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J Goverman

Publications and source records attributed to J Goverman.

At least 19 recordsLinked to original sources
PubMed2001

Rag-1-dependent cells are necessary for 1,25-dihydroxyvitamin D(3) prevention of experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a demyelinating disease involving genetic and environmental risk factors. Geographic, genetic, and biological evidence suggests that one environmental risk factor may be lack of vitamin D. Here, we investigated how 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) inhibits experimental autoimmune encephalomyelitis (EAE), an MS model. The experiments used adoptive transfer of TCR-transgenic (TCR1) cells specific for myelin basic protein (MBP) peptide into unprimed recipients. When unprimed TCR1 splenocytes were transferred, and the recipients were immunized with peptide, the mock-treated mice developed EAE, but the 1,25-(OH)(2)D(3)-treated recipients remained disease-free. Both groups had TCR1 T cells that proliferated in response to MBP Ac1-11 and produced IFN-gamma but not IL-4 in the lymph node. In the central nervous system (CNS), the mock-treated mice had activated TCR1 T cells that produced IFN-gamma but not IL-4, while the 1,25-(OH)(2)D(3)-treated mice had TCR1 T cells with a non-activated phenotype that did not produce IFN-gamma or IL-4. When activated TCR1 T cells producing IFN-gamma were transferred into unprimed mice, the mock-treated and the 1,25-(OH)(2)D(3)-treated recipients developed EAE. Likewise, the 1,25-(OH)(2)D(3) did not inhibit Th1 cell IFN-gamma production or promote Th2 cell genesis or IL-4 production in vitro. Finally, the 1,25-(OH)(2)D(3) inhibited EAE in MBP-specific TCR-transgenic mice that were Rag-1(+), but not in animals that were Rag-1-null. Together, these data refute the hypothesis that the hormone inhibits Th1 cell genesis or function directly or through an action on antigen-presenting cells, or promotes Th2 cell genesis or function. Instead, the evidence supports a model wherein the 1,25-(OH)(2)D(3) acts through a Rag-1-dependent cell to limit the occurrence of activated, autoreactive T cells in the CNS.

Animals↗
PubMed2001

A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) characterized by plaques of infiltrating CD4(+) and CD8(+) T cells. Studies of MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS, focus on the contribution of CD4(+) myelin-specific T cells. The role of CD8(+) myelin-specific T cells in mediating EAE or MS has not been described previously. Here, we demonstrate that myelin-specific CD8(+) T cells induce severe CNS autoimmunity in mice. The pathology and clinical symptoms in CD8(+) T cell-mediated CNS autoimmunity demonstrate similarities to MS not seen in myelin-specific CD4(+) T cell-mediated EAE. These data suggest that myelin-specific CD8(+) T cells could function as effector cells in the pathogenesis of MS.

Adoptive Transfer↗
PubMed2001

Rapid depletion of peripheral antigen-specific T cells in TCR-transgenic mice after oral administration of myelin basic protein.

In myelin basic protein (MBP)-specific TCR-transgenic (Tg) mice, peripheral T cells express the Valpha2.3/Vbeta8.2-Tg TCR, demonstrate vigorous proliferative responses to MBP in vitro, and can exhibit experimental autoimmune encephalomyelitis (EAE) within 5 days of pertussis toxin injection. We explored the effects of oral administration of MBP on the cellular trafficking of the MBP-specific TCR-Tg cells and the ability of oral MBP to protect Tg mice from EAE. Tg mice were fed MBP, OVA or vehicle and sacrificed at various times after feeding. An immediate and dramatic decrease in Valpha2.3/Vbeta8.2(+)-Tg cells was observed in the periphery within 1 h after feeding. By 3 days after feeding, the percentage of Tg cells increased to near control levels, but decreased again by 10 days. When MBP or vehicle-fed Tg mice were challenged for EAE at this point, disease was severe in the vehicle-fed mice and reduced in the MBP-fed mice over the 40-day observation period. In vitro studies revealed a biphasic pattern of MBP proliferative unresponsiveness and an induction of Th1 cytokines. Immunohistochemical staining showed that the number of Tg cells found in the intestinal lamina propria increased dramatically as the number of Tg cells in the periphery decreased. There was no apparent proliferation of Tg cells in the lamina propria, indicating that Tg cells trafficked there from the periphery. Taken together, these results suggest that T cell trafficking into the site of Ag deposition acts to protect the TCR-Tg mouse from EAE.

Animals↗
PubMed2001

Age-dependent T cell tolerance and autoimmunity to myelin basic protein.

Experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, is induced by activating a subset of myelin basic protein (MBP)-specific T cells that have escaped tolerance induction. Here, we define the tolerance mechanisms that eliminate the majority of MBP-specific T cells from the periphery. We show that MBP-specific T cells undergo central tolerance mediated by bone marrow-derived antigen-presenting cells presenting exogenously derived MBP epitopes. The efficiency of tolerance is age dependent, reflecting the developmentally regulated expression of MBP. Dependence of tolerance on the amount of MBP expressed in vivo results in an age window of susceptibility to EAE in mice that peaks during puberty. These results suggest that factors regulating expression of self-antigens in vivo can influence susceptibility to autoimmunity.

Aging↗
PubMed2000

In situ tolerance within the central nervous system as a mechanism for preventing autoimmunity.

Multiple sclerosis (MS) is believed to be an autoimmune disease in which autoreactive T cells infiltrate the central nervous system (CNS). Animal models of MS have shown that CNS-specific T cells are present in the peripheral T cell repertoire of healthy mice and cause autoimmune disease only when they are activated by immunization. T cell entry into the CNS is thought to require some form of peripheral activation because the blood-brain barrier prohibits trafficking of this tissue by naive cells. We report here that naive T cells can traffic to the CNS without prior activation. Comparable numbers of T cells are found in the CNS of both healthy recombinase activating gene (Rag)(-/)- T cell receptor (TCR) transgenic mice and nontransgenic mice even when the transgenic TCR is specific for a CNS antigen. Transgenic T cells isolated from the CNS that are specific for non-CNS antigens are phenotypically naive and proliferate robustly to antigenic stimulation in vitro. Strikingly, transgenic T cells isolated from the CNS that are specific for myelin basic protein (MBP) are also primarily phenotypically naive but are unresponsive to antigenic stimulation in vitro. Mononuclear cells from the CNS of MBP TCR transgenic but not nontransgenic mice can suppress the response of peripheral MBP-specific T cells in vitro. These results indicate that naive MBP-specific T cells can traffic to the CNS but do not trigger autoimmunity because they undergo tolerance induction in situ.

Animals↗
PubMed2000

Scanning electron microscopy and X-ray diffraction studies in the analysis of medical materials: Gore-Tex versus braided polyester tape for repair of the incompetent cervix.

Cathodoluminescence in the scanning electron microscope and roentgenogram diffraction studies were applied to the analysis of two different medical materials used in cervical cerclage, the treatment of cervical incompetence. Braided polyester tape or Gore-Tex was used as suture material and was analyzed both before and after use in cerclage of the cervix. Results of SEM and X-ray diffraction studies showed distinct differences between the two materials, with the Gore-Tex demonstrating a superior morphological integrity and a decreased likelihood of phagocyte adhesion. These results correlated well with the clinical observations, which also showed Gore-Tex to be a superior medical material.

Female↗
PubMed1999

Cutting edge: myelin basic protein-specific cytotoxic T cell tolerance is maintained in vivo by a single dominant epitope in H-2k mice.

Multiple sclerosis (MS) is believed to be an autoimmune disease mediated by T cells specific for CNS Ags. MS lesions contain both CD4+ and CD8+ T lymphocytes. The contribution of CD4+ T cells to CNS autoimmune disease has been extensively studied in an animal model of MS, experimental autoimmune encephalomyelitis. However, little is known about the role of autoreactive CD8+ cytotoxic T cells in MS or experimental autoimmune encephalomyelitis. We demonstrate here that myelin basic protein (MBP) is processed in vivo by the MHC class I pathway leading to a MBP79-87/Kk complex. The recognition of this complex by MBP-specific cytotoxic T cells leads to a high degree of tolerance in vivo. This study is the first to show that the pool of self-reactive lymphocytes specific for MBP contain MHC class I-restricted T cells whose response is regulated in vivo by the induction of tolerance.

Alleles↗
PubMed1999

Highly cross-reactive T cell responses to myelin basic protein epitopes reveal a nonpredictable form of TCR degeneracy.

We identified two nonoverlapping epitopes in myelin basic protein presented by I-Au that are responsible for mediating tolerance induction to this self-Ag. A large number of T cells expressing diverse TCRs are strongly cross-reactive to both epitopes. Surprisingly, the TCR contact residues in each peptide are highly dissimilar. Furthermore, functional TCR contacts cannot be interchanged between the two epitopes, indicating that the TCR contacts in each peptide can only be recognized within the context of the other amino acids present in that peptide's sequence. This observation indicates that both buried and exposed residues of each peptide contribute to the sculpting of completely distinct antigenic surfaces. We propose that the cross-reactive TCRs adopt mutually exclusive conformations to recognize these dissimilar epitopes, adding a new dimension to TCR degeneracy. This unpredictable TCR plasticity indicates that using just the TCR contacts on a single epitope to define other cross-reactive peptides will identify only a subset of the complete repertoire of cross-reactive epitopes.

Amino Acid Sequence↗
PubMed1999

Selection of CD8+ T cells with highly focused specificity during viral persistence in the central nervous system.

The relationships between T cell populations during primary viral infection and persistence are poorly understood. Mice infected with the neurotropic JHMV strain of mouse hepatitis virus mount potent regional CTL responses that effectively reduce infectious virus; nevertheless, viral RNA persists in the central nervous system (CNS). To evaluate whether persistence influences Ag-specific CD8+ T cells, functional TCR diversity was studied in spleen and CNS-derived CTL populations based on differential recognition of variant peptides for the dominant nucleocapsid epitope. Increased specificity of peripheral CTL from persistently infected mice for the index epitope compared with immunized mice suggested T cell selection during persistence. This was confirmed with CD8+ T cell clones derived from the CNS of either acutely (CTLac) or persistently (CTLper) infected mice. Whereas CTLac clones recognized a broad diversity of amino acid substitutions, CTLper clones exhibited exquisite specificity for the wild-type sequence. Highly focused specificity was CD8 independent but correlated with longer complementarity-determining regions 3 characteristic of CTLper clonotypes despite limited TCR alpha/beta-chain heterogeneity. Direct ex vivo analysis of CNS-derived mononuclear cells by IFN-gamma enzyme-linked immunospot assay confirmed the selection of T cells with narrow Ag specificity during persistence at the population level. These data suggest that broadly reactive CTL during primary infection are capable of controlling potentially emerging mutations. By contrast, the predominance of CD8+ T cells with dramatically focused specificity during persistence at the site of infection and in the periphery supports selective pressure driven by persisting Ag.

Amino Acid Sequence↗
PubMed1999

Transducer user syndrome: an occupational hazard of the ultrasonographer.

Since no study to date has assessed the prevalence of scanning-related disorders amongst sonographers in Obstetrics and Gynecology, we distributed a survey to all trained personnel in our ultrasound division. We evaluated the correlation between injuries sustained in the workplace, and factors such as age, gender, work load and intensity, scanning techniques, previous medical problems, and physical activity. Injuries included one or more of the following: carpal tunnel syndrome; carpal instability; tendinitis; back, shoulder, and neck pain; tingling and/or numbness in the extremities; weakness; and motion restriction. Of the 44 respondents, 29 (65%) have experienced some type of injury or symptom over the course of their scanning career. Five (12%) reported having missed work because of their symptoms, 15 (34%) have received orthopedic treatment (medication or physiotherapy), two (4.5%) have been diagnosed with carpal tunnel syndrome, and one (2.3%) with carpal instability based on electrophysiological examinations. These results demonstrate that ultrasound scanning in Obstetrics and Gynecology may pose an occupational risk for doctors and technicians.

Adult↗
PubMed1999

Tolerance and autoimmunity in TCR transgenic mice specific for myelin basic protein.

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

Animals↗
PubMed1998

Differential tolerance is induced in T cells recognizing distinct epitopes of myelin basic protein.

Experimental allergic encephalomyelitis (EAE) is induced by T cell-mediated immunity to central nervous system antigens. In H-2u mice, EAE is mediated primarily by T cells specific for residues 1-11 of myelin basic protein (MBP). We demonstrate that differential tolerance to MBP1-11 versus epitopes in MBP121-150 is induced by expression of endogenous MBP, reflecting extreme differences in stability of peptide/MHC complexes. The diverse MBP121-150-specific TCR repertoire can be divided into three fine specificity groups. Two groups were identified in wild-type mice despite extensive tolerance, but the third group was not detected. Activated MBP121-150-specific T cells induce EAE in wild-type mice. Thus, encephalitogenic T cells that escape tolerance either recognize short-lived peptide/MHC complexes or express TCRs with unique specificities for stable complexes.

Animals↗
PubMed1998

A molecular map of T cell development.

Using a sensitive molecular marker for positive selection, the appearance of a particular functional TCR alpha chain sequence in cells from mice bearing a transgenic beta chain, we address several aspects of intrathymic T cell development. First, by examining specific TCR prior to and after maturation, we demonstrate how a restricted TCR repertoire is positively selected from a highly diverse immature TCR repertoire. Second, since this molecular marker is enriched in cells progressing toward the CD4 lineage and depleted in cells progressing toward the CD8 lineage, a map of the developmental pathway of alphabeta thymocytes can be inferred. Third, the first cells that show clear signs of positive intrathymic selection are identified.

Amino Acid Sequence↗
PubMed1997

Triggers of autoimmune disease in a murine TCR-transgenic model for multiple sclerosis.

The combination of genetic and environmental factors that contribute to human autoimmune responses has made potential triggers of these diseases difficult to identify. We examined how experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis, is triggered using TCR-transgenic mice specific for myelin basic protein (MBP). In these TCR-transgenic mice, EAE can be actively induced and also occurs spontaneously. The incidence of spontaneous EAE in this model is largely confined to adolescence and early adulthood and is more prevalent among males than females, indicating that hormonal influences may contribute to triggering central nervous system autoimmune disease. Disease induction studies show that not all stimuli that activate MBP-specific T cells in vivo also induce EAE. Immunization with MBP peptide stimulates the transgenic T cells to produce Th1 cytokines; however, the activated T cells do not accumulate in the central nervous system and induce EAE unless pertussis toxin is also administered. EAE can be induced by intrathecal injection of either stimulated or nonstimulated transgenic T cells into nontransgenic or transgenic recipients. Therefore, gaining access to the central nervous system appears to be the critical step in this model for the induction of EAE, regardless of the activation state of the T cells.

Animals↗
PubMed1997

Thymic stromal organization is regulated by the specificity of T cell receptor/major histocompatibility complex interactions.

The thymic architecture is normally compartmentalized into a central medulla surrounded by a peripheral cortical region. We investigated how compartmentalization of the thymic stroma is regulated using T cell receptor (TCR)-transgenic mouse models. Our studies show that the signals generated by TCR/peptide/major histocompatibility complex interactions regulate thymic stromal cell compartmentalization. In TCR-transgenic mice, normal stromal cell compartmentalization occurs when the transgenic TCR is expressed on a background that does not result in skewing toward either positive or negative selection. In models representing strong positive selection, the thymic stromal elements do not fully organize into a central medulla. Instead, small medullary foci are dispersed throughout the thymus with some regions residing directly under the capsule. The highest degree of disorganization in medullary epithelial regions is observed in TCR-transgenic mice that exhibit negative selection. Although the medullary foci lack central organization, the expression in these regions of CD80, CD86 and CD40, as well as the clustering of dendritic cells, is similar to that observed in medullae of wild-type mice. Thus, the organization of the medulla appears to occur in two stages: (1) small medullary epithelial regions that are dispersed in fetal thymi expand and associate with antigen-presenting cells, and (2) the expanded medullary foci organize into a central medullary compartment. Our data suggest a model in which this second stage of stromal cell organization is increasingly inhibited as the normal balance of TCR-mediated signals is skewed by higher-avidity interactions between thymocytes and antigen-presenting cells.

Animals↗
PubMed1997

Separately expressed T cell receptor alpha and beta chain transgenes exert opposite effects on T cell differentiation and neoplastic transformation.

Two aspects of T cell differentiation in T cell receptor (TCR)-transgenic mice, the generation of an unusual population of CD4-CD8-TCR+ thymocytes and the absence of gamma delta cells, have been the focus of extensive investigation. To examine the basis for these phenomena, we investigated the effects of separate expression of a transgenic TCR alpha chain and a transgenic TCR beta chain on thymocyte differentiation. Our data indicate that expression of a transgenic TCR alpha chain causes thymocytes to differentiate into a CD4-CD8-TCR+ lineage at an early developmental stage, depleting the number of thymocytes that differentiate into the alpha beta lineage. Surprisingly, expression of the TCR alpha chain transgene is also associated with the development of T cell lymphosarcoma. In contrast, expression of the transgenic TCR beta chain causes immature T cells to accelerate differentiation into the alpha beta lineage and thus inhibits the generation of gamma delta cells. Our observations provide a model for understanding T cell differentiation in TCR-transgenic mice.

Animals↗