Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2001-07-12
2003-12-02
Myers, Carla J. (Department: 1634)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C536S023100, C536S023500, C536S024310, C536S024330
Reexamination Certificate
active
06656691
ABSTRACT:
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to the fields of immunology and molecular biology. More specifically, it relates to methods and reagents for detecting nucleotide sequence variability in the TCF-1 locus that may be associated with risk of developing a Th1- or Th2-mediated inflammatory disease.
DESCRIPTION OF RELATED ART
CD4+ T lymphocytes have been divided into two functionally distinct subsets based on the pattern of cytokines secreted. One subset, designated T helper type 1 (Th1), secrete interleukin 2 (IL-2), IL-12, tumor necrosis factor (TNF), lymphotoxin (LT), and interferon gamma (IFN-&ggr;) upon activation, and are primarily responsible for cell-mediated immunity such as delayed-type hypersensitivity. A second subset, designated T helper type 2 (Th2), secrete IL-4, IL-5, IL-6, IL-9, and IL-13 upon activation, and are primarily responsible for extracellular defense mechanisms. Stimulation of Th2-type lymphocytes results in secretion of lymphokines that induce B cells to produce antibodies and stimulate an increase in eosinophilic cells and IgE production, which results in an increase in mast cells, the release of histamines, and an inflammatory reaction. The role of Th1 and Th2 cells is reviewed in Peltz, 1991, Immunological Reviews 123: 23-35, incorporated herein by reference.
The immunological response to an antigen is mediated through the selective differentiation of CD4+ T helper precursor cells (Th0) to Th1 or Th2 effector cells, with their distinct patterns of lymphokine production. The secretion of the lymphokine subsets further provides a regulatory function in the differentiation of Th0 to Th1 or Th2 effector cells. For example, a lymphokine produced by Th2 cells, IL-4, both promotes the differentiation into Th2 cells and inhibits differentiation into Th1 cells. Conversely, lymphokines produced by Th1 cells, IL-12 and IFN-&ggr;, promote differentiation into Th1 cells, inhibit differentiation into Th2 cells, and suppress IgE synthesis through direct effect on B cells. The reciprocal regulatory effects of the subset-specific lymphokines are involved in the polarization of Th1 or Th2 response.
Human T cells, upon activation in response to antigens involved in the pathogenesis of several chronic inflammatory or allergic diseases, exhibit a selective pattern of lymphokine production characteristic of Th1 or Th2-type cells. Certain autoimmune diseases, such as type 1 diabetes or multiple sclerosis (MS), have been shown to be associated with a predominant Th1 response. Th1-like pattern of lymphokine expression is seen in allergen-specific T cells isolated from patients with chronic Lyme arthritis and in patients with tuberculoid leprosy. In contrast, a Th2-like response of lymphokine expression is seen in allergen-specific T cells isolated from atopic patients. Most of the characteristic features of atopy and asthma, especially IgE synthesis, result from the combined effects of the cytokines secreted from Th2 cells.
It is likely that a selective imbalance or inappropriate activation of Th1 or Th2 T-cell subsets is central to the pathogenesis of certain chronic inflammatory or allergic diseases. Why the immune response of certain individuals to a pathogen or allergen is a protective response, while the immune response of others leads to disease, remains unclear. However, the probability that an individual will develop an inflammatory or allergic disease in response to exposure to a pathogen or allergen may be determined by the type of CD4+ T cell which dominates the response. An immune-mediated disease may develop if the cellular response becomes pathologically fixed in a Th1 or Th2 mode. The ability to clear or resolve a viral infection also may reflect a Th1, rather than a Th2, response.
Genetically determined differences in T-cell differentiation may determine the nature of the T cell response to an antigen, and thus whether there are pathogenic or non-pathogenic consequences. Although the control of T cell differentiation remains to be elucidated, many components of the cascade-like system of genes that control T cell differentiation have been—identified. T cell-specific transcription factor TCF-1 (now officially referred to as TCF-7) is one component of the system of genes that control T cell differentiation. The TCF-1 gene has been cloned and the sequence and structure have been described (see van der Wetering et al., 1992, J. Biol. Chem. 267 (12):8530-8536; van der Wetering et al., 1996, Molecular and Cellular Biology 16(3):745-752; both incorporated herein by reference).
SUMMARY OF INVENTION
The present invention relates to a newly discovered nucleotide sequence polymorphism in exon 2 of the TCF-1 gene and the association of the sequence variants with Th1- and Th2-mediated inflammatory diseases. Identification of the allelic sequence variant(s) present provides information regarding the immune system that may assist in characterizing individuals according to their risk of a disease in which the immune system is a factor, such as an inflammatory disease.
Two allelic sequence variants, which differ by the nucleotide present at nucleotide position 883 of the TCF-1 gene, have been identified. One aspect of the invention relates to genotyping with respect to the sequence variant present at nucleotide position 883.
The TCF-1 allelic differences appear to be associated with the likelihood of a Th1- or Th2-mediated inflammatory disease. As TCF-1 is a component of the system of genes that control T cell differentiation, and genetically determined differences in T-cell differentiation may determine the nature of the T cell response to an antigen, and thus whether there are pathogenic or non-pathogenic consequences, it is expected that allelic differences in the TCF-l gene may affect T-cell differentiation. The association of the TCF-1 allelic differences with the likelihood of a Th1- or Th2-mediated inflammatory disease suggests that TCF-1 allelic differences may be a factor in determining the tendency of a Th1- or Th2-type response. It appears that one of the alleles may be associated with an increased tendency for a Th1-type response in response to an antigen, whereas the other allele may be associated with an increased tendency for a Th2-type response. Thus, the genotyping methods of the present invention provide information regarding a factor that may be relevant to classifying an individual according to their relative tendency to respond to an antigen with a Th1 response or a Th2 response.
As noted above, the probability that an individual will develop an inflammatory or allergic disease in response to exposure to a pathogen or allergen may be determined by the nature of the T cell response. By providing information on the tendency of an individual to respond to an antigen with a Th1 response or a Th2 response, the present invention provides information regarding the individual's immune system that may be relevant to classifying an individual's relative risk of a Th1- or Th2-mediated disease. Thus, the genotyping methods of the present invention provide information regarding a factor that may be relevant to classifying an individual as at increased risk for either a Th1- or Th2-mediated disease.
In particular embodiments, the genotyping methods of the present invention may provide information useful for assessing an individual's risk for particular Th1-mediated diseases, such as multiple sclerosis and type 1 diabetes, or Th2-mediated diseases, such as asthma and atopy. Individuals who have at least one “A” allele possess a factor contributing to the risk of a Th1-mediated disease. Individuals who have at least one “C” allele possess a factor contributing to the risk of a Th2-mediated disease.
As TCF-1 is one component of the complex system of genes that control T cell differentiation, and numerous other genes are involved in an immune response, the TCF-1 genotype on the immune response is one of a number of components which determine the nature of the T cell response and the likelihood of
Begovich Ann Bethea
Erlich Henry Anthony
Grupe Andrew
Noble Janelle Annette
Peltz Gary Allen
Myers Carla J.
Pennie & Edmonds LLP
Roche Molecular Systems Inc.
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