Cancer immunoediting from immune surveillance to immune escape

Cancer immune surveillance is considered to be an important host protection process to inhibit carcinogenesis and to maintain cellular homeostasis. In the interaction of host and tumour cells, three essential phases have been proposed: elimination, equilibrium and escape, which are designated the 'three E's'. Several immune effector cells and secreted cytokines play a critical role in pursuing each process. Nascent transformed cells can initially be eliminated by an innate immune response such as by natural killer cells. During tumour progression, even though an adaptive immune response can be provoked by antigen-specific T cells, immune selection produces tumour cell variants that lose major histocompatibility complex class I and II antigens and decreases amounts of tumour antigens in the equilibrium phase. Furthermore, tumour-derived soluble factors facilitate the escape from immune attack, allowing progression and metastasis. In this review, the central roles of effector cells and cytokines in tumour immunity, and the escape mechanisms of tumour cells during tumour progression are discussed.     

The flip side of immune surveillance: immune dependency

Summary: The growths of many and perhaps all tumors may be stimulated rather than inhibited by a quantitatively low level of immunity. The reason tumors have antigens may be that tumors do not develop in vivo in the absence of at least a minimal immune reaction; in this sense, cancer may be considered an autoimmune disease. This review, based largely on the work of our own laboratory, outlines the data showing that the titration of anti-tumor immunity exhibits the phenomenon of hormesis, i.e. the dose–response curve is non-linear such that low levels of immunity are generally stimulatory but larger quantities of the same immune reactants may inhibit tumor growth. Evidence is also reviewed that suggests that the immune response may vary qualitatively and quantitatively during progression, such that there seems to be, during oncogenesis, a very low level of immune reaction that aids initial tumor growth, followed by a larger reaction that may cause remission of early neoplasms, followed, if the neoplasm survives, by a relative immunologic tolerance to the tumor that may be dependent, at least in part, on suppressor cells. This knowledge may help to explain some clinical observations concerning the relationships among tumor types and the organ distribution of metastases.     

免疫细胞可塑性与免疫病理机制研究进展

免疫细胞是由造血干细胞发育分化而来,是免疫应答的主要执行者。在不同应激或免疫病理状态下,免疫细胞具有较强的可塑性潜能,能够转分化形成不同类型的免疫细胞亚群。转分化的免疫细胞执行特定的免疫功能,从而调控疾病的演进过程。近年来研究发现,终末分化的免疫细胞亚群之间能够互相转换,实现类型和功能的转变,即转分化。目前发现T细胞、固有淋巴样细胞、巨噬细胞和嗜中性粒细胞等均存在细胞类型转分化的现象,细胞的转分化调控着疾病的发生发展进程。免疫细胞的可塑性与感染、肿瘤和自身免疫性疾病等都有密切联系。因此,揭示免疫细胞的可塑性调控机制将为深入理解免疫相关疾病的发生发展进程提供重要的理论依据,并为疾病的干预提供新策略。本文拟将对免疫细胞可塑性的主要细胞类型、免疫细胞可塑性调节机制以及免疫细胞可塑性与疾病等作一综述。     

Role of natural and immune IgM antibodies in immune responses

IgM antibodies constitute the major component of the natural antibodies and is also the first class of antibodies produced during a primary antibody response. The IgM-type antibodies differ from other classes of antibodies in that they are predominantly produced by B1 cells, in the absence of apparent stimulation by specific antigens. In addition, IgM antibodies are mostly encoded by germline V gene segments and have low affinities but broad specificites to both foreign and self structures. New developments regarding the function of both immune IgM antibodies and natural IgM antibodies will be examined here.     

Liver-associated immune abnormalities

In recent years, the cross talk between the liver and the immune system is being uncovered, in part by studying liver involvement in primary immune deficiencies (PID) and in part by investigating the alterations of the immune system following orthotopic liver transplantation (OLT). Here we review some of the reciprocal interactions between the liver and the immune system. Patients with PID, particularly those involving inherited defects in T and B cells or innate immunity are prone to infections and inflammatory responses that often involve the liver. Omenn's syndrome, familial hemophagocytic lymphohistiocytosis, AIRE, FOXP3 and CD25 deficiencies, common variable immunodeficiency, CD40 ligand deficiency, chronic granulomatous disease and autoimmune lymphoproliferative syndrome are some of the notable PID associated with typical hepatobiliary abnormalities. Knowledge gained from studying these PID together with laboratory and histological evaluations can assist in managing PID-associated liver dysfunction. The liver itself also has important effects on the immune system, as evident from the growing experience with patients surviving OLT. Up to 40% of pediatric patients who receive OLT suffer from post transplantation allergy, autoimmunity, and immune-mediated disorders (PTAA). PTAA is more common after liver and heart transplantations than kidney transplantations. Potential contributing factors for the increased frequency of PTAA after OLT include the age of the patients, the prolonged use of tacrolimus and the reduced regulatory immune function with a shift towards a TH2 immune response. Better understanding of the mechanisms leading to the development of PTAA after OLT will also improve the management of these conditions.     

Invertebrate immune diversity

The arms race between hosts and pathogens (and other non-self) drives the molecular diversification of immune response genes in the host. Over long periods of evolutionary time, many different defense strategies have been employed by a wide variety of invertebrates. We review here penaeidins and crustins in crustaceans, the allorecognition system encoded by fuhc, fester and Uncle fester in a colonial tunicate, Dscam and PGRPs in arthropods, FREPs in snails, VCBPs in protochordates, and the Sp185/333 system in the purple sea urchin. Comparisons among immune systems, including those reviewed here have not identified an immune specific regulatory “genetic toolkit”, however, repeatedly identified sequences (or “building materials” on which the tools act) are present in a broad range of immune systems. These include a Toll/TLR system, a primitive complement system, an LPS binding protein, and a RAG core/Transib element. Repeatedly identified domains and motifs that function in immune proteins include NACHT, LRR, Ig, death, TIR, lectin domains, and a thioester motif. In addition, there are repeatedly identified mechanisms (or “construction methods”) that generate sequence diversity in genes with immune function. These include genomic instability, duplications and/or deletions of sequences and the generation of clusters of similar genes or exons that appear as families, gene recombination, gene conversion, retrotransposition, alternative splicing, multiple alleles for single copy genes, and RNA editing. These commonly employed “materials and methods” for building and maintaining an effective immune system that might have been part of that ancestral system appear now as a fragmented and likely incomplete set, likely due to the rapid evolutionary change (or loss) of host genes that are under pressure to keep pace with pathogen diversity.     

The two simultaneously occurring processes in one immune response: the positive immune reaction and immune tolerance

The immune response is tightly shaped by both positive and negative signals on different levels. Based on the accumulating data, we hypothesize that, both immune reaction and immune tolerance processes were potentially and simultaneously triggered after antigen challenging. The actual outcome of immune response is dependent on the sum of these two reactions. The hypothesis, if proved to be correct, will significantly improve our understanding the immunity and its related pathological effects. It will influence our choice on immunosuppressive drugs for patients with transplant grafts, autoimmune diseases. As the immunosuppressive drugs may also block the potential immune tolerance process which is beneficial to the patients. Therefore, we should try to develop novel immunosuppressive medicines that selectively inhibit immune reaction but no effects on immune tolerance for patients with allo-grafts or autoimmune diseases. On the other hand, it will impact the immunotherapy for tumors and the development of vaccines.     

Secreted immune metabolites that mediate immune cell communication and function

Metabolites are emerging as essential factors for the immune system that are involved in both metabolic circuits and signaling cascades. Accumulated evidence suggests that altered metabolic programs initiated by the activation and maturation of immune cell types are accompanied by the delivery of various metabolites into the local environment. We propose that, in addition to protein/peptide ligands, secreted immune metabolites (SIMets) are essential components of immune communication networks that fine-tune immune responses under homeostatic and pathological conditions. We summarize recent advances in our understanding of SIMets and discuss the potential mechanisms by which some metabolites engage in immunological responses through receptor-, transporter-, and post-translational-mediated regulation. These insights may contribute to understanding physiology and developing effective therapeutics for inflammatory and immune-mediated diseases.     

State-of-the-art immune genetic and immune biological aspects of rheumatoid arthritis

One of the actual problems of clinical rheumatology was and remains the necessity of the earliest diagnostics of rheumatoid arthritis (RA) with the aim of adequate therapy for prevention of development of destructive changes, function ability loss and complication leading to reduction in patient's life quality, invalidization and lethal outcome. The predictors of the course of disease in its early stages, knowledge of its development mechanisms, are the base for optimal therapeutic influence on specific targets with the existing drugs and for development new ones. State-of-the-art data in genetic and immunological RA markers, whose detection in RA early stages helps to make RA diagnosis and to predict the disease course are represented. Immunological markers-antibodies to cyclic citrullinized peptide (aCCP) and rheumatoid factor (RF) have high specificity and sensitivity to RA diagnostics. Some alleles of the HLA-DRB1 locus coding shared epitope (SE) play the role of immune genetic factor predisposing to RA development and giving additional information for RA diagnostics in case of negative values of aCCP and RF.     

Conceptualizing immune responsiveness

Communicating about and comprehending immune responses and immunity will be facilitated by greater attention to semantic precision and consistency and increased willingness to engage with the full dimensionality and quantitative nature of immunological phenomena.