Non-Classical-MHC Genetics of Immunological Disease in Man and Mouse. The Key Role of Pro-Inflammatory Cytokine Genes

Daser, Angelika; Mitchison, Hannah M.; Mitchison, Avrion; Müller, Brigitte

doi:10.1006/cyto.1996.0079

Cited by 40 publications

(17 citation statements)

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“…Many studies of humans report nucleotide polymorphisms in promoters of cytokines and other immune regulatory loci (Daser et al, 1996;Mitchison, 1997;Cowell et al, 1998;Mitchison et al, 2000;Terry et al, 2000;Smirnova et al, 2001).…”

Section: Empirical Backgroundmentioning

confidence: 99%

Immune Response to Parasitic Attack: Evolution of a Pulsed Character

Frank

2002

Journal of Theoretical Biology

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Section: Empirical Backgroundmentioning

confidence: 99%

Immune Response to Parasitic Attack: Evolution of a Pulsed Character

Frank

2002

Journal of Theoretical Biology

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“…about is likely to be in selective expression in particular cell types (Daser et al 1996;Mitchison 1997). It is thus interesting that the one Mus MHC class II locus with an invariant promoter, E␣ is the only locus with a variant upstream enhancer (M. Janitz, L. Reiners-Schramm, and R. Lauster, in prep.…”

Section: Mhc Promoter Variability Genome Research 129mentioning

confidence: 99%

“…The presumed advantage of heterozygosity lies in the flexibility that it confers on the immune response: The protein under the control of the promoter in one allele is better able to mediate resistance to one type of pathogen, whereas the other allele is better suited to defense against another pathogen. The means by which this is brought about is likely to be in selective expression in particular cell types (Daser et al 1996;Mitchison 1997). It is thus interesting that the one Mus MHC class II locus with an invariant promoter, E␣ is the only locus with a variant upstream enhancer (M. Janitz, L. Reiners-Schramm, and R. Lauster, in prep.…”

Section: Selective Pressurementioning

confidence: 99%

“…The genes that encode extrovert proteins often vary in their coding sequences, so as to provide a range of binding sites for these foreign structures, and vary also in their noncoding regions (for reference, see Mitchison 1997). Variation in noncoding gene segments is also evident to a lesser extent among genes encoding introvert proteins, particularly among cytokines (and their receptors and natural antagonists) (Daser et al 1996). The functional consequences of this promoter sequence variation is not generally known, but its importance in determining expression level is becoming clearer for the class II MHC genes (Louis et al 1994;Woolfrey and Nepom 1995), the ACE I gene (Villard et al 1996), and cytokines genes (Messer et al 1991;Pociot et al 1992).…”

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confidence: 99%

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The Distribution of Variation in Regulatory Gene Segments, as Present in MHC Class II Promoters

et al. 1998

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Diversity in the antigen-binding receptors of the immune system has long been a primary interest of biologists. Recently it has been suggested that polymorphism in regulatory (noncoding) gene segments is of substantial importance as well. Here, we survey the level of variation in MHC class II gene promoters in man and mouse using extensive collections of published sequences together with unpublished sequences recently deposited by us in the EMBL gene bank using the Shannon entropy to quantify diversity. For comparison, we also apply our analysis to distantly related MHC class II promoters, as well as to class I promoters and to class II coding regions. We observe a high level of intraspecies variability, which in mouse but not in man is localized to a significant extent near the binding sites of transcription factors-sites that are conserved over longer evolutionary distances. This localization may both indicate and enhance heterozygote advantage, as the presence of two functionally different promoters would be expected to confer flexibility in the immune response.A surge of interest in the variability of regulatory, noncoding gene segments is under way. Collections have been made of promoter sequences for MHC class I and class II genes in man (Louis et al. 1993;Yao et al. 1995) and class II in mouse (Janitz et al. 1997a), which add substantially to the information previously available for promoter sequences in the hemoglobin (Weatherall 1986;Labie and Elion 1996) and glucose-6-phosphate dehydrogenase (Vulliamy et al. 1992) genes. These are all genes that encode ''extrovert'' proteins that handle diverse foreign structures such as antigens and parasites, in contrast to the ''introvert'' proteins that handle conserved structures internal to the body (Mitchison 1997); hemoglobin and glucose-6-phosphate dehydrogenase have been included in this list as extrovert proteins, as the high level of polymorphism evident in their structural genes results largely from their interaction with malaria parasites. The genes that encode extrovert proteins often vary in their coding sequences, so as to provide a range of binding sites for these foreign structures, and vary also in their noncoding regions (for reference, see Mitchison 1997). Variation in noncoding gene segments is also evident to a lesser extent among genes encoding introvert proteins, particularly among cytokines (and their receptors and natural antagonists) (Daser et al. 1996). The functional consequences of this promoter sequence variation is not generally known, but its importance in determining expression level is becoming clearer for the class II MHC genes (Louis et al. 1994;Woolfrey and Nepom 1995), the ACE I gene (Villard et al. 1996), and cytokines genes (Messer et al. 1991;Pociot et al. 1992). For these MHC genes, valuable collections have been made of very distantly related sequences (Benoist and Mathis 1990), which enable comparisons to be made with the level of intraspecific variation. Thus, the basis for systematic study of this form of variation is no...

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“…In humans, polymorphism has been identified in a wide range of genes encoding such mediators, including IL-1␣, 1 IL-1␤, 2 the IL-1 receptor antagonist, 2 IL-2, 3 IL-3, 4 IL-4, 5-7 the IL-4 receptor 8 the common ␤ subunit of the GM-CSF, IL-3 and IL-5 receptors, 9 IL-6, 10 IL-10, 11 IL-13, 12 IFN-␥, 13,14 TNF-␣, 15 TNF-␤, 16 the TNF receptor, 17 TGF-␤, 18 22 While some of this diversity may represent random genetic variation, evidence suggests that at least some of these polymorphisms do influence the expression of the genes involved. 2,13,15,20,[23][24][25][26] Logically, it would be expected that these polymorphisms might therefore exert an influence on the course and severity of immunologic disease. Accumulating evidence suggests that this is indeed the case.…”

Section: Introductionmentioning

confidence: 99%

The new genetics of bone marrow transplantation

2000

Genes Immun

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There is now little doubt that functional immune polymorphism exists and can exert a significant effect on the severity of immunologic disease. Studies in this area are driven by the belief that an understanding of the influence of immune polymorphism on immunologic disease will improve our ability to predict disease occurrence and severity. The usefulness of this information is necessarily limited, however, by the fact that an individual has a fixed genome. If an individual has an allele which predisposes to increased disease severity, there is little we can do, other than treat the disease in that individual in a more aggressive manner or attempt to find preventative therapies. There is, however, one unique immunologic disorder that is an exception to this rule. Graft-versus-host disease (GVHD), the major complication of bone marrow transplantation, is an immunologic reaction mediated, in large part, by donor T cells. It is unique in that it is the only immunologic disorder in which we can choose the genetics of the immune system causing the disorder. In this disease, more than any other, an understanding of the role of immune polymorphism is essential since we could hypothetically use this information to choose a donor whose T cells will not mediate GVHD of life-threatening severity. In this review, I argue that there is highly suggestive evidence that allelic polymorphism in non-MHC genes encoding mediators of the immune response exerts a very significant effect on the severity of GVHD and that typing for such allelic polymorphisms will in future be as important as MHC-typing in choosing an appropriate donor for bone marrow transplantation. Genes and Immunity (2000) 1, 316-320.

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Non-Classical-MHC Genetics of Immunological Disease in Man and Mouse. The Key Role of Pro-Inflammatory Cytokine Genes

Cited by 40 publications

References 0 publications

Immune Response to Parasitic Attack: Evolution of a Pulsed Character

Immune Response to Parasitic Attack: Evolution of a Pulsed Character

The Distribution of Variation in Regulatory Gene Segments, as Present in MHC Class II Promoters

The new genetics of bone marrow transplantation

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