Cardiac manifestations are a major cause of morbidity and mortality in patients with eosinophil-a... more Cardiac manifestations are a major cause of morbidity and mortality in patients with eosinophil-associated diseases. Eosinophils are thought to play a pathogenic role in myocarditis. We investigated the pathways that recruit eosinophils to the heart using a model of eosinophilic myocarditis, in which experimental autoimmune myocarditis (EAM) is induced in IFNγ −/− IL-17A −/− mice. Two conditions are necessary for efficient eosinophil trafficking to the heart: high eotaxin (CCL11, CCL24) expression in the heart and expression of the eotaxin receptor CCR3 by eosinophils. We identified cardiac fibro-blasts as the source of CCL11 in the heart interstitium. CCL24 is produced by F4/80 + macrophages localized at inflammatory foci in the heart. Expression of CCL11 and CCL24 is controlled by Th2 cytokines, IL-4 and IL-13. To determine the relevance of this pathway in humans, we analyzed endomyocardial biopsy samples from myocarditis patients. Expression of CCL11 and CCL26 was significantly increased in eosinophilic myocarditis compared to chronic lymphocytic myocarditis and positively correlated with the number of eosinophils. Thus, eosinophil trafficking to the heart is dependent on the eotaxin-CCR3 pathway in a mouse model of EAM and associated with cardiac eotaxin expression in patients with eosinophilic myocarditis. Blocking this pathway may prevent eosinophil-mediated cardiac damage.
Clinical evidence suggests that idiosyncratic hepatitis following administration of halogenated v... more Clinical evidence suggests that idiosyncratic hepatitis following administration of halogenated volatile anesthetics is mediated by autoimmune responses. No murine model to study mechanisms of anesthetic-induced or any other form of drug-induced idiosyncratic hepatitis exists. Anesthetics are believed to trigger hepatitis by covalently linking a trifluoroacetyl (TFA) chloride hapten to hepatic proteins, forming haptenated self-proteins. To test this hypothesis, we developed a hapten-induced model of hepatitis by immunization with syngeneic S100 liver proteins covalently coupled to TFA (TFA-S100). We found that TFA-S100 induced hepatitis was more severe than disease induced by S100 plus adjuvants or by the adjuvant alone and was characterized by neutrophil, mast cell, and eosinophil infiltration. TFA-specific IgG1 antibodies directly correlated with hepatitis, whereas S100 autoantibodies did not. TNF-alpha, IL-1beta, and IL-6 released from splenocytes collected 2 weeks after TFA-S100 inoculation were increased resembling the elevated serum cytokines reported in patients with autoimmune hepatitis (AIH). Three weeks after inoculation, the peak of hepatitis, we noted decreased numbers of Kupffer cells and lower levels of IL-6 and IL-10 in the liver, cytokines produced by Kupffer cells. This is the first report, to our knowledge, of a hapten-induced model of hepatitis with immune and autoimmune features.
Appropriate treatment of autoimmune myocarditis following virus infection remains a major clinica... more Appropriate treatment of autoimmune myocarditis following virus infection remains a major clinical problem. Induction of nasal tolerance may provide a new approach to treatment. However, the exact mechanism of nasal tolerance is unknown. To assess the mechanism of nasal tolerance, we examined the role of IL-10 in the induction and suppression of autoimmune myocarditis. First we showed that blocking IL-10
Experimental biology and medicine (Maywood, N.J.), 2001
The therapeutic effect of a nutritional supplement consisting of a combination of glucosamine hyd... more The therapeutic effect of a nutritional supplement consisting of a combination of glucosamine hydrochloride (FCHG49), purified sodium chondroitin sulfate (TRH122), and manganese ascorbate (GCM)3 was investigated in the rat model of collagen-induced autoimmune arthritis (CIA). The GCM compound was mixed with a palatable nutritional paste (Nutri-cal [NC]). Oral administration of the NC/GCM compound was initiated in 26 rats 10 days before immunization and continued until the day of sacrifice. One group of 12 control rats was given no oral agents; a second group of 12 control rats received NC only. Evaluations included arthritis index (AI) scoring by three independent evaluators, histologic index (HI) scoring of lesions, T-cell proliferation, and serological studies for antibody classes and subclasses. Both the AI and HI criteria showed a statistically significant reduction in the prevalence of CIA in rats pretreated with the NC/GCM (54%) compared to the combined control groups (96%, ch...
Journal of immunology (Baltimore, Md. : 1950), 1999
Autoantibodies to thyroglobulin (Tg) are a prominent feature of the two autoimmune thyroid diseas... more Autoantibodies to thyroglobulin (Tg) are a prominent feature of the two autoimmune thyroid diseases, chronic lymphocytic (Hashimoto's) thyroiditis and Graves' disease. Similar autoantibodies are found in the serum of many normal individuals without evidence of thyroid disease. Previous studies have indicated that patients with autoimmune thyroid disease recognize epitopes of Tg which are not usually recognized by normal individuals. The goal of this investigation was to identify peptide fragments of Tg bearing these disease-associated epitopes. For this purpose, we utilized a panel of mAbs that bind to different epitopes of the Tg molecule. One of these mAbs (137C1) reacted with an epitope that was also recognized by the sera of patients with autoimmune thyroiditis. In the present study, we show that two peptides (15 and 23 kDa) that reacted with mAb 137C1 are located in different parts of the Tg molecule. Each peptide inhibited the binding of mAb 137C1 to the other peptide ...
Excess iodine ingestion has been implicated in induction and exacerbation of autoimmune thyroidit... more Excess iodine ingestion has been implicated in induction and exacerbation of autoimmune thyroiditis in human populations and animal models. We studied the time course and sex-related differences in iodine-induced autoimmune thyroiditis in NOD-H-2h4 mice. This strain, derived from a cross of NOD with B10.A(4R), spontaneously develops autoimmune thyroiditis but not diabetes. NOD-H-2h4 mice were given either plain water or water with 0.05% iodine for 8 weeks. Approximately 54% of female and 70% of male iodine-treated mice developed thyroid lesions, whereas only 1 of 20 control animals had thyroiditis at this time. Levels of serum thyroxin (T4) were similar in the treatment and control groups. Thyroglobulin-specific antibodies were present in the iodine-treated group after 8 weeks of treatment but antibodies to thyroid peroxidase were not apparent in the serum of any of the animals. Levels of thyroglobulin antibodies increased throughout the 8-week iodine ingestion period; however, no c...
To map the antigenic determinants, a panel of 20 mouse monoclonal antibodies (mAbs) to native hum... more To map the antigenic determinants, a panel of 20 mouse monoclonal antibodies (mAbs) to native human thyroglobulin (Tg) was generated. Four criteria were established for distinguishing the determinants recognized by the various mAbs: (i) reactivity to Tgs from eight different species; (ii) reactivity to oxidized and reduced human Tg; (iii) the ability of thyroxine to inhibit binding of mAbs; and (iv) the pattern of antigenic determinant reactivity as determined in reciprocal competitive inhibition binding assays. Of 20 mAbs examined, 12 bound only to human Tg, 3 bound to all eight species tested, and 5 bound to human Tg and to Tg from at least one of the other seven species. Eight mAbs bound oxidized/reduced and native human Tg equally well, 2 bound to the oxidized/reduced protein better than to the native, 7 showed virtually no reactivity to oxidized/reduced human Tg, and 3 others reacted to the oxidized/reduced protein significantly less than they bound to the native. The binding o...
The Journal of experimental medicine, Jan 30, 2014
Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in individuals below... more Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in individuals below the age of 40. We recently reported that IL-17A is required for the development of DCMi. We show a novel pathway connecting IL-17A, cardiac fibroblasts (CFs), GM-CSF, and heart-infiltrating myeloid cells with the pathogenesis of DCMi. Il17ra(-/-) mice were protected from DCMi, and this was associated with significantly diminished neutrophil and Ly6Chi monocyte/macrophage (MO/MΦ) cardiac infiltrates. Depletion of Ly6Chi MO/MΦ also protected mice from DCMi. Mechanistically, IL-17A stimulated CFs to produce key chemokines and cytokines that are critical downstream effectors in the recruitment and differentiation of myeloid cells. Moreover, IL-17A directs Ly6Chi MO/MΦ in trans toward a more proinflammatory phenotype via CF-derived GM-CSF. Collectively, this IL-17A-fibroblast-GM-CSF-MO/MΦ axis could provide a novel target for the treatment of DCMi and related inflammatory cardiac diseases.
An epidemiologic study of the autoimmune diseases taken together has not been done heretofore. Th... more An epidemiologic study of the autoimmune diseases taken together has not been done heretofore. The National Patient Register of Denmark is used to estimate the population prevalence of 31 possible or probable autoimmune diseases. Record linkage is used to estimate 465 pairwise co-morbidities in individuals among the 31 diseases, and familial aggregation among sibs, parents and offspring. The prevalence of
Karger is a medical publisher, scientific publisher and biomedical publisher of print and online ... more Karger is a medical publisher, scientific publisher and biomedical publisher of print and online journals and books.
Page 1. 3 Environmental Factors in Autoimmune Endocrinopathies Rajni B. Sharma, PHD, C. Lynne Bur... more Page 1. 3 Environmental Factors in Autoimmune Endocrinopathies Rajni B. Sharma, PHD, C. Lynne Burek, PHD, Daniela Cihákova, MD, PHD, Dolores B. Njoku, MD, and Noel R. Rose, MD, PHD CONTENTS INTRODUCTION ...
Postinfection sera from A.CA/SnJ A.SW/SnJ, B10.S/SgSf, and B10.PL/SgSf mouse strains which varied... more Postinfection sera from A.CA/SnJ A.SW/SnJ, B10.S/SgSf, and B10.PL/SgSf mouse strains which varied in their susceptibility to Coxsackievirus B3-induced immunopathology were suspected to contain autoantibodies against cardiac tissue. These sera were used to identify the target myocardial autoantigen(s). Sera pools were made during the peak of the early, virus-induced myocarditis at 5 and 7 days and during the peak of the late, immunopathic phase of myocarditis at Days 15 and 21 after infection. Only the A.CA/SnJ and A.SW/SnJ strains which develop the immunopathic heart disease had heart-specific autoantibodies as determined by indirect immunofluorescence. This panel of sera pools was then tested against solubilized extracts from whole heart and skeletal muscles. Results from Western immunoblotting analyses demonstrated that antibodies to myosin were a prominent feature in the sera of strains which developed immunopathic myocarditis. The immunopathic sera pools were subsequently assayed against low-salt, high-salt, and a number of detergent extracts of heart and skeletal muscle. Anti-myosin was still the most notable reactivity, even though other autoantigens were detected. Absorption with cardiac myosin removed the vast majority of heart reactivity from the pooled sera derived from the A.CA/SnJ and A.SW/SnJ strains as determined within the limitations of the immunofluorescent and immunochemical assays. Both sarcolemmal and A-band staining patterns were abolished by the cardiac myosin absorption. These studies suggest that myosin is one of the major autoantigens in Coxsackievirus B3-induced autoimmune myocarditis.
Clinical evidence suggests that idiosyncratic hepatitis following administration of halogenated v... more Clinical evidence suggests that idiosyncratic hepatitis following administration of halogenated volatile anesthetics is mediated by autoimmune responses. No murine model to study mechanisms of anesthetic-induced or any other form of drug-induced idiosyncratic hepatitis exists. Anesthetics are believed to trigger hepatitis by covalently linking a trifluoroacetyl (TFA) chloride hapten to hepatic proteins, forming haptenated self-proteins. To test this hypothesis, we developed a hapten-induced model of hepatitis by immunization with syngeneic S100 liver proteins covalently coupled to TFA (TFA-S100). We found that TFA-S100 induced hepatitis was more severe than disease induced by S100 plus adjuvants or by the adjuvant alone and was characterized by neutrophil, mast cell, and eosinophil infiltration. TFA-specific IgG1 antibodies directly correlated with hepatitis, whereas S100 autoantibodies did not. TNF-alpha, IL-1beta, and IL-6 released from splenocytes collected 2 weeks after TFA-S100 inoculation were increased resembling the elevated serum cytokines reported in patients with autoimmune hepatitis (AIH). Three weeks after inoculation, the peak of hepatitis, we noted decreased numbers of Kupffer cells and lower levels of IL-6 and IL-10 in the liver, cytokines produced by Kupffer cells. This is the first report, to our knowledge, of a hapten-induced model of hepatitis with immune and autoimmune features.
Cardiac manifestations are a major cause of morbidity and mortality in patients with eosinophil-a... more Cardiac manifestations are a major cause of morbidity and mortality in patients with eosinophil-associated diseases. Eosinophils are thought to play a pathogenic role in myocarditis. We investigated the pathways that recruit eosinophils to the heart using a model of eosinophilic myocarditis, in which experimental autoimmune myocarditis (EAM) is induced in IFNγ −/− IL-17A −/− mice. Two conditions are necessary for efficient eosinophil trafficking to the heart: high eotaxin (CCL11, CCL24) expression in the heart and expression of the eotaxin receptor CCR3 by eosinophils. We identified cardiac fibro-blasts as the source of CCL11 in the heart interstitium. CCL24 is produced by F4/80 + macrophages localized at inflammatory foci in the heart. Expression of CCL11 and CCL24 is controlled by Th2 cytokines, IL-4 and IL-13. To determine the relevance of this pathway in humans, we analyzed endomyocardial biopsy samples from myocarditis patients. Expression of CCL11 and CCL26 was significantly increased in eosinophilic myocarditis compared to chronic lymphocytic myocarditis and positively correlated with the number of eosinophils. Thus, eosinophil trafficking to the heart is dependent on the eotaxin-CCR3 pathway in a mouse model of EAM and associated with cardiac eotaxin expression in patients with eosinophilic myocarditis. Blocking this pathway may prevent eosinophil-mediated cardiac damage.
Clinical evidence suggests that idiosyncratic hepatitis following administration of halogenated v... more Clinical evidence suggests that idiosyncratic hepatitis following administration of halogenated volatile anesthetics is mediated by autoimmune responses. No murine model to study mechanisms of anesthetic-induced or any other form of drug-induced idiosyncratic hepatitis exists. Anesthetics are believed to trigger hepatitis by covalently linking a trifluoroacetyl (TFA) chloride hapten to hepatic proteins, forming haptenated self-proteins. To test this hypothesis, we developed a hapten-induced model of hepatitis by immunization with syngeneic S100 liver proteins covalently coupled to TFA (TFA-S100). We found that TFA-S100 induced hepatitis was more severe than disease induced by S100 plus adjuvants or by the adjuvant alone and was characterized by neutrophil, mast cell, and eosinophil infiltration. TFA-specific IgG1 antibodies directly correlated with hepatitis, whereas S100 autoantibodies did not. TNF-alpha, IL-1beta, and IL-6 released from splenocytes collected 2 weeks after TFA-S100 inoculation were increased resembling the elevated serum cytokines reported in patients with autoimmune hepatitis (AIH). Three weeks after inoculation, the peak of hepatitis, we noted decreased numbers of Kupffer cells and lower levels of IL-6 and IL-10 in the liver, cytokines produced by Kupffer cells. This is the first report, to our knowledge, of a hapten-induced model of hepatitis with immune and autoimmune features.
Appropriate treatment of autoimmune myocarditis following virus infection remains a major clinica... more Appropriate treatment of autoimmune myocarditis following virus infection remains a major clinical problem. Induction of nasal tolerance may provide a new approach to treatment. However, the exact mechanism of nasal tolerance is unknown. To assess the mechanism of nasal tolerance, we examined the role of IL-10 in the induction and suppression of autoimmune myocarditis. First we showed that blocking IL-10
Experimental biology and medicine (Maywood, N.J.), 2001
The therapeutic effect of a nutritional supplement consisting of a combination of glucosamine hyd... more The therapeutic effect of a nutritional supplement consisting of a combination of glucosamine hydrochloride (FCHG49), purified sodium chondroitin sulfate (TRH122), and manganese ascorbate (GCM)3 was investigated in the rat model of collagen-induced autoimmune arthritis (CIA). The GCM compound was mixed with a palatable nutritional paste (Nutri-cal [NC]). Oral administration of the NC/GCM compound was initiated in 26 rats 10 days before immunization and continued until the day of sacrifice. One group of 12 control rats was given no oral agents; a second group of 12 control rats received NC only. Evaluations included arthritis index (AI) scoring by three independent evaluators, histologic index (HI) scoring of lesions, T-cell proliferation, and serological studies for antibody classes and subclasses. Both the AI and HI criteria showed a statistically significant reduction in the prevalence of CIA in rats pretreated with the NC/GCM (54%) compared to the combined control groups (96%, ch...
Journal of immunology (Baltimore, Md. : 1950), 1999
Autoantibodies to thyroglobulin (Tg) are a prominent feature of the two autoimmune thyroid diseas... more Autoantibodies to thyroglobulin (Tg) are a prominent feature of the two autoimmune thyroid diseases, chronic lymphocytic (Hashimoto's) thyroiditis and Graves' disease. Similar autoantibodies are found in the serum of many normal individuals without evidence of thyroid disease. Previous studies have indicated that patients with autoimmune thyroid disease recognize epitopes of Tg which are not usually recognized by normal individuals. The goal of this investigation was to identify peptide fragments of Tg bearing these disease-associated epitopes. For this purpose, we utilized a panel of mAbs that bind to different epitopes of the Tg molecule. One of these mAbs (137C1) reacted with an epitope that was also recognized by the sera of patients with autoimmune thyroiditis. In the present study, we show that two peptides (15 and 23 kDa) that reacted with mAb 137C1 are located in different parts of the Tg molecule. Each peptide inhibited the binding of mAb 137C1 to the other peptide ...
Excess iodine ingestion has been implicated in induction and exacerbation of autoimmune thyroidit... more Excess iodine ingestion has been implicated in induction and exacerbation of autoimmune thyroiditis in human populations and animal models. We studied the time course and sex-related differences in iodine-induced autoimmune thyroiditis in NOD-H-2h4 mice. This strain, derived from a cross of NOD with B10.A(4R), spontaneously develops autoimmune thyroiditis but not diabetes. NOD-H-2h4 mice were given either plain water or water with 0.05% iodine for 8 weeks. Approximately 54% of female and 70% of male iodine-treated mice developed thyroid lesions, whereas only 1 of 20 control animals had thyroiditis at this time. Levels of serum thyroxin (T4) were similar in the treatment and control groups. Thyroglobulin-specific antibodies were present in the iodine-treated group after 8 weeks of treatment but antibodies to thyroid peroxidase were not apparent in the serum of any of the animals. Levels of thyroglobulin antibodies increased throughout the 8-week iodine ingestion period; however, no c...
To map the antigenic determinants, a panel of 20 mouse monoclonal antibodies (mAbs) to native hum... more To map the antigenic determinants, a panel of 20 mouse monoclonal antibodies (mAbs) to native human thyroglobulin (Tg) was generated. Four criteria were established for distinguishing the determinants recognized by the various mAbs: (i) reactivity to Tgs from eight different species; (ii) reactivity to oxidized and reduced human Tg; (iii) the ability of thyroxine to inhibit binding of mAbs; and (iv) the pattern of antigenic determinant reactivity as determined in reciprocal competitive inhibition binding assays. Of 20 mAbs examined, 12 bound only to human Tg, 3 bound to all eight species tested, and 5 bound to human Tg and to Tg from at least one of the other seven species. Eight mAbs bound oxidized/reduced and native human Tg equally well, 2 bound to the oxidized/reduced protein better than to the native, 7 showed virtually no reactivity to oxidized/reduced human Tg, and 3 others reacted to the oxidized/reduced protein significantly less than they bound to the native. The binding o...
The Journal of experimental medicine, Jan 30, 2014
Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in individuals below... more Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in individuals below the age of 40. We recently reported that IL-17A is required for the development of DCMi. We show a novel pathway connecting IL-17A, cardiac fibroblasts (CFs), GM-CSF, and heart-infiltrating myeloid cells with the pathogenesis of DCMi. Il17ra(-/-) mice were protected from DCMi, and this was associated with significantly diminished neutrophil and Ly6Chi monocyte/macrophage (MO/MΦ) cardiac infiltrates. Depletion of Ly6Chi MO/MΦ also protected mice from DCMi. Mechanistically, IL-17A stimulated CFs to produce key chemokines and cytokines that are critical downstream effectors in the recruitment and differentiation of myeloid cells. Moreover, IL-17A directs Ly6Chi MO/MΦ in trans toward a more proinflammatory phenotype via CF-derived GM-CSF. Collectively, this IL-17A-fibroblast-GM-CSF-MO/MΦ axis could provide a novel target for the treatment of DCMi and related inflammatory cardiac diseases.
An epidemiologic study of the autoimmune diseases taken together has not been done heretofore. Th... more An epidemiologic study of the autoimmune diseases taken together has not been done heretofore. The National Patient Register of Denmark is used to estimate the population prevalence of 31 possible or probable autoimmune diseases. Record linkage is used to estimate 465 pairwise co-morbidities in individuals among the 31 diseases, and familial aggregation among sibs, parents and offspring. The prevalence of
Karger is a medical publisher, scientific publisher and biomedical publisher of print and online ... more Karger is a medical publisher, scientific publisher and biomedical publisher of print and online journals and books.
Page 1. 3 Environmental Factors in Autoimmune Endocrinopathies Rajni B. Sharma, PHD, C. Lynne Bur... more Page 1. 3 Environmental Factors in Autoimmune Endocrinopathies Rajni B. Sharma, PHD, C. Lynne Burek, PHD, Daniela Cihákova, MD, PHD, Dolores B. Njoku, MD, and Noel R. Rose, MD, PHD CONTENTS INTRODUCTION ...
Postinfection sera from A.CA/SnJ A.SW/SnJ, B10.S/SgSf, and B10.PL/SgSf mouse strains which varied... more Postinfection sera from A.CA/SnJ A.SW/SnJ, B10.S/SgSf, and B10.PL/SgSf mouse strains which varied in their susceptibility to Coxsackievirus B3-induced immunopathology were suspected to contain autoantibodies against cardiac tissue. These sera were used to identify the target myocardial autoantigen(s). Sera pools were made during the peak of the early, virus-induced myocarditis at 5 and 7 days and during the peak of the late, immunopathic phase of myocarditis at Days 15 and 21 after infection. Only the A.CA/SnJ and A.SW/SnJ strains which develop the immunopathic heart disease had heart-specific autoantibodies as determined by indirect immunofluorescence. This panel of sera pools was then tested against solubilized extracts from whole heart and skeletal muscles. Results from Western immunoblotting analyses demonstrated that antibodies to myosin were a prominent feature in the sera of strains which developed immunopathic myocarditis. The immunopathic sera pools were subsequently assayed against low-salt, high-salt, and a number of detergent extracts of heart and skeletal muscle. Anti-myosin was still the most notable reactivity, even though other autoantigens were detected. Absorption with cardiac myosin removed the vast majority of heart reactivity from the pooled sera derived from the A.CA/SnJ and A.SW/SnJ strains as determined within the limitations of the immunofluorescent and immunochemical assays. Both sarcolemmal and A-band staining patterns were abolished by the cardiac myosin absorption. These studies suggest that myosin is one of the major autoantigens in Coxsackievirus B3-induced autoimmune myocarditis.
Clinical evidence suggests that idiosyncratic hepatitis following administration of halogenated v... more Clinical evidence suggests that idiosyncratic hepatitis following administration of halogenated volatile anesthetics is mediated by autoimmune responses. No murine model to study mechanisms of anesthetic-induced or any other form of drug-induced idiosyncratic hepatitis exists. Anesthetics are believed to trigger hepatitis by covalently linking a trifluoroacetyl (TFA) chloride hapten to hepatic proteins, forming haptenated self-proteins. To test this hypothesis, we developed a hapten-induced model of hepatitis by immunization with syngeneic S100 liver proteins covalently coupled to TFA (TFA-S100). We found that TFA-S100 induced hepatitis was more severe than disease induced by S100 plus adjuvants or by the adjuvant alone and was characterized by neutrophil, mast cell, and eosinophil infiltration. TFA-specific IgG1 antibodies directly correlated with hepatitis, whereas S100 autoantibodies did not. TNF-alpha, IL-1beta, and IL-6 released from splenocytes collected 2 weeks after TFA-S100 inoculation were increased resembling the elevated serum cytokines reported in patients with autoimmune hepatitis (AIH). Three weeks after inoculation, the peak of hepatitis, we noted decreased numbers of Kupffer cells and lower levels of IL-6 and IL-10 in the liver, cytokines produced by Kupffer cells. This is the first report, to our knowledge, of a hapten-induced model of hepatitis with immune and autoimmune features.
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