Ir gene control of carrier recognition. I. Immunogenicity of bovine insulin derivatives

Keck, K.

doi:10.1002/eji.1830051202

Cited by 37 publications

(11 citation statements)

References 33 publications

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“…Thus, the pathology of islet {3 cells in dbdb mice appears to result from interactions between the mutant gene and the inbred strain background. Among the other background strain genes thought to influence the expression of the obese/diabetic syn drome are those at the major histocompatibility complex (MHC), which exert major influence on immunologic responsiveness to insulin (117). Other loci involved in modulation of ICA expression include one for steroid sulfatase that is present on both X and Y chromosomes but is differentially expressed in BKs (diabetes susceptible) and B6 (diabetes resistant) strains (125) .…”

Section: Islet Cell Autoantibody Production: Relationship To Ob and Dmentioning

confidence: 99%

Animal Models of Obesity: Genetic Aspects

Johnson¹,

Greenwood²,

Horwitz

et al. 1991

Annu. Rev. Nutr.

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Among the candidate genes that have been reviewed herein, adipsin, calcitonin, cholecystokin, Gi alpha and Gs subunits of G proteins, insulin I and II, and lipoprotein lipase have all been mapped to specific chromosomes in mouse or rat or both. In none of these cases is the chromosomal location syntenic with murine obesity genes db (on chromosome 4), or ob (on chromosome 6). Thus, all of these genes that code for metabolic modulators that are altered in obese animals but not in lean animals can be ruled out as possible loci of the primary genetic defect, at least for the murine models of obesity. In the case of neuropeptide Y, growth hormone, glucose transporter GLUT-4, the insulin receptor, and glyceraldehyde-3-phosphate dehydrogenase, chromosomal mapping has not yet been reported. However, in each of these cases, the evidence available strongly argues against any one of these physiologic modulators as the likely site of the primary defect for any one of the obesity mutations. Rather, in all of these cases, regardless of whether or not the gene has been mapped, the evidence suggests that posttranscriptional and/or post-translational processes are involved in bringing about the specific alterations in level or activity of the protein product that is seen in the obese animal. Often hormonal regulation is invoked as a possible explanation for the changes observed in gene expression. The hormones most commonly identified as having a mediating effect on the particular metabolic pathways involved are insulin and/or the adrenal glucocorticoids. Since in each of the obese mutants, circulating amounts of these hormones are elevated, severely so in the case of insulin, it would not be surprising to find that they influence the levels and activities of many protein products involved in a variety of central nervous system and peripheral metabolic pathways. Glucocorticoids are known to exert direct effects on gene expression; however, with respect to adipsin gene expression, a direct effect has not been found. Furthermore, insulin itself has been considered as a candidate for the genetic lesion in these animals and has been ruled out by chromosomal localization. Thus, while it may certainly prove to be the case that both insulin and glucocorticoids affect these systems in some way, their effects appear to be indirect. The work by Platt and colleagues in transgenic mice provides the first evidence of signal transduction between an obese mutant allele and the promoter sequence for a gene that shows significantly altered expression in the obese animal.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Islet Cell Autoantibody Production: Relationship To Ob and Dmentioning

confidence: 99%

Animal Models of Obesity: Genetic Aspects

Johnson¹,

Greenwood²,

Horwitz

et al. 1991

Annu. Rev. Nutr.

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“…Similar to the response to insulin, it follows that the response to the aggregate will be controlled by the genes of the major histocompatibility complex. In humans, mice, and guinea pigs, l-region genes control T-lymphocyte responses to insulin (17)(18)(19)(20). In vitro studies with human T-lymphocytes have shown that more epitopes can be recognized than would be anticipated from studies of inbred animals and that many of these epitopes are not related to amino acid exchanges (19)(20)(21).…”

Section: Discussionmentioning

confidence: 97%

“…In humans, mice, and guinea pigs, l-region genes control T-lymphocyte responses to insulin (17)(18)(19)(20). In vitro studies with human T-lymphocytes have shown that more epitopes can be recognized than would be anticipated from studies of inbred animals and that many of these epitopes are not related to amino acid exchanges (19)(20)(21). Additionally, anti-insulin antibodies have been demonstrated in subjects treated with human insulin (15) or in type I diabetic patients before therapy (4,5,22).…”

Section: Discussionmentioning

confidence: 99%

Antibodies to Covalent Aggregates of Insulin in Blood of Insulin-Using Diabetic Patients

et al. 1987

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A covalent aggregate twice the size of insulin accounts for approximately 28% of total circulating insulin immunoreactivity in type I diabetic patients. These aggregates are probably covalent dimers of insulin and should contain unique epitopes distinct from the parent molecule. Therapeutic insulin contains a similar material and is the source of the circulating aggregate. Anti-aggregate antibodies were detected by binding-inhibition techniques in 9 of 29 long-term diabetic patients. These antibodies were directed against structures distinct from those of the parent molecule insulin monomer. All antibody-positive patients were men whose blood also contained antibodies to insulin monomer. We conclude that the blood of approximately 30% of insulin-using diabetic patients contains antibodies directed against epitopes unique to the insulin aggregates. Because insulin monomer and aggregates probably share a common primary amino acid sequence, the anti-aggregate antibodies are probably directed against conformational determinants. Further work is needed to determine whether such aggregates promote or accentuate the development of anti-insulin antibodies in certain genetically predisposed individuals.

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“…The former is an antigen whose epitope depends on a specific sequence of 3 amino acids in the A chain loop. It is under Ir gene control, mapping to the I-Ab subregion of the H-2 complex [32,33], and seems to require Ia.W39 for optimal antigen presentation [22]. The latter (TNP-OVA) is a multideterminant antigen, which is not under specific Ir gene control, but requires Ia+ M@ for antigen presentation [34].…”

Section: Expression Of Ia W39 On Antigen-presenting Cellsmentioning

confidence: 99%

Role of Ia.W39 in the interaction of antigen‐presenting cells with T and B lymphocytes

Huber

Rosenwasser

1982

Eur J Immunol

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Ia. W39 is a B cell differentiation antigen whose membrane expression is controlled by the xid gene. In this report we show that, analogous to its B cell expression, Ia. W39 is also present on a subset of Ia+ macrophages, indicating heterogeneity within that cell population. The Ir gene(s) for the antigenic determinants on the A chain loop of beef insulin maps to the I-Ab subregion of the H-2 complex and, as we have previously reported, is associated with the private specificity Ia. W39. Depletion of Ia. W39+ macrophages eliminates their capacity to present beef insulin to immune T cells, whereas the presentation of the multideterminant antigen trinitrophenylated ovalbumin is reduced less than 50%. Furthermore, we found that H-2b mice lacking Ia. W39+ cells are unable to make a secondary in vivo IgG plaque-forming cell (PFC) response to beef insulin, while the primary IgG PFC response is not dependent on Ia. W39. No shift in the kinetics of the response, nor development of suppressor T cells could be detected in Ia. W39- mice, which would explain their apparent nonresponsiveness to beef insulin after boosting with this antigen. These results, therefore, may reflect a difference in the Ir gene control acting at the primary vs. secondary response level.

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Ir gene control of carrier recognition. I. Immunogenicity of bovine insulin derivatives

Cited by 37 publications

References 33 publications

Animal Models of Obesity: Genetic Aspects

Animal Models of Obesity: Genetic Aspects

Antibodies to Covalent Aggregates of Insulin in Blood of Insulin-Using Diabetic Patients

Role of Ia.W39 in the interaction of antigen‐presenting cells with T and B lymphocytes

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