bluuebunny/crossref_metadata_2025 huggingface dataset:
The functional significance of epitope spreading and its regulation by co‐stimulatory molecules
Authors: Vanderlugt Carol L. , Begolka Wendy Smith , Neville Katherine L. , Katz‐Levy Yael , Howard Laurence M. , Eagar Todd N. , Bluestone Jeffrey A. , Miller Stephen D.
Published: April 2006

Summary: Epitope spreading is a process whereby epitopes distinct from and non‐cross‐reactive with an inducing epitope become major targets of an ongoing immune response. This phenomenon has been defined in experimental and natural situations as a consequence of acute or persistent infection and secondary to chronic tissue destruction that occurs during progressive autoimmune disease. We have investigated the functional significance of this process in the chronic stages of both autoimmune and virus‐induced central nervous system (CNS) demyelinating disease models in the SJL/J mouse. During the relapsing‐remitting course of experimental autoimmune encephalomyelitis (R‐EAE) induced with defined encephalitogenic myelin peptides, CD4+ T cells specific for endogenous epitopes on both the initiating myelin protein (intramolecular epitope spreading) and distinct myelin proteins (intermolecular epitope spreading) are primed secondary to myelin destruction during acute disease and play a major functional role in mediating disease relapses. Similarly, epitope spreading to endogenous myelin epitopes appears to play a major functional role in the chronic‐progressive course of Theiler's murine encephalomyelitis virus‐induced demyelinating disease (TMEV‐IDD), a virus‐induced CD4+ T‐cell‐mediated immunopathology. In TMEV‐IDD, myelin destruction is initiated by virus‐specific CD4+ T cells which target virus epitopes persisting in CNS‐derived antigen‐presenting cells. However, the chronic stage of this progressive disease is associated with the activation of CD4+ T cells specific for multiple myelin epitopes. In both models, the temporal course of T‐cell activation occurs in a hierarchical order of epitope dominance, spreading first to the most immunodominant epitope and progressing to lesser immunodominant epitopes. In addition, epitope spreading in R‐EAE is regulated predominantly by CD28/B7‐1 co‐stimulatory interactions, as antagonism of B7‐1‐mediated co‐stimulation using anti‐B7‐1 F(ab) fragments is an effective ameliorative therapy for ongoing disease. The process of epitope spreading bas obvious important implications for the design of antigen‐specific therapies for the treatment of autoimmune disease since these therapies will have to identify and target endogenous self epitopes associated with chronic tissue destruction.
The case against epitope spread in experimental allergic encephalomyelitis
Authors: Takács Katalin , Altmann Daniel M.
Published: April 2006

Summary: Epitope spread has been proposed as a possible mechanism for diversification of the autoimmune T‐cell response during disease. Specifically, it offers a plausible mechanism for the previously obscure cyclical nature of autoimmune demyelination whereby the sequence of attack, quiescence and reactivation may recur over a long period of time. However, we were concerned that previous studies of epitope spread have not necessarily shown it to be well correlated with disease severity or relapse. Furthermore, we had studied two transgenic models of exacerbated experimental allergic encephalomyelitis (EAE) in which no indication of spread away from the initial disease‐inducing peptide could be observed. We conducted a systematic, longitudinal study in SJL mice to look for determinant spread during relapsing and remitting EAE, correlating epitope recognition and cytokine production with disease severity When T cells from spleen, lymph node and central nervous system (CNS) were analysed, little or no determinant spread was found. The best immunological correlate of relapse was the reappearance after remission of CNS‐infiltrating T cells mounting a strong proliferative and interferon (IFN)‐γ response to the original disease‐inducing epitope. Our data do not support a general role for determinant spread in EAE relapse. Rather, they indicate the importance of a focused proliferative and IEN‐γ response to the disease‐inducing peptide.
Epitope dominance: evidence for reciprocal determinant spreading to glutamic acid decarboxylase in non‐obese diabetic mice
Authors: Zechel Marc A. , Krawetz Michael D. , Singh Bhagirath
Published: April 2006

Summary: Autoimmunne T‐cell responses to peptide determinants of several autoantigens have recently been characterized. These data suggest that, in some autoimmune models, such as experimental autoimmune encephalomyelitis, T‐cell responses may diversify from a nested set of peptides to include many other peptide regions. A similar immune phenomenon pertaining to autoimmune diabetes (IDDM) is observed in NOD mice. We have explored a similar pattern of T‐cell responses related to age and disease status in NOD mice termed epitope dominance, which describes immune responses toward a pronounced subset of determinants of the autoantigen glutamic acid decarboxylase (GAD). Our studies have identified a total of five GAD epitopes between the 65 and 67 kDa isoforms. The magnitude of T‐cell responses to these various determinants was dependent on the stage of disease as well as on whether mice were protected from disease. The T‐cell responses of these epitopes in NOD mice correlated with the predicted binding of these peptides to the NOD class II molecule I‐Ag7. We therefore propose a model which implicates antigen presenting cells as critical entities in the propagation of dominant responses to the presentation of autoantigens to T cells, particularly in the Thi environment of the NOD mouse. This hypothesis presents a new framework for the discussion and interpretation of the kinetics of T‐cell responses to different peptide epitopes in autoimmune diseases such as IDDM.
Infectious Th1 and Th2 autoimmunity in diabetes‐prone mice
Authors: Tian Jide , Olcott Angelica P , Hanssen Lorraine R. , Zekzer Dan , Middleton Blake , Kaufman Daniel L
Published: April 2006

Summary: In the non‐obese diabetic (NOD) mouse, a Thl‐biased autoimmune response arises spontaneously against glutamic acid decarboxylase, concurrent with the onset of insulitis. Subsequently, Th1‐type autore‐activity spreads intra‐ and intermolecularly to other β‐cell autoantigens (βCAAs), suggesting that a spontaneous Th1 cascade underlies disease progression. Induction of Th2 immunity to a single βCAA results in the spreading of Th2–type T‐cell and humoral responses to other βCAAs in an infectious manner. Thus, both Th1 and Th2 autoimmunity can evolve in amplificatory cascades defined by site‐specific, but not antigen‐specific, positive feedback circuits. Despite the continued presence of Th1 auto‐immunity, the induction of Th2 spreading is associated with active tolerance to βCAAs and reduced disease incidence. With disease progression there is an attenuation of βCAA‐inducible Th2 spreading, presumably because of a reduced availability of uncommitted βCAA‐reactive precursor T cells. We discuss the implications of these findings for the rational design of antigen‐based immunotherapeutics.
Identification of autoantigen epitopes in MHC Class II transgenic mice
Authors: Sønderstrup Grete , McDevitt Hugh
Published: April 2006

Summary: MHC class II molecules function by selective binding of anti‐genic peptides, thereby both shaping the T‐cell receptor (TCR) repertoire in the thymus and influencing presentation of immunogenic peptides to CD4+ T cells in the periphery. The strong association between a number of human autoimmune diseases (type 1 diabetes, rheumatoid arthritis, and multiple sclerosis) and certain HLA‐DR/DQ alleles suggests that it may be possible to alter pathological autoimmune responses by deliberate introduction of autoantigenic peptides in a “tolerogenic” manner. Since there are likely to be differences in epitope selection and epitope spreading in different patients over time, this approach requires identification of all the immunogenic CD4‐ T‐cell epitopes (dominant, subdominant, or cryptic) of an autoantigen which elicit T‐cell responses restricted to the HLA‐DR/DQ alleles predisposing to these autoimmune diseases. This paper describes a new approach for the identification of immunogenic peptide epitopes of human autoantigenic proteins using HLA‐DR and DQ transgenic mice. These mice are engineered to select a full TCR repertoire which can identify immunogenic peptide epitopes similar or identical to human subjects of the same HLA‐DR/DQ genotype. This experimental system also allows comparison of autoantigenic immune responses restricted to disease‐susceptible and disease‐resistant HLA‐DR/DQ alleles.
Determinant spreading: lessons from animal models and human disease
Authors: McCluskey James , Farris A. Darise , Keech Catherine L. , Purcell Anthony W. , Rischmueller Maureen , Kinoshita Gentaro , Reynolds Pakathip , Gordon Tom P
Published: April 2006

Summary: Spreading of the immune response is a common theme in organ‐specific and systemic autoimmune diseases. We evaluated whether some of the mixed antinuclear antibody patterns characteristic of systemic autoimmunity might be the result of determinant spreading from a single initiating event. Immunisation of healthy mice with individual protein components of the La/Ro ribonudeoprotein (RNP) targeted in systemic lupus erythematosus and primary Sjögren's syndrome induced autoanti‐bodies recognising Ro60 (SS‐A), Ro52 (SS‐A) and La (SS‐B) and in some cases the molecular chaperones calreticulin and Grp78. The endogenous antigen(s) driving determinant spreading might be derived from physiological apoptosis which could explain the involvement of some chaperone proteins in the autoimmune response. Diversified anti‐La/Ro antibody responses were initiated by challenge with a single subdominant T epitope of La even though some self epitopes of La were efficiently tolerised. The pattern of autoantibody responses in primary Sjögren's syndrome was strongly influenced by HLA class II phenotype which we speculate controls activation of T cells recognising defined peptides from the La/Ro RNP In t his way, HLA class II alleles may be critical in influencing initiation and spreading of systemic autoimmune reactions. Molecular mimicry of such determinants by exogenous agents might readily initiate spreading of an autoimmune response in genetically susceptible hosts.
Intramolecular and intermolecular spreading during the course of organ allograft rejection
Authors: Suciu‐Foca Nicole , Harris Paul E. , Cortesini Raffaello
Published: April 2006

Summary: There are two distinct pathways by which T cells may MHC alloantigens. The direct pathway involves T‐cell recognition of intact MHC molecules expressed by donor antigen‐presenting cells (APCs). The second, or indirect, pathway describes T‐cell recognition of peptides derived from the processing and presentation of allogeneic MHC molecules on self APCs. Recent data demonstrates that indirect recognition plays a central role in both acute and chronic rejection of human organ allografts. Our studies have shown that, at the onset of primary acute rejection, recipient T‐cell responses lo donor HLA‐DR alloantigens are limited to a single dominant determinant present on erne of the disparate alloantigens and restricted by one of the responder's HLA‐DR molecules. In allograft recipients with recurring episodes of rejection, and/or at the onset of chronic rejection, recipient T‐cell reactivity may spread lo other epitopes within the allogeneic MHC molecule as well as to other alloantigens expressed by graft tissue. Both quantitative and qualitative alterations in T‐cell allopeptide reactivity are associated with increased risk of cellular and/or humoral rejection. These studies provide a basis for the design of new therapeutic strategies and for immunologic monitoring of transplant recipients.
Natural killer and T cells of innate and adaptive immunity: lymphoid compartments with different requirements for common γ chain‐dependent cytokines
Authors: Di Santo James P. , Colucci Francesco , Guy‐Grand Delphine
Published: April 2006

Summary: A group of cytokines, including interleukin‐2, ‐4, 7, ‐9 and ‐15, are related through the usage of a shared receptor subunit, the common cytokine receptor γ chain, γcγc‐dependent cytokines critically affect the development and maintenance of the lymphoid system. This review will highlight our current knowledge on the γc‐dependent cytokine network and on the non‐redundant roles that these cytokines play in the development and homeostasis of T and natural killer cells involved in innate and adaptive immunity.
The linkage between T‐cell and dendritic cell development in the mouse thymus
Authors: Shortman Ken , Vremec David , Corcoran Lynn M. , Georgopoulos Katia , Lucas Karen , Wu LI
Published: April 2006

Summary: Thymic dendritic cells (DC) mediate negative selection at a relatively late stage of the T‐cell developmental pathway. We present evidence that the development of thymic DC and of T‐stage cells is linked via a common precursor at an early stage of thymocyte development. T‐lineage precursor populations from the adult mouse thymus, prior lo T‐cell receptor gene rearrangement, display a capacity lo produce DC as well as T cells In the thymus, and are very efficient precursors of DC in culture. These lymphoid/DC precursors have little capacity to form myeloid cells, indicating that thymic DC are a lymphoid‐related rather than myeloid‐related lineage. In contrast to myeloid‐related DC, granulocytc‐macrophagc colony‐stimulating factor is not required for the development of these lymphoid‐related DC in vivo or in vitro. DC can develop in mutant mice lacking mattire T cells, provided the common precursors are present. However, in mutant mice lacking functional lkaros transcription factors, there are deficiencies In lymphoid precursor cells, in mature lymphoid cells and in DC.
Early stages in the development of human T, natural killer and thymic dendritic cells
Authors: Spits Hergen , Blom Bianca , Jaleco Ana‐Cristina , Weijer Kees , Verschuren Martie C. M. , van Dongen Jacques J. M. , Heemskerk Mirjam H. M. , Res Pieter C. M.
Published: April 2006

Summary: T‐cell development is initiated when CD34+ pluripotent stem cells or their immediate progeny leave the bone marrow Co migrate to the thymus. Upon arrival in the thymus the stem cell progeny is not yet committed to the T‐cell lineage as it has the capability to develop into T, natural killer (NK) and dendritic cells (DC). Primitive hematopoietic progenitor cells in the human thymus express CD34 and lack CD la. When these progenitor cells develop into T cells they traverse a number of checkpoints. One early checkpoint is the induction of T‐cell commitment, which correlates with appearance of CD la and involves the loss of capacity to develop into NK cells and DC and the initiation of T‐cell receptor (TCR) gene rearrangements, Basic helix‐loop‐helix transcription factors play a role in induction of T‐cell commitment. CDla+CD34+ cells develop into CD4+CD8α+β+ cells by upregulating first CD4, followed by CD8α and then CD8β. Selection for productive TCRβ gene rearrangements (β selection) likely occurs in the CD4+CD8α+β‐ and CD4+CD8α+β+ populations. Although the T and NK‐cell lineages arc closely related to each other, NK cells can develop independently of the thymus. The fetal thymus is most likely one site of NK‐cell development.
The role of the T‐cell receptor (TCR) in αβ/γδ lineage commitment: clues from intracellular TCR staining
Authors: MacDonald H. Robson , Wilson Anne , MacDonald H. Robson , Wilson Anne
Published: April 2006

Summary: T cells belong to two mutually exclusive lineages expressing either αβ orγδ T‐cell receptors (TCR). Although αβ and γδ cells are known to share a common precursor the role of TCR rearrangement and specificity in the lineage commitment process is controversial. Instructive lineage commitment models endow the αβ or γδ TCR with a deterministic role in lineage choice, whereas separate lineage models invoke TCR‐independent lineage commitment followed by TCR‐dependent selection and maturation of αβ and γδ cells. Here we review the published data pertaining to the role of the TCR in αβ/γδ lineage commitment and provide some additional information obtained from recent intracellular TCR staining studies. We conclude that a variant of the separate lineage model is best able to accommodate all of the available experimental results.
Crucial function of the pre‐T‐cell receptor (TCR) in TCRP selection, TCRβ allelic exclusion and αβ versus γδ lineage commitment
Authors: von Boehmer Harald , Aifantis Iannis , Azogui Orly , Feinberg Jacqueline , Saint‐Ruf Claude , Zober Carole , Garcia Corinne , Buer Jan
Published: April 2006

Summary: The analysis of T‐cell receptor (TCR) βselection, TCRβ allelic exclusion and TCRβ rearrangement in γδ T cells from normal and pre‐TCR‐deficient mice has shown that the pre‐TCR has a crucial role in T‐lyinpbocyte development:

The pre‐TCR is by far the most effective receptor that generates large numbers of CD4+8+ T cells with productive TCRβ rearrangements.

In the absence of the pre‐TCR, TCRβ rearrangement proceeds in developing cells irrespective of whether they already contain a productive TCRβ gene.

The pre‐TCR directs developing T cells to the αβ lineage because y5 T cells from pTα‐/‐ mice proceed much further in TCRβ rearrangement than γδ T cells from wild‐type mice. It is argued that the pre‐TCR commits developing T cells to the αβ lineage by an instructive mechanism, which has largely replaced an evolutionarily more ancient mechanism that involves stochastic αβ lineage commitment.
Developmental regulation of V(D)J recombination at the TCR a/5 locus
Authors: Krangel Michael S. , Hernandez‐Munain Cristina , Lauzurica Pilar , McMurry Michelle , Roberts Joseph L. , Zhong Xiao‐Ping
Published: April 2006

Summary:The T‐cell receptor (TCR) α/σ locus includes a large number of V, D, J and C gene segments that are used lo produce functional TCR 8 and TCR a chains expressed by distinct subsets of T lymphocytes. V(D)J recombination events within the locus are regulated as a function of developmental stage and cell lineage during T‐lymphocyte differentiation in the thymus. The process of V(D)J recombination is regulated by cis‐acting elements that modulate the accessibility of chromosomal substrates to the recombinase. Here we evaluate how the assembly of transcription factor complexes onto enhancers, promoters and other regulatory elements within the TCR α/σ locus imparts developmental control to VDJσ and VJα rearrangement events. Furthermore, we develop the notion that within a complex locus such as the TCR α/σ locus, highly localized and region‐specific control is likely to require an interplay between positive regulatory elements and blocking or boundary elements that restrict the influence of the positive elements to defined regions of the locus.
Thymocyte selection in Vav and IRF‐1 gene‐deficient mice
Authors: Penninger Josef M. , Mak Tak W.
Published: April 2006

Summary: T cells undergo a defined program of phenotypic and genetic changes during differentiation within the thymus. These changes define commitment of T‐cell receptor (TCR)γσ and TCRαβ cells and lineage differentiation into CD4+ T helper and CD8+ cytotoxic T cells, T‐cell differentiation and selection in the thymus constitute a tightly co‐ordinated multistep journey through a network that can be envisaged as a three‐dimensional informational highway made up of stromal cells and extracellular matrix molecules. This intrathymic journey is controlled by information exchange, with thymocytes depending on two‐way cellular interactions with thymic stromal cells in order to receive essential signals for maturation and selection. Genetic inactivation of surface receptors, signal transduction molecules, and transcription factors using homologous recombination has provided novel insight into the signaling cascades that relay surface receptor engagement to gene transcription and subsequent progression of the developmental program. In this review we discuss molecular mechanisms of T lymphocyte development in mice that harbour genetic mutations in the guanine nucleotide exchange factor Vav and the interferon regulatory transcription factor 1 (IRF‐1). We also propose a novel model of T‐cell selection based on TCRα chain‐directed signals for allelic exclusion and TCRα‐based selection for single receptor usage.
Molecular requirements for lineage commitment in the thymus – antibody‐mediated receptor engagements reveal a central role for lck in lineage decisions
Authors: Basson M. Albert , Bommhardt Ursula , Mee P. Joe , Tybulewicz Victor L. J. , Zamoyska Rose
Published: April 2006

Summary: Recent experiments in our laboratory have focused on the receptor engagements required for the differentiation of fully mature, single positive thymocytes from their double positive precursors. We have used a novel approach which involves the ligation of surface receptors on immature thymocytes with genetically engineered F(ab′)2 reagents, which, unlike conventional antibodies, do not aggregate the CD3 complex to such an extent as to induce extensive deletion of these cells. The experimental data presented in this review indicate that differentiation of the two mature CD4 and CD8 lineages occurs in response to distinct intracellular signals induced by particular receptor engagements. The data suggest that the tyrosine kinase p56kk (lck) plays a crucial role in determining lineage choice, in that maturation of thymocytes into the CD4 lineage occurs upon recruitment of active lck to the T‐cell receptor (TCR)7CD3 complex, whereas CDS maturation can be induced by CD3 ligation in the absence of CO‐receptor‐mediated lck recruitment. A central role for lck activity in determining the threshold for differentiation of the CD4 lineage is revealed in experiments with thymi deficient for a regulator of lck activity, CD4‐5. A model of thymocyte differentiation is presented in which we propose that the relative balance of signals delivered by TCR engagement and lck activation determines lineage choice.
Thymocyte selection: not by TCR alone
Authors: Amsen Dark , Kruisbeek Ada M.
Published: April 2006

Summary: During development of T cells in the thymus. T‐cell receptor (TCR)‐mediated recognition of self‐MHC/self‐peptide complexes on thy‐mic stroma dictates the developmental fate of immature CD4+CD8+ (double positive) thymocytes. Intriguingly, TCR‐generated intracellular signals tan elicit two entirely different cellular responses in such thymocytes: apoptosis or further differentiation. The critical issue in understanding end‐stage T‐cell development is how TCR occupancy can be perceived in such markedly different ways by the TCR.

Here, we review the cytoplasmic and nuclear events that result from TCR signaling during thymocyte selection. Studies aimed ac distinguishing molecular components involved in positive selection (resulting in signals for further differentiation) and negative selection (resulting in apoptosis) will help solve this fascinating feature of T‐Iymphocyte biology. We also discuss how non‐TCR‐derived signaling might serve to fine tune the TCR‐driven selection events in thymocytes. Central to this aspect of the conceptual framework needed to explain thymocyte selection is the observation that thymic antigen‐presenting cells appear to be specialized in the induction of either positive or negative selection. Finally, we suggest a hypothesis that integrates the facts currently available on developing thymocytes, and which may serve to refine our exploration of unresolved issues in thymocyte selection. This hypothesis expands our focus to include signals from receptors other than TCRs as modulating and amplifying factors in thymocyte signaling.
The role of B7 co‐stimulation in activation and differentiation ofCD4+and CD8+T cells
Authors: Mc Adam Alexander J. , Schweitzer A. Nicola , Sharpe Arlene H.
Published: April 2006

Summary: The functional significance of B7 co‐stimulation in T‐cell activation was described first in the context of preventing the induction of anergy. The functions of this pathway are far more complex than initially appreciated in view of the existence of two B7 molecules which have specificities for both CD28 and CTLA‐4, which serve to amplify and terminate T‐cell responses respectively Mice lacking B7 co‐stimulators and CD28 and CTLA‐4 co‐stimulatory receptors are helping to clarify the functions of this key immunoregulatory pathway. In this review we will focus on the role of B7 co‐stimulation in the activation and differentiation of CD4+ helper cells and CD8+ cytotoxic cells. The contribution of B7 co‐stimulation to CD+ responses depends upon the activation history of the T‐cell and the strength of the T‐cell antigen receptor signal. B7 co‐stimulation contributes to in Cerleukin (IL)‐2 production by both naive and previously activated CD4+ T cells. B7 co‐stimulation is most critical for the differentiation of naive CD4+ T cells to IL‐4 producers, but predominately influences IL‐2 production by previously activated CD4+ cells. B7 co‐stimulation is important in development of cytotoxic T cells through both effects on T‐helper cells and by direct co‐stimulation of CDS+ cells.
Evolution and diversity of the complement system of poikilothermic vertebrates
Authors: Sunyer J. Oriol , Lambris John D.
Published: April 2006

Summary:In mammals the complement system plays an important role in innate and acquired host defense mechanisms against infection and in various immunoregulatory processes. The complement system is an ancient defense mechanism that is already present in the invertebrate deuterostomes. In these species as well as in agnathans (the most primitive vertebrate species), both the alternative and lectin pathway of complement activation are already present, and the complement system appears to be involved mainly in opsonization of foreign material. With the emergence of immunoglobulins in cartilaginous fish, the classical and lytic pathways first appear. The rest of the poikilothermic species, from teleosts to reptilians, appear to contain a well‐developed complement system resembling that of homeothermic vertebrates. However, important differences remain. Unlike homeotherms, several species of poikilotherms have recently been shown to possess multiple forms of complement components (C3 and factor B) that are structurally and functionally more diverse than those of higher vertebrates. It is noteworthy that the multiple forms of C3 that have been characterized in several teleost fish are able to hind with varying efficiencies to various complement‐activating surfaces. We hypothesize that this diversity has allowed these animals to expand their innate capacity for immune recognition.
Towards understanding the evolutionary origins and early diversification of rearranging antigen receptors
Authors: Rast Jonathan P. , Litman Gary W.
Published: April 2006

Summary: The rearranging antigen binding receptors, immunoglobulin heavy (IgH) and light (IgL) chains and the four classes of T‐cell antigen receptors (TCR) are found in all contemporary species of jawed vertebrates examined thus far. Ig genes have undergone marked changes in organization and mechanisms ot diversification during vertebrate phylogeny: whereas TCR genes, which are found in species as phylogenetically removed as man and cartilaginous fishes (e.g. skate), are generally similar in terms of structure, diversification and, presumably, function. The patterns of Ig divergence in cartilaginous fish are informative as to both the potential for genetic variation and the mechanisms that bring about such change. No evidence has been found for homologs of cither Ig, TCR, recombination activating gene (RAG) I or RAG2 in jawless vertebrates or invertebrates. Thus, a phylogenetic demarcation exists in terms of the presence and absence of the rearranging antigen binding receptor genes. It is presumed that the rearranging antigen binding receptors arose from a non‐rearranging predecessor. The recent discovery of non‐rearranging homologs of antigen binding receptor genes in several species offers insight into alternative forms of recognition, relationships between adaptive and innate mechanisms of immunity, and the origins of antigen recognition.
Evolutionary variation of immunoglobulin μ heavy chain RNA processing pathways: origins, effects, and implications
Authors: Ross David A. , Wilson Melanie R. , Miller Norman W , Clem L. William , Warr Gregory W , Ross David A. , Wilson Melanie R. , Miller Normon W. , Clem L. William , Warr Gregory W.
Published: April 2006

Summary: Immunoglobulins (Ig) can occur in two physical forms, soluble (secreted) and membrane bound. The soluble form is secreted from B cells, and is present in the blood and other fluids where it plays a role as an immune effector molecule. The membrane‐bound form of the Ig molecule is inserted into the B‐cell membrane, where it serves as a receptor for antigen. The function of the membrane‐bound Ig as a receptor for antigen requires additional accessory molecules: the membrane Ig plus accessory molecules are referred to, collectively, as the B‐cell receptor (BCR) complex. The secreted and membrane‐bound forms of an Ig result from alternative patterns of RNA processing of the primary transcript from the heavy chain gene. IgM is the only class of Ig known to be conserved in all vertebrate species (perhaps exclusive of the agnathan fish). While the structure of the IgM heavy (i) chain gene has been highly conserved in vertebrate evolution, the patterns of alternative RNA processing of the μ transcript show surprising diversity. In particular, the bony fish (teleosts) produce membrane μ‐chain message by a splicing pathway that is quite different from that seen in other vertebrates; it results in the production of membrane IgM that lacks the Cμ4 domain. How this unusual RNA splicing pattern could have evolved and its implications for the function of the BCR in the bony fishes are considered here.
What do the paralogous regions in the genome tell us about the origin of the adaptive immune system?
Authors: Kasahara Musanori
Published: April 2006

Summary: During the last decade, our understanding of the immune system of ectothermic vertebrates has advanced significantly. It is now clear that all jawed vertebrates are equipped with the adaptive immune system characterized by the MHC molecules and the rearranging receptors. In contrast, there is no molecular evidence that suggests the existence of adaptive immunity in jawless vertebrates. How did the adaptive immune system emerge? Our recent work suggests that one of the driving forces that enabled the emergence of the adaptive immune system was one or more genome‐wide or large‐scale chromosomal duplications presumed to have taken place in a common ancestor of jawed vertebrates.
Functional and molecular characterization of teleost leukocytes
Authors: Miller N. , Wilson M. , Bfufltén E. , Stuge T. , Warr G. , Ciem W
Published: April 2006

Summary: The coupling of immunologically relevant in vitro assay systems, cell separation techniques, and the development of distinct clonal leukocyte lines has established the existence of T, B, natural killer, and accessory cell equivalents in teleosts. B cells are directly defined by monoclonal antibodies to teleost immunoglobulin (Ig) and identification of IgH and L chain genes. As in mammals, fish B cells show IgH‐chain gene rearrangements, allelic exclusion, produce both membrane‐bound and secreted forms of Ig, and transduce intracellular proliferative signals upon anti‐Ig cross‐linking. It has also been found that some fish B cells express a unique chimeric Ig chain with sequence homology to mammalian Igσ. Teleost T cells are still indirectly defined as sIg‐ lymphocytes due to a lack of definitive surface markers. These mig‐ lymphocytes are the responding cells in mixed leukocyte cultures, proliferate specifically to autologously processed and presented antigen, provide helper function for in vitro antibody responses, and produce interleukin‐like factors upon activation. Recent identification of teleost T‐cell receptor a and β genes has now permitted the unequivocal genetic demonstration that some of these mIg‐ cells are bono fide T cells. It is anticipated that such long‐term clonal cell lines will be indispensable tools for dissecting the physiology, biochemistry and molecular biology of teleost immune responses.
Lymphocyte development in fish and amphibians
Authors: Hansen John D. , Zapata Agustin G.
Published: April 2006

Summary: Recently, molecular markers such as recombination activating genes (RAG), terminal deoxynucleotidyl transferase (TdT), stem cell leukemia hematopoletic transcription factor (SCL), Ikaros and gata‐binding protein (Gata) ‐family members have been isolated and characterized from key lower vertebrates, adding to our growing knowledge of lymphopolesis in ectotherms. In all gnathostomes there appear to be two main embryonic locations derived from the early mesoderm, both intra‐ and extraembryonic, which contribute to primitive and dermitive hematopolesis based upon their differential expression of SCL, Gaia‐1, Gata‐2 and tnyeloblasto‐sis oncogene (c‐myb). In teleosts. a unique intraembryonic location for hematopoletic stem cells termed the intermediate cell mass (ICM) of Oellacter appears to be responsible for primitive or definitive hematopolesis depending upon the species being investigated. In Xenopus, elegant grafting studies in combination with specific molecular markers has led to a better definition of the roles that ventral blood islands and dorsal lateral plate play in amphibian hematopolesis, that of primitive and deffinitive lymphopolesis. After the early embryonic contribution to hematopolesis. specialized tissues must assume the role of providing the proper microenvironment for T and B‐lymphocyte development from progenitor stem cells. In all gnathostomes, the thymus is the major site for T‐cell maturation as evidenced by strong expression of developmental markers such as Ikaros, Rag and TdT plus expression of T‐cell specific markers such as T‐cell receptor β and lck. In this respect, several zebrafish mutants have provided new insights on the development of the thymopoletic environment. On the other band, the sites for B‐cell lymphopolesis are less clear among the lower vertebrates. In elasmobranchs, the spleen, Leydig's organ and the spiral valve may all contribute to B‐cell development, although pre‐B cells have yet to be fully addressed in fish. In teleosts, the kidney is undeniably the major source of B‐cell development based upon functional, cellular and molecular indices. Amphibians appear to use several different sites (spleen, bone marrow and/or kidney) depending upon the species in question.
Metamorphosis and the amphibian immune system
Authors: Rollins‐Smith Louise A.
Published: April 2006

Summary: Studies of the ontogeny of immunity in a limited number of representative amphibians have shown that while the immune systems of the larval forms are competent to defend against potential pathogens in the temporary ponds they inhabit, they arc not equivalent to the mature immune systems that develop after metamorphosis. Metamorphosis is a critical time of transition when increased concentrations of metamorphic hormones, principally thyroid hormones (TH) and corticosteroid hormones (CH), orchestrate the loss or reorganization of many tissues and organ systems, including the immune system. Immune system reorganization may serve to eliminate unnecessary lymphocytes that could be destructive if they recognized newly emerging adult specific antigens on the adult tissues. Increased corticosteroids during metamorphosis appeal to induce apoptosis of susceptible lymphocytes. This cell death can be inhibited in vitro or in vivo by the corticosteroid receptor antagonist, RU486, A coordinate increase in both TH and CH at metamorphosis may be common to all amphibians that undergo metamorphosis. Current evidence suggests that the central hypothalamic mediator that induces pituitary production of both thyroid‐stimulating hormone and adrenocorticotropic hormone in larval amphibians is corticotropin‐releasing hormone. Most amphibians probably survive the temporary immunosuppression associated with metamorphosis with no deleterious effects. However, it is hypothesized that if environmental stressors result in the induction of metamorphosis at a less than optimal body size and state of immune maturation, the immune system destruction would be more significant, and the amphibians could be at greater risk of infection and death.
The salmonid class I MHC: limited diversity in a primitive teleost
Authors: Miller Kristina M. , Withler Ruffi E.
Published: April 2006

Summary: Three MHC class I genes have been characterized in salmonids: A, B, and UA. Levels of polymorphism vary among the genes, but they all share one common feature: a lack of sequence diversity. Although individual species can carry over 3.0 alleles at a given locus (A), intraspecific diversity is generally less than 5% in Pacific salmon (genus Oncorhynchus). and less Chan 10% in Atlantic salmon (genus Salmo). These levels of diversity suggest that few ancient allelic lineages have persisted within species, and that most of the allelic radiation has occurred during or since speciation. Also apparent is the greater retention of allelic lineages in Atlantic salmon than Pacific salmon, which reflects historic differences of the two genera. Comparison of the salmonid class I sequences with those of other teleosts reveals two well supported groups: one containing the Cypriniformes and the salmonid UA, and the other containing the neoteleosts and the salmonid A and B, There is no homology between known Cypriniformes; and neoteleostean sequences. If this relationship is borne out, it offers strong support for the hypothesis that the higher teleosts diverged more recently from the Salmoniformes than the Cypriniformes, The salmonid MHC may provide a snapshot of the neoteleostean MHC prior to the extensive class I duplication that has taken place in at least some of the more advanced species.
What sharks can tell us about the evolution of MHC genes
Authors: Bartl Simona
Published: April 2006

Summary: Similarity in structural features would argue that sharks possess class I. class IIA and class IIB genes, coding for classical peptide‐presenting molecules, as well as non‐classical class I genes. Some aspects of shark major histocompatibility complex genes are similar to teleost genes and others are similar to tetrapod genes. Shark class I genes form a monophyletic group, as also seen for tetrapods, but the classical and nonclassical genes form two orthologous clades, as seen for teleosts. Teleost class I genes arose independently at least four different times with the nonclassical genes of ray‐finned fishes and all the shark and lobe‐finned fish class I genes forming 1 clade. The ray‐finned fish classical class I genes arose separately. In phylogenetic trees of class II α2 and β2 domains, the shark and tetrapod genes cluster more closely than the teleost genes and, unlike the teleost sequences, the class II α1 domains of sharks and tetrapods lack cysteines. On the other hand, both shark and teleost genes display sequence motifs in che antigen‐binding cleft that have persisted over very long time periods. The similarities may reflect common selective pressures on species in aqueous environments while differences may be due to different evolutionary rates.
Whirling disease: re‐emergence among wild trout
Authors: Hedrick Ronald P. , Adkison Mark A. , El‐Matbouli Mansour , MacConnell Elizabeth
Published: April 2006

Summary: Whirling disease of rainbow trout is caused by Myxobolus cerebralis, a myxozoan parasite possessing a life cycle well adapted to the natural environments where salmonid fish are found. Whirling disease was first described in Europe in 1898 among farmed rainbow trout but recent occurrences have been devastating to wild trout in North America. The disease is considered a major threat to survival of wild rainbow trout in the intermountain west of the United States. Difficulties in containing the spread and potentially eliminating the pathogen are tied to features of a complex life cycle involving two hosts, the salmonid fish and an aquatic oligochaete. Details of the morphologic development of the parasite have been described in each host but only now are we beginning to appreciate the breadth of interactions between these developmental forms and the sequential responses of the host. Fundamental mechanisms of the recognition and attachment of the parasite to the hosts, how host immunity is evaded and the unknown influences of environmental factors all contribute to a rather poor understanding of the biology of the parasite. Although the biology and ecology of the salmonid host are better known than for the oligochaete host, our knowledge is inadequate to interpret their complex interactions with the parasite. This uncertainty precludes the development of effective management activities designed to enhance the viability and productivity of wild trout populations in M. cerebralis‐ positive river systems. Improving our understanding of the hosts, the parasite and the environmental factors determining their interaction should provide for more focused and effective control methods for containing the spread and devastating effects whirling disease is causing to our wild trout populations.
A single VH family and long CDR3s are the targets for hypermutation in bovine immunoglobulin heavy chains
Authors: Lopez Osvdldo , Perez Carlos , Wylle Dwane
Published: April 2006

Summary: Bovine immunoglobulins are made from genes belonging to a small family of closely related Vh, genes. In this respect cattle resemble all species of domesticated mammals, which also use one VH family The family, named BoVH1, is homologous to the mouse Q52 family, and there are no more than 20 genes of this family in the bovine genome. Another feature of bovine heavy chains is the use of long CDR3s, which have an average of 21 codons. It seems that there are several families of long, closely related D genes rich in glycine and tyrosine responsible for this length. Sequences described as targets for mutations in other species can be found in CDR1, CDR2, and the putative D genes. The mutation mechanism starts at some point between late fetal stage and birth and seems to be antigen Independent. Diversity seems to be generated by hypermutation, although other mechanistns cannot be discomited at this time. Contrary to humans and mice, which have several Vh gene families comprising more than 100 genes, cattle use only a few genes and long CDR3s followed by somatic mutation to generate the necessary diversity to recognize the universe of antigens they will encounter during their life.
Dual enigma of somatic hypermutation of immunoglobulin variable genes: targeting and mechanism
Authors: Winter David B. , Gearhart Patricia I.
Published: April 2006

Summary: The immunoglobulin loci are uniquely unstable regions of the genome which undergo as much mutation and selection in a matter of days as a species can undergo in generations of evolution. We have studied the mutational pattern and targeting of this manual hypermutation process over the past 16 years. The pattern of somatic mutations in rearranged variable (V) genes differs from the pattern of meiotic mutations, indicating that a different mechanism generates hypermutation than generates spontaneous mutation. Hypermutations begin on the 5’ end of rearranged V genes downstream of the transcription initiation site and continue through the V exon and into the 3′‐flanking region before tapering off Mutations are located randomly throughout the DNA sequence and exhibit strand bias. The targeting of mutations to the region in and around the rearranged V gene appears to require interactions between the promoter and downstream intronic DNA sequences. The same mechanism that initiates hypermutation around V genes may also produce double‐strand breaks that catalyze homologous recombination between rearranged V genes on two chromosomal alleles. With this data we have built a model of hypermutation which predicts that V‐region DNA is destabilized at the nuclear matrix during transcription and undergoes strand breaks.
The signature of somatic hypermutation appears to be written into the germline IgV segment repertoire
Authors: Blanden Robert V. , Ruthmfluh Harold S. , Zylstrn Paula , Weiller Geoig E , Steele Edward J.
Published: April 2006

Summary: We present here a unifying hypothesis for the molecular mechanism of somatic hypermutation and somatic gene conversion in IgV genes involving reverse transcription using RNA templates from the V‐gene loci to produce cDNA which undergoes homologous recombination with chromosomal V(D)J DNA. Experimental evidence produced over the last 20 years is essentially consistent with this hypothesis. We also review evidence suggesting that somatically generated lgV sequences from B lymphocytes have been fed back to germline DNA over evolutionary time.
Immunoglobulin gene hypermutation in germinal centers is independent of the RAG‐1 V(D)J recombinase
Authors: Zheng Biao , Han Shuhua , Spanopoulou Eugenia , Kdsoe Garnelt
Published: April 2006

Summary: Antigen‐driven somatic hypermutation in immunoglobulin genes coupled with stringent selection leads to affinity maturation in the B‐lymphocyte populations present in germinal centers. To date, no gene(s) has been identified that drives the hypermutation process. The site‐specific recombination of antigen‐receptor gene segments in T and B lymphocytes is dependent on the expression of two recombination activating genes, RAG‐1 and RAG‐2, The RAG‐1 and RAG‐2 proteins are essential for the cleavage of DNA at highly conserved recombination signals to make double‐strand breaks and their expression is sufficient to confer V(D)J recombination activity to non‐lymphoid cells. Until very recently, expression of the V(D)J recombinase in adults was believed to be restricted to sites of primary lymphogenesis. However, several laboratories have now demonstrated expression of RAG‐1 and RAG‐2 and active V‐to‐(D)J recombination in germinal center B cells. This observation of active recombinase in germinal centers raises the issue of RAG‐mediated nuclease activity as a component of V(D)J hypermutation. Here, we show that a tratisgenic K‐light chain gene in a RAG‐1‐/‐ genetic background can acquire high frequencies of mutations. Thus, the RAG‐1 protein is not essential for the machinery of immunoglobulin hypermutation. The genetic approaches to identifying the genes necessary for sotnatic hypermutation will require further studies on DNA‐repair and immunodeficient models.
Amino acid insertions and deletions contribute to diversify the human Ig repertoire
Authors: Wilson Patrick , Liu Yong‐Jun , Bonchereau Jacques , Capra J. Donald , Pascual Virginia
Published: April 2006

Summary: The sequence analysis of Ig variable region genes transcribed within different B‐cell subpopulations from human tonsil led us to identify a rare DNA sequence modification event consisting of Lip insertions and/or deletions (I/D). Although these events were previously reported, they had never been formally associated with the somatic hypermutation process. I/D events share with more convemtional somatic hypermutation events their localization within hypervariable regions and, most particularly, within DNA motifs known to be mutational hoc spots, Repetitive; DNA tracts or DNA elements capable of forming DNA loop intermediates seem to be the preferred substrate for I/D to occur. These characteristics suggest a model for somatic hypermutation reminiscent of the “polymerase slippage” model involved in replication and repair mutations in prokaryotes, yeast, and mammals.