Abnormal TNF production in prediabetic BB rats is linked to defective CD45R expression

The genetic basis and diabetes association of aberrant tumour necrosis factor-alpha (TNF-alpha) production by activated peritoneal macrophages in diabetes-prone (dp) biobreeding (BB) rats was analysed. Southern blot analysis could not detect a restriction fragment length polymorphism for the TNF gen...

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Bibliographic Details
Published in:Immunology 1992-09, Vol.77 (1), p.1-6
Main Authors: Rothe, H, Schuller, I, Richter, G, Jongeneel, C V, Kiesel, U, Diamantstein, T, Blankenstein, T, Kolb, H
Format: Article
Language:English
Subjects:
Animals
Blotting, Southern
Diabetes Mellitus, Type 1 - genetics
Diabetes Mellitus, Type 1 - immunology
Female
Genes - immunology
Leukocyte Common Antigens - analysis
Macrophages - immunology
Male
Polymerase Chain Reaction
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Rats
Rats, Inbred BB
Rats, Inbred Lew
Rats, Inbred Strains
Tumor Necrosis Factor-alpha - biosynthesis
Tumor Necrosis Factor-alpha - genetics
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Summary:The genetic basis and diabetes association of aberrant tumour necrosis factor-alpha (TNF-alpha) production by activated peritoneal macrophages in diabetes-prone (dp) biobreeding (BB) rats was analysed. Southern blot analysis could not detect a restriction fragment length polymorphism for the TNF gene distinguishing dp BB rats from Wistar (Wi) rats and diabetes resistant (dr) BB rats. The contiguous genetic arrangement of lymphotoxin (LT) and TNF genes described in mouse and man was also found in the rat by cloning a chromosomal region covering both genes. In search of a polymorphic marker we amplified a (CA)n:(GT)n microsatellite in the TNF promoter region by polymerase chain reaction (PCR). We detected two alleles, (CA)26 and (CA)33, but no correlation with diabetes risk was seen. Crosses between dp BB rats and Wi or Lewis. 1A (Lew. 1A) rats, respectively, indicated that aberrant TNF-alpha production of activated macrophages is inherited dominantly with only weak penetrance. Analysis of the F2 generation and backcrosses with the two parental strains showed that aberrant TNF production co-segregates with lymphopaenia and defective CD45R expression, markers known to reflect a diabetes predisposing gene(s) outside the RT1 complex. We conclude that a single linkage group is responsible for both aberrant TNF production and defective T-cell maturation in dp BB rats.
ISSN:0019-2805
1365-2567