Human immune diseasegene identification

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The majority of common diseases such as cancer, allergy, diabetes or heart disease are characterized by complex genetic traits where genetic and environmental components contribute to disease susceptibility (Hirschhorn et al 2002). Our knowledge of genetic factors contributing to the risk of common diseases is, however, limited. A major goal in the post-genomic era is to identify and characterize disease susceptibility genes and to define strategies to use this knowledge for disease treatment and prevention. The mouse is the most important model organism for the study of human disease genetics, and discovery and validation of potential therapies. Genetic manipulations that can be performed in the mouse include point mutations, gene disruptions, insertions, deletions, or chromosomal rearrangements or random genome-wide mutagenesis (Muller 1999, Zambrowicz & Friedrich 1998). The FANTOM2 project has focused on the functional annotation of 60770 cDNA RIKEN clones by large-

scale, computerized annotation followed by manual curation. Being the most complete picture of the mouse transcriptome to date, the FANTOM2 dataset provides an ideal opportunity for identification of novel mouse orthologues of human genes involved in normal immune function and/or immune disease. We analysed the RIKEN dataset to identify potential novel genes in mouse that are highly similar (70—85% in more than 70% length) to human counterparts that have been described in relation to immune disease and found 14 mouse clones related to rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease and Sjogren's syndrome with nine of the genes encoding autoantigens.

Systemic lupus erythematosus (SLE) is an autoimmune disease associated with impaired humoral and cellular immune responses characterized by a chronic inflammation of the connective tissue, affecting different systems such as joints, kidneys, serous surfaces, and vessel walls (Oelke & Richardson 2002). Antibodies to multiple different self proteins are found in the serum of these patients (Lim et al 2002). Antibodies against DNA, nucleoproteins, histones, nuclear ribonucleoprotein and other nuclear constituents (anti-nuclear antibodies) are found in more than 98% of patient with SLE. Identification of these autoantibodies is of high diagnostic value for SLE. An immunoinformatic search of the RIKEN dataset found novel mouse transcripts similar to the SLE autoantigens, DEK protein, AHNAK, replication protein A and U1 small nuclear ribonucleoprotein C. Rheumatoid arthritis (RA) is a chronic disease characterized by the presence of an inflammatory infiltrate in the synovial capsule inducing progressive destruction of bone and cartilage in the joints. We identified novel mouse proteins similar to L1 retrotransposable elements, small nuclear ribonucleoprotein-associated protein and cAMP-responsive element binding protein, which have all been previously described as autoantigens in RA. We found a mouse transcript similar to Golgin-97, a Golgi complex antigen that is an autoantigen in patients with Sjogren's syndrome (Griffith et al 1997). We also identified a mouse sequence similar to the human zinc finger protein, Cezanne (cellular zinc finger anti-NFkB), a NFkB negative regulator (Evans et al 2001). NFkB is related to multiple inflammatory diseases including rheumatoid arthritis (Muller-Ladner et al 2002). A mouse clone was identified that bore close similarity to NOD2, a member of the Apaf1/Ced4 superfamily of apoptosis regulators that activates the nuclear factor NFkB to enable monocytes in response to bacterial challenges, and is defective in patients with Crohn's disease (Hugot et al 2001). Finally, a mouse clone similar to human HA-1 was identified that may represent a novel minor histocompatability antigen. Minor histocompatibility complexes play a key role in graft versus host (GVH) as well as playing a beneficial role in the graft versus leukaemia response (GVL). Identification of antigenic peptides related to minor histocompatibility molecules responsible for the induction of

GVL and not GVHD is a promising avenue for treatment of allogeneic bone marrow and haematopoietic stem-cell transplantation (Warren et al 1998).

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