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1.
J Clin Immunol ; 33(8): 1341-8, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24158785

ABSTRACT

PURPOSE: Almost all patients with autoimmune polyendocrine syndrome (APS)-I have high titer neutralizing autoantibodies to type I interferons (IFN), especially IFN-ω and IFN-α2, whatever their clinical features and onset-ages. About 90 % also have antibodies to interleukin (IL)-17A, IL-17F and/or IL-22; they correlate with the chronic mucocutaneous candidiasis (CMC) that affects ~90 % of patients. Our aim was to explore how early the manifestations and endocrine and cytokine autoantibodies appear in young APS-I patients. That may hold clues to very early events in the autoimmunization process in these patients. METHODS: Clinical investigations and autoantibody measurements in 13 APS-I patients sampled before age 7 years, and 3 pre-symptomatic siblings with AIRE-mutations in both alleles. RESULTS: Antibody titers were already high against IFN-α2 and IFN-ω at age 6 months in one sibling-8 months before onset of APS-I-and also against IL-22 at 7 months in another (still unaffected at age 5 years). In 12 of the 13 APS-I patients, antibody levels were high against IFN-ω and/or IL-22 when first tested, but only modestly positive against IFN-ω in one patient who had only hypo-parathyroidism. Endocrine organ-specific antibodies were present at age 6 months in one sibling, and as early as 36 and 48 months in two of the six informative subjects. CONCLUSION: This is the first study to collate the onset of clinical features, cytokine and endocrine autoantibodies in APS-I infants and siblings. The highly restricted early autoantibody responses and clinical features they show are not easily explained by mere loss of broad-specific self-tolerance inducing mechanisms, but hint at some more sharply focused early event(s) in autoimmunization.


Subject(s)
Autoantibodies/blood , Cytokines/immunology , Polyendocrinopathies, Autoimmune/diagnosis , Polyendocrinopathies, Autoimmune/immunology , Adolescent , Adult , Autoantibodies/biosynthesis , Child , Child, Preschool , Early Diagnosis , Female , Humans , Infant , Interferon-alpha/immunology , Interleukin-17/immunology , Interleukins/immunology , Male , Polyendocrinopathies, Autoimmune/metabolism , Syndrome , Young Adult , Interleukin-22
2.
Clin Exp Immunol ; 171(3): 263-72, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23379432

ABSTRACT

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a recessive disorder resulting from mutations in the autoimmune regulator (AIRE). The patients' autoantibodies recognize not only multiple organ-specific targets, but also many type I interferons (IFNs) and most T helper type 17 (Th17) cell-associated cytokines, whose biological actions they neutralize in vitro. These anti-cytokine autoantibodies are highly disease-specific: otherwise, they have been found only in patients with thymomas, tumours of thymic epithelial cells that fail to express AIRE. Moreover, autoantibodies against Th17 cell-associated cytokines correlate with chronic mucocutaneous candidiasis in both syndromes. Here, we demonstrate that the immunoglobulin (Ig)Gs but not the IgAs in APECED sera are responsible for neutralizing IFN-ω, IFN-α2a, interleukin (IL)-17A and IL-22. Their dominant subclasses proved to be IgG1 and, surprisingly, IgG4 without IgE, possibly implicating regulatory T cell responses and/or epithelia in their initiation in these AIRE-deficiency states. The epitopes on IL-22 and IFN-α2a appeared mainly conformational. We also found mainly IgG1 neutralizing autoantibodies to IL-17A in aged AIRE-deficient BALB/c mice - the first report of any target shared by these human and murine AIRE-deficiency states. We conclude that autoimmunization against cytokines in AIRE deficiency is not simply a mere side effect of chronic mucosal Candida infection, but appears to be related more closely to disease initiation.


Subject(s)
Autoantibodies/immunology , Cytokines/immunology , Polyendocrinopathies, Autoimmune/immunology , Transcription Factors/deficiency , Animals , Autoantibodies/blood , Humans , Immunodominant Epitopes , Immunoglobulin G/blood , Interferon-alpha/immunology , Interleukin-17/immunology , Interleukins/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Transcription Factors/physiology , AIRE Protein , Interleukin-22
3.
J Bone Joint Surg Br ; 94(9): 1234-40, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22933496

ABSTRACT

We compared lower limb coronal alignment measurements obtained pre- and post-operatively with long-leg radiographs and computer navigation in patients undergoing primary total knee replacement (TKR). A series of 185 patients had their pre- and post-implant radiological and computer-navigation system measurements of coronal alignment compared using the Bland-Altman method. The study included 81 men and 104 women with a mean age of 68.5 years (32 to 87) and a mean body mass index of 31.7 kg/m(2) (19 to 49). Pre-implant Bland-Altman limits of agreement were -9.4° to 8.6° with a repeatability coefficient of 9.0°. The Bland-Altman plot showed a tendency for the radiological measurement to indicate a higher level of pre-operative deformity than the corresponding navigation measurement. Post-implant limits of agreement were -5.0° to 5.4° with a repeatability coefficient of 5.2°. The tendency for valgus knees to have greater deformity on the radiograph was still seen, but was weaker for varus knees. The alignment seen or measured intra-operatively during TKR is not necessarily the same as the deformity seen on a standing long-leg radiograph either pre- or post-operatively. Further investigation into the effect of weight-bearing and surgical exposure of the joint on the mechanical femorotibial angle is required to enable the most appropriate intra-operative alignment to be selected.


Subject(s)
Arthroplasty, Replacement, Knee , Knee/diagnostic imaging , Leg Bones/diagnostic imaging , Surgery, Computer-Assisted , Adult , Aged , Aged, 80 and over , Biomechanical Phenomena , Female , Follow-Up Studies , Humans , Male , Middle Aged , Observer Variation , Organ Size , Postoperative Period , Posture , Radiography , Retrospective Studies
4.
Autoimmunity ; 43(5-6): 413-27, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20380583

ABSTRACT

Paraneoplastic autoimmune diseases associate occasionally with small cell lung cancers and gynecologic tumors. However, myasthenia gravis (MG) occurs in at least 30% of all patients with thymomas (usually present at MG diagnosis). These epithelial neoplasms almost always have numerous admixed maturing polyclonal T cells (thymocytes). This thymopoiesis-and export of mature CD4(+)T cells-particularly associates with MG, though there are rare/puzzling exceptions in apparently pure epithelial WHO type A thymomas. Other features potentially leading to inefficient self-tolerance induction include defective epithelial expression of the autoimmune regulator (AIRE) gene and/or of major histocompatibility complex class II molecules in thymomas, absence of myoid cells, failure to generate FOXP3(+) regulatory T cells, and genetic polymorphisms affecting T-cell signaling. However, the strong focus on MG/neuromuscular targets remains unexplained and suggests some biased autoantigen expression, T-cell selection, or autoimmunization within thymomas. There must be further clues in the intriguing serological and cellular parallels in some patients with late-onset MG but without thymomas-and in others with AIRE mutations-and in the contrasts with early-onset MG, as discussed here.


Subject(s)
Myasthenia Gravis/immunology , Paraneoplastic Syndromes, Nervous System/immunology , Thymoma/immunology , Thymus Gland/physiopathology , Autoantibodies/immunology , Autoantigens/immunology , Autoantigens/metabolism , Epithelial Cells/pathology , Genes, MHC Class II , Humans , Immunoglobulin G/immunology , Lymphopoiesis , Myasthenia Gravis/genetics , Myasthenia Gravis/physiopathology , Paraneoplastic Syndromes, Nervous System/genetics , Polyendocrinopathies, Autoimmune/immunology , T-Lymphocytes/immunology , Thymoma/genetics , Thymoma/pathology , Thymoma/physiopathology , Transcription Factors/genetics , AIRE Protein
5.
J Neuroimmunol ; 216(1-2): 85-91, 2009 Nov 30.
Article in English | MEDLINE | ID: mdl-19781791

ABSTRACT

Little is known about pathogenesis -- and especially about involvement of CD8(+) T-cells -- in late-onset myasthenia gravis (LOMG). Remarkably, outstanding CD8(+) TCRVbeta-subset expansions were found in 64% and 72% of recent onset LOMG or thymoma-associated MG (vs. 16% with early-onset MG (p<0.0002); 21% in older controls (p<0.001)). In LOMG, ~25% of the expanded cells initially showed a naïve CD62L(+hi)/CD45RA(+) recent thymic emigrant (RTE)-like phenotype. These expansions associated significantly with IgG antibodies against cytomegalovirus (p<0.036), IL-12 and/ or IFN-alpha2 (p<0.03). The CD8(+) TCRVbeta expansions were stable over 5years, but RTE markers declined.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Myasthenia Gravis/immunology , Receptors, Antigen, T-Cell, alpha-beta/physiology , Thymoma/immunology , Adult , Age of Onset , Aged , Autoantibodies/blood , CD8-Positive T-Lymphocytes/metabolism , Cytomegalovirus/immunology , Diagnosis, Differential , Female , Humans , Immunophenotyping , Interferon-gamma/immunology , Interleukin-12/immunology , L-Selectin/metabolism , Leukocyte Common Antigens/metabolism , Lymphocyte Activation/immunology , Male , Middle Aged , Myasthenia Gravis/metabolism , Myasthenia Gravis/physiopathology , Recombinant Proteins , Thymoma/metabolism , Thymoma/physiopathology
6.
Clin Exp Immunol ; 154(1): 141-51, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18727623

ABSTRACT

In sporadic autoimmune disorders, dendritic cells are increasingly being incriminated as agents provocateurs. However, the mechanisms and any 'danger signals' that induce them to autoimmunize remain enigmatic. Here, we focus on unexpected clues from two prototypic/ highly informative autoimmune syndromes, acquired thymoma-associated myasthenia gravis and the monogenic autoimmune polyendocrine syndrome type-1 (APS1), caused by mutations in the AutoImmune Regulator (AIRE). Both involve the thymus, and in both we find early, persistent, highly prevalent and high-titre neutralizing autoantibodies against type-I interferons, regardless of the exact AIRE genotype or the characteristically variable clinical phenotype in APS1. Thus these key innate<-->adaptive immune intermediaries are now implicated in APS1 and paraneoplastic myasthenia as well as in systemic lupus erythematosus and other sporadic autoimmune disorders. The currently accepted notion that autoimmunization proceeds automatically (by 'default') does not explain how, when or where autoimmune responses are initiated against which targets in APS1, or whether exogenous or internal danger signals are involved, or predict whether the primary auto-immunogenic targets are AIRE-dependent. As the parallels between these syndromes must hold novel clues to these puzzles, they demand explanations. To unify these and other findings, we propose that autoimmunization occurs centrally in aberrant thymic environments rendered 'dangerous' by AIRE-deficiency (possibly by excess undegraded nucleic acids/dead cell debris). The ensuing autoreactivity focuses early on the locally abundant type I interferons and then on other peripheral tissue autoantigens that are still expressed despite the absence of AIRE. These ideas raise numerous questions that others may already have the materials to address.


Subject(s)
Autoantibodies/immunology , Interferon Type I/immunology , Models, Immunological , Polyendocrinopathies, Autoimmune/immunology , Thymus Gland/immunology , Cytokines/immunology , Dendritic Cells/immunology , Humans , Paraneoplastic Syndromes/immunology , Self Tolerance , Thymoma/immunology
7.
J Pathol ; 211(5): 563-571, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17334980

ABSTRACT

Thymomas are thymic epithelial neoplasms, associated with a variety of autoimmune disorders (especially myasthenia gravis), that apparently result from aberrant intra-tumourous thymopoiesis and export of inefficiently tolerized T-cells to the periphery. The autoimmune regulator (AIRE) drives the expression of self-antigens in the thymic medulla and plays an essential role in 'central' tolerance in both humans and mice. However, while inactivating AIRE mutations result in the 'autoimmune polyendocrinopathy syndrome type 1' (APS-1), its major features are not well reproduced in AIRE-knock-out mice. Therefore, alternative human disease scenarios with concomitant AIRE deficiency may be valuable tools to test conclusions drawn from mouse models. Here we show, in a large series, that approximately 95% of thymoma patients are 'chimeric'; expression of AIRE and major AIRE-related autoantigens (eg insulin) were undetectable in their tumours but maintained in their remnant thymic tissue and lymph nodes. Notably, despite the AIRE-deficient thymopoiesis in thymomas, disorders and autoantibodies typical of APS-1 were distinctly uncommon in these patients. The one striking similarity was in the recently observed neutralizing anti-type I interferon (IFN) antibodies, which are found at diagnosis in 100% of patients with APS-1 and in approximately 60% of patients with thymomas, as we show here. We conclude that APS-1 type autoantigens must be protected from autoimmunity by mechanisms that do not extend to the muscle autoantigens so frequently targeted in thymoma patients but so rarely recognized in APS-1. Thus our findings argue strongly for a tolerogenic function of AIRE beyond its role in negative T-cell selection in human thymopoiesis, and/or for specific autoimmunization against muscle in thymomas.


Subject(s)
Neoplasm Proteins/deficiency , Polyendocrinopathies, Autoimmune/immunology , Thymoma/chemistry , Thymus Neoplasms/chemistry , Transcription Factors/deficiency , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Neoplasm/immunology , Antigens, Neoplasm/analysis , Autoantibodies/blood , Autoantigens/analysis , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , Cytokines/immunology , Female , Humans , Immunohistochemistry/methods , Interferon Type I/immunology , Male , Middle Aged , Myasthenia Gravis/immunology , Myasthenia Gravis/metabolism , Thymus Gland/immunology , Thymus Gland/metabolism , AIRE Protein
8.
Ann N Y Acad Sci ; 998: 237-56, 2003 Sep.
Article in English | MEDLINE | ID: mdl-14592881

ABSTRACT

We have studied responses in thymoma patients to interferon-alpha and to the acetylcholine receptor (AChR) in early-onset myasthenia gravis (EOMG), seeking clues to autoimmunizing mechanisms. Our new evidence implicates a two-step process: (step 1) professional antigen-presenting cells and thymic epithelial cells prime AChR-specific T cells; then (step 2) thymic myoid cells subsequently provoke germinal center formation in EOMG. Our unifying hypothesis proposes that AChR epitopes expressed by neoplastic or hyperplastic thymic epithelial cells aberrantly prime helper T cells, whether generated locally or infiltrating from the circulation. These helper T cells then induce antibody responses against linear epitopes that cross-react with whole AChR and attack myoid cells in the EOMG thymus. The resulting antigen-antibody complexes and the recruitment of professional antigen-presenting cells increase the exposure of thymic cells to the infiltrates and provoke local germinal center formation and determinant spreading. Both these and the consequently enhanced heterogeneity and pathogenicity of the autoantibodies should be minimized by early thymectomy.


Subject(s)
Autoimmunity , B-Lymphocytes/immunology , Myasthenia Gravis/immunology , T-Lymphocytes/immunology , Age of Onset , Animals , Autoantibodies , Bungarotoxins/metabolism , Enzyme-Linked Immunosorbent Assay , Epithelial Cells/physiology , Epitopes/immunology , Fluorescent Antibody Technique , Germinal Center , Histocompatibility Antigens Class II/metabolism , Humans , Insulin/metabolism , Interferon-alpha/immunology , Interleukin-2/immunology , Keratins/metabolism , Models, Immunological , Mutation , Myasthenia Gravis/metabolism , Receptors, Cholinergic/immunology , Stromal Cells , T-Lymphocytes/classification , Thymoma/immunology , Thymus Gland/cytology , Thymus Gland/physiology , Thymus Neoplasms , Troponin I/metabolism
9.
Autoimmunity ; 36(2): 117-21, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12820694

ABSTRACT

In myasthenia gravis (MG), humoral and cellular immune mechanisms are involved in the autoimmune pathogenesis. In this study, we investigated the role of the CD45 molecule in MG, having recently reported an association in multiple sclerosis. CD45, a protein-tyrosine phophatase receptor type C (PTPRC), is essential for both thymic selection and peripheral activation of T and B cells. Our aims were to determine (a) the prevalence of a functional mutation in the CD45 gene (exon 4 77C --> G; prevalence analysis), and (b) the distribution of memory (CD45RO+) and naive (CD45RA+) T cells in the peripheral blood (subset analysis). T cells from 78 patients with generalised MG were stained with monoclonal antibodies against CD45RO, CD45RA, CD4 and CD8 and quantified by four-colour flow cytometry. The control panel for the prevalence analysis (a) consisted of 303 healthy individuals. (b) From those, 67 age- and sex-matched probands were randomly selected as controls for the subset analysis. Patients were stratified according to their MG onset age, thymic pathology and immunosuppressive treatment. Statistical analysis was performed by Fisher's exact test, asymptotic chi2 test, the two-sided Mann-Whitney test and Spearman's correlation coefficient. As a result, the 77C --> G mutation in exon 4 of the CD45 gene was found in 1 of 78 patients versus none of the 303 controls. Thus, no association was detected with this single nucleotide polymorphism in MG patients overall. Surprisingly, however, ratios of CD45RO+ to CD45RA+ T cells were lower among CD8+ T cells from patients with late-onset MG (P = 0.023). Thymoma patients also showed a similar trend among CD4+ and CD8+ T-cells, as expected. These differences were not related to immunosuppressive drug treatment or thymectomy (in the 67 informative patients). Since there is no other evidence for increased thymopoiesis in late-onset MG, we propose an altered subset balance in the circulation.


Subject(s)
Leukocyte Common Antigens/immunology , Myasthenia Gravis/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Case-Control Studies , Exons , Female , Genetic Variation , Humans , Immunologic Memory , Leukocyte Common Antigens/genetics , Leukocyte Common Antigens/metabolism , Male , Myasthenia Gravis/etiology , Myasthenia Gravis/genetics , Point Mutation , Protein Isoforms/genetics , Protein Isoforms/immunology , Protein Isoforms/metabolism
10.
J Neuroimmunol ; 139(1-2): 102-8, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12799027

ABSTRACT

In humans, interleukin-12 (IL-12) and interferon-alpha (IFN-alpha) normally favor IFN-gamma-producing "Th1" T cell responses. Myasthenia gravis (MG) patients with thymomas frequently have high-titer neutralizing autoantibodies against these cytokines, but not against IFN-gamma. Because they occasionally develop intractable (even fatal) infections, we have tested effects of their sera on the generation of IFN-gamma responses by healthy adult T cells to autologous lipopolysaccharide (LPS)-treated dendritic cells (DC). Anti-IL-12(+) sera consistently reduced IFN-gamma responses substantially, whether assessed by intracellular staining or ELISA. Therefore, thymoma patients with intractable infections might benefit from cautious IFN-gamma therapy. We discuss wider implications of the surprising rarity of clear clinical hazards-or benefits-of these autoantibodies.


Subject(s)
Autoantibodies/immunology , CD4-Positive T-Lymphocytes/immunology , Interferon-gamma/immunology , Interleukin-12/immunology , Myasthenia Gravis/complications , Myasthenia Gravis/immunology , Thymoma/complications , Thymoma/immunology , Adult , Aged , Autoantibodies/blood , Autoantibodies/pharmacology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/metabolism , Cell Communication/drug effects , Cell Communication/immunology , Dendritic Cells/drug effects , Dendritic Cells/immunology , Dendritic Cells/metabolism , Female , Humans , Immunity, Cellular/drug effects , Immunity, Cellular/immunology , Immunoglobulin G/pharmacology , Interferon-alpha/blood , Interferon-alpha/immunology , Interferon-gamma/metabolism , Interferon-gamma/therapeutic use , Interleukin-12/blood , Interleukin-4/blood , Lipopolysaccharides/pharmacology , Male , Middle Aged , Myasthenia Gravis/blood , Thymoma/blood
12.
Clin Exp Immunol ; 132(1): 128-36, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12653847

ABSTRACT

We have screened for spontaneous anticytokine autoantibodies in patients with infections, neoplasms and autoimmune diseases, because of their increasingly reported co-occurrence. We tested for both binding and neutralizing autoantibodies to a range of human cytokines, including interleukin-1alpha (IL-1alpha), IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-18, interferon-alpha2 (IFN-alpha2), IFN-omega, IFN-beta, IFN-gamma, tumour necrosis factor alpha (TNF-alpha), transforming growth factor beta-1 (TGF-beta1) and granulocyte-macrophage colony stimulating factor (GM-CSF), in plasmas or sera. With two notable exceptions described below, we found only occasional, mostly low-titre, non-neutralizing antibodies, mainly to GM-CSF; also to IL-10 in pemphigoid. Strikingly, however, high-titre, mainly IgG, autoantibodies to IFN-alpha2, IFN-omega and IL-12 were common at diagnosis in patients with late-onset myasthenia gravis (LOMG+), thymoma (T) but no MG (TMG-) and especially with both thymoma and MG together (TMG+). The antibodies recognized other closely related type I IFN-alpha subtypes, but rarely the distantly related type I IFN-beta, and never (detectably) the unrelated type II IFN-gamma. Antibodies to IL-12 showed a similar distribution to those against IFN-alpha2, although prevalences were slightly lower; correlations between individual titres against each were so modest that they appear to be entirely different specificities. Neither showed any obvious correlations with clinical parameters including thymoma histology and HLA type, but they did increase sharply if the tumours recurred. These antibodies neutralized their respective cytokine in bioassays in vitro; although they persisted for years severe infections were surprisingly uncommon, despite the immunosuppressive therapy also used in most cases. These findings must hold valuable clues to autoimmunizing mechanisms in paraneoplastic autoimmunity.


Subject(s)
Autoantibodies/blood , Cytokines/immunology , Myasthenia Gravis/immunology , Thymoma/immunology , Adolescent , Breast Neoplasms/immunology , Case-Control Studies , Child , Child, Preschool , Diabetes Mellitus, Type 1/immunology , Enzyme-Linked Immunosorbent Assay , Female , Humans , Interferon Type I/immunology , Interferon-alpha/immunology , Interleukin-12/immunology , Melanoma/immunology , Multiple Sclerosis/immunology , Myasthenia Gravis/complications , Ovarian Neoplasms/immunology , Pemphigus/immunology , Protein Binding , Thymoma/complications
13.
Neurology ; 57(9): 1579-82, 2001 Nov 13.
Article in English | MEDLINE | ID: mdl-11706095

ABSTRACT

BACKGROUND: Patients with MG often have other autoantibodies in addition to those against the acetylcholine receptor (AChR). It has been suggested that antibodies to the muscle protein titin may be diagnostic of a thymoma, but they have also been found in patients with late-onset MG. Antibodies to certain cytokines have also been detected in patients with MG and thymoma, and it is not clear whether these antibodies could be more useful clinically. The authors measured antibodies against titin and the cytokines interferon alpha (IFNalpha) and interleukin 12 (IL12) in patients with MG and thymoma or thymoma recurrence, and in patients with MG but without thymoma presenting before (early-onset MG) or after (late-onset MG) 40 years of age. METHOD: Levels of titin, IFNalpha, and IL12 antibodies were determined by radioimmunoassay in 191 patients with MG and 82 controls. RESULTS: As previously reported, titin antibodies were uncommon in patients with early-onset MG. However, in patients with late-onset MG, titin antibodies had similar prevalence and levels to those in patients with MG and thymoma, although the antibodies were uncommon in patients between 40 and 60 years of age presenting without a tumor. By contrast, cytokine antibodies were more common in patients with thymoma than in patients without thymoma, and cytokine antibodies typically increased substantially if the thymoma recurred. CONCLUSIONS: Measurement of titin antibodies has limited use in predicting the presence of a tumor, unless the patient is less than 60 years of age, but measurement of IFNalpha and IL12 antibodies may be helpful in identifying patients with a thymoma recurrence, particularly when mediastinal imaging is equivocal.


Subject(s)
Interferon-alpha/immunology , Interleukin-12/immunology , Muscle Proteins/immunology , Myasthenia Gravis/immunology , Protein Kinases/immunology , Thymoma/immunology , Thymus Neoplasms/immunology , Adult , Aged , Aged, 80 and over , Autoantibodies/blood , Connectin , Female , Humans , Male , Middle Aged , Myasthenia Gravis/epidemiology , Neoplasm Recurrence, Local/epidemiology , Neoplasm Recurrence, Local/immunology , Predictive Value of Tests , Seroepidemiologic Studies , Thymoma/epidemiology , Thymus Neoplasms/epidemiology
14.
J Immunol ; 167(4): 1935-44, 2001 Aug 15.
Article in English | MEDLINE | ID: mdl-11489973

ABSTRACT

The muscle weakness in myasthenia gravis (MG) is mediated by autoantibodies against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction. Production of these pathogenic autoantibodies is believed to be associated with germinal centers (GC) and anti-AChR-secreting plasma cells in the hyperplastic thymus of patients with early onset MG (EOMG). Here, we describe the repertoire of rearranged heavy chain V genes and their clonal origins in GC from a typical EOMG patient. Three hundred fifteen rearranged Ig V(H) genes were amplified, cloned, and sequenced from sections of four thymic GC containing AChR-specific B cells. We found that thymic GC contain a remarkably heterogeneous population of B cells. Both naive and circulating memory B cells undergo Ag-driven clonal proliferation, somatic hypermutation, and selection. Numerous B cell clones were present, with no individual clone dominating the response. Comparisons of B cell clonal sequences from different GC and known anti-AChR Abs from other patients showed convergent mutations in the complementarity determining regions. These results are consistent with AChR driving an ongoing GC response in the thymus of EOMG patients. This is the first detailed analysis of B cell clones in human GC responding to a defined protein Ag, and the response we observed may reflect the effects of chronic stimulation by autoantigen.


Subject(s)
B-Lymphocyte Subsets/metabolism , Gene Rearrangement, B-Lymphocyte, Heavy Chain/genetics , Germinal Center/metabolism , Mutation , Myasthenia Gravis/genetics , Myasthenia Gravis/immunology , Receptors, Cholinergic/immunology , Thymus Gland/metabolism , Adult , Amino Acid Sequence , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/pathology , Bungarotoxins/metabolism , Clone Cells , Complementarity Determining Regions/biosynthesis , Complementarity Determining Regions/genetics , Female , Gene Amplification , Germinal Center/cytology , Germinal Center/immunology , Germinal Center/pathology , Humans , Immunoglobulin Heavy Chains/biosynthesis , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/biosynthesis , Immunoglobulin Variable Region/genetics , Immunologic Memory/genetics , Interphase/genetics , Interphase/immunology , Iodine Radioisotopes/metabolism , Lymphocyte Activation/genetics , Lymphoid Tissue/cytology , Molecular Sequence Data , Multigene Family/immunology , Receptors, Cholinergic/metabolism , Thymus Gland/cytology , Thymus Gland/immunology , Thymus Gland/pathology , Tumor Cells, Cultured
15.
Proc Natl Acad Sci U S A ; 98(15): 8750-5, 2001 Jul 17.
Article in English | MEDLINE | ID: mdl-11447263

ABSTRACT

Dendritic cells (DC) are crucial for the induction of immune responses and thus an inviting target for modulation by pathogens. We have previously shown that Plasmodium falciparum-infected erythrocytes inhibit the maturation of DCs. Intact P. falciparum-infected erythrocytes can bind directly to CD36 and indirectly to CD51. It is striking that these receptors, at least in part, also mediate the phagocytosis of apoptotic cells. Here we show that antibodies against CD36 or CD51, as well as exposure to early apoptotic cells, profoundly modulate DC maturation and function in response to inflammatory signals. Although modulated DCs still secrete tumor necrosis factor-alpha, they fail to activate T cells and now secrete IL-10. We therefore propose that intact P. falciparum-infected erythrocytes and apoptotic cells engage similar pathways regulating DC function. These findings may have important consequences for the treatment of malaria and may suggest strategies for modulating pathological immune responses in autoimmune diseases.


Subject(s)
Antigens, CD/immunology , Apoptosis/immunology , CD36 Antigens/immunology , Dendritic Cells/immunology , Integrins/immunology , Animals , Antibodies, Monoclonal/immunology , Cell Differentiation , Cells, Cultured , Dendritic Cells/cytology , Dendritic Cells/parasitology , Humans , Integrin alphaV , Interleukin-10/metabolism , Interleukin-12/metabolism , Lymphocyte Activation/immunology , Plasmodium falciparum/immunology , T-Lymphocytes/immunology
16.
Ann Neurol ; 50(1): 64-72, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11456312

ABSTRACT

Antibodies to muscle acetylcholine receptors, to other muscle antigens, and to some cytokines are found in the majority of patients with thymic tumors (thymomas) and myasthenia gravis (MG). The role of the tumor in initiating autoimmunity, however, is unclear; in particular, it is not known whether the thymoma exports mature and long-lived T cells, which could provide help for antibody production in the periphery. Here, we quantified recently exported thymic T cells using the approach of measuring episomal DNA fragments [T-cell receptor excision circles (TRECs)], generated by T-cell receptor gene rearrangement. Compared to values in healthy individuals (n = 10) or in patients with late-onset MG (n = 8), TREC levels were significantly raised in both the CD4+ and CD8+ peripheral blood compartments of patients with thymoma and MG (n = 14, p = 0.002 and p = 0.0004 compared to healthy controls) but only in the CD8+ compartment of the three patients with thymoma without MG (p = 0.4 and p = 0.01 for CD4+ and CD8+). TREC levels decreased following thymectomy to values similar to controls but were substantially raised in patients who had developed tumor recurrence (n = 6, p = 0.04 and p = 0.02 for CD4+ and CD8+); this was associated with increased antibodies to interferon-alpha and interleukin-12 in the one case studied serially. Collectively, these results support the hypothesis that the neoplastic thymoma tissue itself can generate and export mature, long-lived T cells and that these T cells reflect the thymic pathology and are likely to be related to the associated autoimmune diseases. The results also provide a new approach for early diagnosis of thymoma recurrence.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Myasthenia Gravis/immunology , Thymoma/immunology , Thymus Neoplasms/immunology , Adult , Aged , Autoantibodies/immunology , Female , Humans , Lymphocyte Subsets/immunology , Male , Middle Aged , Receptors, Antigen, T-Cell/immunology
17.
J Neuroimmunol ; 115(1-2): 127-34, 2001 Apr 02.
Article in English | MEDLINE | ID: mdl-11282162

ABSTRACT

It is generally considered that myoblasts are unable to prime naive T cell responses without help from professional antigen-presenting cells (APC). However, their ability to present endogenous antigens to previously primed T lymphocytes in the secondary phase of a T cell response has not been well studied. We show here that primary human myoblasts, when stimulated with IFNgamma to express class II MHC, can present an endogenous epitope, probably an acetylcholine receptor (AChR) peptide, to a CD4(+) AChR-specific T helper lymphocyte clone. Presentation leads to secretion of IFNgamma by the T cell clone and, in addition, killing of the myoblast. Our results suggest that, during the effector phase of the immune response, myoblasts could enhance the inflammatory response by presenting endogenous antigen, and thereby become targets for CD4(+) T lymphocyte-induced cytotoxicity; subsequent release of myoblast antigens could then lead to inter- and intra-molecular determinant spreading.


Subject(s)
Autoimmunity/immunology , Epitopes/immunology , Muscles/immunology , Myasthenia Gravis/immunology , Receptors, Cholinergic/immunology , Antigen Presentation/immunology , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cell Division/immunology , Cells, Cultured , Clone Cells , Cytokines/biosynthesis , Dose-Response Relationship, Immunologic , Humans , Muscles/cytology , Muscles/metabolism , Peptide Fragments/immunology , Receptors, Cholinergic/biosynthesis
18.
J Neuroimmunol ; 112(1-2): 163-73, 2001 Jan 01.
Article in English | MEDLINE | ID: mdl-11108945

ABSTRACT

The early-onset myasthenia gravis (EOMG) thymus shows characteristic medullary epithelial bands (MEB), greatly expanded perivascular infiltrates and fenestrations of the intervening basement membranes. We now compare epithelial expression of epidermal growth factor receptor (EGFR) and many integrins in EOMG and control samples. The main differences are striking/consistent thickening (in MEB) of what is normally a monolayer of perivascular epithelium, with focal protrusion into the infiltrates. This evidently hyperplastic epithelial subpopulation also strongly expresses EGFR and certain integrins. We suggest that its enhanced interactions with the locally increased extracellular matrix protein deposits may play an important role in autosensitization.


Subject(s)
Myasthenia Gravis/pathology , Thymus Gland/pathology , Adolescent , Adult , Cell Movement , Child , Epithelial Cells/pathology , Epithelial Cells/physiology , ErbB Receptors/analysis , Extracellular Matrix Proteins/analysis , Female , Humans , Hyperplasia , Integrins/analysis , Male , Myasthenia Gravis/etiology , Myasthenia Gravis/immunology , Phenotype , Thymus Gland/chemistry
20.
Hum Immunol ; 60(9): 909-17, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10527401

ABSTRACT

We have analyzed a series of HLA region markers in 207 UK Caucasoids with early-onset myasthenia gravis (EOMG, onset before age 40), where there is a strong female bias. The well known associations with HLA-DR3 and -B8 have now proved to be significantly stronger in the 165 females than in the 42 males. In patients (of either sex) lacking -DR3, there was also a significant increase in HLA-DR2. Although the muscle weakness in EOMG is clearly mediated by autoantibodies, the associations are consistently stronger with HLA-B8 (in class I) than with HLADR3 (in class II), as confirmed here. We therefore typed 87-137 cases for polymorphisms at four loci in the intervening class III region, and also at three in the adjacent stretch of class I. At each locus, one allele tended to co-occur with HLA-B8 and showed strong and highly significant associations in the patients. There appeared to be a region of maximal susceptibility extending from HSP70 (in class III) past HLA-B and HLA-C at least 600 kb telomerically into the class I region, which is now being mapped in detail. Any candidate genes here that act shortly after puberty may allow more precise localization of susceptibility.


Subject(s)
HLA-C Antigens/genetics , Myasthenia Gravis/genetics , Telomere , Adult , Disease Susceptibility , Female , Genetic Markers , Genetic Predisposition to Disease , HLA-B8 Antigen/genetics , Histocompatibility Testing , Humans , Male , Myasthenia Gravis/immunology
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