Current Immunology Reviews (Discontinued) - Volume 6, Issue 1, 2010

This year we continue the high quality articles both on basic immunology and at the interface between basic and clinical immunology and immunopathology. This first issue of the year provides a great starting point for showing the range of topics that serve our goals. In particular, this issue contains articles covering basic immune regulation, host-pathogen relationships, especially in viral infection, and finally, applications of our knowledge of the immune system to engineer practical immunotherapies. Basic immune regulation is addressed in the first article, from Veit et al., which brings us up to date on the role of HLA-G in immunological tolerance of the fetal allograft, and its broader immunoregulatory role in settings from transplantation to inflammatory disease. The next article also fills in details on immune regulation, this time with regard to the cytokine IL-17, and its role in the function of the interesting T helper subset known as Th17 cells. Detailed studies on host-pathogen relationships have turned to yield critically important details about immune regulation that cannot be brought out by many basic immunology studies; viruses and other pathogens have developed numerous clever mechanisms for evading or shaping immune responses, and in many cases they can be unique to each infectious organism and are quite often unique to each species host as well. Three articles help bring out these details, in discussion of various viral infections. Klein and Claesson discuss the particular role of Leukotriene B4 on the biology of Epstein Barr Virus. Inflammatory mediators such as Leukotriene B4 may contribute negatively to the infectious immunopathology of this infection despite its important role in other inflammatory responses. A close analysis of the role of T cell responses in Epstein Barr virus and Cytomegalovirus is also provided by Scherrenburg and van Baarle. Suppression of viral infection depends on broad T cell reactivity and functionality, which may be a critical issue in the setting of immunodeficiency. Similarly, the development and maturity of the immune system is a critical factor in the ability of the host to respond to these viruses. Muller et al. provide us with a summary of the immune responses of the fetus and newborn in the face of Herpes Simplex Virus and Cytomegalovirus. In view of the broad diversity in pathogen mechanisms for subverting the immune system, investigators have sought engineering strategies to provide immunity that the patient cannot provide on his own. Tomita and Tsumoto describe advances in technologies to develop antigen-specific monoclonal antibodies, with approaches enabling much more precisely defined specificities. Antibody therapeutics should continue their dominance in the biotech industry with continuing advances in these technologies. Rajapaksa and Lo describe the development of polymer microparticles for use in vaccines, though rather than produce these simply as antigen depot carriers, these particles can also provide targeted delivery in settings such as needle-free mucosal (intranasal or oral) administration. Finally, this year we are thrilled to be launching the publication of special issues on various Hot Topics in immunology. These issues, assembled and edited by guest editors, have put together coordinated articles on focused topics along the lines of regular articles already being published in CIR. Each issue is a fascinating read, with enlightening articles on a selected topic of high interest to CIR readers.

The Human Leukocyte Antigen G (HLA-G) is a non-classical class I MHC which is characterized by low polymorphism at the DNA level, limited tissue distribution in non-pathological conditions and the expression of both membrane-bound and soluble isoforms by alternative splicing. This molecule has become the object of interest because of its possible role in pregnancy maintenance. HLA-G seems to be involved in the induction and maintenance of tolerance between the mother immune system and the semi-allogeneic fetus at the fetal-placentary interface, and also seems to play an important role in embryo implantation. Besides, several studies point out to a broader immunoregulatory role for this molecule. Here we review the potential roles of the HLA-G molecule on the immune system, the unique regulatory region of its gene, the influence of gene polymorphisms on HLA-G expression, as well as several situations in which this molecule has been involved, such as pregnancy, transplantation, cancer, viral infections and, more recently, inflammatory diseases.

Interleukin 17 (IL-17) is the group of proteins known as pro-inflammatory cytokines produced mainly by activated CD4+ T helper (Th) cells. The family includes six members: IL-17A, B, C, D, E (known as IL-25) and IL-17F. The discovery of this cytokine provided a new light into immunoregulation, host defense as well as the pathogenesis of some immunological disorders. It was also noticed that it may play a role in allograft rejection. It is believed that IL-17 stimulates production of different cytokines like TNF-α, IL-1β, IL-21 and IL-6 or chemokines which was influence on neutrophils and macrophages, their recruitment, activation or migration. Specific transcription factors are needed for their differentiation, e.g. TGF-β, IL-6 or IL-23. The aim of our work was to introduce the current knowledge about IL-17 family and its presence or participation in the development of inflammation (e.g. inflammatory bowel disease, infection of Helicobacter pylori) and immunological diseases such as e.g. allergic asthma or rheumatoid arthritis. This study is based on clinical and experimental observations shown in the literature.

Leukotriene B4 (LTB4) is a potent fast acting lipid mediator produced mainly by activated granulocytes and monocytes. Epstein Barr Virus (EBV) is ubiquitous in humans. Primary infection is usually asymptomatic in young children, but in adolescents, who are most often the subjects of the infection, it is followed often by the characteristic syndrome of infectious mononucleosis (IM). We have assessed the contribution of LTB4 to the primary response in EBV infected cord blood leukocyte cultures and found that addition of LTB4 led to inhibition of the EBV induced B lymphocyte proliferation. Some of the symptoms of IM can be regarded as a consequence of the activation of the innate immunity system. Our results indicate that LTB4 may play a pathophysiological role in this process. The overall effect of LTB4 in mononucleosis is hard to predict. The endogenous production of LTB4 in affected IM tissue might be of importance for the host defence but at the same time strengthen the symptoms. Therefore further studies are warranted to elucidate whether LTB4 is involved in the symptomatology of mononucleosis. If so, administration of pharmacological inhibitors of the synthesis or the action of leukotrienes may be beneficial in severe cases.

Delivery of vaccine antigens that can trigger potent mucosal immune response is one of the effective strategies to overcome a wide array of infectious diseases. Microencapsulation of vaccine antigens with Poly(lactide-co-glycolic acids) (PLGA), an FDA approved biodegradable polymer, has been investigated for targeted M-cell uptake. While PLGA possesses many attractive properties, a successful PLGA based mucosal-targeted vaccine has yet to be introduced. This review focuses on the physiochemical properties important in the preparation of antigen-loaded PLGA microparticles, properties that influence M-cell specific uptake, and the induction of effective immune responses. In addition, a possible role of microparticle properties in immune adjuvant activity is discussed. A careful consideration of these factors may yet lead to the development of an effective needle-free mucosal vaccine using polymer microparticles.

Immunologic “immaturity” is often blamed for the increased susceptibility of newborn humans to infection, but the precise mechanisms and details of immunologic development remain somewhat obscure. Herpes simplex virus (HSV) and cytomegalovirus (CMV) are two of the more common severe infectious agents of the fetal and newborn periods. HSV infection in the newborn most commonly occurs after exposure to the virus during delivery, and can lead to a spectrum of clinical disease ranging from isolated skin-eye-mucous membrane infection to severe disseminated multiorgan disease, often including encephalitis. In contrast to HSV, clinically severe CMV infections early in life are usually acquired during the intrauterine period. These infections can result in a range of clinical disease, including hearing loss and neurodevelopmental delay. However, term newborns infected with CMV after delivery are generally asymptomatic, and older children and adults often acquire infection with HSV or CMV with either no or mild clinical symptoms. The reasons for these widely variable clinical presentations are not completely understood, but likely relate to developmental differences in immune responses. This review summarizes recent human and animal studies of the immunologic response of the fetus and newborn to these two infections, in comparison to the responses of older children and adults. The immunologic defense of the newborn against each virus is considered under the broader categories of (i) the placental barrier to infection, (ii) skin and mucosal barriers (including antimicrobial peptides), (iii) innate responses, (iv) humoral responses, and (v) cellular responses. A specific focus is made on recent studies of innate and cellular immunity to HSV and CMV.

Monoclonal antibodies are highly specific for antigens of interest, and have been widely used for many purposes. For their generation, antigen-sensitized B lymphocytes need to be somatically fused with cancerous cells to give rise to hybridoma cells that can continuously secrete the targeted monoclonal antibodies. Several protocols using viruses, or chemical and physical approach have been established. With conventional means, however, efficiency is very low because of the failure to control cell fusion of targeted B lymphocytes with myeloma cells. To address this problem, we have developed a new technology, termed antigen-based B-cell targeting, which features obvious advantages over the conventional methods. It confers at least a 5-40-fold increase in efficiency over that obtained with the poly(ethylene glycol)(PEG)-mediated method. A particular feature is that sensitized B lymphocytes can be stringently isolated in advance based on immunoglobulin receptors on B lymphocytes, so that antigen-selected B lymphocytes and myeloma cell complexes can be preferentially fused by electrical pulses. This antigen-based novel technology allows rapid production of monoclonal antibodies based on in vitro immunization, and also selective production of conformation-specific monoclonal antibodies against antigens with native structure.

During the past years a wide array of immunologic tools has become available to study antigen-specific T cell immunity by flow cytometry. By means of these assays progress has been made in our understanding of virus-specific T cell immunity and the role of virus-specific CD4+ and CD8+ T-cell responses in protection against disease. In this review we describe advances made in understanding Epstein Barr-virus (EBV) and cytomegalovirus (CMV) specific T-cell immunity in healthy individuals and immunocompromised patients, such as HIV infected individuals and stem cell transplant (SCT) recipients, using flow cytometry based assays. EBV and CMV are both herpesviruses, which are characterised by a life-long persistence of the virus in the human body. It now becomes clear that the functional capacity, and more specifically poly-functionality, is the most important feature of virus-specific T-cells to protect against disease progression. However, responses directed to different proteins may have different effects, in relation to viral control and subsequent protection against disease. Improved knowledge on these factors may be translated to clinical applications.