Self-tolerance Mechanisms Research Articles

Hematopoietic Stem Cell-Based Therapy for HIV Disease: A Role for Regulatory T Cells

The goal of this review is to develop insight and understanding of the effect of deleting the chemokine receptor CCR5 in T cells, and its interplay with immune regulation of Human Immunodeficiency Virus type–1 (HIV-1), to enable a novel technology platform to cure HIV disease. A critical point is the use Hematopoietic Stem Cell (HSC) transplantation of the cells resistant to HIV such as CCR5Δ32 cells, which harbor deletion in the CCR5 promoter. Such mutations, which spontaneously occur in 4-15% of the European or US populations confer resistance to CCR5-tropic HIV-1 in homozygous individuals and could cure HIV-1 disease based on the outcome of bone marrow engraftment in HIV+ leukemic patients using a CCR5Δ32 homozygous donor (e.g. ‘Berlin Patient’). However, potential shift of HIV tropism to CXCR-4 tropic strains of HIV-1 is limiting after HSC transplantation with CCR5Δ32/Δ32 donor since it could lead to recurrence of viremia (e.g. ‘Essen patient’). In addition, patients receiving allogeneic bone marrow transplantation often suffer from Graft-Versus-Host Disease (GvHD), and for that reason HIV infection is not considered an indication, unless a hematologic malignancy warrants transplantation. To advance this field, it is, however, vital i) to search for novel determinants to HIV susceptibility using genome-wide analyses and ii) exploit mechanisms, which play a crucial role in amelioration of GvHD such as repression of conventional CD4+ T cells (Tcons) by naturally occurring regulatory CD4+CD25+ T cells (nTregs). Transfer of cyclic AMP (cAMP) from nTregs to Tcons underpins function of potent transcriptional repressor termed inducible cAMP early repressor (ICER) leading to suppression of interleukin-2 (IL-2) synthesis in Tcons. Further understanding of the mechanisms of immunological self-tolerance will also provide insights into how strong immune responses such as graft rejection could be restrained and engraftment of HIV resistant cells in HIV+ leukemic patients could be augmented.

Effector B cells in autoimmune diseases

The advent of B-cell targeted agents has prompted reappraisal of the role of B cells in the pathogenesis of autoimmune diseases (AID). Most notably, pathogenic B cells not only are the source of antibodies but also function as potent effectors mainly via antigen presentation and costimulation, and release of pro-inflammatory cytokines. Along with recent findings showing the existence of regulatory B cells, the role of B cells in AID seems more complicated than previously thought. Autoreactive B cells normally remain innocuous by the multi-layered mechanisms of self-tolerance during ontogeny. Disruption of these mechanisms, however, leads to the development of AID, where pathogenic effector B cells are enriched in particular B cell subsets. Given risk/benefit considerations, a novel strategy to selectively target the function of effector B cells would be more preferable than the nonselective B-cell depletion achieved by anti-CD20 therapy in AID.

Annexin1 regulates DC efferocytosis and cross-presentation during Mycobacterium tuberculosis infection.

The phagocytosis of apoptotic cells and associated vesicles (efferocytosis) by DCs is an important mechanism for both self tolerance and host defense. Although some of the engulfment ligands involved in efferocytosis have been identified and studied in vitro, the contributions of these ligands in vivo remain ill defined. Here, we determined that during Mycobacterium tuberculosis (Mtb) infection, the engulfment ligand annexin1 is an important mediator in DC cross-presentation that increases efferocytosis in DCs and intrinsically enhances the capacity of the DC antigen-presenting machinery. Annexin1-deficient mice were highly susceptible to Mtb infection and showed an impaired Mtb antigen-specific CD8+ T cell response. Importantly, annexin1 expression was greatly downregulated in Mtb-infected human blood monocyte-derived DCs, indicating that reduction of annexin1 is a critical mechanism for immune evasion by Mtb. Collectively, these data indicate that annexin1 is essential in immunity to Mtb infection and mediates the power of DC efferocytosis and cross-presentation.

Natural Killer Cells Adapt to Major Histocompatibility Complex: Implications for Hematopoietic Cell Transplantation

Natural Killer (NK) cells play several important roles in hematopoietic cell transplantation. Host NK cells can reject allogeneic transplants that lack major histocompatibility complex (MHC) molecules of the host (so-called “missing self” reactivity), whereas donor NK cells in the marrow can promote engraftment, inhibit graft versus host disease, and mediate rejection of host leukemic cells (graft versus tumor (GVT) response). Like T cells, NK cells can distinguish allogeneic cells from self-cells, and “learn” self vs. non-self so as to establish self-tolerance. This presentation will summarize current understanding of some of these processes based primarily on studies in mice, and present new data that may be relevant for the success of human bone marrow transplantation. The self-tolerance of T cells and B cells is established in large part by developmental processes that either remove or suppress self-reactive clones as the cells differentiate from hematopoietic stem cells. Studies will be presented that show that NK cell self-tolerance is regulated quite differently, by an adaptation process that occurs quite rapidly and acts on mature NK cells. NK cell reactivity against susceptible untransformed cells (e.g., cells from animals lacking MHC of the NK cell donor) is rapidly lost after transfer of such NK cells to susceptible hosts, indicating that self-tolerance is an adaptation that occurs rapidly under non-inflammatory conditions. Irradiation chimeras were employed to identify the cell types that induce tolerance of NK cells to cells from MHC-deficient mice, as one model of missing self-recognition. Stable tolerance of wild type NK cells to MHC-deficient cells was established when NK cells were exposed in chimeras to either MHC-deficient hematopoietic cells or MHC-deficient non-hematopoietic cells. Interestingly, however, tolerance induced by exposure solely to MHC-deficient hematopoietic cells was unstable in the face of inflammatory conditions arising from infections or exposures to inflammatory cytokines in vivo. Specifically, mixed chimeras consisting of WT and MHC-deficient hematopoietic cells in WT hosts were stably chimeric until the mice were exposed to viral or bacterial infections, at which time the MHC-deficient cells were rapidly eliminated. In contrast, tolerance induced by non-hematopoietic cells was much more stable. Specifically, mixed chimeras consisting of WT and MHC-deficient hematopoietic cells in MHC-deficient hosts were stably chimeric whether or not they underwent infections. These findings suggest that tolerance may be imposed by multiple mechanisms depending on the cell types that induce tolerance, with distinct properties as a result. Most importantly from a clinical perspective, the results suggest that depending on the host/donor combination, intense infections may jeopardize the stability of bone marrow transplants. Previous studies have shown that tolerance of NK cells to MHC-deficient cells is accompanied by a state of hyporesponsiveness of the NK cells, characterized by low functional responses to stimulation via crosslinking of activating receptors ex vivo. Accordingly, it has been widely accepted that hyporesponsiveness to stimulation is the mechanism of NK cell self-tolerance when NK cells lack inhibitory receptors specific for host MHC molecules. However, our recent analysis of chimeric NK cells showed that this cannot be the sole explanation. When NK cells developed in MHC+ hosts in the presence of MHC-deficient hematopoietic cells, the cells became responsive to activating receptor stimulation despite being tolerant of MHC-deficient cells. Hence, tolerance can occur even when NK cells are responsive to stimulation. In contrast, when NK cells developed in MHC-deficient hosts, they became hyporesponsive. These data suggest that non-hematopoietic cells in the host impart hyporesponsiveness. Furthermore, exposure to MHC-deficient hematopoietic cells induces tolerance by a mechanism distinct from hyporesponsiveness. The latter mechanism is relatively unstable as it can be broken as a result of infections. DisclosuresRaulet:Innate Pharma: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Consultancy.

Identification of NY-BR-1-specific CD4(+) T cell epitopes using HLA-transgenic mice.

Breast cancer represents the second most common cancer type worldwide and has remained the leading cause of cancer-related deaths among women. The differentiation antigen NY-BR-1 appears overexpressed in invasive mammary carcinomas compared to healthy breast tissue, thus representing a promising target antigen for T cell based tumor immunotherapy approaches. Since efficient immune attack of tumors depends on the activity of tumor antigen-specific CD4(+) effector T cells, NY-BR-1 was screened for the presence of HLA-restricted CD4(+) T cell epitopes that could be included in immunological treatment approaches. Upon NY-BR-1-specific DNA immunization of HLA-transgenic mice and functional ex vivo analysis, a panel of NY-BR-1-derived library peptides was determined that specifically stimulated IFNγ secretion among splenocytes of immunized mice. Following in silico analyses, four candidate epitopes were determined which were successfully used for peptide immunization to establish NY-BR-1-specific, HLA-DRB1*0301- or HLA-DRB1*0401-restricted CD4(+) T cell lines from splenocytes of peptide immunized HLA-transgenic mice. Notably, all four CD4(+) T cell lines recognized human HLA-DR-matched dendritic cells (DC) pulsed with lysates of NY-BR-1 expressing human tumor cells, demonstrating natural processing of these epitopes also within the human system. Finally, CD4(+) T cells specific for all four CD4(+) T cell epitopes were detectable among PBMC of breast cancer patients, showing that CD4(+) T cell responses against the new epitopes are not deleted nor inactivated by self-tolerance mechanisms. Our results present the first NY-BR-1-specific HLA-DRB1*0301- and HLA-DRB1*0401-restricted T cell epitopes that could be exploited for therapeutic intervention against breast cancer.

TIGIT safeguards liver regeneration through regulating natural killer cell-hepatocyte crosstalk.

Overactivation of innate immunity, particularly natural killer (NK) cells, is harmful to liver regeneration; however, the molecular mechanisms that limit NK cell overactivation during liver regeneration are still elusive. Here we show that a coinhibitory receptor, T cell Ig and ITIM domain (TIGIT), was selectively up-regulated on NK cells, along with high expression of its ligand, poliovirus receptor (PVR/CD155), on hepatocytes during liver regeneration. The absence of TIGIT impaired liver regeneration in vivo, along with overactivation of NK cells and higher NK-derived interferon-gamma (IFN-γ) production. We also show that both depletion of NK cells and deficiency of IFN-γ, but not deficiency of RAG1, rescued impaired liver regeneration caused by the absence of TIGIT. Adoptive transfer of Tigit(-/-) NK cells into NK-deficient Nfil3(-/-) mice sufficiently led to impairment of liver regeneration. On the other hand, silencing PVR in hepatocytes rescued impaired liver regeneration caused by TIGIT deficiency in vivo, while blockade of TIGIT in NK-hepatocyte coculture increased IFN-γ production by NK cells in vitro. TIGIT is a safeguard molecule to improve liver regeneration through negatively regulating NK-hepatocyte crosstalk. This finding suggests a novel mechanism of NK cell self-tolerance towards regenerative hyperplasia of the host.

Temporal regeneration of aire-expressing medullary epithelial cells and its impacts on reestablishing central immune tolerance (BA8P.122)

Abstract The essential role of tissue specific antigen (TSA) expression in medullary thymic epithelial cells (mTECs) in mediating central tolerance has been well-established. We have previously shown that mice with mTEC-specific insulin deletion develop autoimmune diabetes within 3 weeks postnatal. To further understand the mechanisms of mTEC-mediated self-tolerance, we generated the Aire-YFP mice by crossing R26R-YFP reporters with Aire-Cre transgenic mice. Three subsets of mTECs were isolated from these mice: the YFPLOWCD80LOWClass IILOW pre-Aire cells; the YFPHICD80HIClass IIHI Aire+ cells; and the YFPHICD80INTClass IIINT post-Aire cells. Diverse TSA transcripts were detected in Aire+ mTECs, but not, or more restricted in pre- and post-Aire subsets, respectively. To investigate the temporal differentiation of mTECs, we generated the Aire-Cre:R26R-DTR (Aire-DTR) mice, which marked both Aire+ and post-Aire mTECs with diphtheria toxin (DT) receptors. Consecutive administration of DT resulted in ablation of both subsets, whereas pre-Aire mTECs remained intact. Upon DT withdrawal, transcripts of Aire and TSAs remained absent at day 3, but became detectable at day 5. Interestingly, no autoimmunity was observed in Aire-DTR mice treated weekly with a single dose of DT, suggesting that the newly generated Aire+ mTECs could reestablish self-tolerance in a timely manner. Our data provide new insights into the temporal regeneration of mTECs and its importance in maintaining central tolerance.

NKG2D ligation relieves 2B4‐mediated NK‐cell self‐tolerance in mice

Along with MHC class I (MHCI), 2B4 provides nonredundant NK-cell inhibition in mice. The immunoregulatory role of 2B4 has been increasingly appreciated in models of tumor and viral infection, however, the interactions among 2B4, MHCI, and other activating NK-cell receptors remain uncertain. Here, we dissect the influence of two distinct inhibitory pathways in modulating NK-cell-mediated control of tumors expressing strong activating ligands, including RAE-1γ. In vitro cytotoxicity and in vivo peritoneal clearance assays using MHCI(+) CD48(+) (RMA-neo), MHCI(+) CD48(+) RAE-1γ (RMA-RAE-1γ), MHCI(-) CD48(+) (RMA-S-neo), and MHCI(-) CD48(+) RAE-1γ (RMA-S-RAE-1γ) tumor lines demonstrated that NKG2D activation supersedes the inhibitory effect of both 2B4- and MHCI-mediated immune-tolerance systems. Furthermore, 2B4KO mice subcutaneously challenged with RMA-neo and RMA-S-neo exhibited reduced tumor growth and significantly prolonged survival compared with WT mice, implying that 2B4 is constitutively engaged in the NK-cell tolerance mechanism in vivo. Nevertheless, the inhibitory effect of 2B4 is significantly attenuated when NK cells encountered highly stressed tumor cells expressing RAE-1γ, resulting in an immune response shift toward NK-cell activation and tumor regression. Therefore, our data highlight the importance of the 2B4-mediated inhibitory system as an alternate self-tolerance mechanism, whose role can be modulated by the strength of activating receptor signaling within the tumor microenvironment.

T-cell Ig and ITIM domain regulates natural killer cell activation in murine acute viral hepatitis

Uncontrolled natural killer (NK) cell activation during the early response to acute viral infection can lead to severe immunopathology, and the mechanisms NK cells use to achieve self-tolerance in such contexts are currently unclear. Here, NK cells up-regulated a coinhibitory receptor, T-cell Ig and ITIM domain (TIGIT), during challenge with the viral double-stranded RNA (dsRNA) analog poly I:C. Blocking TIGIT by antibody treatment in vivo or a genetic deficiency in Tigit enhanced NK cell activation and aggravated liver injury in a poly I:C/D-GalN-induced model of acute fulminant hepatitis, suggesting that TIGIT is normally required for protecting against NK cell-mediated liver injury. Furthermore, adoptively transferring Tigit(-/-) NK cells into NK cell-deficient Nfil3(-/-) mice also resulted in elevated liver injury. Reconstituting Kupffer cell-depleted mice with poliovirus receptor (PVR/CD155, a TIGIT ligand)-silenced Kupffer cells led to aggravated liver injury in a TIGIT-dependent manner. Blocking TIGIT in an NK-Kupffer cell coculture in vitro enhanced NK cell activation and interferon-gamma (IFN-γ) production in a PVR-dependent manner. We also found that TIGIT was up-regulated selectively on NK cells and protected against liver injury in an acute adenovirus infection model in both an NK cell- and Kupffer cell-dependent manner. Knocking down PVR in Kupffer cells resulted in aggravated liver injury in response to adenovirus infection in a TIGIT-dependent manner. TIGIT negatively regulates NK-Kupffer cell crosstalk and alleviates liver injury in response to poly I:C/D-GalN challenge or acute adenovirus infection, suggesting a novel mechanism of NK cell self-tolerance in liver homeostasis during acute viral infection.

Ipilimumab in the treatment of metastatic melanoma: management of adverse events

Recently, “ipilimumab,” an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody, has been demonstrated to improve overall survival in metastatic melanoma. “CTLA-4” is an immune-checkpoint molecule that downregulates pathways of T-cell activation. Ipilimumab, by targeting CTLA-4, is able to remove the CTLA-4 inhibitory signal, allowing the immune system to react to cancer cells. Due to its immune-based mechanism of action, ipilimumab causes the inhibition of CTLA-4-mediated immunomodulatory effects, the enhancement of antitumor specific immune response mediated by the weakening of self-tolerance mechanisms while exacerbating the development of autoimmune diseases and immune-related adverse events, including dermatitis, hepatitis, enterocolitis, hypophysitis, and uveitis.

Light chain editors of anti-DNA receptors in human B cells

Receptor editing is a mechanism of self-tolerance used in newly generated B cells. The expressed heavy (H) or light (L) chain of an autoreactive receptor is replaced by upstream V genes which eliminate or modify autoreactivity. Editing of anti-DNA receptors has been characterized in anti-DNA transgenic mouse models including 3H9, 3H9/56R, and their revertant 3H9GL. Certain L chains, termed editors, rescue anti-DNA B cells by neutralizing or modifying DNA binding of the H chain. This editing mechanism acts on the natural H chain repertoire; endogenous H chains with anti-DNA features are expressed primarily in combination with editor L chains. We ask whether a similar set of L chains exists in the human repertoire, and if so, do they edit H chains with anti-DNA signatures? We compared the protein sequences of mouse editors to all human L chains and found several human L chains similar to mouse editors. These L chains diminish or veto anti-DNA binding when expressed with anti-DNA H chains. The human H chains expressed with these L chains also have relatively high arginine (Arg) content in the H chain complementarity determining region (H3), suggesting that receptor editing plays a role in establishing tolerance to DNA in humans.

Excess CD40L does not rescue anti-DNA B cells from clonal anergy

CD40L, a member of the tumor necrosis factor (TNF) ligand family, is overexpressed in patients with systemic lupus erythematosus and in lupus mouse models. Previously, we demonstrated that B cells producing pathogenic anti-Sm/RNP antibodies are deleted in the splenic marginal zone (MZ), and that MZ deletion of these self-reactive B cells is reversed by excess CD40L, leading to autoantibody production. To address whether excess CD40L also perturbs clonal anergy, another self-tolerance mechanism of B cells whereby B cells are functionally inactivated and excluded from follicles in the peripheral lymphoid tissue, we crossed CD40L-transgenic mice with the anti-DNA H chain transgenic mouse line 3H9, in which Ig λ1+ anti-DNA B cells are anergized. However, the percentage and localization of Ig λ1+ B cells in CD40L/3H9 double transgenic mice were no different from those in 3H9 mice. This result indicates that excess CD40L does not perturb clonal anergy, including follicular exclusion. Thus, MZ deletion is distinct from clonal anergy, and is more liable to tolerance break.

Autoimmune retinopathy

Autoimmune retinopathy (AIR) is an immune-mediated disorder characterized by progressive visual loss, abnormal electroretinographic and visual field findings in the presence of circulating anti-retinal antibodies. This review highlights advances made toward understanding the pathophysiology, clinical manifestations, and trends in the management of AIR. The pathophysiology of AIR is likely antibody-mediated. AIR serum autoantibodies are variable in their size and retinal tissue they target and can also be present in healthy controls and multiple autoimmune diseases. Rarely, AIR may be associated with dysregulated self-tolerance mechanisms in the thymus. Despite progress in research, our understanding of AIR remains incomplete. Lack of standardized methods for anti-retinal antibody testing continues to challenge the interpretation of seropositivity. Conventional immunosuppressives have been further studied, and promising immunomodulatory therapies, such as targeted B-cell therapy, have been introduced. Newer imaging modalities such as fundus autofluorescence and spectral domain optical coherence tomography may be helpful in diagnosis, monitoring progression of disease and response to treatment. AIR is a rare but vision-threatening disease whose pathogenesis is poorly defined. Lack of standardized clinical or laboratory criteria further complicates the diagnosis and management. Despite recent progress, further basic science research into the autoimmune process is needed. Prospective controlled clinical trials with immunomodulatory therapy can help define future treatment paradigms.

Excess CD40L does not rescue anti-DNA B cells from clonal anergy

CD40L, a member of the tumor necrosis factor (TNF) ligand family, is overexpressed in patients with systemic lupus erythematosus and in lupus mouse models. Previously, we demonstrated that B cells producing pathogenic anti-Sm/RNP antibodies are deleted in the splenic marginal zone (MZ), and that MZ deletion of these self-reactive B cells is reversed by excess CD40L, leading to autoantibody production. To address whether excess CD40L also perturbs clonal anergy, another self-tolerance mechanism of B cells whereby B cells are functionally inactivated and excluded from follicles in the peripheral lymphoid tissue, we crossed CD40L-transgenic mice with the anti-DNA H chain transgenic mouse line 3H9, in which Ig λ1+ anti-DNA B cells are anergized. However, the percentage and localization of Ig λ1+ B cells in CD40L/3H9 double transgenic mice were no different from those in 3H9 mice. This result indicates that excess CD40L does not perturb clonal anergy, including follicular exclusion. Thus, MZ deletion is distinct from clonal anergy, and is more liable to tolerance break.

Excess CD40L does not rescue anti-DNA B cells from clonal anergy

CD40L, a member of the tumor necrosis factor (TNF) ligand family, is overexpressed in patients with systemic lupus erythematosus and in lupus mouse models. Previously, we demonstrated that B cells producing pathogenic anti-Sm/RNP antibodies are deleted in the splenic marginal zone (MZ), and that MZ deletion of these self-reactive B cells is reversed by excess CD40L, leading to autoantibody production. To address whether excess CD40L also perturbs clonal anergy, another self-tolerance mechanism of B cells whereby B cells are functionally inactivated and excluded from follicles in the peripheral lymphoid tissue, we crossed CD40L-transgenic mice with the anti-DNA H chain transgenic mouse line 3H9, in which Ig λ1+ anti-DNA B cells are anergized. However, the percentage and localization of Ig λ1+ B cells in CD40L/3H9 double transgenic mice were no different from those in 3H9 mice. This result indicates that excess CD40L does not perturb clonal anergy, including follicular exclusion. Thus, MZ deletion is distinct from clonal anergy, and is more liable to tolerance break.

Regulatory T cells from another bench: ready for the bedside?

Before the days of flow cytometry analysis, the field of immunology was already replete with “modern” terminologies of “suppression,” “killing,” “tolerance” and “defense.” The problem in those days was the lack of a clear molecular description of these anthropomorphic functions. Although we understood that there was a “yin” to every “yang” that regulates the immune system, we could not progress beyond the point of phenomenology. This situation changed with the seminal discoveries of Sakaguchi et al. ( 1 Sakaguchi S. Sakaguchi N. Asano M. Itoh M. Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995; 155: 1151-1164 PubMed Google Scholar ), which elevated the suppressor T cell beyond its phenomenonologic status to an “identifiable population”: the regulatory T (Treg) cell.

Treg Cells in Rheumatoid Arthritis: An Update

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease arising from a breakdown in immunological self-tolerance, which leads to aberrant immune responses to autoantigens. Regulatory CD4(+) T-cells (Tregs) underpin one of the key mechanisms of self-tolerance and are a major focus of study in RA and other autoimmune diseases. In order to design new and improved therapies to reinstate self-tolerance, and perhaps cure disease, we need to understand the complex mechanism of action of Tregs. This review addresses recent findings in the field of Tregs in RA, with particular focus on identification of potential defects in Treg-mediated self-tolerance mechanisms present in RA patients, as well as how Tregs interact with other cells in the inflamed joints. As antigen-specific Tregs are a potential route for the reinstatement of immune tolerance, we also discuss new strategies currently being investigated which expand or induce de novo generation of Tregs.

Two Sides to Every Proinflammatory Coin

Myocarditis is a major cause of heart failure in young adults that is typically precipitated by cardiac infection with organisms such as Coxsackie B virus or the parasite Trypanosoma Cruzi 1 . Myocarditis has a variety of clinical presentations but is often characterized by severe ventricular dysfunction and risk of fatal arrhythmia. Tissue injury during myocarditis is caused by direct infection of cardiomyoctes and immune-mediated responses to microbial antigens; in addition, autoimmune T cell and antibody responses to myocardial antigens can develop and persist even after the inciting infection has been cleared. The autoimmune component of myocarditis indicates a failure of self-tolerance mechanisms, and may be driven by molecular mimicry between microbial and myocardial self-antigens. Although there has been an emphasis on the role of autoantibodies in autoimmune myocarditis, such as those targeting the β1 adrenergic receptor or the αmyosin heavy chain αMHC), this may reflect the relative ease of their experimental detection as compared to assays of T cell activation by specific self-antigens. Nonetheless, the relevance of T cells is supported by the fact that lymphocytic infiltrates including CD4 + helper T cells can be demonstrated in endocardial biopsy or autopsy sections taken from patients with myocarditis, and by the fact that many of the cardiac auto-antibodies in human myocarditis have undergone IgG class switching, which reflects T helper dependent B cell responses.

Postinfectious Guillain-Barre syndrome in a patient with methimazole-induced agranulocytosis

Both Graves disease and Guillain-Barre syndrome (GBS) are autoimmune disorders caused by impaired self-tolerance mechanisms and triggered by interactions between genetic and environmental factors. GBS in patients who suffer from other autoimmune diseases is rarely reported, and the development of postinfectious GBS in a patient with Graves disease has not been previously reported in the literature. Herein, we report a patient with Graves disease who developed postinfectious GBS during a course of methimazole-induced agranulocytosis.

A Broad Range of Self-Reactivity Drives Thymic Regulatory T Cell Selection to Limit Responses to Self

The degree of T cell self-reactivity considered dangerous by the immune system, thereby requiring thymic selection processes to prevent autoimmunity, is unknown. Here, we analyzed a panel of T cell receptors (TCRs) with a broad range of reactivity to ovalbumin (OVA(323-339)) in the rat insulin promoter (RIP)-mOVA self-antigen model for their ability to trigger thymic self-tolerance mechanisms. Thymic regulatory T (Treg) cell generation in vivo was directly correlated with in vitro TCR reactivity to OVA-peptide in a broad ~1,000-fold range. Interestingly, higher TCR affinity was associated with a larger Treg cell developmental "niche" size, even though the amount of antigen should remain constant. The TCR-reactivity threshold to elicit thymic negative selection and peripheral T cell responses was ~100-fold higher than that of Treg cell differentiation. Thus, these data suggest that the broad range of self-reactivity that elicits thymic Treg cell generation is tuned to secure peripheral tolerance to self.