Many autoimmune diseases are driven by self-reactive T helper (Th) cells. A new population of effector CD4+ T cells characterized by the secretion of interleukin (IL)-17, referred to as Th17 cells, has been demonstrated to be phenotypically, functionally, and developmentally distinct from Th1 and Th2 cells. Because the liver is known to be an important source of transforming growth factor-β and IL-6, which are cytokines that are crucial for Th17 differentiation, it is very likely that Th17 cells contribute to liver inflammation and autoimmunity. In contrast, another distinct subset of T cells, regulatory T cells (Treg), downregulate immune responses and play an important role in maintaining self-tolerance. In addition, there is a reciprocal relationship between Th17 cells and Tregs, in development and effector functions, and the balance between Th17 and Treg cells can affect the outcome of immune responses, particularly in autoimmune diseases. In this review, we will focus on the latest investigative findings related to Th17 cells in autoimmune liver disease.

Objective. Presence of anti-HLA antibodies has a well-known impact on kidney grafts survival; however their role in liver transplantation has not been fully elucidated. We conducted a 7-year prospective study to show correlation between presence of anti-HLA and anti-MICA antibodies and liver graft survival. Methods. Blood samples from 123 liver transplant recipients were collected during patients routine visits. Time from transplantation to blood sample collection was different for each patient. Blood samples were tested for anti-HLA (separately class I and II) and MICA antibodies using Luminex assays. Results. There were 32 (26%) patients with positive anti-HLA and 37 (30%) with positive anti-MICA antibodies. Graft loss occurred in 7 cases (23%) in anti-HLA positive group compared to 20 (22%) in anti-HLA negative group (P = ns) and in 8 cases (22%) in anti-MICA positive group but 19 (23%) in anti-MICA negative group (P = ns). No correlations were detected between presence of antibodies and acute graft rejection (AGR). Presence of any antibodies (anti-HLA or anti-MICA antibodies) correlated with late graft rejection (P = 0.04). Conclusion. Presence of anti-HLA or anti-MICA had no impact on long-term liver graft survival; however, detection of any antibodies was correlated with episodes of late graft rejection.

Enteropathic arthritis (EA) is a spondyloarthritis (SpA) which occurs in patients with inflammatory bowel diseases (IBDs) and other gastrointestinal diseases. Diagnosis is generally established on the medical history and physical examination. It was, generally, made according to the European Spondyloarthropathy Study Group (ESSG) criteria. Rheumatic manifestations are the most frequent extraintestinal findings of IBD with a prevalence between 17% and 39%, and IBD is associated, less frequently, with other rheumatic disease such as rheumatoid arthritis, Sjogren syndrome, Takayasu arteritis, and fibromyalgia. Although the pathogenesis of EA has not been plainly clarified, the most popular theory supposes that joint inflammation occurs in genetically predisposed subjects with bacterial gut infections, provided an important evidence for a possible relationship between inflammation of the gut mucosa and arthritis. The management of patients with EA requires an active cooperation between the gastroenterologist and rheumatologist.

A number of trials of adoptive transfer of tumor-specific T lymphocytes have been performed in the last 20 years in metastatic melanoma, with increasingly encouraging results as the relevant melanoma antigens were identified and the purity/specificity of injected T cells improved. We have previously described a sorting method of epitope-specific T lymphocytes that uses magnetic beads coated with HLA/peptide complexes and we suggested that this method could be applied to a clinical setting. In the present work, we provide a detailed description of the whole GMP process of sorting and amplification of clinical grade T cells specific for the melanoma antigens Melan-A and MELOE-1. All the reagents used in this process including the sorting reagent were produced in GMP conditions and we document the optimization of the different steps of the process such as peptide stimulation, sorting, and amplification. The optimized procedure, validated in 3 blank runs in a clinical setting, allowed the production of at least 108 pure (>90%) Melan-A- and MELOE-1-specific T cells within 28 days starting with 100 mL of blood from metastatic melanoma patients. This GMP process is thus ready to be used in an upcoming phase I/II clinical trial on metastatic melanoma patients.

Interleukin-33 (IL-33), a novel member of IL-1 family, has been recently implicated in several inflammatory and autoimmune diseases. IL-33 can be produced by various types of tissues and cells and induce gene expression of Th2-associated cytokines via binding to the orphan receptor ST2. By promoting Th2 type immune response, IL-33 plays important roles in the allergy, whereas its function in autoimmune diseases attracts more attention. Recent studies reported the correlation of IL-33 with rheumatic diseases, and most of them found that the IL-33 expression levels were consistent with disease activity and development. Furthermore, evidence has indicated that IL-33-related treatment may ameliorate the pathogenic conditions and attenuate disease progression of those rheumatic diseases. Therefore, elucidation of the roles of IL-33 in rheumatic diseases would be beneficial to understand the pathogenesis and therapy of these diseases. In this paper, we will summarize the roles of IL-33 in the rheumatic diseases.

One of the challenges faced by the infant immune system is learning to distinguish the myriad of foreign but nonthreatening antigens encountered from those expressed by true pathogens. This balance is reflected in the diminished production of proinflammatory cytokines by both innate and adaptive immune cells in the infant. A downside of this bias is that several factors critical for controlling Mycobacterium tuberculosis infection are significantly restricted in infants, including TNF, IL-1, and IL-12. Furthermore, infant T cells are inherently less capable of differentiating into IFN-γ-producing T cells. As a result, infected infants are 5–10 times more likely than adults to develop active tuberculosis (TB) and have higher rates of severe disseminated disease, including miliary TB and meningitis. Infant TB is a fundamentally different disease than TB in immune competent adults. Immunotherapeutics, therefore, should be specifically evaluated in infants before they are routinely employed to treat TB in this age group. Modalities aimed at reducing inflammation, which may be beneficial for adjunctive therapy of some forms of TB in older children and adults, may be of no benefit or even harmful in infants who manifest much less inflammatory disease.

Previous genome-wide association study by WTCCC identified many susceptibility loci of common autoimmune diseases in British, including rheumatoid arthritis (RA). Because of the genetic heterogeneity of RA, it is necessary to replicate these susceptibility loci in other populations. Here, three SNPs with strong RA association signal in the British were analyzed in Han Chinese, and two SNPs (rs6457617 and rs11761231) were genotyped in the test cohort firstly. The rs6457617 was significantly associated with RA in the test cohort. The individuals bearing the homozygous genotype CC had 0.39-fold risk than these bearing the wild-type genotype TT (P = 0.004, OR 0.39, [95% CI 0.21–0.74]). And the protective effect of allele C was confirmed in another validation cohort with 1514 samples (P genotye CC/TT = 5.9 × 10−10, OR 0.34, [95% CI 0.24–0.48]). The rs6457617 can be used as a tagSNP of HLA-DQA1∗03 which encoded MHC-II α chain. Since MHC restriction is important for primary T-cells in positive selection and negative selection stages, MHC protein polymorphisms may be implicated in shaping the T-cell repertoire, including the emergence of a T-cell clone involved in the inflammatory arthritis.

To circumvent pathology caused by infectious microbes and tumor growth, the host immune system must constantly clear harmful microorganisms and potentially malignant transformed cells. This task is accomplished in part by T-cells, which can directly kill infected or tumorigenic cells. A crucial event determining the recognition and elimination of detrimental cells is antigen recognition by the T cell receptor (TCR) expressed on the surface of T cells. Upon binding of the TCR to cognate peptide-MHC complexes presented on the surface of antigen presenting cells (APCs), a specialized supramolecular structure known as the immunological synapse (IS) assembles at the T cell-APC interface. Such a structure involves massive redistribution of membrane proteins, including TCR/pMHC complexes, modulatory receptor pairs, and adhesion molecules. Furthermore, assembly of the immunological synapse leads to intracellular events that modulate and define the magnitude and characteristics of the T cell response. Here, we discuss recent literature on the regulation and assembly of IS and the mechanisms evolved by tumors to modulate its function to escape T cell cytotoxicity, as well as novel strategies targeting the IS for therapy.

Antigen presenting cells (APCs), especially dendritic cells (DCs), play a major role in the hierarchy of the induction of immune reactions. DCs are widely accepted as the most potent APCs capable of inducing protective adaptive immune responses in addition to tolerance to self-antigens. The role of DCs is currently being investigated in the context of many disease and therapeutic settings. In response to a variety of microbial and endogenous stimuli, resting DCs in peripheral tissues undergo a complex maturation process that might involve the regulation of genes that control distinct DC functions. The different functional properties of DCs are also linked to the existence of several subpopulations in humans and animals that differ in response to stimuli. In this special issue, several articles addressed some recent findings highlighting the interactions between key immune effectors both in vitro and in vivo and in different disease settings. V. R. Yanofsky et al. provided an in-depth analysis of DC biology, with a particular focus on skin DCs and their role in cutaneous carcinoma. C. Y. J. Chung et al. provided an overview of the role of DCs in the immunopathogenesis of autoimmunity, as well as recent concepts of DC-based therapeutic opportunities in autoimmune diseases. On the other hand, P. Ruiz et al. described the different treatments and some of the novel immunotherapeutic strategies undertaken to induce transplantation tolerance in general. More specifically, M. Michael et al. discussed the current knowledge of Treg biology and its potential for cell-based immunotherapy in allogeneic stem cell transplantation. The review by A. K. Gloudemans et al. summarized the latest literature on the role of mucosal IgA in protection against allergic airway disease, the mechanisms described to induce secretory IgA, and the role of (mucosal) DCs in this process. D.-Y. Chen et al. examined the effect of dextromethorphan (DXM), a common cough suppressant, on the activation and function of DCs. Interestingly, DXM decreased the LPS-induced surface expression of CD80, CD83, and HLA-DR and the secretion of IL-6 and IL-12 in human monocyte-derived DCs. These findings provide a new insight into the impact of DXM treatment on DCs and suggest that DXM has the potential to be used in treating DC-related acute and chronic diseases. Similarly, L. Adalid-Peralta et al. showed that cysticerci may modulate DCs to favor a suppressive environment, which may help parasite establishment, minimizing the excessive inflammation, which may lead to tissue damage. In the same line, R. N. Ramos et al. described that cytokines such as IL-10 and TGF-beta, as well as cell surface molecules like PD-L1 and ICOS, seem to be significantly involved in the redirection of DCs towards tolerance induction, and tumor cells may modulate distinct DC subpopulations through the involvement of these molecules. Another work from X. Gu et al. suggested that regulation of B7-H1 expression on hepatic stellate cells by IFN-γ represents an important mechanism that regulates immune responses in the liver favoring tolerogenicity rather than immunogenicity. Finally, A. Brosbol-Ravnborg et al. described how vitamin D3 and TLR agonists acted in synergy to alter secretion of cytokines from human DCs in a direction that may provide an anti-inflammatory environment. From a therapeutic perspective, C. Penna et al. elegantly showed that a combined treatment, including dexamethasone preconditioning followed by an inoculation of short-term LPS-stimulated type II collagen-loaded DCs, provides an improved strategy for attenuating arthritis severity. On the other hand, data from S. O. Akefeldt et al. suggested that targeting MCL1 and BCL2A1 in infiltrating DC may affect the clinical outcomes in rheumatoid arthritis (RA) and Langerhans cell histiocytosis (LCH). P. Cordiali-Fei et al. showed that in patients with limited systemic sclerosis, Treg cells were inversely correlated to disease duration, suggesting that their levels may represent a marker of disease progression. Interestingly, C. Donas et al. showed that Trichostatin A (TSA) could potentially be used to enhance the differentiation and suppressive function of CD4+Foxp3+ Treg cells. Finally, L. de la Cruz-Merino et al. reviewed some important aspects about the role of tumor-infiltrating lymphocytes (TIL) and their subtypes, tumor-associated macrophages (TAM), and myeloid-derived suppressive cells (MDSC) that will eventually be incorporated into diagnostic and therapeutic algorithms of breast cancer. The work from W. Maes et al. discussed based on an animal model the value of local elimination of Tregs within the tumor microenvironment which might represent an important tool from both fundamental and clinical perspectives. All in all, articles published in this special issue clearly show that DCs and Tregs are currently being considered as attractive targets towards manipulation of the immune system for therapeutic purposes in different human disease settings. Mohamad Mohty Arnon Nagler Nicolaus Kroger Beatrice Gaugler

Objective. To evaluate the efficacy of autologous cytokine-induced killer (CIK) cells in patients with renal cell carcinoma (RCC). Methods. 20 patients diagnosed with TNM stage I or II RCC were randomly divided into two groups, a CIK cell treatment group and a control group. The endpoint was progression-free survival (PFS) evaluated by Kaplan-Meier analyses. Results. CD3+, CD3+/CD8+, CD3+/CD4+, and CD3+/CD56+ levels increased after CIK cell culture (P < 0.01). The median PFS in CIK cell treatment group was significantly longer than that in control group (PFS, 32.2 months versus 21.6 months; log-rank, P = 0.032), all patients were alive during the course of followup, and there are no statistically significant differences between two groups in OS (log-rank, P = 0.214). Grade III or greater adverse events were not observed. Conclusions. CIK cells treatment could prolong survival in patients with RCC after radical nephrectomy and showed acceptable curative effect with potential enhancement of cellular immune function. This trial is registered with Clinicaltrials.gov NCT01799083.