bluuebunny/crossref_metadata_2025 huggingface dataset:
From naive to effector ‐ alterations with aging
Authors: Linton Phyllis‐Jean , Haynes Laura , Tsui Lisa , Zhang Xiaohong , Swain Susan
Published: April 2006

Summary: We have used a T‐cell receptor transgenic mouse model to study the role of antigen in the changes that occur as T cells age. We find that the characteristic shift in the CD4 population to a predominance of memory phenotype T cells which accompanies aging in non‐transgenic mice does not occur, suggesting that this shift is a result of antigenic stimulation. Thus at least one component of aging must he antigen dependent. When responses of naive CD4 T cells from aged and young mice are directly compared in vitro, the former are relatively deficient in their ability m pro duce IL‐2 and IL‐3, they express altered levels of P‐glycoprotein and they proliferate less well m the absence of exogenous cytokines. When the ability of both naive populations to generate effectors is compared, the number of effectors generated from aged naive cells is much reduced and the effectors generated express lower levels of IL‐2Ra and produce reduced levels of cytokines. Importantly, addition of IL‐2 restores proliferation of aged naive T cells, restores efficient effector generation and results in effectors seemingly indistinguishable from those derived from young CD4 cells.

Similar phenotypic and functional changes seen with aging are also found in T‐cell populations from IL‐2 and IL‐ 2Ra knockout mice. Thus the loss of optimal IL‐2 production may participate in the aging process and may represent the main antigen‐independent defect in the CD4 T‐cell population.
Tales of tails: regulation of telomere length and telomerase activity during lymphocyte development, differentiation, activation, and aging
Authors: Weng Nan‐ping , Palmer Larry D. , Levine Bruce L , Lane H. Clifford , June Carl H. , Hodes Richard J.
Published: April 2006

Summary: Telomerase activity and the regulation of telomere length are factors which have been implicated in the control of cellular replication. These variables have been examined during human lymphocyte development, differentiation, activation, and aging. It was found that telomere length of peripheral blood CD4+ T cells decreases with age as well as with differentiation from naive to memory cells in vivo, and decreases with cell division in vitro. These results provide evidence that telomere length correlates with lymphocyte replicative history and residual replicative potential. In contrast, telomere length appears to increase during tonsil B‐cell differentiation and germinal center (GC) formation in vivo. It was also found that telomerase activity is highly regulated during T‐cell development and B‐cell differentiation in vivo, with high levels of telomerase activity expressed in thymocytes and GC B cells, and low levels of telomerase activity in resting mature peripheral blood lymphocytes. Finally, resting lymphocytes retain the ability to upregulate telomerase activity upon activation, and this capacity does not appear to decline with age. Although the precise role of telomerase in lymphocyte function remains to be elucidated, telomerase may contribute to protection from telomere shortening in T and B lymphocytes, and may thus play a critical role in lymphocyte development, differentiation and activation. The future study of study telomerase and its regulation of telomere length may enhance our understanding of bow the replicative lifespan is regulated in lymphocytes.
Age‐related changes in antibody repertoire: contribution from T cells
Authors: Song Haifeng , Price Paul W. , Cerny Jan
Published: April 2006

Summary: The immune system of aged mice produces antibodies that are characterized by low affinity, diminished protection against infections and autoreactivity. It has been shown that these antibodies may be encoded by different immunoglobulin V genes and that the mechanism of somatic hypermutation in the V genes is inefficient. Studies on scid mice reconstituted with B and T cells from donors of different ages suggested that both lymphocyte subsets may contribute to the age‐related changes in antibody repertoire. With help provided by T cells from young mice, the response to a hapten, nitrophenyl(acetyl), became gradually dominated by B‐cell clones that rearranged a particular germline VH gene (V186.2). However, help from the aged T cells resulted in A heterogeneous response of B cells expressing many different V segments. Analysis of discrete foci of primary antibody‐forming cells suggested that the aged T‐helper cells are unable to govern the normally‐occurring competition between the B‐cell clones that have different affinities for the hapten. It is proposed that a signaling disequilibrium from the aged T cells, which provide less efficient help in quantitative terms, supports the growth of low‐affinity B cells. This process may be exacerbated due to the apparent hyperactivity of aged B cells to CD40‐mediated mitogenic signal.
Immunosenescence and germinal center reaction
Authors: Zheng Biao , Han Shuhua , Takahashi Yoshimasa , Kelsoe Garnett
Published: April 2006

Summary: Dysfunction of the immune system in aged individuals includes at least two important factors: accumulation of immunocytes with reduced function and accumulation of lymphocyte clones with self‐reactive potential. Coincidently, there is a profound reduction of the germinal center reaction in the aged. While this reduction is likely the result of age‐associated impairment in lymphocyte function (e.g. diminished response to costimulus, altered lymphokine production etc.). the reduction of germinal centers may itself make an important contribution to further immunological dysfunction.
Early activation defects in T lymphocytes from aged mice
Authors: Miller Richurd A. , Gorcia Gonzalo , Kirk Christopher J. , Witkowski Jacek M.
Published: April 2006

Summary: Aging affects both calcium signals and protein kinase cascades in mouse T lymphocytes. The decline in calcium signal development largely represents differences between naive and memory T cells: the latter are resistant to increases in calcium concentration, and are more common in aged mice. Aging leads to declines in phosphorylation of a wide range of substrates in T cells stimulated by either anti‐CD 3 antibodies or by substances, such as phorbol myristate acetate (PMA) or ionomycin, that act at intracellular sites, but some phosphoproteins respond only in old T cells, and others respond regardless of age, Tyrosine phosphorylation of die CD3ζ chain declines with age, both in resting T cells and after activation. but the proportion of Zap‐70 that is bound to CD3C increases in T cells from old mice, Zap‐70 function and phosphorylation of CD3ζ‐associated Zap‐70 change only slightly after stimulation of T cells by anti‐CD3 and aiHi‐CD4, and are at similar levels in activated old and young T cells. Nonetheless, induction of Raf‐ l, MEK, and ERK kinase activity declines with age in CD4T cells. The effect of aging on T‐cell activation is not simply an overall decline in signal intensity, but a set of qualitative changes that differ among subsets and depend at least partly on the nature of the stimulus.
The B‐cell biology of aging
Authors: Klinman Norman R. , Kline Gregory H.
Published: April 2006

Summary: Although both the number and responsiveness of peripheral B cells in aged mice remain relatively intact, there are dramatic changes in B‐cell generation. Alterations in B‐cell development include both a skewing of V‐gene utilization, especially in cells responsive to phosphorylcholine, and a decrease in the generation of various developmental B‐cell sub‐sets. The altered representation of these subsets appears to be the consequence of two developmental blocks. The first developmental block occurs during the maturation of pro‐B cells and is evidenced by a decrease in the number of pre‐B cells. The second developmental block occurs at the earliest stage of slg+‐cell maturation (slgMvery lo). Because of this block in B‐cell maturation, it spite of a decrease in incoming pre‐B cells, the number of sIgMvery lo cells appears to increase in aged mice. Additionally, the time of residence of cells within this maturational stage increases dramatically, While the proportion of cells in more mature (sIgMhi) stages of bone marrow development are decreased. In addition to the decreased number of maturing bone marrow B cells, the population of splenic B cells that represent recent bone marrow émigrés (HSAvery hi) is markedly decreased. In the face of this decrease in newly emerging cells from the bone marrow, the population of mature splenic B cells is maintained by their increased longevity.
Effect of age on humoral immunity, selection of the B‐cell repertoire and B‐cell development
Authors: LeMaoult Joël , Szabo Paul , Weksler Marc E.
Published: April 2006

Summary: The age‐associated changes in humoral Immunity affect the quality more than the quality of the antibody response. Changes in the quality of the antibody response with age include shifts in antibody specificities from foreign to autoantigens. in antibody isotypes from IgG to IgM, in antibody affinities from HIGH to low and in the antibody idiotypic repertoire. These changes can be traced to an impaired capacity of T cells to facilitate: (a) the maturation of B cells respect to isotype and affinity maturation in the periphery and (b) the development of a diverse B‐cell repertoire from precursors within the bone marrow. In contrast, there is no evidence that the amount of immunoglobulin produced before or after immunization diminishes with age. Nonetheless, the impaired responses of the elderly to most vaccines and the greater susceptibility of the elderly to infections has fostered a view that immune senescence leads to a state of immune deficiency. However, it is more precise to describe immune senescence as leading to a state of immune dysregulation. The dysregulation of the humoral immunity is manifested by a shift from adaptive humoral Immunity, characterized by the production of a highly specific, high‐affinity, IgG antibody response to foreign antigens, to a process of natural antibody‐mediated immunity, dominated by low‐affinity, polyreactive, IgM antibodies which react with autoantigens, Age‐associated T‐cell impairments appear to be the basis for the shift from adaptive to natural humoral immunity and their reversal should permit the restoration of an adaptive antibody response in the elderly.
Co‐receptor and accessory regulation of B‐cell antigen receptor signal transduction
Authors: Buhl Anne Matte , Cambier John C.
Published: April 2006

Summary: The development and function of the immune system is precisely regulated to assure the generation of protective immune responses while avoiding autoimmunity. This regulation is accomplished by the engagement of a multitude of cell‐surface receptors which transduce signals that activate or regulate cell differentiative and proliferative pathways. In some cases biologic responses reflect the integration of signals generated by co‐aggregation of multiple receptors by complex ligands. For example, B‐cell responses to antigen receptor aggregation can be modulated by co‐aggregation of receptors for immunoglobulin G (FcγRIIB1), complement components (CR2). and 4aL2,6‐sialoglycoproteins (CD22). Here we review our recent studies of molecular mechanisms underlying co‐receptor modulation of B‐cell antigen receptor signaling. Our results define interesting circuitry involving interactions among the B‐cell antigen receptor, CD 19 and FcγRIIB1. CD 19 may function as an important integrator of positive and negative signals that regulate B‐cell antigen receptor signal output.
Genes, immunity, and senescence: looking for a link
Authors: Doria Gino , Frasca Daniela
Published: April 2006

Summary: Aging is under the control of a small number of regulatory genes. Mice genetically selected for high immune responses, in most cases, exhibit longer life span and lower lymphoma incidence than do mice selected for low responses. The link between immunity and aging is further evidenced by the age‐related alterations of the immune system, mostly of the T‐cell population, in terms of replacement of virgin by memory cells, accumulation of cells with signal transduction defects, and changes in the profile of Thl and Th2 type cytokines. Also, B cells exhibit intrinsic defects, and natural killer (NK) cell activity is profoundly depressed by aging. In vitro experiments indicate that IL‐2, IFN‐γ, and IL‐4 production by mouse spleen cells changes with aging and may be upregulated by recombinant cytokines. These findings suggest possible cytokine interventions to prevent or treat age‐related immune disorders, as they may affect the duration and the biological quality of life.
The C‐type lectin superfamily in the immune system
Authors: Weis William I. , Taylor Maureen E. , Drickamer Kurt
Published: April 2006

Summary: Protein‐carbohydrate interactions serve multiple functions in the immune system. Many animal lectins (sugar‐binding proteins) mediate both pathogen recognition and cell‐cell interactions using structurally related Ca2+‐dependent carbohydrate‐recognition domains (C‐type CRDs). Pathogen recognition by soluble collections such as serum mannose‐binding protein and pulmonary surfactant proteins, and also the macrophage cell‐surface mannose receptor, is effected by binding of terminal monosaccharide residues characteristic of bacterial and fungal cell surfaces. The broad selectivity of the monosaccharide‐binding site and the geometrical arrangement of multiple CRDs in the intact lectins explains the ability of the proteins to mediate discrimination between self and non‐self. In contrast, the much narrower binding specificity of selectin cell adhesion molecules results from an extended binding site within a single CRD. Other proteins, particularly receptors on the surface of natural killer cells, contain C‐type lectin‐like domains (CTLDs) that are evolutionarily divergent from the C‐type lectins and which would be predicted to function through different mechanisms.
Anatomy of an antibody molecule: structure, kinetics, thermodynamics and mutational studies of the antilysozyme antibody D1.3
Authors: Braden Bradford C. , Goldman Ellen R. , Mariuzza Roy A. , Poljak Roberto J.
Published: April 2006

Summary: Using site‐directed mutagenesis, x‐ray crystallograpby, micro‐calorimetric, equilibrium sedimentation and surface plasmon resonance detection techniques, we have examined the structure of an antibody‐antigen complex and (he structural and thermodynamic consequences of removing specific hydrogen bonds and van der Waals interactions in the antibody‐antigen interface. These observations show that the complex is considerably tolerant, both structurally and thermodynamically, to the truncation of antibody and antigen side chains that form contacts. Alterations ill interface solvent structure for two of the mutant complexes appear to compensate for the unfavorable enthalpy changes when antibody‐antigen interactions are removed. These changes in solvent structure, along with the increased mobility of side chains near the mutation site, probably contribute to the observed entropy compensation. In concert, data from structural studies, reaction rates, calorimetric measurements and site‐directed mutations are beginning to detail the nature of antibody‐protein antigen interactions.
Anatomy of the antigenic structure of a large memberane autoantigen, the muscle‐type nicotinic acetylcholine receptor
Authors: Tzartos Socrates J. , Barkas Tom , Cung M. Thong , Mamalaki Avgi , Marraud Michel , Orlewski Piotr , Papanastasiou Danai , Sakarellos Constantinos , Sakarellos‐Daitsiotis Maria , Tsantili Panayota , Tsikaris Vassilios
Published: April 2006

Summary: The neuromuscular junction nicotinic acetylcholine receptor (AChR), a pentameric membrane glycoprotein, is the autoantigen involved in the autoimmune disease myasthenia gravis (MG). In animals immunized with intact AChR and in human MG, the anti‐AChR antibody response is polyclonal. However, a small extracellular region of the AChR a‐subunit, the main immunogenic region (MIR), seems to be a major target for anti‐AChR antibodies. A major loop containing overlapping epitopes for several anti‐MIR monoclonal antibodies (mAbs) lies within residues α67–76 at the extreme synaptic end of each a‐subunit; however, anti‐MIR mAbs are functionally and structurally quite heterogeneous. Anti‐MIR mAbs do not affect channel gating, but are very effective in the passive transfer of MG to animals; in contrast, their Fab or Fv fragments protect the AChR from the pathogenic effects of the intact antibodies. Antibodies against the cytoplas‐mic region of the AChR can be elicited by immunization with denatured AChR and the precise epitopes of many such mAbs have been identified; however, it is unlikely that such antibodies are present in significant amounts in human MG. Antibodies to other extracellular epitopes on all AChR subunits are present in both experimental and human MG; these include antibodies to the acetylcholine‐binding site which affect AChR function in various ways and also induce acute experimental MG. Finally, anti‐AChR antibodies cross‐reactive with noti‐AChR antigens exist, suggesting that MG may result from molecular mimicry. Despite extensive studies, many gaps remain in our understanding of the antigenic structure of the AChR, especially in relation to human MG. A thorough understanding of the antigenic structure of the AChR is required for an in‐depth understanding, and for possible specific immunotherapy, of MG.
Structure and function of the human MHC class Ib molecules HLA‐E, HLA‐F and HLA‐G
Authors: O'Callaghan Christopher A. , Bell John I.
Published: April 2006

Summary: The major histocompatibility (MHC) class Ib molecules HLA‐E, HIA‐F and HLA‐G are relatively non‐polymorphic compared to class la molecules. Both HLA‐E and HLA‐G bind peptides and are involved in natural killer (NK)‐cell recognition, but the role of HLA‐F is unclear. HLA‐E binds specifically to the conserved leader sequence peptides from the class la MHC molecules and interacts on the cell surface with the CD94/NKG2 class of NK‐cell receptors. The framework structure of HLA‐E is similar to that of the MHC class la molecules, but the peptide‐binding groove is highly adapted for the specific binding of the leader sequence peptides. This is different from class la molecules, which have highly promiscuous peptide‐binding grooves. The HLA‐E groove makes full use of all the available pockets and imposes specificity along the entire length of the peptide. HLA‐G binds nonamer peptides with leucine or isoleucine at position 2, proline at position 3 and leucine at position 9. Expression of HLA‐G inhibits NK cells expressing the CD94/NKG2 class of receptors, though an interaction with these receptors has not been directly demonstrated.
Antigen‐presenting function of mouse CD 1: one molecule with two different kinds of antigenic ligands
Authors: Brossay Laurent , Burdin Nicolas , Tangri Shabnam , Kronenbers Mitchell
Published: April 2006

Summary: Mouse CDl (mCDl) is an antigen‐presenting molecule that is constitutively expressed by most bone marrow‐derived cells. Peptides with a hydrophobic binding motif can bind to mCDl, and the peptide‐CDl complex is recognized by CD8+ cytolytic T cells. In contrast, NK1.1+ T cells, which are CD8‐, are autoreactive for mCD 1 molecules. This autore‐activity, along with the ability of NK T cells to rapidly produce large amounts of cytokine, has led to the suggestion that these cells may be immunoregulatory We have shown that die mCD l ‐autoreactive T cells can distinguish between different cell types that express similar levels of mCDl, suggesting that mCDl ‐bound autologous ligands may be critical for T‐cell stimulation. Consistent with this, some of these mCDl‐restricted T cells can recognize the glycolipid a‐galactosyiceramide presented by mCDl, while others do not respond. The mCDl crystal structure reveals a deep and narrow hydrophobic antigen‐binding site which can more easily bind lipid antigens than the long hydrophobic peptides that we have defined as mCDl antigens. The ability of mCDl to bind and present two different types of ligands raises the question as to how mCDl can accommodate both types of antigens.
The MHC class I ligand‐generating system: roles of immunoproteasomes and the interferon‐4gMY‐inducible proteasome activator PA28
Authors: Tanoka Keiji , Kasahara Masanori
Published: April 2006

Summary: Production of antigenic peptides that serve as MHC class I ligands is essential for initiation of cell‐mediated immunity. Accumulating evidence indicates that the proteasome, a large multisubunit protein degradative machine in eukaryotes, functions as a processing enzyme responsible for the generation of MHC class I ligands. This processing system is elaborately regulated by various immunomodulatory cytokines. In particular, incerferon‐γ induces the formation of immunoproteasomes and a recently identified proteasomal regulatory factor, PA28, which in concert contribute co efficient production of MHC class I ligands. Many of the MHC‐encoded genes including LMP appear to have emerged by an ancient chromosomal duplication, suggesting that modifications and renewal of pre‐existing non‐immune genes were instrumental in the emergence of adaptive immunity.
Structure‐function studies of T‐cell receptor‐superantigen interactions
Authors: Li Hongmin , Llera Andrea , Mariuzza Roy A.
Published: April 2006

Summary: Superantigens (SAGs) are a class of disease‐causing and immunostimulatory proteins of bacterial or viral origin that activate T cells by binding to the Vβ domain of the T‐cell antigen receptor (TCR), The three‐dimensional structure of the complex between a TCR β chain (mouse Vβ8.2‐Jβ2.l‐Cβ1) and the SAG staphylococcal enterotoxin d (SEC3) has been recently determined. The complementarity‐determining region 2 (CDR2) of the β chain and, to lesser extents, CDR1 and hypervariable region 4 (HV4) bind in a cleft between the small and large domains of the SAG, A model of the TCR‐SAG‐peptide/MHC complex constructed from available crystal structures reveals how the SAG acts as a wedge between the TCR and MHC, thereby displacing die antigen in peptide away from the TCR and circumventing the normal mechanism for T‐cell activation by peptide/MHC, To evaluate the actual contribution of individual SAG residues to stabilizing the VβCβ‐SEC3 complex, as well as to investigate the relationship between the affinity of SAGs for TCR and MHC and their ability to activate T cells, we measured the binding of a set of SEC3 mutants to a soluble recombinant TCR β chain and to the human MHC class II molecule HLA‐DR1. We show that there is direct correlation between affinity and ability to stimulate T cells, with SAGs having the highest affinity for the TCR being die most biologically active. We also find that there is an interplay between TCR‐SAG and SAG‐MHC interactions in determining mitogenic potency, such that a small increase in die affinity of a SAG for MHC can overcome a large decrease in the SAG's affinity for die TCR, Finally, we observe that those SEC3 residues that make the greatest energetic contribution to stabilizing the VβCβ‐SEC3 complex are strictly conserved among enterotoxins reactive with mouse Vβ8.2, thereby explaining why SAGs having other residues at diese positions show different Vβ‐binding specificities.
Glimpses at the recognition of peptide/MHC complexes by T‐cell antigen receptors
Authors: Mazza Gilbert , Housset Dominique , Piras Claudine , Gregoire Claude , Lin Shih‐Yao , Fontecilla‐Camps Juan Carlos , Malissen Bernard , Mazza Gilbert , Housset Dominique , Piras Claudine , Gregoire Claude , Lin Shih‐Yao , Fontecilla‐Camps Juan Carlos , Malissen Bernard
Published: April 2006

Summary: More than a decade after the first description of the primary structure of a T‐cell antigen receptor (TCR), the recent determination of the crystal structure of several unliganded TCR ectodomains and of two TCRs complexed to peptide‐MHC ligand provides a structural basis for understanding the initial event that triggers T‐cell activation. This review focuses on the topology of the variable (V) domains found in TCRs and immunoglobulins and attempts to delineate the structural features that may render the TCR complementarity‐determining regions particularly suited to dock on the peptide/MHC surface. Finally, the available TCR structures provide an opportunity to re‐evaluate the molecular basis for intrathymic positive selection as well as the mechanisms that make a given TCR neither infinitely specific, nor so flexible that it engages productively any MHC‐binding peptides.
Analogy and solution scattering modelling: new structural strategies for the multidomain proteins of complement, cartilage and the immunoglobulin superfamily
Authors: Perkins Stephen J. , Ullman Christopher G. , Brissett Nigel C. , Chamberlain Deon , Boehm Mark K.
Published: April 2006

Summary:Many immunologically relevant proteins possess multidomain structures. Molecular structures both at the level of the individual domain and that of the intact protein are required for a full appreciation of function and control. Two recently developed structural approaches are reviewed here. Analogy modelling methods are based on the current understanding of many protein structures, and make possible the identification of folds for superfamilies of unknown structures. An integrated multidisciplinary predictive approach has been successfully applied to the von Willebrand factor type A, proteoglycan tandem repeat and factor I/membrane attack complex domains. The available experimental and predictive evidence is assembled in order to identify a known three‐dimensional structure related to the unknown one of interest. Neutron and X‐ray scattering curve modelling provides information on the full multidomain structure in solution. As scattering curves can be calculated from known atomic structures, the present availability of structures for many domains in conjunction with tight constraints based on these structures and the covalent connections between them results in a small family of allowed best‐fit structures for a given scattering curve. The curve‐fit procedure can be automated, and whole multidomain structures can be determined to a positional precision of the order of 0.2–1 nm. Such models are informative on the steric accessibility of each domain and their functional activity, and this is illustrated for antibody, cell‐surface and complement proteins.
Persisting viruses and chronic inflammation: understanding their relation to autoimmunity
Authors: Di Rosa Francesca , Barnaba Vincenzo
Published: April 2006

Summary: Viral infections may induce and sustain autoimmune processes via several and overlapping mechanisms. We outline how chronic inflammation, sustained by persisting viruses, may be “the prerequisite” for initiation and maintenance of the multistep process leading to autoimmunity. Chronic inflammation may favour priming of autoreactive T cells which have escaped thymic tolerance and are able to mount a cross‐reactive response to self‐mimicking antigens carried by viruses in the periphery. Moreover, chronic inflammation and persisting viruses can synergistically support autoimmunity through other relevant mechanisms: unveiling of cryptic self‐epitopes, determinant spreading, activation of dendritic cells, constant priming of new autoreactive T cells, and efficient generation and restimulation of memory cells. Therefore, viruses seem lo play a key role among the many environmental factors which, together with the genetic background, have been implicated in the pathogenesis of autoimmune diseases. We will also discuss some hypotheses explaining why autoimmunity IS a rare event.
Hierarchies of antigen‐specific cytotoxic T‐cell responses
Authors: Gallimore Awen , Hengartner Hans , Zinkernagel Rolf
Published: April 2006

Summary: Studies carried out using either mice or humans have shown that cytotoxic T‐lymphocyte (CTL) responses to many different pathogenic organisms often comprise CTL specific for multiple class I‐restricted pep‐tide epitopes. Differences in the magnitude of epitope‐specific CTL responses appear to arise mainly from differences in the expression level of the corresponding class I/peptide complex on the surface of the antigen‐presenting cell. The size of the CTL response may be United by the frequency and possibly by the affinity of specific CTL precursors in the naive T‐cell pool. Thus, both the efficiency of antigen processing and the composition of the peripheral T‐cell pool impose direct limitations on the extent of a T‐cell response to a given peptide epitope. Studies of CTL hierarchies have resulted in the identification of immunodominant epitopes i.e. peptide epitopes which stimulate the largest number of specific CTL and which are therefore generally believed to offer the best level of protection against the pathogen from which they were derived. It is also thought that CTL responses to non‐dominant epitopes mediate protection against pathogenic challenge. These ideas are considered here with respect to experimental data collected following infection of mice with lymphocytic choriomeningitis virus.
Cytotoxic T‐lymphocyte escape viral variants: how important are they in viral evasion of immune clearance in vivo?
Authors: Borrow Persephone , Shaw George M.
Published: April 2006

Summary: Although viral variants which are not recognized by epitope‐specific cytotoxic T lymphocytes (CTL) have been shown lo arise during a number of persistent virus infections, in many cases their significance remains controversial: it has been argued that the immune response is sufficiently plastic to contain their replication. In this review, we describe the mechanisms by which amino acid changes in viral proteins may affect epitope recognition by virus‐specific CTL, and discuss the viral and immunological basis for the emergence of viral variants bearing such amino acid changes during infection. We then consider the impact that viral variation may have on the host CTL response and its ability to contain virus replication. We argue that the emergence of a viral variant demonstrates that it must have an in vivo replicative advantage, and that as such, the variant must tip the balance between virus replication and immune control somewhat in favor of the virus. Further, we suggest that although the immune response can evolve to recognize new viral epitopes, the CTL generated following such evolution frequently have a reduced ability to contain virus replication. We conclude that this escape mechanism likely does make a significant contribution to persistence/pathogenesis during a number of different virus infections.
Shifting T‐cell activation thresholds in autoimmunity and determinant spreading
Authors: Lehmann Paul V. , Targoni Oleg S. , Forsthuber Thomas G.
Published: April 2006

Summary: The best‐characterized autoimmune T‐cell response is that to myelin basic protein (MBP), MBP has classically been regarded as a sequestered antigen that does not cause negative selection. This view has been fostered by the observation that T‐cell receptor‐transgenic T cells that are specific for the “immunodominant determinant” on the molecule, MBP:Ac 1–11, persist as naive cells in MBP‐expressing H‐Z” mice. The same T cells, however, can cause autoimmune pathology once they have been primed by environmental stimulation to become memory cells. Once the autoimmune response to Ac1‐11 has been engaged, determinant spreading occurs and second‐wave T‐cell responses that are specific for weaker, “cryptic” determinants like MBP: 121–140 develop. Although the nature of these cryptic determinants has been enigmatic, recent studies using MBP‐”‐mice have provided new insights. These studies showed that MBP is not a sequestered antigen, but one that causes negative selection; as MBP: 121–140 is actually the immunodominant determinant in MBP‐/‐ mice, it tolerizes high avidity clones in MBP+/+ mice, making it appear cryptic. Based on this new information, we attempt here to redefine the MBP‐specific repertoire within the theoretical framework of the threshold model for negative selection, and we propose a model of shifting T‐cell activation thresholds to explain how ignorant/naive T cells can become effector cells of autoimmune pathology and why this effector cell repertoire spreads.
Determinant spreading during experimental autoimmune encephalomyelitis: is it potentiating, protecting or participating in the disease?
Authors: Kumar Vipin
Published: April 2006

Summary: During many autoimmune conditions, a T‐cell response initially focused to a self‐antigen evolves towards the recruitment of T cells to multiple antigenic determinants. Here we discuss whether such determinant spreading involves T cells activated in the peripheral lymphoid organs, or alternatively, whether the diversification occurs after infiltration of the initiating T cells into the target organ, for example, into the central nervous system during experimental autoimmune encephalomyelitis, a prototype for multiple sclerosis. The expression of myelin antigens in the thymus and spleen may not only contribute to the induction of tolerance but also to determinant spreading. In this case, the outcome of in vivo diversification may ultimately be determined by the balance between type 1 and type 2 responses to antigenic determinants derived from myelin components. Thus, spreading T cells could modulate disease progression positively or negatively, depending upon the nature of the accompanying cytokine secretion profile.
The epitope spreading cascade during progression of experimental autoimmune encephalomyelitis and multiple sclerosis
Authors: Tuohy Vincent K. , Yu Min , Yin Ling , Kawczak Julie A. , Johnson Justin M. , Mathisen Peter M. , Weinstock‐Guttnnan Bianca , Kinkel R. Philip
Published: April 2006

Summary: We have made the following observations regarding self‐recognition during the development and progression of murine experimental autoimmune encephalomyelitis (EAE) and human multiple sclerosis (MS); I) chronic progression of EAE is accompanied by a sequential, predictable cascade of neo‐autoreactivity, commonly referred to as epitope spreading, presumably caused by endogenous self‐priming during autoimmune‐mediated tissue damage; 2) there is an invariant relationship between the progression of EAE and the emergence of epitope spreading; 3) progression of EAE can be inhibited by the induction of antigen‐specific tolerance to spreading determinants after onset of initial neurologic symptoms; 4) CD4+ Th1 cells responding to spreading determinants are autonomously encephalitogenic; 5) epitope spreading occurs during the development of MS and in some cases involves HLA‐DP class II‐restricted self‐recognition; and 6) progression of both EAE and MS is accompanied by the decline of primary T‐cell autoreactivity associated with disease onset and by the concurrent emergence of the epitope spreading cascade. Our studies directly challenge the traditional view that EAE and MS are initiated and maintained by autoreactivity directed against a single predominant myelin protein or determinant. Our results indicate that progression of EAE and MS involves a shifting of T‐cell autoreactivity from primary initialing self‐determinants to defined cascades of secondary determinants that sustain the inflammatory self‐recognition process during disease progression.
Are there unique autoantigens triggering autoimmune diseases?
Authors: Bach J. F. , Koutouzov S. , van Endert P. M.
Published: April 2006

Summary: Using three reference disease models ‐ insulin‐dependent diabetes mellitus (IDDM) as a prototype of T‐cell mediated organ‐specific autoimmune disease, myasthenia gravis (MG) as a prototype of auto and‐body‐inediated organ‐specific autoimmune disease and systemic lupus erythematosus (SLE) as a prototype of non‐organ‐specific autoimmune disease ‐ we have reached several conclusions: 1) All three diseases are associated with the presence of multiple autoantibodies and/or autoreactive T cells that recognize a large number of antigenic molecules. The apparent predominant role of certain antibodies in sotne diseases could relate to their functional properties stich as acetylcholine receptor (AChR) blockade for anti‐AChR autoantibodies in MG or anti‐dsDNA in SLE, 2) Major target antigens are clustered in the target cell affected by organ‐specific autoimmune diseases: β cells in IDDM, striated‐muscle cells in MG, or apopiotic cells in the case of SLE. 3) Antibodies and T cells recognize multiple epitopes in these molecules, 4) The most evident explanation for the observed clustering and diversity is autoantigen spreading. Spreading probably involves T cells secreting proinflammatory cytokines but also possibly antibodies as in the case of nucleosome autoantibodies in SLE. 5) The counterpart of antigen spreading is bystander suppression in which regulatory cytokines deviate the immune response towards a protective response, 6) The mechanisms underlying the initiation of the autoimmune response and antigen spreading are still undetermined. They could imply a direct abnormality of the target cell in the case of organ‐specific autoimmune diseases (e.g. infection with a virus showing a selective tropism for the target cell in organ‐specific autoimmune diseases, or loss of physiological regulation of major histocompatibility complex molecule expression) or could be consequence of a ubiquitous cell abnormality such as increased apoptosis in SLE. The respective roles of genetic and environmental factors in these triggering events remain to be determined.
Determinant spreading and immune responses to acetylcholine receptors in myasthenia gravis
Authors: Vincent Angela , Willcox Nick , Hill Marguerite , Curnow John , MacLennan Cal , Beeson David
Published: April 2006

Summary: In myasthenia gravis (MG), antibodies to the muscle acetylcholine receptor (AChR) cause muscle weakness. Experimental autoimmune myaschenia gravis (EAMG) can be induced by immunisation against purified AChR; the main immunogenic region (MIR) is a conformation‐dependent site that includes α67‐76, EAMG can also occur after immunisation against extracellular AChR sequences, but this probably involves intramolecular determinant spreading.

In MG patients, thymic hyperplasia and germinal centres are found in about 50%, and thymoma in 10–15%. The heterogeneous, high affinity, IgG anti‐AChR antibodies appear to be end‐products of germinal centre responses, and react mainly with the MIR or a site on fetal AChR; the latter contains a y subunit and is mainly expressed on myoid cells in the thymic medulla, T cells cloned against recombinant AChR subunits recognise principally two naturally processed epitopes: ɛ201 ‐219 derived from adult AChR which is expressed in muscle, and sometimes in thymic epithelium, and α 146–160, common to fetal and adult AChR. Since AChR is not normally co‐expressed with class II, it is unclear how CD4* responses to AChR a and E subunits are initiated, and how and where these spread to induce antibodies against fetal AChR, Various possibilities, including upregulation of class II on muscle/myoid cells and involvement of CD8+ responses to AChR and other muscle antigens, are discussed.
Heat‐shock protein T‐cell epitopes trigger a spreading regulatory control in a diversified arthritogenic T‐cell response
Authors: van Eden Willem , van der Zee Ruurd , Taams Leonie S. , Prakken A. Berent J. , van Roon Joël , Wauben Marca H. M.
Published: April 2006

Summary: Adjuvant arthritis (AA) in Lewis rats is T‐cell mediated and seems to depend on T cells recognising the 180–188 epitope of mycobacterial heat‐shock protein (hsp) 60. Analysis of arthritogenic T‐cell clone A2b has revealed a mimicry of this particular epitope with an articular cartilage‐associated target T‐cell epitope. Nasal administration of synthetic peptides covering this 180–188 sequence led to epitope‐.specific tolerance and resistance to AA. Since this tolerisation protocol also inhibited avridine arthritis, one may conclude that this form of epitope‐specific tolerance had effectuated a spreading tolerisation at the level of target antigens that included a diverse set of possible arthritis ‐associated antigens.

In vitro anergised T cells exhibited suppressive activity in a co‐culture system. As in this case ‐ depending on the presence of the antigen of the anergic T cell – such T cells suppressed responder T cells of a different antigenic specificity, we postulated that anergic T cells may be responsible for a spreading of tolerance. It seemed that such spreading of tolerance was channelled through the antigen‐presenting cells (APC) and was dependent on direct cell‐cell contact. This and additional forms of spreading of tolerance could be responsible for specific nasal tolerance, causing inhibition of the development of an arthritogenic inflammatory response. This can be similarly che case for the arthritis protection that resulted from immunisation with hsps. Analysis of T‐cell responses following hsp immunisations revealed that the arthritis inhibitory activity resided in T cells with specificity for a conserved part of microbial hsp60. The same T cells cross‐responded to rat self‐hsp60. Low level expression of the latter molecule on non‐professional APC could possibly have induced a suppressive anergic state in these autoreactive cells. Thus, immunisation with microbial hsp would have led to an expansion of such T cells, leading to raised disease‐suppressive potential when selectively trapped and activated in the inflamed self‐hsp‐overexpressing joint. Alternatively the cross‐recognised self‐hsp epitope could have the regulatory qualities of an altered peptide ligand or a partial agonist for T cells that see the microbial homologue as the full agonist.
B‐cell epitope spreading in autoimmunity
Authors: James Judith A. , Harley John B.
Published: April 2006

Summary: How the immune response matures from recognizing a single or a few structures of the antigen to many is an obviously important process. Models of B‐cell epitope spreading have been developed in a variety of systems. For example, immunization of animals with PPPGMRPP, one of the earliest B‐cell epitopes in the anti‐Sm response found in human lupus, leads to antispliceosomal autoimmunity and features of lupus. The humoral immune response spreads from PPPGMRPP to other structures of the spliceosome in an apparently reproducible sequence. B‐cell epitope spreading has provided the experimental basis from which a relationship between lupus and Epstein‐Barr virus was suspected. An understanding of B‐cell epitope spreading is likely to lead to important principles in basic immunology and to answers to human disease problems.
Reciprocal T‐B determinant spreading develops spontaneously in murine lupus: implications for pathogenesis
Authors: Singh Ram Raj , Hahn Bevra H.
Published: April 2006

Summary: Recent work from several laboratories has shown that, in contrast to the widely held notion that one autoimmune disease is caused by one or a few related autoantigenic determinants, autoimmunity is fundamentally a continuously evolving process. The autoimmune responses shift, drift and diversify with time not only to other determinants in the original antigen but also to other antigens. We have described a form of determinant spreading ‐ reciprocal T‐B determinant spreading–where the induction of first T cells by peptides from an autoantibody molecule could lead to help provided to a variety of B cells displaying a cross‐reactive version of the original determinant. The response spreads in this way by reciprocal T‐B stimulation until large cohorts of T and B cells have expanded. Such spontaneous expansion must be important in clinical disease, since tolerance induction to a limited set of T‐cell determinant peptides derived from an anti‐DNA antibody VH region delayed the appearance of IgG anti‐dsDNA antibodies and onset of lupus nephritis in the NZB/NZW Fl mouse model of systemic lupus erythematosus. Understanding the diversification patterns in autoimmune responses has enormous implications in developing peptide‐targeted therapies.
Epitope spreading: the role of self peptides and autoantigen processing by B lymphocytes
Authors: Mamula Mark J. , Mamula Mark J.
Published: April 2006

Summary: A complex interplay of cells, soluble macromolecules, and antigen lead to a productive immune response that evolved for the survival of species. While the immune system is intended to protect from foreign agents, such as bacterial and viral infection, the presence of autoimmune diseases indicates that the system is not perfect in differentiating antigen that they cause harm from benign self constituents. The concept of epitope spreading, where many determinants on an offending antigen are the focus of immune attack, is an efficient means of clearing an infections agent. However, the same mechanisms that lead to a diverse immune response may be harmful when the targets of attack are self tissues or self macromolecules. This review with examine the forms of self antigens that may initiate autoimmunity and the potential role of B lymphocytes, as autoantigen‐presenting cells, as one mechanism by which diversification of autoimmunity may occur.
Natural killer cell differentiation: insights from knockout and transgenic mouse models and in vitro systems
Authors: Williams Noelle Sevilir , Klem Jennifer , Puzanov Igor J. , Sivakumar P. V. , Schatzle John D. , Bennett Michael , Kumar Vinay
Published: April 2006

Summary: In the last few years, the routine development of knockout and transgenic mice and the ease with which rare progenitor populations can be isolated from hematopoietic organs and cultured in vitro has facilitated significant advances in understanding the lineage and development of natural killer (NK) cells. Fluorescence‐activated cell sorter analyses have identified a common lymphoid progenitor capable of giving rise to NK, T, and B cells, confirming the lymphoid origin of NK cells. Knockout and transgenic mouse models have pointed to an absolutely critical role for signals sent through the interleukin (IL)‐2/lS receptor β (CD 122) chain and common γ (γc) chain for NK development. Such signals are likely relayed inside the cell by the tyrosine kinase Jak3, which associates with γc. Recently developed IL‐15 and IL‐15 receptor a knockout mice have pinpointed IL‐15 as the mediator of this signal. Other mouse models have indicated an unexpected role for flt3 ligand in early NK‐cell development as well as minor roles for stem cell factor and IL‐7 in expanding NK‐cell progenitor numbers. Finally, in vitro culture systems have proven useful in identifying the point in NK development at which each of these signals is critical.
Lineage commitment and differentiation of T and natural killer lymphocytes in the fetal mouse
Authors: Carlyle James R. , Zúñiga‐Pflücker Juan Curios
Published: April 2006

Summary: T cells and natural killer (NK) cells are presumed to share a common intrathymic precursor. The development of conventional a|3 T lymphocytes begins within the early fetal thymus, after the colonization of multipotent CDl1 71 precursors. Irrevocable commitment to the T lineage is marked by thymus‐induced expression of CD25. However, the contribution of the fetal thymus to NK lineage commitment and differentiation remains largely unappreciated. Recently, we demonstrated that the development of functional mouse NK cells occurs first in the fetal thymus. Moreover, the appearance of mature fetal thymic NK cells (NK1.1+/CD 117‐) is preceded by a thymus‐induced developmental stage (NKl.1+/CD1 17+) that marks lineage commitment of multipotent hematopoietic precursors to the T and NK‐cell fates. Commitment to the T/NK bipotent stage is induced by fetal thymic stroma, but is not thymus dependent. Recent data indicate that CD90+/CD117lo fetal blood prothymocytes exhibit NK lineage potential and are phenotypically and functionally identical to fetal thymic NK1,1+/CD1 17+ progenitors. This finding also indicates that full commitment of circulating precursors to the T‐cell lineage occurs after thymus colonization. In this review, we discuss recent insights into the cellular and molecular events involved in fetal mouse T and NK lineage commitment and differentiation to unipotent progenitors.