bluuebunny/crossref_metadata_2025 huggingface dataset:
Harmful somatic mutations: lessons from the dark side
Authors: Wiens Gregory D. , Robert Victoria A. , Whitcomb Elizabeth A , O'Hare Thomas , Stenzel‐Poore Mary P. , Rittenberg Marvin B.
Published: April 2006

Summary: The ability of somatic mutation to modify the course of an immune response is well documented. However, emphasis has been placed almost exclusively on the ability of somatic mutation to improve the functional characteristics of representative antibodies. The harmful effects of somatic mutation, its dark side, have been far less well characterized. Yet evidence suggests that the number of B cells directed to wastage pathways as a result of harmful somatic mutation probably far exceeds the number of cells whose antibodies have been improved. Here we review our recent findings in understanding the structural and functional consequences of V‐region mutation.
Somatic origin of T‐cell epitopes within antibody variable regions: significance to monoclonal therapy and genesis of systemic autoimmune disease
Authors: Wysocki Lawrence J. , Zhanfl Xianghua , Smith Diana S. , Snyder Christopher M. , Bonorino Cristina
Published: April 2006

Summary: During an immune response, specific antibody variable region genes are diversified by a somatic point mutation process that generates de novo “foreign” V‐region sequences. This creates an interesting problem in immune regulation because B cells are highly proficient at self‐presenting V‐region peptides in the context of class IIMHC, Though our studies indicate that [he corresponding T‐cell repertoire attains a state of tolerance to germline‐encoded antibody V‐region diversity, it is presently unknown whether the same is true of mutationally generated diversity On the basis of immunoregulatory considerations. we hypothesize that contact exclusion or tolerance normally precludes T cells from helping B cells via self‐presented mutant V‐region peptides. The lack of recurrent somatic mutations that create known T‐cell epitopes in antibody V regions lends some support to this idea. In contrast, our studies of spontaneously auto reactive B cells in systemic autoimmune disease strongly suggest that precursors of cells are recruited by T‐cell help directed to self‐presented mutant idiopeptides. Failures in tolerance or contact exclusion mechanisms may be responsible for this apparently abnormal event, In addition to their importance in immune regulation, somatic mutations or other differences from germline‐encoded V‐region sequence may be largely responsible for undesirable patient responses to therapeutic monoclonal antibodies. These reactions might be averted or diminished by inducing tolerance in the T‐cell repertoire with synthetic peptide correlates of non‐germline‐encoded V‐region sequences in humanized antibodies.
Somatic hypermutation in normal and transformed human B cells
Authors: Klien Ulf , Goasens Tina , Fischer Motthias , Kanzler Holger , Braeuninger Andreas , Rajewsky Klaus , Küppers Ralf
Published: April 2006

Summary: In the human, most IgM+IgD+ as well as CD5* peripheral blood B cells express unmutated V genes and thus can be assigned to a pre‐germinal centre (GC) stage of development. The memory B‐cell compartment generated in die GC reaction and characterized by cells bearing somatically mutated V‐region genes consists not only of class‐switched cells, but also of lgM‐only B cells and perhaps a subset of IgM+IgD+ B cells expressing the CD27 antigen. Comparison of the rearranged V‐region genes of human B‐cell lymphomas with those of the normal B‐cell subsets allows the identification of the progenitor cells of these tumours in terms of their stage of maturation. On this basis, most B‐cell on‐Hodgkin lymphomas, and in addition Hodgkin and Reed‐Stern berg (HRS) cells in Hodgkin's disease (HD). are derived from B cells ac a GC or post‐GC stage of development. The mutation pattern indicates that the precursors of the tumour clones have been stringently selected for expression of a functional antigen receptor with one notable exception: HRS cells in classical (but: not lymphocyte‐predominant) HD appear to be derived from “crippled” GC B cells. Sequence analysis of rearranged V genes amplified from single tonsillar GC B cells revealed that the somatic hypermutation process introduces deletions and/or insertions into V‐region genes more frequently that indicated by previous investigations. Presumably, this feature of the hypermutation mechanism is often responsible for the generation of heavy chain disease, and also several types of chromosomal translocations of oncogenes into immunoglobulin loci in human B‐cell lymphomas.
The enigmatic role of glutamyl aminopeptidase (BP‐1/6C3 antigen) in immune system development
Authors: Wang Jiyang , Lin Qun , Wu Qi , Cooper Max D.
Published: April 2006

Summary: The murine B‐lymphocyte differentiation antigen BP‐1 /6C3, a homodimeric integral membrane protein composed of M, 140,000 sub‐units, has been identified as glutamyl aminopeptidase (EAR EC 3,4. 11.7). This ecto‐enzyme cleaves acidic amino acid residues from the amino terminal of polypeptide substrates such as angiotensin II and cholecystoki‐nin‐8. Although BP‐1/6C3/EAP is expressed by cells in many tissues, among hematopoietic cell lineages this ecto‐enzyme is restricted to immature B‐lineage cells where its expression is upregulated by interleukin‐7 and viral transformation, BP‐1/6C3/EAP thus serves as a valuable marker of progression along the B‐cell differentiation pathway, but a corresponding biological role has not yet been established.
Ecto‐enzyme and signaling functions of lymphocyte CD 7 3
Authors: Resta Regina , Yamashita Yoshio , Thompson Linda F.
Published: April 2006

Summary: CD73 or ecto‐5′‐nucleotidase (S‐NT) is a widely expressed ecto‐enzyme which catalyzes the dephosphorylation of AMP and other nucleoside monophosphates. CD 73 participates in purine salvage through this enzymatic activity, supplying cells with precursors for energy metabolism and nucleic acid biosynthesis. As an enzyme that produces adenosine, CD 73 can also regulate adenosine receptor engagement in many tissues. However, CD73 also has functions independent of its enzyme activity like many glycosyl phosphatidylinositol (GPI)‐anchored molecules, it transmits potent activation signals in T cells when ligated by antibodies. Less compelling evidence suggests that CD 73 may function as a cell adhesion molecule. In the human immune system, CD73 is expressed on subsets of T and B cells, on germinal center follicular dendritic cells, and on thymic medullary reticular fibroblasts and epithelial cells. Many challenging areas remain to be explored before the role of CD73 in the immune system will be fully understood. These include an evaluation of the role of adenosine receptors in lymphoid development, the identification of physiological CD73 ligands, a functional assessment of the GPI anchor, and an analysis of the intricate cell‐type‐specific and developmental regulation of CD 73 expression.
Cellular carboxypeptidases
Authors: Skidgel Randal A. , Erdös Ervin G.
Published: April 2006

Summary: This article focuses on four human carboxypeptidases (CPs): two metallo‐CPs and two serine CPs. The metallo‐CPs are members of the so‐called B‐type regulatory CP family, as they cleave only the C‐terminal basic amino acids Arg or Lys. The plasma membrane‐bound CPM and the mainly, but not exclusively, intracellular CPD are surveyed from this group of enzymes. These enzymes can regulate pep tide hormone activity at the cell surface and possibly intracellularly after receptor‐mediated endocytosis and may also participate in peptide hormone processing. The serine CPs, as their name indicates, contain a serine residue in the active center essential for catalytic activity that reacts with organophosphorus inhibitors, Prolylcarboxypeptidase (PRCP) (angiotensinase C) and deamidase (cathepsin A, lysosomal protective protein) are discussed here. These two enzymes are highly concentrated in lysosomes: however, they may also be active extracellularly after their release from lysosomes in soluble form or in a plasma membrane‐bound complex. Whereas deamidase cleaves a variety of peptides with C‐terminal or penultimate hydrophobic residues (e.g. substance P, angiotensin I, bradykinin, endothelin, fMet‐Leu‐Phe), PRCP cleaves only peptides with a penultimate Pro residue (e.g. des‐Arg°‐bradykinin, angiotensin II). These enzymes may also be involved in terminating signal transduction by inactivating peptide ligands after receptor endocytosis.
Simian virus 40 infection via MHC class I molecules and caveolae
Authors: Norkin Leonard C.
Published: April 2006

Summary: MHC class I molecules are a necessary component of the cell surface receptor for simian virus 40 (SV40). After binding to class I molecules, SV40 enters cells via a unique endocytic pathway that involves caveolae, rather than clathrin‐coated pits. This pathway is dependent on a transmembrane signal that SV40 transmits from the cell surface. Furthermore, it delivers SV40 to the endoplasmic reticulum, rather than to the endosomal/lysosomal compartment, which is the usual target for endocytic traffic. The glycosphingolipid and cholesterol‐enriched plasma membrane domains that contain caveolae are also enriched for class I molecules, relative to whole plasma membrane. Nevertheless, although class I molecules bind SV40, they do not enter with SV40, nor do they enter spontaneously into uninfected SV40 host cells. Instead, they are shed from the cell surface by the activity of a metalloprotease. These results imply the existence of a putative secondary receptor for SV40 that might mediate SV40 entry. It is not yet clear whether class I molecules are active in transmitting the SV40 signal. Monoclonal antibodies against class I molecules also induce a signal in the SV40 host cells. However, the antibody‐induced signal is mediated by mitogen‐activated protein kinase (MAP kinase), whereas the SV40 signal is independent of MAP kinase.
Exploitation of major histocompatibility complex class I molecules and caveolae by simian virus 40
Authors: Parton Robert G. , Lindsay Margaret
Published: April 2006

Summary: Simian virus 40 (SV40), a non‐enveloped DNA virus, is transported from the cell surface to the nucleus where virus replication occurs. This pathway of virus uptake involves binding to surface MHC class I molecules, entry via non‐coated pits, and subsequent transport to the endoplasmic reticulum (ER). At some stage in this pathway the virus must cross a membrane to reach the cytosol. In the present review, the cellular machinery which the virus bas utilized to enter the cell will be examined. In particular, we will consider recent evidence for the involvement of caveolae in the infectious entry step and propose a model involving recruitment of caveolar proteins around the membrane‐bound virus. We also speculate that a similar mechanism may have been exploited by bacterial pathogens. The subsequent steps by which SV40 reaches the ER remain unclear but recent evidence suggests that this pathway may be shared with several other proteins that are transported from surface caveolae to the ER.
HIV's evasion of the cellular immune response
Authors: Collins Kathleen L. , Baltimore David
Published: April 2006

Summary: Despite a strong cytotoxic T‐lymphocyte (CTL) response directed against viral antigens, untreated individuals infected with the human immunodeficiency virus (HIV‐1) develop AIDS, We have found that primary T cells infected with HIV‐1 downregulate surface MHC class I antigens and are resistant to lysis by HLA‐A2‐restricted CTL clones. In contrast, cells infected with an HIV‐1 in which the nef gene is disrupted are sensitive to CTLs in an MHC and peptide‐specific manner. In primary T cells HLA‐A2 antigens are downmodulated more dramatically than total MHC class I antigens, suggesting that nef selectively downmodulates certain MHC class I antigens. In support of this, studies on ceils expressing individual MHC class I alietes have revealed that nef does not downmodulate HLA‐C and HLA‐E antigens, This selective downmodulation allows Infected cells to maintain resistance to certain natural killer cells that lyse infected cells expressing low levels of MHC class I antigens. Downmodulation of MHC class I HLA‐A2 antigens occurs not only in primary T cells, but also in B and astrocytoma cell lines. No effect of other HIV‐1 accessory proteins such as vpu and vpr was observed. Thus Nef is a protein that may promote escape of HIV‐1 from immune surveillance.
Immunomodulation by viruses: the myxoma virus story
Authors: Nash Piers , Barrett John , Cao Jing‐Xin , Hota‐Mitchell Sheela , Lalani Alshad S. , Everett Helen , Xu Xiao‐Ming , Robichaud Janine , Hnatiuk Shawna , Ainslie Cheryl , Seet Bruce T. , McFadden Grant
Published: April 2006

Summary: Myxoma virus is a poxvirus pathogen of rabbits that has evolved to replicate successfully in the presence of an active immune response by an infected host. To accomplish this, the virus has developed a variety of strategies to avoid detection by or obstruct specific aspects of the antiviral response whose consolidated action is antagonistic to virus survival. We describe two distinct viral strategies carried out by viral proteins with which myxoma virus subverts the host immune response. The first strategy is the production of virus‐encoded proteins known as viroceptors or virokines that mimic host receptors or cytokines. These seek to actively block extracellular immune signals required for effective virus clearance and produce a local environment in the infected tissue that is “virus friendly”. The second strategy, carried out by intracellular viral proteins, seeks to retard the innate antiviral responses such as apoptosis, and hinder attempts by the infected cell to communicate with the cellular arm of the immune system. By studying these viral strategies of immune evasion, the myxoma system can provide insights into virus‐host interactions and also provide new insights into the complex immune system.
Immune evasion by adenoviruses
Authors: Mahr Jeffrey A. , Gooding Linda R.
Published: April 2006

Summary: .Adenovirus is a human pathogen that infects mainly respiratory and gastrointestinal epithelia. While the pathology caused by this virus is generally not life threatening in immunocompetent individuals, there is a large literature describing its ability to establish a persistent infection. These persistent infections typically occur in apparently healthy individuals with no outward signs of disease. Such a long term and benign interaction between virus and immune system requires adenoviruses to dampen host antiviral effector mechanisms that would otherwise eliminate the virus and cause immune‐mediated pathology to the host. Adenovirus devotes a significant portion of its genome to gene products whose sole function seems to be the modulation of host immune responses. This review focuses on what is currently understood about how these immuno‐modulatory mechanisms work and how they might play a role in maintaining the virus in a persistent state.
Varicella‐zoster virus immune evasion
Authors: Abendroth Allison , Arvin Ann
Published: April 2006

Summary: CD4+ and CD8+ T cells play dual roles in varicella‐zoster virus (VZV) pathogenesis. The first role is to deliver the virus to cutaneous sites during primary VZV infection, permitting replication at these sites and the successful transmission of the virus to other susceptible individuals. The second contribution of T cells is to provide the critical antigen‐specific adaptive immunity needed to stop viral replication and maintain VZV latency in sensory ganglia. The equilibrium between VZV and the host can be predicted co be served by immune evasion mechanisms in at least two important ways, including the facilitation of cell‐associated viremia during primary VZV infection and silent persistence in dorsal root ganglia. Interference with antigen presentation by MHC class I downregulation may be expected to play a role in both circumstances. Transient interference with MHG class II expression in varicella skin lesions should facilitate local replication and transmission. In addition, when VZV reactivates, the capacity of viral gene produces to block the upregulation of MHC class II expression triggered by interferon‐y should permit a sufficient period of viral replication to cause the lesions of herpes zoster, despite the presence of VZV‐specific T cells, and to allow transmission of the virus to susceptible individuals. Although the effort is at an early stage compared to studies of other viral pathogens, identifying the VZV gene products that exert these effects and their mechanisms of interference has the potential to reveal novel aspects of MHG class I and class II antigen processing and presentation.
A comparison of viral immune escape strategies targeting the MHC class I assembly pathway
Authors: Früh Klaus , Gruhler Albrecht , Krishna Raman Murli , Schoenhals Gary J.
Published: April 2006

Summary: Peptide fragments from proteins of intracellular pathogens such as viruses are displayed at the cell surface hy MHC class I molecules thus enabling surveillance by cytotoxic T cells. Peptides are produced in the cytosol by proteasomal degradation and translocated into the endoplasmic reticulum by the peptide transporter TAP Empty MHC dass I molecules associate with TAP prior to their acquisition of peptides, a process which is assisted and controlled by a series of chaperones. The first part of this review summarizes our current knowledge of this assembly pathway and describes recent observations that tapasin functions as an endoplasmic reticulum retention molecule for empty MHC class I molecules. To defeat the presentation of virus‐derived peptides, several DNA viruses have devised strategies to interfere with MHC class I assembly. Although these evasion strategies have evolved independently and differ mechanistically they often target the same step in this pathway. We compare escape mechanisms of different viruses with particular emphasis on the retention of newly synthesized MHC class 1 molecules in the endoplasmic reticulum and the inhibition of peptide transport by viral proteins.
Human cytomegalovirus, MHC class I and inhibitory signalling receptors: more questions than answers
Authors: Cosman David , Fanger Neil , Borges Luis
Published: April 2006

Summary: The human cytomegalovirus UL18 protein, an MHC class I homologue, has been shown to bind to leucocyte immunoglobulin‐like receptor (LIR)‐1, a member of a family of nine closely related immunoglobulin superfamily receptors expressed on leucocytes. The LIRs are related to the natural killer (NK)‐cell immunoglobulin‐like receptors and to several other immunoreceptors. Three groups of LIR molecules have been defined: those containing cytoplasmic domain inhibitory signalling motifs, those with short cytoplasmic domains and a charged residue within the trans‐membrane domain, and a secreted molecule. LIR‐1 and LIR‐2 bind to a broad spectrum of cellular MHC class I antigens, including HLA‐A, ‐B and ‐C alleles, LIR‐2 is expressed by all monocytes and dendritic cells, whereas LIR‐1 is additionally expressed by B cells and subsets of T and NK cells. Upon tyrosine phosphorylation, LIR‐ 1 and LIR‐2 associate with the tyrosine phosphatase, SHP‐1, and have been shown to inhibit FcγRI signalling when co‐crosslinked in monocytes. Evidence for and against a role of UL18 as ail inhibitor of NK‐cell function is discussed, as are possible functional outcomes of UL18‐LIR‐1 interactions in monocytic cells.
Cytomegalovirus evasion of natural killer cell responses
Authors: Farrell Helen E. , Degli‐Esposti Mariapia A. , Davis‐Poynter Nicholas J.
Published: April 2006

Summary: Natural killer (NK) cells are an important component of the innate cellular immune system. They are particularly important during the early immune responses following virus infection, prior to the induction of cytotoxic T cells (CTL). Unlike CTL, which recognize specific peptides displayed on the surface of cells by class I MHC, NK cells respond to aberrant expression of cell surface molecules, in particular class I MHC, in a non‐specific manner. Thus, cells expressing low levels of surface dass I MHC are susceptible to recognition by NK cells, with concomitant triggering of cytolytic and cytokine‐mediated responses. Many viruses, including the cytomegaloviruses, downregulate cell surface MHC class I: this is likely to provide protection against CTL‐mediated clearance of infected cells, but may also render infected cells sensitive to NK‐cell attack. This review focuses upon cytomegalovirus‐encoded proteins that are believed to promote evasion of NK‐cell‐mediated immunity. The class I MHC homologues, encoded by all cytomegaloviruses characterised to date, have been implicated as molecular ‘decoys’, which may mimic the ability of cellular MHC class I to inhibit NK‐cell functions. Results from studies in vitro are not uniform, but in general they support the proposal that the class I homologues engage inhibitory receptors from NK cells and other cell types that normally interact with cellular class I. Consistent with this, in vivo studies of murine cytomegalovirus indicate that the class I homologue is required for efficient evasion of NK‐cell‐mediated clearance. Recently a second murine cytomegalovirus protein, a C‐C chemokine homologue, has been implicated as promoting evasion of NK and T‐cell‐mediated clearance in vivo.
Phagocytic antigen processing and effects of microbial products on antigen processing and T‐cell responses
Authors: Ramachandra Lakshmi , Chu Rose S. , Askew David , Noss Erika H. , Canaday David H. , Potter N. Stevenson , Johnsen Alyssa , Krieg Arthur M. , Nedrud John G. , Boom W. Henry , Harding Clifford V.
Published: April 2006

Summary: Processing of exogenous antigens and microbes involves contributions by multiple different endocytic and phagocytic compartments. During the processing of soluble antigens, different endocytic compartments have been demonstrated to use distinct antigen‐processing mechanisms and to process distinct sets of antigenic epitopes. Processing of particulate and microbial antigens involves phagocytosis and functions contributed by phagocytic compartments. Recent data from our laboratory demonstrate that phagosomes containing antigen‐conjugated latex beads are fully competent class U MHC (MHC‐II) antigen‐processing organelles, which generate peptide:MHC‐II complexes. In addition, phagocytosed antigen enters an alternate dass I MHC (MHC‐I) processing pathway that results in loading of peptides derived from exogenous antigens onto MHC‐I molecules, in contrast to the cytosolic antigen source utilized by the conventional MHC‐I antigen‐processing pathway. Antigen processing and other Immune response mechanisms may be activated or inhibited by microbial components to the benefit of either the host or the pathogen. For example, antigen processing and T‐cell responses (e.g. Th1 vs Th2 differentiation) are modulated by multiple distinct microbial components, including lipopolysaccharide, cholera toxin, heat labile enterotoxin of Escherichia coli, DNA containing CpG motifs (found in prokaryotic and invertebrate DNA but not mammalian DNA) and components of Mycobacterium tuberculosis.
Type III secretion machines and the pathogenesis of enteric infections caused by Yersinia and Salmonella spp.
Authors: Lee Vincent T , Schneewind Olaf
Published: April 2006

Summary: Salmonella and Yersinin spp. infect the intestinal tract of humans. Although these organisms cause fundamentally different diseases, each pathogen relies on type III secretion machines to either inject virulence factors into the cytosol of eukaryotic cells or release toxins into the extracellular milieu. Type III secretion machines are composed of many different subunits and export several polypeptides with unique substrate requirements. During Salmonella pathogenesis, the type III machine encoded by che Salmonella pathogenicity island (SPI)‐1 genetic element functions to cause invasion of the intestinal epithelium, whereas another type III machine (SPI‐2) Is required for survival in macrophages, Yersinia enterocolitica and Yersinia pseudotuberculosis employ type III machines to resist macrophage phagocytosis and to manipulate the host's immune response, thereby colonizing intestinal lymphoid tissues. We describe what is known about the pathogenic functions of virulence factors secreted by type III machines. Furthermore, type III secretion machines may be exploited for the injection of recombinant proteins, a strategy that has already been successfully employed to elicit a cell‐mediated immune response.
Understanding the mechanism of action of bacterial superantigens from a decade of research
Authors: Lavoie Pascal M. , Thibodeau Jacques , Erard François , Sékaly Rafick‐Pierre
Published: April 2006

Summary: In the face of the unique diversity and plasticity of the immune system pathogenic organisms have developed multiple mechanisms in adaptation to their hosts, including the expression of a particular class of molecules called superantigens. Bacterial superantigens are the most potent stimulators of T cells. The functional consequences of the expression of superantigens by bacteria can be extended not only to T lymphocytes, but also to B lymphocytes and to cells of the myeloid compartment, including antigen‐presenting cells and phagocytes. The biological effects of bacterial superantigens as well as their molecular aspects have now been studied for a decade. Although there is still a long way to go to clearly understand the role these molecules play in the establishment of disease, recently acquired knowledge of their biochemistry now offers unique experimental opportunities in defining the molecular rules of T‐cell activation. Here, we present some of the most recent functional and molecular aspects of the interaction of bacterial superantigens with MHC class II molecules and the T‐cell receptor.
CD 30 prevents T‐cell responses to non‐lymphoid tissues
Authors: Heath William R. , Kurts Christian , Caminschi Irina , Carbone Francis R. , Miller Jacques F. A. P.
Published: April 2006

Summary: Self antigens can induce T‐cell tolerance via a mechanism termed cross‐tolerance. This involves the transfer of peripheral tissue antigens to professional APC for presentation in the draining lymph nodes. In this site, CD8+ T cells are activated, proliferate, and are slowly deleted by a CD95‐dependent mechanism. Prior to their deletion, some activated cells leave the lymph nodes and encounter antigens on peripheral parenchymal tissues. Without functional CD30, these cells proliferate extensively and cause substantial tissue damage. Thus, CD30 limits autoreactivity, acting as a ‘brake’ on T‐cell proliferation after recognition of autoantigens on parenchymal tissues.
Lipid antigen presentation in the immune system; lessons learned from CD 1 d knockout mice
Authors: Hong Seokmann , Scherer David C. , Singh Nagendra , Mendiratta Sanjeev K. , Serizawa Isao , Koezuka Yasuhiko , Van Kaer Luc
Published: April 2006

Summary: CD I molecules represent a distinct lineage of antigen‐presenting molecules chat are evolutionarily related to the classical major histocompatility complex (MHC) dass I and class II molecules, Unlike the classical MHC products that bind peptides, GDI molecules have evolved Co bind lipids and glycolipids, Murine and human CD Id molecules can present glycolipid antigens such as α‐galactosylceramide (α‐GalCer) to CD 1d‐restricced natural killer (NK) T cells. Using CD 1d knockout mice we demonstrated chat CDI d expression is required for the development of NK T cells. These animals were also deficient in the rapid production of inter‐leukin‐4 and intcrferon‐γ in response to stimulation by anti‐CD3 antibodies. Despite these defects, CD Id knockout animals were able to generate strong T‐helper type 1 (TH1) and TH2 responses. Spleen cells from these animals neither proliferated nor produced cytokines in response to stimulation by α‐GalCer, Repeated injection of α‐GalCer into wild‐type but not CD 1 d mutant mice was able to clear metastatic tumors. We further showed that α‐GalCer can inhibit disease in diabetes‐prone non‐obese diabetic mice. Collectively, these findings with CD ld knockout animals indicate a critical role for CD 1 d‐dependent T cells in various disease conditions, and suggest that α‐GalCer may be useful for therapeutic intervention in these diseases.
Role of dendritic cells in the induction and maintenance of autoimmune diseases
Authors: Ludewig Burkhard , Odermati Bernhard , Ochsenbein Adrian F. , Zinkemagel Rolf M. , Hengortner Hans
Published: April 2006

Summary: Autoimmune diseases are characterised by the loss of tolerance against self‐determinants, activation of autoreactive lymphocytes and pathological damage to single or multiple organs. The mechanisms by which autoimmune responses are triggered and activation of autoreactive lymphocytes is initiated and maintained are not yet fully understood, Translocation of previously immunologically ignored antigens from the periphery to secondary lymphoid organs is probably a key step in the initiation of autoimmunity. Antigen transport and primary sensitisation of T lymphocytes is mainly mediated by dendritic tells which reside in peripheral non‐lymphoid tissues and maintain a continuous gradient of antigens towards secondary lymphoid tissues. In the transgenic rat insulin promoter‐glycoprotein model of autoimmune diabetes, dendritic cell (DC)‐mediated antigen transport initiates an autoimmune response against a pancreatic neoself‐antigen. Dose and timing of antigen delivery by DC and turnover of antigenic peptides presented by DC are the main parameters regulating the outcome of autoimmune diabetes in this model system. An important sequel of continued antigenic stimulation via DC is the formation of lymphoid structures in the pancreas. Thus, appropriate and repeated activation of cytotoxic T lymphocytes by DC, in concert with local inflammatory processes leading to formation of organised lymphoid tissue in the target organ, is likely to be crucial in the development of destructive autoimmunity. Therapeutic intervention to selectively manipulate antigen transport by dendritic cells or to influence antigen presentation may prove beneficial for the treatment of autoimmune diseases. Furthermore, the capacity of DC to induce potent antiself responses might have implications for the use of DC presenting self‐antigens in treatment of established tumours.
HLA class II transgenic mice as models of human diseases
Authors: Taneja Veena , David Chella S.
Published: April 2006

Summary: Predisposition co develop Various autoimmune disorders has been associated with certain HLA class II molecules but there is a lack of information on che pathophysiological rule of HLA genes in conferring susceptibility Various experimental animal models of autoimmune disease have been studied to address the role of immune response genes. To study the interactions involved between class II molecules (DQ and DR) and define the immunologic mechanisms in various diseases, we generated HLA‐DR and DQ transgenic mice that lacked endogenous class II molecules. The HLA molecules in these mice arc expressed on the cell surface and can positively select CD4+ T cells expressing Various Vβ T‐cell receptors (TCR). A peripheral tolerance is maintained co transgenic HLA molecules thus indicating that these molecules act as self, Mouse co stimulatory and accessory molecules can interact with the HLA‐peptide‐TCR complex leading to efficient T‐cell activation. In this review, we describe immunogenetic models for human diseases using these transgenic mice. Our studies show that HLA class II transgene‐restricted T cells recognize the immunodominant antigens and peptide epitopes, similar to HLA class II‐restricted human T cells. Thus these mice provide powerful tools to understand the role of HLA class II molecules in predisposition and onset of human diseases and to develop immunotherapy and vaccines.
Role of autoreactive CD8+ T cells in organ‐specific autoimmune diseases: insight from transgenic mouse models
Authors: Vizier Csaba , Bercovici Nadége , Cornet Anne , Cambouris Christophe , Libiau Roland S.
Published: April 2006

Summary: There is now convincing evidence that autoreactive CD8+ T cells can contribute to the pathogenesis of organ‐specific autoimmune diseases. In the non‐obese diabetic mouse, there is direct evidence that β‐islet cell‐specific CD8+ cytotoxic T cells have a pathogenic effect. In human diseases such as autoimmune diabetes and multiple sclerosis, indirect evidence also suggests a role for CD8+ T cells in tissue damage, although their antigen specificity is unknown. Transgenic mouse models as well as the use of knockout mite have been instrumental in the identification of the role of autoreactive CD8+ T cells. Spontaneous models of CD8+ T‐cell‐mediated autoimmunity generated through transgenesis should help delineate the effector mechanisms leading to tissue destruction. The study of autoreactive CD8+ T cells and the characterization of their antigenic specificity should help unravel the pathophysiology of organ‐specific autoimmune diseases, help identify exacerbating foreign antigens, and allow the design of antigen‐specific immunotherapy targeting the pathogenic autoreactive T cells.
Mechanisms of central and peripehral T‐cell tolerance: lessons from experimental models of multiple sclerosis
Authors: Anderton Stephen , Burkhart Christoph , Metzler Barbara , Wraith David
Published: April 2006

Summary: Studies of experimental autoimmune encephalomyelitis in conventional and transgenic mouse models have clarified mechanisms of central and peripheral tolerance to myelin antigens. It is now clear that myelin antigens are expressed in the thymus and their expression can influence generation of the potential autoimmune T‐cell repertoire. How autoreactive T cells escape tolerance in the thymus is largely unclear. One mechanism has been revealed through the use of a transgenic mouse expressing a T‐cell receptor specific for a myelin antigen. T cells specific for the N‐terminal epitope of myelin basic protein escape tolerance through low avidity interaction. The affinity of antigen binding to MHC also proves to be important for induction of peripheral tolerance. Peptides may be administered in solution to adults in order to reinstate peripheral tolerance and suppress disease. Induction of antigen‐specific suppression with synthetic peptides can result in either linked or bystander suppression and this appears to involve the generation of T cells secreting suppressive cytokines. The use of altered peptide ligands fur induction of peripheral tolerance has been investigated. This can be achieved but the complexity of the approach argues against its use for treatment of human autoimmune diseases.
Tolerance and autoimmunity in TCR transgenic mice specific for myelin basic protein
Authors: Goverman Joan
Published: April 2006

Summary: T‐cell receptor (TCR) transgenic mice provide the ability to follow the maturation and fate of T cells specific for self‐antigens in vivo. This technology represents a major breakthrough in the study of autoimmune diseases in which specific antigens have been implicated. Proteins expressed within the central nervous system are believed to be important autoantigens in multiple sclerosis, TCR transgenic models specific for myelin basic protein (MBP) allowed us to assess the role of tolerance in providing protection from T cells with this specificity Our studies demonstrate that T cells specific for the immunodominant epitope of MBP do not undergo tolerance in vivo and that TCR transgenic mice are susceptible to spontaneous autoimmune disease. The susceptibility to spontaneous disease is dependent on exposure to microbial antigens, MBP TCR transgenic models expressing TCRs specific for the same epitope of MBP but utilizing different Vα genes exhibit differing susceptibilities to, spontaneous disease. These data support the idea that genetic and environmental differences play a role in susceptibility to autoimmunity MBP TCR transgenic models are playing an important role in defining mechanisms by which infectious agents trigger autoimmune disease as well as defining mechanisms by which tolerance is induced to distinct epitopes within self‐antigens.
Transgenic mouse models of rheumatoid arthritis
Authors: Holmdahl Rikard , Andersson Ellen Christina , Andersen Claus B. , Svejgaard Arne , Fugger Lars
Published: April 2006

Summary: A combined analysis of data available m the literature has demonstrated that the strongest association in rheumatoid arthritis (RA) is with DR genes rather than DQ or DP genes. Functional and structural data of RA‐associated DR molecules suggest that selective binding of peptides is the molecular basis for this association. The establishment of functional transgenic mice expressing RA‐associated HLA class II molecules has proven to be useful in the delineation of the role of these molecules in immune responses possibly related to RA and in the development of humanized models for this disease. Such humanized mice develop arthritis upon immunization with type II collagen (CII), which shows similarities with RA, Interestingly, the immunodominant T‐cell determinant in CII is derived from positions 261–273, which overlap with a previously identified CII T‐cell epitope restricted by the mouse Ai molecule, which is associated with collagen‐induced arthritis. Studies in collagen transgenic mice have shown that recognition of this peptide may lead either to T‐cell tolerance or to an arthritogenic response. It is therefore proposed that the T‐cell recognition of the CII peptide bound by DR molecules is one of the molecular interactions of critical importance in the development of RA and accordingly also an important target for prevention and treatment of this disease.
Colitis in transgenic and knockout animals as models of human inflammatory bowel disease
Authors: Bhan Atul K. , Mizoguthi Emiko , Smith R. Neal , Mizoguchi Atsushi
Published: April 2006

Summary: Spontaneous colitis In knockout (KO) and transgenic rodents provides experimental models to study the development of mucosal inflammation and inflaminatory bowel disease (Crohn's disease and interactive colitis). Genetic and environmental factors, particularly the normal enteric flora, are important factors in the development of mucosal inflammation. The normal mucosal homeostasis is disrupted when there is either cytokine imbalance, abrogation of oral tolerance, alteration of epithelial barrier and function or loss of immunoregulatory cells. Some but not all immunodeficiencies, in the appropriate setting, lead to colitis. CD4‐’ T cells have been identified as the pathogenic T ceils in colitis, which mediate inflammation by either the Thl or the Th2 pathway. The Thi pathway dominates most colitis models and in Crohn's disease. In contrase. the colitis in TCRa KO mice shares many features of ulcerative colitis including the dominance of Th2 pathway in colonic inflammation. A major benefit of these models is in the development of therapeutic strategies for the treatment of inflammatory bowel disease.
Inflammatory disease in HLA‐B27 transgenic rats
Authors: Taugor Joel D. , Maika Shanna D. , Satumtira Nimman , Dorris Martha L. , McLean Ian Lochlan , Yanagisawa Hiromi , Sayad Alain , Stagg Andrew J. , Fox Graham M. , Le O'Brein Anne , Rehman Muhammad , Zhou Ming , Weiner Allison L. , Splawski Judy B. , Richardson James A. , Hammer Robert E.
Published: April 2006

Summary:A spontaneous inflammatory disease in rats transgenic for HLAB27 resembles the B27‐associated human spondyloarthropathies, Colitis and arthritis, the two most important features, require T cells, gut bacteria, and high expression of B27 in bone marrow‐derived cells, Control rats with HLA‐B7 remain healthy. Most rats with HLA‐Cw6 (associated with psoriasis vulgaris) remain healthy; a minority develop mild and transient disease. Rats with a mutant B27 with a Cys67←Ser substitution resemble wild‐type B27 transgenics, but with a lower prevalence of arthritis. A similar phenotype is seen in B2 7 rats co‐expressing a viral peptide that binds B27. Disease‐prone LEW but not F344 B27 rats develop high serum IgA levels concurrent with disease progression. Colitis is associated with high interferon‐y, arthritis with high interleukin‐6. Disease is similar in B27 LEW, F344, and PVG rats, but the DA background is protective. Conclusions: The spondyloarthropathy‐like disease in rats is specific for HLA‐B27 but does not require Cys67. Arthritis but not colitis is particularly sensitive to B27 peptide‐binding specificity. Genetic background exerts a strong influence, but some phenotypic differences exist between permissive strains that do not influence disease susceptibility The data favor a role for B27 peptide presentation in arthritis, but other mechanisms to explain the role of B27 have not been excluded.
Integrating innate and adaptive immunity in the whole animal
Authors: Lo David , Feng Lili , Li Li , Carson Monica J. , Crowley Mary , Pauza Mary , Nguyen Andrea , Reilly Christina R.
Published: April 2006

Summary: The mammalian defense system can respond to a variety of threats, but this capability is not just a simple alarm system for triggering antigen‐presenting cells and initiating cellular immunity. Instead, the body is at integrated system in which nearly every ceil type can relay the alarm through the production of chemokines, which recruit specific inflammatory cells to the target tissues. This chemokine production is carefully regulated at several levels so that the kinetics and character of local tissue inflammation is tailored to the specific threat. First, the production of nuclear factor‐KB‐regulated chemokines can be modulated in non‐bone marrow‐derived cells through transcriptional repression mediated by RelB. RelB is also implicated in the differentiation of lymphoid dendritic cells, suggesting that this gene regulates the transition from acute inflammation to adaptive immunity. Second, tissue parenchymal cells, in their capacity as sentinel cells, are able to produce different patterns of chemokines in response to different alarm stimuli. Third, cells from different tissues also show distinct potentials for chemokine responses so that the non‐specific damage from inflammation might he avoided in some cases. Finally, the differentiation of T‐cell effectors allows for further regulation of local inflammation as their cytokines can also affect chemokine production. This integration of innate and adaptive immunity allows for both rapid responses and dynamic regulation of inflammation in vivo.
Genetic models of abnormal apoptosis in lymphocytes
Authors: Refaeli Yosef , Van Parijs Luk , Abbas Abul K.
Published: April 2006

Summary: Apoptosis is a critical mechanism for regulating cell numbers during development, normal responses to hormones and other stimuli, and immune and inflammatory reactions. Recent advances in defining the biochemical mechanisms of cell death, and the development of animal models with isolated defects in cell death pathways, have led to an increasing appreciation of the pathophysiologic importance of lymphocyte apoptosis. In this article, we review our current understanding of the pathways and roles of apoptosis in lymphocytes, with an emphasis on trans‐genic and knockout models. We also summarize the relevance of these animal models to human diseases.
Personal historical chronicle of six decades of basic and applied research in virology, immunology, and vaccinology
Authors: Hilleman Maurice R.
Published: April 2006

Summary: The sciences of vaccinology and of immunology were created just two centuries ago by Jenner's studies of prevention of smallpox by inoculation with cowpox virus. Tins rudimentary beginning was expanded greatly by the giants of late 19th and early 10th centuries, bio‐medical sciences. The period from 1930 to 1950 was a transitional era with the introduction of chick embryos and minced tissues for propagating viruses and rickettsiae in vitro for vaccines. Modern era vaccinology began about i950 as a continuum of notable advances made during the 1940s and World War II. Present vaccinology is based largely on breakthroughs in cell culture, bacterial polysaccharide chemistry, molecular biology, and immunology By invitation, the author, who is a microbe hunter in fact, was asked to chronicle his six decades of pioneering achievements in basic and applied virology, bacteriology, immunology, molecular biology, epidemiology, and cancer, with special reference to the pioneering creation of most of the present day vaccines. Knowledge of the past may guide the present and future. This chronicle will have achieved its legacy if it helps others to understand the why and how of the past that may help to create the substance of the future.
Induction of CD8+ T cells using heterologous prime‐boost immunisation strategies
Authors: Schneider Jörg , Gilbert Sarah C. , Hannan Carolyn M. , Dégano Pilar , Prieur Eric , Sheu Eric G. , Plebanski Magdalena , Hill Adrian V. S.
Published: April 2006

Summary: One of the current challenges in vaccine design is the development of antigen delivery systems or vaccination strategies that induce higb protective levels of CD8+ T cells. These cells are crucial for protection against certain tumours and intracellular pathogens such as the liver‐stage parasite of malaria, A liver‐stage malaria vaccine should therefore include CD8+ T‐cell‐inducing components. This review provides an overview of prime‐boost immunisation strategies that result in protective CD8’ T‐cell responses against malaria with an emphasis on work from our laboratory. Possible mechanisms explaining why heterologous prime‐boost strategies, in particular boosting with replication‐impaired recombinant poxviruses, are so effective are discussed.
Stimulation of naive and memory T cells by cytokines
Authors: Tough David R , Sun Siquan , Zhang Xiaohong , Sprent Jonathan
Published: April 2006

Summary: On the basis of cell surface markers, mature T cells are considered to have either a naïve or a memory phenotype. These cells exhibit distinct types of kinetic behaviour in vivo. While naive‐phenotype cells persist long term in a non‐dividing state. memory phenotype T cells include cycling cells and exhibit a more rapid rate of turnover; this has also been shown to be true for cells that can be definitively identified as naive or memory T cells respectively. The number of memory‐phenotype (CD44in) CD8+ T cells entering cell cycle is greatly increased after In vivo exposure to viruses, bacteria or components of bacteria. Accelerated turnover of memory T cells also occurs after the injection of a variety cytokines that are induced by infectious agents, including type I interferon (IFN‐I), Although naive‐phenotype T cells do not divide in response to these cytokines, they do exhibit signs of activation, including upregulation of CD69 after exposure to lFN‐1, These findings suggest that the dissimilar in vivo kinetics of naive‐ and memory‐phenotype T cells might reflect their divergent responses to cytokines. Furthermore, the ability of infection‐ induced cytokines to stimulate non‐specific proliferation of memory phenotype T cells and partial activation of naive‐phenotype T cells implies that they play a complex role during primary immune responses w infectious agents.
Vaccine strategies against Epstein‐Barr virus‐associated diseases: lessons from studies on cytotoxic T‐cell‐mediated immune regulation
Authors: Khanna Rajiv , Moss Denis J. , Burrows Scott R.
Published: April 2006

Summary: Development of a vaccine against Epstein‐Barr virus (HBV) is constrained by the latency phenotypes adopted by different EBV‐associated diseases. Over the last few years an immense body of information on the pattern of viral gene expression in EBV‐associated diseases and the rote of cytotoxic T cells in the control of these diseases has accumulated. It would seem reasonable to suggest that emerging technologies are at a level where vaccine trials aimed at controlling infectious mononucleosis, post‐transplant lymphoproliferative disease, nasopharyngeal carcinoma and Hodgkln's disease are justified. On the other hand, a more cautious approach may be required for the development of vaccines or immunotherapeutic strategies against Burkitt's lymphoma.