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Graves' disease (GD) is a thyroid-specific autoimmune disease with a high prevalence worldwide. The disease is primarily mediated by B cells, which produce autoantibodies against the thyroid-stimulating hormone receptor (TSHR), chronically stimulating it and leading to high levels of thyroid hormones in the body. Interest in characterizing the immune response in GD has motivated many phenotyping studies. The immunophenotype of the cells involved and the interplay between them and their secreted factors are crucial to understanding disease progression and future treatment options. T cell populations are markedly distinct, including increased levels of Th17 and follicular helper T cells (Tfh), while Treg cells appear to be impaired. Some B cells subsets are autoreactive, and anti-TSHR antibodies are the key disease-causing outcome of this interplay. Though some consensus across phenotyping studies will be discussed here, there are also complexities that are yet to be resolved. A better understanding of the immunophenotype of Graves' disease can lead to improved treatment strategies and novel drug targets. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Numerous clinical studies have investigated the anti-CD3ɛ monoclonal antibody otelixizumab in individuals with type 1 diabetes, but limited progress has been made in identifying the optimal clinical dose with acceptable tolerability and safety. The aim of this study was to evaluate the association between dose–response, safety and tolerability, beta cell function preservation and the immunological effects of otelixizumab in new-onset type 1 diabetes. Methods: In this randomised, single-blind, placebo-controlled, 24 month study, conducted in five centres in Belgium via the Belgian Diabetes Registry, participants (16–27 years old, <32 days from diagnosis of type 1 diabetes) were scheduled to receive placebo or otelixizumab in one of four dose cohorts (cumulative i.v. dose 9, 18, 27 or 36 mg over 6 days; planned n = 40). Randomisation to treatment was by a central computer system; only participants and bedside study personnel were blinded to study treatment. The co-primary endpoints were the incidence of adverse events, the rate of Epstein–Barr virus (EBV) reactivation, and laboratory measures and vital signs. A mixed-meal tolerance test was used to assess beta cell function; exploratory biomarkers were used to measure T cell responses. Results: Thirty participants were randomised/28 were analysed (placebo, n = 6/5; otelixizumab 9 mg, n = 9/8; otelixizumab 18 mg, n = 8/8; otelixizumab 27 mg, n = 7/7; otelixizumab 36 mg, n = 0). Dosing was stopped at otelixizumab 27 mg as the predefined EBV reactivation stopping criteria were met. Adverse event frequency and severity were dose dependent; all participants on otelixizumab experienced at least one adverse event related to cytokine release syndrome during the dosing period. EBV reactivation (otelixizumab 9 mg, n = 2/9; 18 mg, n = 4/8: 27 mg, n = 5/7) and clinical manifestations (otelixizumab 9 mg, n = 0/9; 18 mg, n = 1/8; 27 mg, n = 3/7) were rapid, dose dependent and transient, and were associated with increased productive T cell clonality that diminished over time. Change from baseline mixed-meal tolerance test C-peptide weighted mean AUC0–120 min following otelixizumab 9 mg was above baseline for up to 18 months (difference from placebo 0.39 [95% CI 0.06, 0.72]; p = 0.023); no beta cell function preservation was observed at otelixizumab 18 and 27 mg. Conclusions/interpretation: A metabolic response was observed with otelixizumab 9 mg, while doses higher than 18 mg increased the risk of unwanted clinical EBV reactivation. Although otelixizumab can temporarily compromise immunocompetence, allowing EBV to reactivate, the effect is dose dependent and transient, as evidenced by a rapid emergence of EBV-specific T cells preceding long-term control over EBV reactivation. Trial registration: ClinicalTrials.gov NCT02000817. Funding: The study was funded by GlaxoSmithKline. [ABSTRACT FROM AUTHOR]

B cells are unique antigen-presenting cells because their antigen presentation machinery is closely tied to the B cell receptor. Autoreactive thymic B cells can efficiently present cognate self-antigens to mediate CD4+ T cell-negative selection. However, the nature of thymocyte-thymic B cell interaction and how this interaction affects the selection of thymic B cell repertoire and, in turn, the T cell repertoire are not well understood. Here we demonstrate that a large percentage of thymic B cells have undergone class switching intrathymically. Thymic B cell class switching requires cognate interaction with specific T cells. Class-switched thymic B cells have a distinct repertoire compared with unswitched thymic B cells or splenic B cells. Particularly, autoreactive B cell specificities preferentially expand in the thymus by undergoing class switching, and these enriched, class-switched autoreactive thymic B cells play an important role in CD4 T cell tolerance.

Summary B cells are unique antigen-presenting cells because their antigen presentation machinery is closely tied to the B cell receptor. Autoreactive thymic B cells can efficiently present cognate self-antigens to mediate CD4 + T cell-negative selection. However, the nature of thymocyte-thymic B cell interaction and how this interaction affects the selection of thymic B cell repertoire and, in turn, the T cell repertoire are not well understood. Here we demonstrate that a large percentage of thymic B cells have undergone class switching intrathymically. Thymic B cell class switching requires cognate interaction with specific T cells. Class-switched thymic B cells have a distinct repertoire compared with unswitched thymic B cells or splenic B cells. Particularly, autoreactive B cell specificities preferentially expand in the thymus by undergoing class switching, and these enriched, class-switched autoreactive thymic B cells play an important role in CD4 T cell tolerance. [ABSTRACT FROM AUTHOR]

Purpose: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system mediated by T cells. B7-H3 plays a diverse role in regulating T cell responses. However, its expression and clinical significance in MS are not well known. This study analyzed the expression of membrane B7-H3 (mB7-H3) and levels of soluble B7-H3 (sB7-H3) in MS patients to determine its clinical significance. Methods: Peripheral blood (PB) or cerebrospinal fluid (CSF) samples from healthy controls, other noninflammatory neurological disorders, viral encephalitis, and MS patients were collected. Expression of mB7-H3 on immune cells was detected by flow cytometry. Levels of sB7-H3 in serum or CSF samples were measured by ELISA. Results: mB7-H3 expression was up-regulated in CSF from MS patients compared to PB ( p < 0.001). However, serum or CSF levels of sB7-H3 in MS patients were significantly lower than those in controls ( p < 0.05). Relapsing-MS patients had higher CSF mB7-H3 expression than the remitting subgroup. Relapsing-MS patients had decreased serum and CSF sB7-H3 levels compared with the remitting subgroup. Neurological deficits showed negative correlations with serum or CSF sB7-H3 levels, but a positive correlation with CSF mB7-H3 expression. Methylprednisolone therapy significantly elevated sB7-H3 levels and reduced mB7-H3 expression compared with pre-therapy levels. sB7-H3 levels did not correlate with mB7-H3 expression. Conclusions: We demonstrated enhanced mB7-H3 expression and reduced sB7-H3 levels in MS patients which correlated with the clinical characteristics of MS patients. These results suggest that B7-H3 may be a promising biomarker and associated with the pathogenesis of MS. [ABSTRACT FROM AUTHOR]

Experimental autoimmune encephalomyelitis (EAE) is characterized by uncontrolled proliferation of autoreactive T lymphocytes, with markedly increased secretion of pro-inflammatory cytokines. To further dissect the pathogenetic pathways of this disease, we exposed T lymphocytes from EAE rats, which were specific for myelin basic protein (MBP) to a modeled microgravity (MMG) environment, using a rotated cell culture system (RCCS) that was known to suppress proliferation of normal T cells. Following exposure to MMG, the proliferation of EAE lymphocytes decreased dramatically compared to those cultured in unit gravity (UG). At the beginning of MMG, a significant increase of apoptosis of MBP-specific T lymphocytes was observed, while at a later stage, the cytokine secretion profile of exposed MBP-specific T lymphocytes was altered, as was the differentiation of Th subsets. We concluded that the function of MBP-specific T lymphocytes was disordered after exposure to MMG. [ABSTRACT FROM AUTHOR]

An immunogenic peptide (p277) from the 60-kDa heat shock protein (hsp60) arrested beta-cell destruction in non-obese diabetic mice. A randomized, double-blind, phase Ib/II clinical trial of DiaPep277 peptide treatment was performed in recent-onset type 1 diabetes patients with remaining insulin production. We studied the immunological efficacy of this peptide therapy and correlated this with clinical outcome. Forty-eight C-peptide-positive patients were assigned subcutaneous injections of 0·2, 1·0 or 2·5 mg p277 ( n = 12 per dosage) at entry, and 1, 6 and 12 months, or four placebo injections ( n = 12). T cell autoimmunity to hsp60, DiaPep277, glutamic acid decarboxylase and tetanus toxoid (recall response control) were assayed by proliferation and cytokine secretion assays (enzyme-linked immunospot) at regular intervals until 18 months after the first injection. All treated patients at each dosage of peptide demonstrated an altered immune response to DiaPep277, while the majority of placebo-treated patients remained non-responsive to treatment ( P = 0·00001), indicating a 100% efficacy of immunization. Cytokine production in response to therapy was dominated by interleukin (IL)-10. IL-10 production before therapy and decreasing autoantigen-specific T cell proliferation were associated with beta-cell preservation. Third-party control immune responses were unaffected by therapy. No potentially adverse immunological side effects were noted. DiaPep277 is immunogenic in type 1 diabetic subjects and has immune modulating properties. Immunological monitoring distinguished therapy from placebo treatment and could determine immunological efficacy. Declining or temporary proliferative responses to peptide DiaPep277 treatment may serve as an immunological biomarker for clinical efficacy. [ABSTRACT FROM AUTHOR]

Abstract: Recurrent uveitis is a common cause of vision blindness. Using a rat model of chronic recurrent uveitis, we examined the relationship between clinical expression, pathological changes, and the heterogeneity of the disease. Chronic recurrent uveitis was induced by adoptive transfer of interphotoreceptor retinoid-binding protein (IRBP)-specific T cells in a total of more than 60 Lewis rats. In about 75% of cases recurrent uveitis was pathologically a chronic and progressive disease. The major pathological changes included the gradual loss of photoreceptor cells. However, disease progression did not always parallel the severity of ocular inflammation and clinical recurrent disease, with about a quarter showing no pathological damage in the eye. [Copyright &y& Elsevier]

Antiphospholipid syndrome (APS) is characterized by recurrent thrombosis and intrauterine fetal loss in association with antiphospholipid antibodies (aPL). We have recently identified autoreactive CD4+ T cells to β2-glycoprotein I (β2GPI) that promote aPL production in APS patients. β2GPI-specific CD4+ T cells preferentially recognize the antigenic peptide containing the major phospholipid-binding site in the context of DRB4*0103 (DR53). T-cell receptor β chains of β2GPI-specific T cells are highly restricted and mainly utilize rearranged Vβ7 or Vβ8 gene segments. T-cell helper activity that stimulates B cells to produce anti-β2GPI antibodies is mediated through IL-6 and CD40–CD40 ligand engagement. β2GPI-specific T cells respond to reduced β2GPI and recombinant β2GPI fragments produced in bacteria, but not to native β2GPI, indicating that the epitopes recognized by β2GPI-specific T cells are apparently cryptic. Activation of β2GPI-specific T cells resulting in production of pathogenic anti-β2GPI antibodies can be induced by the exposure to cryptic peptides of β2GPI. Finally, β2GPI-specific T cell is a reasonable target of potential therapeutic strategies that selectively suppress pathogenic aPL production in APS patients. [Copyright &y& Elsevier]

It is well known that individuals who are positive for particular HLA class II alleles show a high risk of developing autoimmune diseases. HLA class II molecules expressed on antigen-presenting cells present antigenic peptides to CD4+ T cells. Their extensive polymorphism affects the structures of peptides bound to HLA class II molecules to create individual differences in immune responses to antigenic peptides. In order to gain a better understanding of mechanisms of the association between HLA class II alleles and susceptibility to autoimmune diseases, it is important to identify self-peptides presented by disease-susceptible HLA class II molecules and triggering disease-causative T cells. Many of the autoimmune diseases are observed in all ethnic groups, whereas the incidence of diseases, clinical manifestations and disease-susceptible HLA class II alleles are different among various ethnic groups for some autoimmune diseases. These phenomena suggest that differences in autoimmune self-peptide(s) in the context of disease-susceptible HLA class II molecules may cause these differences. Therefore, comparisons among disease-susceptible HLA class II alleles, autoantigenic peptides, and clinical manifestations of autoimmune diseases in different ethnic groups would be helpful in elucidating the pathogenesis of the diseases. In this review, we describe our recent findings on (1) the uniqueness of both clinical manifestations and the HLA-linked genetic background of Asian-type (opticospinal form) multiple sclerosis, (2) the characteristics of glutamic acid decarboxylase 65 (GAD65) or β2-glycoprotein I (β2-GPI) autoreactive T cells in Japanese patients with insulin-dependent diabetes mellitus (IDDM) or anti-β2-GPI antibody-associated autoimmunity, respectively, and (3) the generation of an efficient delivery system of peptides to the HLA class II-restricted antigen presentation path-way by utilizing a class II-associated invariant chain peptide (CLIP)-substituted invariant chain, which may be applicable to an evaluation of the "molecular mimicry hypothesis" for the activation of autoreactive T cells. [ABSTRACT FROM AUTHOR]

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Autoantibodies of the IgG isotype, specifically directed against intestinal alkaline phosphatase (IAP), occur transiently in the majority of sera from patients with acute bacterial infections. Sometimes they are observed in autoimmune diseases. Using a T cell proliferation assay, it was found that isolated peripheral blood mononuclear cells (PBMC) from IAP autoantibody (IAPA)-positive patients (n= 18) responded significantly to IAP, whereas proliferation could not be induced in PBMC from healthy donors (n = II). Significant stimulation of PBMC from patients (n = 11) was not obtained by use of transferring, a common autoantigen in humans, indicating the specificity of stimulation of IAP-reactive T cells. Furthermore, T cell proliferation was observed when a highly purified IAP fragment (CNBr 21) spanning amino acids 334-462 of the primary structure of IAP was used as antigen. Thus, it was shown that an immunodominant T cell epitope resides within the CNBr 21 fragment which also contains a discontinuous B cell epitope as evaluated previously. Double immunocytochemical staining of T cell depleted PBMC with IAP and an anti-human CD5 antibody allowed the detection of CD5+ B lymphocytes, which probably produce natural IAPA (nIAPA). These nIAPA-specific CD5+ B cells occurred with approximately the same frequency among T cell-depleted PBMC from healthy donors and those from patients. In contrast, IAPA-producing CD5- B cells were found in B cell-enriched preparations from patients, but not in those from healthy individuals. [ABSTRACT FROM AUTHOR]

An HLA-DR restricted T cell clone (26G11) which recognized a lymphoid cell-derived autoantigen associated with DR4 molecule was shown to induce not only autologous but also allogenic DR4+ B cells to produce large amounts of antibodies of the IgG and IgM classes. Using the helper activity of this clone, we investigated the mechanism of anti-DNA antibody production in DR-matched patients with systemic lupus erythematosus (SLE). When cultured with 26G11 cells, B cells from DR-matched normal control subjects produced large amounts of IgM anti-DNA antibody, but did not produce IgG anti-DNA antibody which is thought to have a pathological role in SLE, In contrast, B cells from DR-matched patients with active SLE spontaneously produced a fairly large amount of IgG anti- DNA antibody, and the production was augumented by the T cell clone. Little IgG anti-DNA antibody was produced by the B cells of patients with inactive SLE in either the presence or absence of T cell clone. We next fractionated B cells into low density B (LD-B) and high density B (HD-B) cells by centrifugation on discontinuous Pereoll density gradients. IgG anti-DNA antibody was spontaneously produced by LD-B cells of active SLE patients but not by those either of inactive SLE patients or normal controls. On the other hand, although IgG anti-DNA antibody was not spontaneously produced by the HD-B cells of both active and inactive SLE patients, it could easily be induced by their culture with the T cell clone. Our results clearly show the existence of IgG anti-DNA antibody-producing B cells in the peripheral blood of SLE patients irrespective of their disease activity and suggest that autoreactive T cells may play a pathogenic role in SLE through the induction of autoantibody production. [ABSTRACT FROM AUTHOR]

Regulatory mechanisms of T cell autoreactivity to MHC class II molecules were studied in transgenic (Tg) mice with auto-I-Ak-reactive TCR αβ transgenes (designated as MS Tg mice). Our previous study revealed that the T cell tolerance established in autoreactive MS Tg mice was not due to either clonal deletion in the thymus, anergy or an active suppression in the periphery. We proposed a novel form of self tolerance termed `clonal insufficiency', where autoreactive T cells were conditionally rendered unresponsiveness to self antigen in vivo, although retaining full potential reactivity in in vitro conditions. Here, we investigated the role of co-stimulatory molecules for the induction of self tolerance with `clonal insufficiency'. MS Tg mice were mated with CD80 (B7-1) Tg mice in which B cells exclusively and constitutively expressed CD80 molecules. Both MS Tg mice and CD80 Tg mice by themselves showed no evidence for activation of T cells and B cells, whereas MS x CD80 double-Tg mice with a H-2k background revealed an abnormal increase in the number of splenocytes and in the expression of activation markers (CD69 and CD25) on CD4 T cells in the spleen. These results indicated that the self tolerance established in MS Tg mice involved a down-regulation of CD80 molecules on B cells in vivo, resulting in a failure of sufficient T-B interactions. In addition, the serum concentration of IL-10, one of the down-regulators of CD80 expression, was found to be increased significantly in MS Tg mice. The autoreactivity of MS Tg T cells detected in vitro was significantly blocked by recombinant IL-10. Thus, IL-10-mediated down-regulation of CD80 on B cells was suggested to be involved in the clonal insufficiency in MS Tg mice in vivo. [ABSTRACT FROM PUBLISHER]

Transgenic (TG) mice with TCR α and β chain genes from a CD4-dependent auto-l-A reactive T cell clone were generated. H-2 TG mice had a large number of thymic and splenic CD4 T cells expressing the autoreactive TCR without manifestation of autolmmunlty. The cells were not anergic, as they could respond to autologous antigen presenting cells and antl-TCR antibodies to proliferate and to produce interleuklns. Various degrees of down-regulation of CD2 and CD44 was observed in TG mice, Indicating the presence of a defective co-stlmulatory process in TG T cells. These features indicate that the self tolerance in autoreactive TCR TG mice is due not to clonal deletion and anergy but to a novel mechanism where T cells cannot sufficiently respond to normally existing self ligand . That such an in vivo unresponsiveness of autoreactive T cells is dictated in the thymus during CD4 T cell differentiation as an atypical form of positive selection of autoreactive T cells was suggested by the abnormal surface expression of CD69 and HSA. [ABSTRACT FROM PUBLISHER]

We established a TCR V6 CD4 autoreactive T cell line from lymph nodecells of unprimed BALB/c mice bred in a specific pathogen-free condition. The T cell line proliferated In the presenceof Irradiated spleen cells expressing MHC class II I-A and/or I-E molecules. The proliferatlveresponse of the autoreactive T cell line was significantly enhanced In response to 65 kd heat-shock protein (hsp) from Mycobacterium bovis, a member of the hsp60 family, which is highly conserved in both prokaryotes and eukaryotes. Our results suggest that the autoreactive T cells in normal mice may recognize endogenous peptldes of self-hsp60 bound to MHC class IIgene products and are cross-reactive to mycobacterial 65 kd hsp. The autoreactive hsp-specific T cells may therefore play an important role in the immune surveillance against invasion of various pathogens and tumors by recognizing Infected and transformed autoiogous cells that express high levels of endogenous hsp60. [ABSTRACT FROM PUBLISHER]

Two lines of Eα-expressing NOD mice were established by continuously backcrosslng [Eα B6 transgenic mice × NOD] F1 to parental NOD or directly microinjecting the Eα gene into fertilized NOD eggs. Similarly, Aβ-expressing transgenic NOD mice were produced. Subsequent histological examination of pancreatic tissues revealed that autoimmune insulitls was prevented in Eα backcross and transgenic mice but not in Aβ transgenic mice. [ABSTRACT FROM PUBLISHER]

The mechanism by which anti-DNA antibodies cause glomerulonephritis in systemic lupus erythematosus (SLE) has not been fully elucidated. However, not a few recent studies suggest the pivotal role of nucleosomal histones in the binding of immune complexes to the glomerular basement membrane. Some antibodies cross-react with both double-stranded (ds) DNA and nucleosome, but antibodies exclusively specific to the nucleosome have also been described. In lupus model mice, anti-nucleosome antibodies are reported to emerge even before the production of anti-dsDNA antibodies. BK virus T antigen, bacterial DNA, a DNA binding protein nucleobindin and autoreactive helper T cells specific to nucleosome or anti-DNA antibody-derived peptides have been shown to induce or enhance anti-DNA antibody production in normal or lupus-prone animals. These new experimental models are expected to be helpful in the exploration of the true antigen that elicits autoimmune reactions in SLE. [ABSTRACT FROM AUTHOR]

Background Chronic spontaneous urticaria (CSU) is the recurrence of urticaria without an apparent trigger. Half of the patients with CSU have IgG autoantibodies to FcεRIα on dermal mast cells and basophils, which on activation release mediators responsible for urticaria. IgG autoantibodies infer the presence of antigen/disease-specific T cells and CSU lesions are characterized by T-cell infiltration, but antigen/disease-specific T cells have not been documented in patients with CSU. Objective We aimed to identify autoreactive T cells to FcεRIα in patients with CSU and determine their relationship with autoantibodies to FcεRIα and their diagnostic value. Methods T-cell responses to FcεRIα were measured as proliferation by carboxy-fluorescein diacetate succinimidyl ester dye dilution and cytokine secretion by ELISpot. Serum autoantibodies to FcεRIα were detected by radioimmunoprecipitation. Results Blood CD4 + T-cell proliferation to FcεRIα was detected in 27% of the subjects with CSU and 0% of controls; IFN-γ responses to FcεRIα were detected in 53%, and IL-5 or IL-13 responses in a minority of subjects with CSU. Serum FcεRIα autoantibodies were detected in 43% of subjects with CSU and 0% of controls. IFN-γ and autoantibody responses to FcεRIα were inversely related, with IFN-γ responses being detected earlier than autoantibodies in disease. Combined with autoantibody, T-cell responses to FcεRIα conferred high diagnostic sensitivity and specificity. Conclusions Autoreactive CD4 + T cells that target FcεRIα were detected in most subjects with CSU, with a cytokine secretion profile more typical of a T H 1-cell response. The inverse relationship between IFN-γ and autoantibody responses to FcεRIα may signify different stages in the disease course. Our findings suggest that measurement of T-cell as well as autoantibody responses to FcεRIα could improve diagnostic accuracy in subjects with CSU. [ABSTRACT FROM AUTHOR]