimine-superparamagnetic iron oxide nanoparticles (bPEI-SPIONs) on tumor cells loaded onto DCs. The tumor antigens were prepared as follows: (1) apoptotic U266 cells with ultraviolet B (UVB) irradiation followed by a 2 h incubation in the absence (2 h postirradiated cells) or (2) presence of bPEI-SPIONs (bPEI-SPION 2 h postirradiated cells) and (3) apoptotic U266 cells with UVB irradiation followed by an overnight 16 h incubation (16 h postirradiated cells). bPEI-SPIONs render U266 cells sensitive to UVB irradiation through reactive oxygen species production to accelerate apoptotic death. The 2 h postirradiated cells and bPEI-SPION 2 h postirradiated cells released immunogenic proteins, including Hsp70, Hsp90, and HMGB1. The DCs loaded with bPEI-SPION 2 h postirradiated cells showed the highest IL-12p70 production and Th1 polarization compared with other DCs. These results suggest that bPEI-SPIONs are a promising method of enhancing the immunogenicity of tumor cells and promoting Th1 polarization of DCs loaded with these tumor cells. My-Dung Hoang, Hwa-Jeong Lee, Hyun-Ju Lee, Sung-Hoon Jung, Nu-Ri Choi, Manh-Cuong Vo, Thanh-Nhan Nguyen-Pham, Hyeoung-Joon Kim, In-Kyu Park, and Je-Jung Lee Copyright © 2015 My-Dung Hoang et al. All rights reserved. The Complex Role of STAT3 in Viral Infections Thu, 25 Jun 2015 13:58:20 +0000 Signal transducer and activators of transcription-3 (STAT3) regulates diverse biological functions including cell growth, differentiation, and apoptosis. In addition, STAT3 plays a key role in regulating host immune and inflammatory responses and in the pathogenesis of many cancers. Several studies reported differential regulation of STAT3 in a range of viral infections. Interestingly, STAT3 appears to direct seemingly contradictory responses and both pro- and antiviral roles of STAT3 have been described. This review summarized the currently known functions of STAT3 in the regulation of viral replication and pathogenesis of viral infections. Some of the key unanswered questions and the gap in our current understanding of the role of STAT3 in viral pathogenesis are discussed. Suresh V. Kuchipudi Copyright © 2015 Suresh V. Kuchipudi. All rights reserved. The Pathogenicity of Anti-β2GP1-IgG Autoantibodies Depends on Fc Glycosylation Mon, 22 Jun 2015 13:42:49 +0000 To analyze the glycosylation of anti-β2GP1, we investigated purified IgG from healthy children, patients with APS, and asymptomatic adult carriers of antiphospholipid antibodies. We observed that in the sera of healthy children and of patients with APS, IgG3 and IgG2 were predominant, respectively. The potentially protective anti-β2GP1-IgM was lower in the sera of healthy children. Although anti-β2GP1-associated C1q did not differ between children and patients with antiphospholipid syndrome, the associated C3c was significantly higher in the sera of healthy children. This indicates a more efficient clearance of anti-β2GP1 immune complexes in the healthy children. This clearance is not accompanied by inflammation or coagulatory events. It is likely that the most important pathogenic factor of the anti-β2GP1-IgG is related to the different glycosylation observed in healthy and diseased individuals. We detected a significantly higher sialylation of anti-β2GP1-IgG isolated from the sera of healthy children and asymptomatic adults when compared with that of patients with clinically apparent antiphospholipid syndrome. Low sialylated IgG reportedly ameliorates inflammation and inflammation promotes hyposialylation. Thus, both reactions create a vicious circle that precipitates the pathology of the antiphospholipid syndrome including thrombus-formation. We conclude that the increased sialylation of anti-β2GP1-IgG of sera of healthy individuals limits their pathogenicity. Christoph Fickentscher, Iryna Magorivska, Christina Janko, Mona Biermann, Rostyslav Bilyy, Cecilia Nalli, Angela Tincani, Veronica Medeghini, Antonella Meini, Falk Nimmerjahn, Georg Schett, Luis E. Muñoz, Laura Andreoli, and Martin Herrmann Copyright © 2015 Christoph Fickentscher et al. All rights reserved. IFI16 Expression Is Related to Selected Transcription Factors during B-Cell Differentiation Mon, 22 Jun 2015 12:37:00 +0000 The interferon-inducible DNA sensor IFI16 is involved in the modulation of cellular survival, proliferation, and differentiation. In the hematopoietic system, IFI16 is consistently expressed in the CD34+ stem cells and in peripheral blood lymphocytes; however, little is known regarding its regulation during maturation of B- and T-cells. We explored the role of IFI16 in normal B-cell subsets by analysing its expression and relationship with the major transcription factors involved in germinal center (GC) development and plasma-cell (PC) maturation. IFI16 mRNA was differentially expressed in B-cell subsets with significant decrease in IFI16 mRNA in GC and PCs with respect to naïve and memory subsets. IFI16 mRNA expression is inversely correlated with a few master regulators of B-cell differentiation such as BCL6, XBP1, POU2AF1, and BLIMP1. In contrast, IFI16 expression positively correlated with STAT3, REL, SPIB, RELA, RELB, IRF4, STAT5B, and STAT5A. ARACNE algorithm indicated a direct regulation of IFI16 by BCL6, STAT5B, and RELB, whereas the relationship between IFI16 and the other factors is modulated by intermediate factors. In addition, analysis of the CD40 signaling pathway showed that IFI16 gene expression directly correlated with NF-κB activation, indicating that IFI16 could be considered an upstream modulator of NF-κB in human B-cells. Pier Paolo Piccaluga, Claudio Agostinelli, Fabio Fuligni, Simona Righi, Claudio Tripodo, Maria Carla Re, Alberto Clò, Anna Miserocchi, Silvia Morini, Marisa Gariglio, Gian Gaetano Ferri, Alberto Rinaldi-Ceroni, Ottavio Piccin, Marco De Andrea, Stefano A. Pileri, Santo Landolfo, and Davide Gibellini Copyright © 2015 Pier Paolo Piccaluga et al. All rights reserved. Kinetics of Circulating Damage-Associated Molecular Patterns in Sepsis Tue, 16 Jun 2015 07:57:27 +0000 Circulating levels of conventional biomarkers and damage-associated molecular patterns were examined in 30 severe sepsis patients (20 survivors and 10 nonsurvivors). Plasma levels of interleukin 6, CRP, and procalcitonin reached their peaks on Day 0 (onset of sepsis) or Day 1 and declined rapidly thereafter despite the persistent severity. In contrast, elevated levels of histone H3, nucleosome, and high-mobility group protein Box 1 remained for longer periods of time. The peak level of histone H3 in the nonsurvivors was higher than that of the survivors ( on Day 7). The cutoff value of the histone H3 on Day 7 for death was 0.08 AU and the area under the receiver operating characteristic curve showed discriminative powers of 0.74. Measurement of circulating levels of the histone H3 provides additional information to that of the conventional indicators of inflammation for determining the severity of sepsis. Takahiro Miki and Toshiaki Iba Copyright © 2015 Takahiro Miki and Toshiaki Iba. All rights reserved. Lymphocytes as an Indicator for Initial Kidney Function: A Single Center Analysis of Outcome after Alemtuzumab or Basiliximab Induction Thu, 11 Jun 2015 17:24:40 +0000 Alemtuzumab, an anti-CD52 T-cell and B-cell depleting monoclonal antibody, is established for induction therapy in renal transplantation (KTx). We herein provide a comparative analysis between alemtuzumab and basiliximab induction therapy and correlate lymphocyte depletion and recovery with the clinical course after KTx. This is a single center retrospective analysis of 225 patients/consecutive kidney transplantations treated with alemtuzumab for lymphocyte depletion and 205 recipients treated with basiliximab. Mean lymphocyte counts were 22.8 ± 9.41% before Tx and 2.61 ± 3.11% between week 1 and week 3 in the alemtuzumab group and 23.77 ± 10.42% before Tx and 13.92 ± 8.20% in the basiliximab group. Delayed graft function (DGF), cytomegalovirus (CMV) status, and recipient age showed a significant correlation with lymphocyte counts in the alemtuzumab group only. The outcome was read in reference to the velocity of lymphocyte recovery and in comparison to the control group. Lymphocyte counts early after transplantation, following alemtuzumab treatment, could be identified as a predictive factor for kidney function early after transplantation. A detailed analysis of phenotype and function of lymphocytes after alemtuzumab induction together with a correlation with the clinical course is warranted. Annemarie Weissenbacher, Theresa Hautz, Michael Kimelman, Rupert Oberhuber, Hanno Ulmer, Claudia Bösmüller, Manuel Maglione, and Stefan Schneeberger Copyright © 2015 Annemarie Weissenbacher et al. All rights reserved. The Human IL-22 Receptor Is Regulated through the Action of the Novel E3 Ligase Subunit FBXW12, Which Functions as an Epithelial Growth Suppressor Thu, 11 Jun 2015 14:22:24 +0000 Interleukin- (IL-) 22 signaling is protective in animal models of pneumonia and bacteremia by Klebsiella pneumoniae and mediates tissue recovery from influenza and Staph aureus infection. We recently described processing of mouse lung epithelial IL-22 receptor (IL-22R) by ubiquitination on the intracellular C-terminal. To identify cellular factors that regulate human IL-22R, we screened receptor abundance while overexpressing constituents of the ubiquitin system and identify that IL-22R can be shuttled for degradation by multiple previously uncharacterized F-box protein E3 ligase subunits. We observe that in human cells IL-22R is destabilized by FBXW12. FBXW12 causes depletion of endogenous and plasmid-derived IL-22R in lung epithelia, binds the E3 ligase constituent Skp-1, and facilitates ubiquitination of IL-22R in vitro. FBXW12 knockdown with shRNA increases IL-22R abundance and STAT3 phosphorylation in response to IL-22 cytokine treatment. FBXW12 shRNA increases human epithelial cell growth and cell cycle progression with enhanced constitutive activity of map kinases JNK and ERK. These findings indicate that the heretofore-undescribed protein FBXW12 functions as an E3 ligase constituent to ubiquitinate and degrade IL-22R and that therapeutic FBXW12 inhibition may enhance IL-22 signaling and bolster mucosal host defense and infection containment. Joseph Franz, Jacob Jerome, Travis Lear, Qiaoke Gong, and Nathaniel M. Weathington Copyright © 2015 Joseph Franz et al. All rights reserved. Renal and Hematological Effects of CLCF-1, a B-Cell-Stimulating Cytokine of the IL-6 Family Thu, 04 Jun 2015 08:20:33 +0000 CLCF-1 is a cytokine known for B-cell stimulation and for neurotrophic properties. We have identified CLCF-1 as a potential injurious factor in the human renal disease focal segmental glomerulosclerosis (FSGS). We investigated its effects on renal cells and renal function in in vitro and in vivo studies. Methods include measurement of the effect of CLCF-1 on phosphorylation of target molecules of the JAK/STAT pathway, on cytoskeleton and cell morphology in cultured podocytes, on albumin permeability of isolated rat glomeruli, and on tissue phosphorylation and urine albumin after acute or chronic CLCF-1 injection. In addition, cell sorting was performed to determine the presence of cells expressing CLCF-1 in spleen and bone marrow of normal mice and the effect of CLCF-1 infusion on splenic B-cell populations. CLCF-1 increased phosphorylation of STAT3 in multiple cell types, activated podocytes leading to formation of lamellipodia and decrease in basal stress fibers, increased glomerular albumin permeability, and increased STAT3 phosphorylation of peripheral blood cells and renal cortex. CLCF-1 increased urine albumin/creatinine ratio in mice and increased B-cell expression of IgG in mouse spleen. We conclude that CLCF-1 has potentially important systemic effects, alters podocyte function, and may contribute to renal dysfunction and albuminuria. Virginia J. Savin, Mukut Sharma, Jianping Zhou, David Gennochi, Timothy Fields, Ram Sharma, Ellen T. McCarthy, Tarak Srivastava, Jos Domen, Aurélie Tormo, and Jean-François Gauchat Copyright © 2015 Virginia J. Savin et al. All rights reserved. Spontaneous Intestinal Tumorigenesis in Mice Requires Altered T Cell Development with IL-17A Wed, 03 Jun 2015 12:04:32 +0000 The control of inflammatory diseases requires functional regulatory T cells (Tregs) with significant Gata-3 expression. Here we address the inhibitory role of Tregs on intestinal tumorigenesis in the mouse model that resembles human familial adenomatous polyposis (FAP). mice had a markedly increased frequency of Foxp3+ Tregs and yet decreased Gata-3 expression in the lamina propria. To address the role of heterozygous Apc gene mutation in Tregs, we generated Foxp3-Cre, Apcflox/+ mice. Tregs from these mice effectively inhibited tumorigenesis comparable to wild type Tregs after adoptive transfer into mice, demonstrating that the heterozygous Apc gene mutation in Tregs does not induce the loss of control over tumor microenvironment. Adoptive transfer of in vitro generated iTregs (inducible Tregs) failed to inhibit intestinal tumorigenesis, suggesting that naïve CD4 T cells generated from mice thymus were impaired. We also showed that adoptively transferred IL-17A-deficient Tregs inhibited tumor growth, suggesting that IL-17A was critical to impair the tumor regression function of Tregs. Taken together, our results suggest that both T cell development in a functional thymus and IL-17A control the ability of Treg to inhibit intestinal tumorigenesis in mice. Wook-Jin Chae and Alfred L. M. Bothwell Copyright © 2015 Wook-Jin Chae and Alfred L. M. Bothwell. All rights reserved. Vaccines for TB: Lessons from the Past Translating into Future Potentials Wed, 03 Jun 2015 07:27:37 +0000 Development of vaccines for infectious diseases has come a long way with recent advancements in adjuvant developments and discovery of new antigens that are capable of eliciting strong immunological responses for sterile eradication of disease. Tuberculosis (TB) that kills nearly 2 million of the population every year is also one of the highlights of the recent developments. The availability or not of diagnostic methods for infection has implications for the control of the disease by the health systems but is not related to the immune surveillance, a phenomenon derived from the interaction between the bacteria and their host. Here, we will review the immunology of TB and current vaccine candidates for TB. Current strategies of developing new vaccines against TB will also be reviewed in order to further discuss new insights into immunotherapeutic approaches involving adjuvant and antigens combinations that might be of potential for the control of TB. Gee Jun Tye, Min Han Lew, Yee Siew Choong, Theam Soon Lim, Maria Elena Sarmiento, Armando Acosta, and Mohd Nor Norazmi Copyright © 2015 Gee Jun Tye et al. All rights reserved. IL-34 Suppresses Candida albicans Induced TNFα Production in M1 Macrophages by Downregulating Expression of Dectin-1 and TLR2 Wed, 03 Jun 2015 07:11:12 +0000 Candida albicans is a fungus that is an opportunistic pathogen of humans. Normally, C. albicans exists as a harmless commensal and does not trigger inflammatory responses by resident macrophages in skin mucosa, which may be caused by a tolerance of skin macrophage to C. albicans. IL-34 is a recently discovered cytokine, constitutively expressed by keratinocytes in the skin. IL-34 binds to the receptor of M-CSF, thereby stimulating tissue macrophage maturation and differentiation. Resident macrophages exhibit phenotypic plasticity and may transform into inflammatory M1 macrophages for immunity or anti-inflammatory M2 macrophages for tissue repair. M1 macrophages produce higher levels of inflammatory cytokines such as TNFα in response to C. albicans stimulation. In this study, it was demonstrated that IL-34 attenuated TNFα production by M1 macrophages challenged with heat killed Candida (HKC). The molecular mechanism of IL-34 mediated suppression of HKC induced TNFα production by M1 macrophages was by the inhibition of M1 macrophage expression of key C. albicans pattern recognition receptors (PPRs), namely, Toll-like receptor (TLR) 2 and Dectin-1. The results of this study indicated that constitutive IL-34 expressed by skin keratinocytes might suppress resident macrophage responses to C. albicans colonisation by maintaining low levels TLR2 and Dectin-1 expression by macrophages. Rong Xu, Hong-Fan Sun, David W. Williams, Adam V. Jones, Ali Al-Hussaini, Bing Song, and Xiao-Qing Wei Copyright © 2015 Rong Xu et al. All rights reserved. NK and NKT Cell Depletion Alters the Outcome of Experimental Pneumococcal Pneumonia: Relationship with Regulation of Interferon-γ Production Sun, 31 May 2015 16:48:30 +0000 Background. Natural killer (NK) and natural killer T (NKT) cells contribute to the innate host defense but their role in bacterial sepsis remains controversial. Methods. C57BL/6 mice were infected intratracheally with 5 × 105 cfu of Streptococcus pneumoniae. Animals were divided into sham group (Sham); pretreated with isotype control antibody (CON) group; pretreated with anti-asialo GM1 antibody (NKd) group; and pretreated with anti-CD1d monoclonal antibody (NKTd) group before bacterial challenge. Serum and tissue samples were analyzed for bacterial load, cytokine levels, splenocyte apoptosis rates, and cell characteristics by flow cytometry. Splenocyte miRNA expression was also analyzed and survival was assessed. Results. NK cell depletion prolonged survival. Upon inhibition of NKT cell activation, spleen NK (CD3−/NK1.1+) cells increased compared to all other groups. Inhibition of NKT cell activation led to higher bacterial loads and increased levels of serum and splenocyte IFN-γ. Splenocyte miRNA analysis showed that miR-200c and miR-29a were downregulated, while miR-125a-5p was upregulated, in anti-CD1d treated animals. These changes were moderate after NK cell depletion. Conclusions. NK cells appear to contribute to mortality in pneumococcal pneumonia. Inhibition of NKT cell activation resulted in an increase in spleen NK (CD3−/NK1.1+) cells and a higher IFN-γ production, while altering splenocyte miRNA expression. Eirini Christaki, Evdoxia Diza, Evangelos J. Giamarellos-Bourboulis, Nikoletta Papadopoulou, Aikaterini Pistiki, Dionysia-Irini Droggiti, Marianna Georgitsi, Alzbeta Machova, Dimitra Lambrelli, Nicolaos Malisiovas, Pavlos Nikolaidis, and Steven M. Opal Copyright © 2015 Eirini Christaki et al. All rights reserved. The Lung Immune Response to Nontypeable Haemophilus influenzae (Lung Immunity to NTHi) Sun, 31 May 2015 08:22:51 +0000 Haemophilus influenzae is divided into typeable or nontypeable strains based on the presence or absence of a polysaccharide capsule. The typeable strains (such as type b) are an important cause of systemic infection, whilst the nontypeable strains (designated as NTHi) are predominantly respiratory mucosal pathogens. NTHi is present as part of the normal microbiome in the nasopharynx, from where it may spread down to the lower respiratory tract. In this context it is no longer a commensal and becomes an important respiratory pathogen associated with a range of common conditions including bronchitis, bronchiectasis, pneumonia, and particularly chronic obstructive pulmonary disease. NTHi induces a strong inflammatory response in the respiratory tract with activation of immune responses, which often fail to clear the bacteria from the lung. This results in recurrent/persistent infection and chronic inflammation with consequent lung pathology. This review will summarise the current literature about the lung immune response to nontypeable Haemophilus influenzae, a topic that has important implications for patient management. Paul T. King and Roleen Sharma Copyright © 2015 Paul T. King and Roleen Sharma. All rights reserved. Secretory Products of Trichinella spiralis Muscle Larvae and Immunomodulation: Implication for Autoimmune Diseases, Allergies, and Malignancies Sun, 31 May 2015 06:21:24 +0000 Trichinella spiralis has the unique ability to make itself “at home” by creating and hiding in a new type of cell in the host body that is the nurse cell. From this immunologically privileged place, the parasite orchestrates a long-lasting molecular cross talk with the host through muscle larvae excretory-secretory products (ES L1). Those products can successfully modulate parasite-specific immune responses as well as responses to unrelated antigens (either self or nonself in origin), providing an anti-inflammatory milieu and maintaining homeostasis. It is clear, based on the findings from animal model studies, that T. spiralis and its products induce an immunomodulatory network (which encompasses Th2- and Treg-type responses) that may allow the host to deal with various hyperimmune-associated disorders as well as tumor growth, although the latter still remains unclear. This review focuses on studies of the molecules released by T. spiralis, their interaction with pattern recognition receptors on antigen presenting cells, and subsequently provoked responses. This paper also addresses the immunomodulatory properties of ES L1 molecules and how the induced immunomodulation influences the course of different experimental inflammatory and malignant diseases. Ljiljana Sofronic-Milosavljevic, Natasa Ilic, Elena Pinelli, and Alisa Gruden-Movsesijan Copyright © 2015 Ljiljana Sofronic-Milosavljevic et al. All rights reserved. Regulatory T Cells in Autoimmune and Viral Chronic Hepatitis Thu, 28 May 2015 13:38:36 +0000 In both autoimmune liver disease and chronic viral hepatitis, the injury results from an immune-mediated cytotoxic T cell response to liver cells. As such, it is not surprising that CD4+ regulatory T cells, a key regulatory population of T cells able to curb immune responses, could be involved in both autoimmune hepatitis and chronic viral hepatitis. The liver can induce the conversion of naïve CD4+ T cells to CD4+ regulatory T cells and induce tolerance to locally expressed antigens. This tolerance mechanism is carefully regulated in physiological conditions but any imbalance could be pathological. An overly tolerant immune response can lead to chronic infections while an overreactive and unbridled immune response can lead to autoimmune hepatitis. With the recent advent of monoclonal antibodies able to target regulatory T cells (daclizumab) and improve immune responses and several ongoing clinical trials analysing the impact of regulatory T cell infusion on autoimmune liver disease or liver transplant tolerance, modulation of immunological tolerance through CD4+ regulatory T cells could be a key element of future immunotherapies for several liver diseases allowing restoring the balance between proper immune responses and tolerance.   Pascal Lapierre and Alain Lamarre Copyright © 2015 Pascal Lapierre and Alain Lamarre. All rights reserved. Harnessing the Microbiome to Enhance Cancer Immunotherapy Mon, 25 May 2015 07:05:44 +0000 The microbiota plays a key role in regulating the innate and adaptive immune system. Herein, we review the immunological aspects of the microbiota in tumor immunity in mice and man, with a focus on toll-like receptor (TLR) agonists, vaccines, checkpoint modulators, chemotherapy, and adoptive T cell transfer (ACT) therapies. We propose innovative treatments that may safely harness the microbiota to enhance T cell-based therapies in cancer patients. Finally, we highlight recent developments in tumor immunotherapy, particularly novel ways to modulate the microbiome and memory T cell responses to human malignancies. Michelle H. Nelson, Marshall A. Diven, Logan W. Huff, and Chrystal M. Paulos Copyright © 2015 Michelle H. Nelson et al. All rights reserved. Correlates of Protection for M Protein-Based Vaccines against Group A Streptococcus Mon, 25 May 2015 06:36:45 +0000 Group A streptococcus (GAS) is known to cause a broad spectrum of illness, from pharyngitis and impetigo, to autoimmune sequelae such as rheumatic heart disease, and invasive diseases. It is a significant cause of infectious disease morbidity and mortality worldwide, but no efficacious vaccine is currently available. Progress in GAS vaccine development has been hindered by a number of obstacles, including a lack of standardization in immunoassays and the need to define human correlates of protection. In this review, we have examined the current immunoassays used in both GAS and other organisms, and explored the various challenges in their implementation in order to propose potential future directions to identify a correlate of protection and facilitate the development of M protein-based vaccines, which are currently the main GAS vaccine candidates. Shu Ki Tsoi, Pierre R. Smeesters, Hannah R. C. Frost, Paul Licciardi, and Andrew C. Steer Copyright © 2015 Shu Ki Tsoi et al. All rights reserved. Trans-Species Polymorphism in Immune Genes: General Pattern or MHC-Restricted Phenomenon? Sun, 24 May 2015 13:00:40 +0000 Immunity exhibits extraordinarily high levels of variation. Evolution of the immune system in response to host-pathogen interactions in particular ecological contexts appears to be frequently associated with diversifying selection increasing the genetic variability. Many studies have documented that immunologically relevant polymorphism observed today may be tens of millions years old and may predate the emergence of present species. This pattern can be explained by the concept of trans-species polymorphism (TSP) predicting the maintenance and sharing of favourable functionally important alleles of immune-related genes between species due to ongoing balancing selection. Despite the generality of this concept explaining the long-lasting adaptive variation inherited from ancestors, current research in TSP has vastly focused only on major histocompatibility complex (MHC). In this review we summarise the evidence available on TSP in human and animal immune genes to reveal that TSP is not a MHC-specific evolutionary pattern. Further research should clearly pay more attention to the investigation of TSP in innate immune genes and especially pattern recognition receptors which are promising candidates for this type of evolution. More effort should also be made to distinguish TSP from convergent evolution and adaptive introgression. Identification of balanced TSP variants may represent an accurate approach in evolutionary medicine to recognise disease-resistance alleles. Martin Těšický and Michal Vinkler Copyright © 2015 Martin Těšický and Michal Vinkler. All rights reserved. Systemic Autoimmune Diseases 2014 Sun, 24 May 2015 07:34:03 +0000 Guixiu Shi, Jianying Zhang, Zhixin (Jason) Zhang, and Xuan Zhang Copyright © 2015 Guixiu Shi et al. All rights reserved. The Interactions between Innate Immunity and Microbiota in Gastrointestinal Diseases Wed, 20 May 2015 13:42:01 +0000 Danilo Pagliari, Ciriaco A. Piccirillo, Anis Larbi, and Rossella Cianci Copyright © 2015 Danilo Pagliari et al. All rights reserved. Achalasia—An Autoimmune Inflammatory Disease: A Cross-Sectional Study Wed, 20 May 2015 12:15:58 +0000 Idiopathic achalasia is a disease of unknown etiology. The loss of myenteric plexus associated with inflammatory infiltrates and autoantibodies support the hypothesis of an autoimmune mechanism. Thirty-two patients diagnosed by high-resolution manometry with achalasia were included. Twenty-six specimens from lower esophageal sphincter muscle were compared with 5 esophagectomy biopsies (control). Immunohistochemical (biopsies) and flow cytometry (peripheral blood) analyses were performed. Circulating anti-myenteric autoantibodies were evaluated by indirect immunofluorescence. Herpes simplex virus-1 (HSV-1) infection was determined by in situ hybridization, RT-PCR, and immunohistochemistry. Histopathological analysis showed capillaritis (51%), plexitis (23%), nerve hypertrophy (16%), venulitis (7%), and fibrosis (3%). Achalasia tissue exhibited an increase in the expression of proteins involved in extracellular matrix turnover, apoptosis, proinflammatory and profibrogenic cytokines, and Tregs and Bregs versus controls (). Circulating Th22/Th17/Th2/Th1 percentage showed a significant increase versus healthy donors (). Type III achalasia patients exhibited the highest inflammatory response versus types I and II. Prevalence of both anti-myenteric antibodies and HSV-1 infection in achalasia patients was 100% versus 0% in controls. Our results suggest that achalasia is a disease with an important local and systemic inflammatory autoimmune component, associated with the presence of specific anti-myenteric autoantibodies, as well as HSV-1 infection. J. Furuzawa-Carballeda, D. Aguilar-León, A. Gamboa-Domínguez, M. A. Valdovinos, C. Nuñez-Álvarez, L. A. Martín-del-Campo, A. B. Enríquez, E. Coss-Adame, A. E. Svarch, A. Flores-Nájera, A. Villa-Baños, J. C. Ceballos, and G. Torres-Villalobos Copyright © 2015 J. Furuzawa-Carballeda et al. All rights reserved. Anti-Phosphatidylserine/Prothrombin Antibodies Are Associated with Adverse Pregnancy Outcomes Wed, 20 May 2015 06:57:24 +0000 Objective. To determine the prevalence and clinical association of anti-phosphatidylserine/prothrombin antibodies (aPS/PT) in patients with a history of pregnancy complications relevant to antiphospholipid syndrome (APS). Materials and Methods. Two hundred and eleven patients with a history of (a) three or more consecutive miscarriages before 10th week of gestation (WG) (), (b) death of a morphologically normal fetus beyond 10th WG (), (c) premature birth of a morphologically normal neonate before 34th WG due to eclampsia, preeclamsia and placental insufficiency (), and (d) less than three unexplained consecutive miscarriages before 10th WG (). Subjects sera were analyzed for lupus anticoagulant (LA), anti-cardiolipin (aCL), anti--glycoprotein I (anti-GPI), and aPS/PT antibodies. Results. 41/169 (24.3%) of patients were positive for at least one measured aPL. The highest prevalence was found for aPS/PT and aCL (13.0% and 12.4%, resp.) followed by LA (7.7%) and anti-GPI (7.1%). 11/169 with APS-related obstetric manifestations had only aPS/PT. 17.8% of patients were positive for LA or aCL and/or anti-GPI; however when adding the aPS/PT results, an additional 7% of patients could be evaluated for APS. Conclusion. aPS/PT are associated with recurrent early or late abortions and with premature delivery irrespective of other aPL. Polona Žigon, Katja Perdan Pirkmajer, Matija Tomšič, Tanja Kveder, Borut Božič, Snežna Sodin Šemrl, Saša Čučnik, and Aleš Ambrožič Copyright © 2015 Polona Žigon et al. All rights reserved. Anti-Cyclic Citrullinated Peptide Antibodies and Severity of Interstitial Lung Disease in Women with Rheumatoid Arthritis Tue, 19 May 2015 12:52:50 +0000 Objective. To evaluate whether serum titers of second-generation anticyclic citrullinated peptide antibodies (anti-CCP2) are associated with the severity and extent of interstitial lung disease in rheumatoid arthritis (RA-ILD). Methods. In across-sectional study, 39 RA-ILD patients confirmed by high-resolution computed tomography (HRCT) were compared with 42 RA without lung involvement (RA only). Characteristics related to RA-ILD were assessed in all of the patients and serum anti-CCP2 titers quantified. Results. Higher anti-CCP2 titers were found in RA-ILD compared with RA only (medians 77.9 versus 30.2 U/mL, ). In the logistic regression analysis after adjustment for age, disease duration (DD), smoke exposure, disease activity, functioning, erythrocyte sedimentation rate, and methotrexate (MTX) treatment duration, the characteristics associated with RA-ILD were higher anti-CCP2 titers () and + RF (). In multivariate linear regression, the variables associated with severity of ground-glass score were anti-CCP2 titers () and with fibrosis score DD (), anti-CCP2 titers (), and MTX treatment duration (). Conclusions. Anti-CCP2 antibodies are markers of severity and extent of RA-ILD in HRCT. Further longitudinal studies are required to identify if higher anti-CCP2 titers are associated with worst prognosis in RA-ILD. Alberto Daniel Rocha-Muñoz, Manuel Ponce-Guarneros, Jorge Ivan Gamez-Nava, Eva Maria Olivas-Flores, Mayra Mejía, Pablo Juárez-Contreras, Erika Aurora Martínez-García, Esther Guadalupe Corona-Sánchez, Tania Marlen Rodríguez-Hernández, Mónica Vázquez-del Mercado, Mario Salazar-Páramo, Arnulfo Hernan Nava-Zavala, Ernesto German Cardona-Muñoz, Alfredo Celis, and Laura González-Lopez Copyright © 2015 Alberto Daniel Rocha-Muñoz et al. All rights reserved. Induction of Apoptosis Coupled to Endoplasmic Reticulum Stress through Regulation of CHOP and JNK in Bone Marrow Mesenchymal Stem Cells from Patients with Systemic Lupus Erythematosus Tue, 19 May 2015 09:01:55 +0000 Previous studies indicated that bone marrow mesenchymal stem cells (BM-MSCs) from patients with systemic lupus erythematosus (SLE) exhibited the phenomenon of apoptosis. In this study, we aimed to investigate whether apoptosis of BM-MSCs from SLE patients were dysregulated. In this paper, endoplasmic reticulum stress (ERS) was evidenced by increased expression of phosphorylated protein kinase RNA-like ER kinase (PERK) and inositol-requiring protein-1 (IRE-1). We also found the activation of downstream target eukaryotic translation initiator factor 2α (eIF 2α) and CCAAT/enhancer-binding protein- (C/EBP-) homologous protein (CHOP) in BM-MSCs from SLE patients. Interestingly, we discovered that 4-phenylbutyric acid (4-PBA), a selective inhibitor of ERS, blocked the apoptosis of BM-MSCs from SLE patients and alleviated the level of Jun N-terminal kinase1/2 (JNK1/2) and CHOP. Furthermore, blockage of PERK signaling expression by siRNA not only significantly reduced the expression of CHOP, but also activated the anti-apoptotic regulator B-cell lymphoma-2 (Bcl-2). Blockage of IRE-1 or JNK1/2 by siRNA resulted in the decreased expression of JNK1/2 and proapoptosis protein Bcl-2 associated protein X (BAX). These results implicated that ERS-mediated apoptosis was a critical determinant of BM-MSCs from SLE patients. Genkai Guo, Yan Meng, Wei Tan, Yunfei Xia, Chun Cheng, Xiaolan Chen, and Zhifeng Gu Copyright © 2015 Genkai Guo et al. All rights reserved. Characterization of CD30/CD30L+ Cells in Peripheral Blood and Synovial Fluid of Patients with Rheumatoid Arthritis Tue, 19 May 2015 08:07:59 +0000 The CD30/CD30L signalling system has been implicated in the pathogenesis of several autoimmune and inflammatory conditions. In rheumatoid arthritis (RA), soluble CD30 (sCD30) levels reflect the recruitment of CD30+ T cells into the inflamed joints and correlate with a positive response to immunosuppressive therapy. The aim of our report was to clarify the role of CD30/CD30L signalling system in the pathogenesis of RA. Our analysis of the CD30L+ T cell subsets in peripheral blood (PB) and synovial fluid (SF) of RA patients and of the related cytokine profiles suggests the involvement of CD30/CD30L signalling in polarization of T cells towards a Th17 phenotype with proinflammatory features. Moreover, in RA SF nearly 50% of Treg cells express CD30, probably as an attempt to downmodulate the ongoing inflammation. We also show here that the engagement of CD30L on neutrophils stimulated with CD30/Fc chimera may play a crucial role in RA inflammation since activated neutrophils release IL-8, thus potentially amplifying the local inflammatory damage. In conclusion, the results obtained suggest that the complex CD30/CD30L signalling pathway is implicated in the pathogenesis and progression of RA synovitis through a concerted action on several immune effector cells. Alessandro Barbieri, Marzia Dolcino, Elisa Tinazzi, Antonella Rigo, Giuseppe Argentino, Giuseppe Patuzzo, Andrea Ottria, Ruggero Beri, Antonio Puccetti, and Claudio Lunardi Copyright © 2015 Alessandro Barbieri et al. All rights reserved. Clinical Characteristics of Cerebral Venous Sinus Thrombosis in Patients with Systemic Lupus Erythematosus: A Single-Centre Experience in China Tue, 19 May 2015 07:39:45 +0000 Clinical characteristics of systemic lupus erythematosus (SLE) patients complicated with cerebral venous sinus thrombosis (CVST) between 2000 and 2013 were analyzed through this retrospective, single-centre study. Of 4747 hospitalized SLE patients, 17 (0.36%, 12 females, average age 30) had CVST. Headache (88.2%) was the most common neurological symptom followed by nausea or vomiting (47.1%), conscious disturbance (41.2%), edema of eyelids or conjunctiva (35.3%), blurred vision or diplopia (35.3%), and seizure (35.3%). Increased intracranial pressure (ICP) occurred in 13 cases (76.5%). Magnetic resonance venography (MRV) detected thrombosis in the transverse (82.4%), sigmoid (52.9%), and sagittal (35.3%) sinuses, with frequent (70.6%) multiple sinus occlusions. Compared to SLE patients without CVST, SLE patients with CVST had a higher prevalence of thrombocytopenia and positive antiphospholipid antibodies and a higher SLE disease activity index (SLEDAI) score. 13 patients achieved improvement following glucocorticoids and immunosuppressants treatment, as well as anticoagulants, while 3 patients died at the hospital. CVST is relatively rare in SLE and tends to occur in active lupus patients. Intracranial hypertension is common but nonspecific clinical feature, so MRV evaluation is necessary to establish a diagnosis. Aggressive treatment for the rapid control of SLE activity combined with anticoagulants can improve the prognosis. Li Wang, Hua Chen, Yao Zhang, Wanli Liu, Wenjie Zheng, Xuan Zhang, and Fengchun Zhang Copyright © 2015 Li Wang et al. All rights reserved. HMGB1 Promotes Systemic Lupus Erythematosus by Enhancing Macrophage Inflammatory Response Tue, 19 May 2015 07:15:40 +0000 Background/Purpose. HMGB1, which may act as a proinflammatory mediator, has been proposed to contribute to the pathogenesis of multiple chronic inflammatory and autoimmune diseases including systemic lupus erythematosus (SLE); however, the precise mechanism of HMGB1 in the pathogenic process of SLE remains obscure. Method. The expression of HMGB1 was measured by ELISA and western blot. The ELISA was also applied to detect proinflammatory cytokines levels. Furthermore, nephritic pathology was evaluated by H&E staining of renal tissues. Results. In this study, we found that HMGB1 levels were significantly increased and correlated with SLE disease activity in both clinical patients and murine model. Furthermore, gain- and loss-of-function analysis showed that HMGB1 exacerbated the severity of SLE. Of note, the HMGB1 levels were found to be associated with the levels of proinflammatory cytokines such as TNF-α and IL-6 in SLE patients. Further study demonstrated that increased HMGB1 expression deteriorated the severity of SLE via enhancing macrophage inflammatory response. Moreover, we found that receptor of advanced glycation end products played a critical role in HMGB1-mediated macrophage inflammatory response. Conclusion. These findings suggested that HMGB1 might be a risk factor for SLE, and manipulation of HMGB1 signaling might provide a therapeutic strategy for SLE. Mudan Lu, Shanshan Yu, Wei Xu, Bo Gao, and Sidong Xiong Copyright © 2015 Mudan Lu et al. All rights reserved. Lessons from Microglia Aging for the Link between Inflammatory Bone Disorders and Alzheimer’s Disease Tue, 19 May 2015 06:37:10 +0000 Bone is sensitive to overactive immune responses, which initiate the onset of inflammatory bone disorders, such as rheumatoid arthritis and periodontitis, resulting in a significant systemic inflammatory response. On the other hand, neuroinflammation is strongly implicated in Alzheimer’s disease (AD), which can be enhanced by systemic inflammation, such as that due to cardiovascular disease and diabetes. There is growing clinical evidence supporting the concept that rheumatoid arthritis and periodontitis are positively linked to AD, suggesting that inflammatory bone disorders are risk factors for this condition. Recent studies have suggested that leptomeningeal cells play an important role in transducing systemic inflammatory signals to brain-resident microglia. More importantly, senescent-type, but not juvenile-type, microglia provoke neuroinflammation in response to systemic inflammation. Because the prevalence of rheumatoid arthritis and periodontitis increases with age, inflammatory bone disorders may be significant sources of covert systemic inflammation among elderly people. The present review article highlights our current understanding of the link between inflammatory bone disorders and AD with a special focus on microglia aging. Zhou Wu and Hiroshi Nakanishi Copyright © 2015 Zhou Wu and Hiroshi Nakanishi. All rights reserved.