Showing papers in "International Reviews of Immunology in 2000"

Vaccination in the neonatal period and early infancy.

Abstract: Immune maturation is responsible for a progressive increase in antibody responses that can be elicited during the first year of life, such that neonatal immunization may currently not be expected to induce strong antibody responses. In contrast, B and T cell priming can be induced very early in life, without interference of maternal immunity. Strong IL-5 and IL-13 responses in young mice, and limited IL-12 and IFN-gamma release capacity by early life APC and T cells both in young mice and infants, could contribute to the severity of infections with intracellular pathogens in early life. It calls for evaluation of novel delivery systems, adjuvants and/or prime-boost immunization strategies capable to meet the challenge of both strong neonatal immunogenicity and acceptable reactogenicity. The extent to which early life murine immunization models may be useful for preclinical evaluation of infant responses is outlined in this review.

Development of Neonatal Th1/Th2 Function

Abstract: Newborn animals generally mount poor T cell-mediated immune responses in vivo. As a result, neonates fall prey to infectious agents and diseases which have little impact on immunocompetent adult animals. For some time, it was believed that this phenomenon was due to an intrinsic inability of newborns to mount developmentally mature Th1 responses. Recent studies in mice have challenged that view; under certain conditions, adult-level Th1 function has been achieved in newborns. More often, however, neonates develop Th2-dominant responses. A major challenge in the field of developmental immunology is to understand why the 'default' response for neonates is Th2 function. Cell intrinsic as well as environmental influences may contribute to Th2 skewing in neonates.

Genetics of Systemic Autoimmunity in Mouse Models of Lupus

Abstract: Systemic lupus erythematosus (SLE) is inherited as a complex polygenic trait, involving genetic, environmental and stochastic factors. Although definition of these etiologic processes has been elusive, solid progress has been made toward elucidating the genetic basis for susceptibility. Herein, we summarize our genome wide mapping effort that has defined loci for component phenotypes for lupus-prone NZB, NZW, MRL-Fas(lpr) and BXSB strains. With this framework in place, identification of the specific genetic alterations and mechanisms is now proceeding through the generation of interval congenic lines, precise mapping and screening of candidate genes. In addition to this approach, transgenic and gene knockout studies have begun to identify genes that can induce or modify autoimmunity in nonautoimmune and lupus-prone background mice, including studies by us and others on Th1 and Th2 cytokine genes in lupus. It is apparent that a diversity of genes and mechanisms can independently or in combination promote systemic autoimmunity in mice. This complexity, which is also observed in human lupus, emphasizes the importance of using experimental and less complex mouse models to define these processes, a tactic that has already yielded new insights. With current technologies and the anticipated definition of mammalian genomes, identification of genes predisposing to lupus and elucidation of processes critical for disease pathogenesis appear within grasp.

Chronic colitis in IL-10-/- mice: insufficient counter regulation of a Th1 response.

Abstract: IL-10-deficient (IL-10-/-) mice, generated by a gene-targeted mutation, develop abnormal immune responses as a result of uncontrolled interactions between antigen presenting cells and lymphocytes. The studies reviewed herein have focused on the enterocolitis that spontaneously develops in IL-10-/- mice. Not unexpectedly, heightened production of proinflammatory mediators accompanied pathologic changes in the gastrointestinal tract of young mutants. In a series of studies, the proinflammatory mediators responsible for initiating the pathogenic response were distinguished from those that were elicited as a consequence of persistent inflammation. We have also investigated the possibility that different mediators are involved in the inductive versus the maintenance phase of disease. The findings of these mechanistic studies as they relate to our understanding of progressive inflammatory disease and the role of IL-10 in controlling the acute and chronic stages are discussed.

Cellular immune responses in neonates.

Abstract: Reduced numbers of lymphocytes and antigen presenting cells have been described as some of the main factors responsible for antigenic tolerance or low responsiveness in neonates. However, by changing the parameters of immunization, such as dose of antigen and frequency of antigen presenting cells we and others have shown that neonates have the option of developing the same variety of immune responses seen in adults. Several aspects of the development of cellular immunity in human and murine neonates are reviewed in this article, with a special focus on the development of T cell mediated responses, from ontogeny to effector function.

Autoimmune response to the thyroid in humans: thyroid peroxidase--the common autoantigenic denominator.

Abstract: Autoimmunity to thyroid peroxidase (TPO), manifest as high affinity IgG class auto-antibodies, is the common denominator of human thyroid autoimmunity, encompassing patients with overt hyper-or hypothyroidism as well as euthyroid individuals with subclinical disease. The identification and cloning of TPO (the “thyroid microsomal antigen”) provided the critical tool for analyzing B and T cell reactivity to this major thyroid autoantigen. In particular, the availability of immunoreactive TPO permitted the isolation of essentially the entire repertoire of human monoclonal antibodies, a feat unparalled in an organ-specific autoimmune disease. These recombinant autoantibodies (expressed as Fab) provide insight into the genes encoding their H and L chains as well as the conformational epitopes on TPO with which serum autoantibodies interact. Analyses of TPO autoantibody epitopic “fingerprints” indicate a lack of epitope spreading as well as a genetic basis for their inheritance. Limited data are available for t...

Lupus Susceptibility Genes on Human Chromosome 1

Abstract: During the past five years, there has been an intense interest in studying candidate susceptibility genes for systemic lupus erythematosus (SLE). Many such studies have been focused on candidates located on chromosome 1, demonstrating association of certain genetic variants with SLE. Some of the tested candidate genes were chosen because they encode molecules with relevant immunological functions that may play a role in the pathogenesis of SLE. More recently, the identification of genomic segments linked to SLE has suggested novel positional candidate genes. Thus far, there is considerable evidence supporting that multiple genes on this chromosome contribute to the development and expression of SLE. This review highlights the genetic loci located on chromosome 1 that have recently been associated with SLE. These include loci encoding the tumor necrosis factor receptor 2 (TNFR2), complement component C1q, Fcgamma receptors, T cell receptor zeta chain, interleukin-10 (IL-10), poly (ADP-ribose) polymerase (PARP), and HRES-1.

Lessons from BXSB and related mouse models

Abstract: The BXSB murine strain spontaneously develops an autoimmune syndrome with features of systemic lupus erythematosus (SLE) that affects males much earlier than females, due to the presence of an as yet unidentified mutant gene located on its Y chromosome, designated Yaa (Y-linked autoimmune acceleration). The Yaa gene by itself is unable to induce significant autoimmune responses in mice without an apparent SLE background, while it can induce and accelerate the development of an SLE in combination with autosomal susceptibility alleles present in lupus-prone mice. Although the genes encoded within or closely linked to the MHC locus play an important role in the development or protection of SLE, the MHC effect can be completely masked by the presence of the Yaa gene in mice highly predisposed to SLE. The role of the Yaa gene for the acceleration of SLE is apparently two-fold; it enhances overall autoimmune responses against autoantigens to which mice respond relatively weakly, and promotes Th 1 responses against autoantigens to which mice respond relatively well, leading to the production of more pathogenic autoantibodies, i.e., FcgammaR-fixing IgG2a and cryoglobulin IgG3 autoantibodies. Yaa+ - Yaa- double bone marrow chimera experiments revealed that the Yaa defect is expressed in B cells, but not in T cells, and that T cells from non-autoimmune mice are capable of providing help for autoimmune responses by collaborating Yaa+ B cells. We speculate that the Yaa defect may decrease the threshold for antigen receptor-dependent stimulation, leading to the triggering and excessive stimulation of autoreactive T and B cells.

Spontaneous Chronic Colitis in TCRα-Mutant Mice; an Experimental Model of Human Ulcerative Colitis

Abstract: Mice with targeted disruption of the T cell receptor α gene (TCRα-/-) spontaneously develop chronic colitis. Colonic inflammation begins at 6–8 weeks of age and chronic colitis is established in about 60% of mice by 16–20 weeks of age. The disease is also associated with autoantibodies (anti-tropomyosin antibodies, anti-neutrophil cytoplasmic antibodies) and an oligoclonal immune response to luminal bacterial antigens. Although T cells, but not B cells or autoantibodies, are essential for the development of colitis, B cells and/or autoantibodies may have a regulatory role in the pathogenesis of this colitis because the colitis is more severe in B cell deficient TCRα-/- mice. Cytokines, specifically IL-4 and IL-1, also play an important role in the development of colitis in TCRα-/- mice. Enteric bacteria located in the large intestine are an important factor in the pathogenesis of this colitis because germ-free TCRα-/- mice do not develop colitis and appendectomy at an early age delays the onset of this co...

Newer Insights into the Pathogenesis of Experimental Autoimmune Thyroiditis

Abstract: Experimental autoimmune thyroiditis (EAT), produced in the mouse by immunization with murine thyroglobulin plus complete Freund's adjuvant, represents a valuable model for studying the pathogenesis of human chronic (Hashimoto's) thyroiditis. A major issue requiring clarification is the difference between benign autoimmunity, characterized solely by production of autoantibodies to thyroglobulin, and pathogenic autoimmunity where injury occurs to the thyroid cells. In this article, we describe the role of two key cytokines, IL12 and IFNγ, in modifying the pathogenic immune response. EAT, defined by cellular infiltration of the thyroid and the development of thyroglobulin-specific autoantibodies, is a dynamic process. Consequently, a cytokine may exert a different effect at different times during the disease process. For purposes of discussion, we propose that there are three stages in the development of EAT: priming; initiation; and progression. Administration of anti-IL12 during the priming stage and initi...

Lessons from the NZM2410 Model and Related Strains

Abstract: SLE susceptibility requires the interplay of an unknown number of genes and equally unidentified triggering events. The past few years have seen significant advances in our understanding of SLE susceptibility through the genetic analysis of murine models. The NZM2410 strain, which is derived from the NZB/WF1 model has played a significant role in these advances. The main advantages presented by this strain over other models are the genetic homozygozity at all loci and an highly penetrant early onset lupus nephritis in both males and females, indicating that the strongest BWFj susceptibility loci were retained in NZM2410. After identification of NZM2410 susceptibility loci via linkage analyses, congenic strains have been derived in order to convert a polygenic system into a series of monogenic traits. These congenic strains have been analyzed in an integrated process which has provided simultaneously 1) novel functional characterization of the Sle susceptibility loci, 2) high resolution genetic maps that w...

The C3H/HeJBir Mouse Model: A High Susceptibility Phenotype for Colitis

Abstract: C3H/HeJBir is a substrain of C3H/HeJ mice that was generated by selective breeding for the phenotype of spontaneous colitis. These mice show increased B cell and T cell reactivity to antigens of the enteric bacterial flora. CD4+ T cells from this strain cause colitis, when activated by enteric bacterial antigens and transferred to histocompatible severe combined immunodeficient recipients. The expression of the disease phenotype of spontaneous colitis is greatly influenced by housing conditions and probably requires an immunostimulatory enteric flora. This strain seems to carry multiple susceptibility genes for colitis as does the parental C3H/HeJ strain; the genes involved are being mapped. This strain represents a high susceptibility phenotype for colitis that is providing insight into the interactions among immune, environmental and genetic factors that can result in IBD.

Graves’ Disease: A Host Defense Mechanism Gone Awry

Abstract: In this report we summarize evidence to support a model for the development of Graves' disease. The model suggests that Graves' disease is initiated by an insult to the thyrocyte in an individual with a normal immune system. The insult, infectious or otherwise, causes double strand DNA or RNA to enter the cytoplasm of the cell. This causes abnormal expression of major histocompatibility (MHC) class I as a dominant feature, but also aberrant expression of MHC class II, as well as changes in genes or gene products needed for the thyrocyte to become an antigen presenting cell (APC). These include increased expression of proteasome processing proteins (LMP2), transporters of antigen peptides (TAP), invariant chain (Ii), HLA-DM, and the co-stimulatory molecule, B7, as well as STAT and NF-kappaB activation. A critical factor in these changes is the loss of normal negative regulation of MHC class I, class II, and thyrotropin receptor (TSHR) gene expression, which is necessary to maintain self-tolerance during the normal changes in gene expression involved in hormonally-increased growth and function of the cell. Self-tolerance to the TSHR is maintained in normals because there is a population of CD8- cells which normally suppresses a population of CD4+ cells that can interact with the TSHR if thyrocytes become APCs. This is a host self-defense mechanism that we hypothesize leads to autoimmune disease in persons, for example, with a specific viral infection, a genetic predisposition, or even, possibly, a TSHR polymorphism. The model is suggested to be important to explain the development of other autoimmune diseases including systemic lupus or diabetes.

Colitis in HLA-B27/β2 Microglobulin Transgenic Rats

Abstract: Rats of susceptible genetic backgrounds expressing high copy numbers of the transgene encoding HLA-B27 and human beta 2 mu develop chronic colitis complicated in the advanced stage by adenomatous polyps progressing to adenocarcinoma. Unique features of this model include a spectrum of extraintestinal manifestations resembling to some extent human spondyloarthropathy, with peripheral and axial joint, dermatologic and male genital inflammation. Inflammation is T lymphocyte mediated, although surprisingly CD4+ cells are more active in transferring disease than CD8+ cells, which would be expected to be preferentially activated by Class I MHC peptides. Inflammation is dependent on a nonlymphoid bone marrow-derived cell, expressing high copy numbers of B27, probably APCs. In vitro function of transgenic dendritic cells is deficient, and in vivo competition for peptide binding in the antigen binding site of B27 attenuates arthritis. Normal bacteria are required for disease expression, with B. vulgatus preferentially able to induce colitis, whereas other bacteria such as E. coli stimulate no inflammatory response. Inflammation and resulted complications are modulated by non-MHC genes and are amenable to treatment by bone marrow transplant from normal donors. These results support the hypothesis that gastrointestinal and systemic inflammation in B27 transgenic rats is the result of loss of tolerance to enteric bacteria, as a consequence of defective APC (? dendritic cells) function. Whether disease is the result of selective MHC binding of enteric antigens uniquely capable of inducing disease, lack of appropriate induction of a CD8+ suppressor cell population, or skewed cytokine (IL-12, IL-18) secretion by APCs remains to be determined.

A role for MHC class II antigen processing in B cell development

Abstract: For mature B cells, the encounter with foreign antigen results in the selective expansion of the cells and their differentiation into antibody secreting cells or memory B cells. The response of mature B cells to antigen requires not only antigen binding to and signaling through the B cell antigen receptor (BCR) but also the processing and presentation of the BCR bound antigen to helper T cells. Thus, in mature B cells, the ability to process and present antigen to helper T cells plays a critical role in determining the outcome of antigen encounter. In immature B cells, the binding of antigen results in negative selection of the B cell, inducing apoptosis, anergy or receptor editing. Negative selection of immature B cells requires antigen induced signaling through the BCR, analogous to the signaling function of the BCR in mature B cells. However, the role of class II antigen processing and presentation in immature B cells is less well understood. Current evidence indicates that the ability to process and p...

DNA vaccination and the immune responsiveness of neonates.

Abstract: Neonates often respond poorly to conventional vaccines or microbial infections. Immaturity of the immune system has been considered to play a role in this regard. However, accumulating evidence shows that in certain conditions, neonatal inoculation of antigens leads to protective immunity. In the particular case of DNA vaccines administered to neonates, the rule is immunity rather than tolerance. Exceptions to the rule give opportunities to further understand the neonatal responsiveness and the mechanism of DNA vaccination. Due to the very nature of the vaccine vector, inhibition of neonatal DNA vaccination by maternal antibodies may be limited to the humoral immunity.

Adoptive transfer murine model of granulomatous experimental autoimmune thyroiditis

Abstract: Experimental autoimmune thyroiditis (EAT) is a chronic inflammatory autoimmune disease that can be induced in genetically susceptible animals by immunization with mouse thyroglobulin (MTg) in an appropriate adjuvant or by the adoptive transfer of MTg-sensitized donor spleen cells, activated in vitro with MTg, into naive recipients. In the adoptive transfer model used in our laboratory, donor cells activated with MTg alone induce a relatively mild chronic lymphocytic form of EAT (L-EAT), in which the thyroid infiltrate consists primarily of mononuclear cells, and the thyroid inflammation persists for several months. When the same donor cells are activated with MTg together with anti-IL-2R and/or IL-12, a more severe and histologically distinct granulomatous form of EAT is induced in recipient mice. In addition to having distinct histopathologic features, granulomatous EAT (G-EAT) differs from L-EAT in that granulomatous thyroid lesions are not chronic. After reaching maximal severity 21 days after cell transfer, G-EAT thyroid lesions either resolve or the thyroids become atrophic and fibrotic by day 35. In this review, the histopathologic features of G-EAT and L-EAT are described, and our studies with the adoptive transfer G-EAT model which have focused on the mechanisms involved in induction of G-EAT in mice, and the evolution of G-EAT lesions to resolution of inflammation or fibrosis, are reviewed.

Pathogenic thyroglobulin peptides as model antigens: insights on the induction and maintenance of autoimmune thyroiditis.

Abstract: In recent years, the discovery of pathogenic thyroglobulin (Tg) peptides has given a new impetus to study, at the basic level, mechanisms of induction and immunoregulation of autoimmune thyroiditis The genetic control of the immune response against defined Tg epitopes and the diversity of the T-cell receptor repertoire recruited for their recognition were among the first issues examined Some of these epitopes contained hormonogenic sites, ie thyroxine residues, and thus offered an excellent opportunity to study how post-translational modifications such as iodination, can influence induction of thyroiditogenic cells The delineation of pathogenic Tg determinants also enabled the search for “molecular mimics” ie peptides of microbial origin that may be involved in the pathogenesis of the disease In addition, factors promoting the generation of pathogenic epitopes during Tg processing in antigen presenting cells could now be systematically investigated This review summarizes recent findings in these

Genetic aspects of inherent B-cell abnormalities associated with SLE and B-cell malignancy: lessons from New Zealand mouse models.

Abstract: Genes that predispose to SLE are closely related to key events in pathogenesis of this disease. As much of the pathology can be attributed to high affinity autoantibodies and/or their immune complexes, some of the genes may exert effects in the process of emergence, escape from tolerance mechanisms, activation, clonal expansion, differentiation, class switching and affinity maturation of self-reactive B cells. A number of growth and differentiation factors and signaling molecules, including positive and negative regulators, are involved in this process. Genetic variations associated with functional deficits in some of such molecules can be involved in the susceptibility for SLE. As is the case with SLE, hereditary factors play significant roles in the pathogenesis of B cell chronic lymphocytic leukemia (B-CLL). Patients with B-CLL or their family members frequently have immunological abnormalities, including those associated with SLE. It is suggested that certain genetically determined regulatory abnormal...

A novel mouse model of Graves' disease: implications for a role of aberrant MHC class II expression in its pathogenesis.

Abstract: Mice immunized with fibroblasts expressing an MHC class II molecule and human thyrotropin receptor (TSHR), but not either alone, develop major features characteristic of Graves’ disease (GD), such as thyroid-stimulating autoantibodies directed against TSHR, increased serum thyroid hormone levels, and enlarged thyroid glands. The results indicate the need for the simultaneous expression of a class II molecule and the TSHR on the surface of the fibroblasts to develop stimulating anti-TSHR antibodies and fullblown GD in our model. A T cell line established from a mouse with hyperthyroidism proliferates in response to fibroblasts expressing a class II molecule and TSHR, but not to the fibroblasts expressing only TSHR, indicating that the class II molecules on the fibroblasts present TSHR-derived peptide(s) to T cells. These results strongly suggest that the acquisition of antigen-presenting ability by thyrocytes can lead to the induction or progression of GD. We identified a T cell epitope of TSHR by the prol...

Genetic Studies of Human Lupus in Families

Abstract: Systemic lupus erythematosus (SLE) is a complex multigenic disease in which the contributing genetic systems are being rapidly identified. Most of the currently recognized genes have been discovered from case-control association studies, but, increasingly, family linkage studies are being employed to confirm previous genetic associations, to examine their relative contributions, and to identify new susceptibility loci. Most of the loci identified thus far appear to contribute only modest effects on susceptibility overall but rather influence more strongly disease expression and/or severity. MHC class II alleles, for example, seem to show only weak linkage to SLE itself but instead mediate specific T cell driven pathogenic autoantibodies which produce many of the clinical disease features, similar to their effects in many other autoimmune diseases. On the other hand, complete and partial hereditary deficiencies of early complement components are more lupus-specific. Homozygous complement deficiencies, whil...

Neonatal Tolerant Immunity for Vaccination against Autoimmunity

Abstract: Autoimmunity arises when the immune system no longer tolerates self and precipitates lymphocyte reactivity against our own antigens. Although the developing T cell repertoire is constantly purging, self-recognition events do exist when such tight control is evaded and autoreactive lymphocytes escape the thymus (the sites of T cell development) and migrate to the periphery. Upon activation these autoreactive cells may exert aggressive behavior toward one's own tissues and organs leading to autoimmune disease. Multiple sclerosis, Rheumatoid arthritis, and type I diabetes are autoimmune diseases mediated by autoreactive T cells. A logical approach to prevent such autoimmunity would be to reprogram those lymphocytes to tolerate the self antigen. Injection of antigen at the neonatal stage promotes a state of tolerance such that successive encounter with antigen does not precipitate aggressive reactions. The mechanism underlying neonatal tolerance involves priming of T cells whose effector functions do not cause inflammatory reactions upon recognition of antigen but rather induce protective immunity. This form of tolerant immunity provides an attractive strategy for vaccination against autoimmunity. Herein, it is shown that neonatal exposure to a self-peptide-immunoglobulin chimera drives a tolerant immunity toward the self-peptide and protects against the autoimmune disease, experimental allergic encephalomyelitis.

Preface and overview: genetics of SLE; a sine qua non for identification.

Abstract: Clinical manifestations of systemic lupus erythematosus (SLE) are extremely diverse and variable, mainly because SLE is a multi-factorial disease. Variable combinations of contributing genes at multiple loci in individual patients probably result in diverse disease phenotypes. Genes that predispose to SLE are undoubtedly related to key events in pathogenesis, and may involve a variety of genes in immune system. These genes are currently unidentified, mostly because of the complexity of multi-factorial inheritance. Recently, the application of the polymerase chain reaction and the availability of maps of microsatellites have facilitated a genome-wide scan to define the number and locations of genes for complex traits. However, extensive genetic heterogeneities and polymorphisms and complex modes of inheritance of disease phenotypes have delayed completion of a genome-wide analysis of susceptibility loci for human SLE. Since many SLE-susceptibility genes show low penetrance, several hundred affected sibpair...

Pathways of T cell pathology in models of chronic intestinal inflammation.

Abstract: The prominence of the immune system within the intestinal mucosa of the small and large bowel testifies to the importance of these organs as major sites of entry for pathogenic organisms. At the same time immune responses might equally be elicited to dietary antigens and commensal bacteria, yet it is only rarely that this appears to happen, demonstrating the tight regulation to which immune responses within the gastrointestinal (GI) tract are normally subject. Human inflammatory bowel diseases (IBD) arise from disturbances in immuno-regulation, appearing as seemingly spontaneous inflammation of the intestinal mucosa. Although some evidence exists for infectious etiology in IBD [I] evidence pointing towards a noninfectious component is plentiful, yet the initiating factors and the

Neonatal immunity and somatic mutation.

Abstract: Neonatal animals are able to mount an effective immune response, both humoral and cellular, when immunized using conditions that maximize stimulation of antigen presenting cells, T cells, and B cells. In adults, somatic mutation is a key feature of the humoral immune response because it contributes to the generation of high affinity memory B cells. Recent evidence that B cells in neonatal mice and human infants can somatically mutate their immunoglobulin heavy chains suggests that neonates can utilize somatic mutation not only to diversify their restricted germline antibody repertoire, but also to improve upon this repertoire by the generation of B cells which can produce higher affinity antibodies. By extrapolation, if vaccination of children early in life resulted in somatic mutation and affinity maturation, this could provide a more protective antibody response to childhood diseases.

Genetic basis of the complex pathological manifestations of collagen disease: lessons from MRL/lpr and related mouse models.

Abstract: The pathological findings in collagen disease including systemic lupus erythematosus show complex lesions such as glomerulonephritis, systemic vasculitis, polyarthritis, sialoadenitis, etc. Moreover, some cases of collagen disease are categorized into overlapping syndromes. It is still controversial whether such diversity and similarity of pathological manifestations among the collagen disease depends on ambiguity in diagnosis or is an intrinsic quality of the collagen diseases themselves. In this paper, we reviewed this subject focusing on a series of our genetic studies of murine models of collagen disease, MRL strains of mice with a deficit in Fas-mediated apoptosis, which spontaneously develop glomerulonephritis, systemic vasculitis, polyarthritis and sialoadenitis. We observed that each lesion was controlled by a different set of genes and they appeared to act in an additve manner on the development of each lesion. We conclude that various disease categories in collagen disease will be a result of th...

New revelations in susceptibility to autoimmune thyroiditis by the use of H2 and HLA class II transgenic models.

Abstract: H2 and HLA transgenes were utilized to clarify the role of class II genes in susceptibility to experimental autoimmune thyroiditis (EAT), a model for Hashimoto's thyroiditis (HT). Susceptibility was transferred by H2 class II transgenes to a resistant haplotype and by HLA-DRA/DRB1*0301 (DR3) transgene into class II-negative Ab0 mice. Mice with a HLA-DRB1*1502 (DR2) transgene remain resistant to mouse thyroglobulin (mTg)-induced EAT, illustrating the role of HLA-DRB1 polymorphism. A role for HLA-DQ polymorphism was shown with hTg-induced EAT in HLA-DQ*0301/DQB1*0302 (DQ8), but not HLA-DQ*0103/DQB1*0601 (DQ6), transgenic mice. Yet, both DQ8+ and DQ6+ mice were unresponsive to mTg. Single transgenes obviate the problems from DR/DQ linkage disequilibrium and may distinguish the degree of susceptibility and the response to shared or specific epitopes. The introduction of conserved Eak transgene into Ab0 mice reveals a new role for H2E molecules in EAT. Without H2A molecules, EalphaEbetab molecules and T cells respond to hTg or pTg with severe thyroiditis, but not to mTg, thus distinguishing self from nonself. However, IAb genes in resistant mice ameliorate Eak transgene-mediated thyroiditis, similar to the effect of Eak transgene on IAs-mediated EAT. Studies in HLA DQ/DR double transgenic mice simulating human haplotypes could reveal HLA class II gene interactions in HT.

The development of animal models of inflammatory bowel disease.

Abstract: The inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), are a set of intestinal disorders characterized by chronic inflammation leading to the symptoms of abdominal pain, diarrhea, rectal bleeding and occasionally obstruction. These diseases are associated with an increased incidence of intestinal malignancy (UC>CD) and the incidence of surgical intervention as a treatment modality is quite high (especially in CD). The mainstay of therapy has been non-specific anti-inflammatory agents such as 5-aminosalicylic acid compounds and steroids. As a growing awareness of the role that the mucosal immune response plays in the pathogenesis of CD and UC has been recognized, a number that additional immunomodulatory agents have entered the therapeutic armamentarium. It is truly over the past decade that a better understanding of these diseases has been achieved. The fortuitous development of a number of animal models

Practical approaches to determining disease-susceptible loci in multigenic autoimmune models.

Abstract: Linkage analysis using polymorphic DNA markers has paved the way toward the identification of genes responsible for rare recessive traits and for the susceptibility to certain tumors in humans. However, genetic susceptibility to common diseases, including systemic autoimmune diseases, is difficult to determine, hence has remained a challenging problem in the field of molecular genetics. Elucidation of multiple quantitative trait loci that predispose individuals to multi-phenotypic systemic autoimmune disease requires formidable research efforts, and there is a growing consensus that mouse models are required. This review provides a guide to methods that can be used in linkage studies of autoimmune mice. Mouse studies in relation to recent advances in bio-informatics are also discussed.