Biosynthesis and secretion of MHC class III gene products (complement C4 and factor B) in the exocrine pancreas

The second (C2) and fourth (C4) components of complement and factor B (B) are coded for by genes within the major histocompatibility complex (MHC). These proteins are synthesized in liver and in extrahepatic mononuclear phagocytes. The isolation of complementary DNA probes corresponding to each of these proteins now permits analysis of the molecular mechanisms controlling expression of the class III MHC genes. Genetic control of C4 gene expression has been examined in two model systems. A defect in post transcriptional processing of C4-specific RNA accounts for a failure to generate mature C4 mRNA in homozygous deficients of a C4 deficient guinea-pig strain. On the other hand, a quantitative difference in the amounts of mature C4 liver mRNA accounts for the genetic variation in C4 levels observed among several mouse strains. The maturation of monocytes to macrophages results in changes in biosynthesis of the MHC class III products; for example, a significant increase in rate of secretion of C2 and B is noted in human monocytes during the first 3 d in culture and the proportion of C2-producing cells is greater in freshly isolated macrophages than in monocytes. Macrophages demonstrate selective increases in factor B and C2 mRNA characteristic of specific tissues. In the guinea-pig macrophage, C4 gene expression is regulated by a selective feedback mechanism induced by extracellular native C4. The C4 binds to the macrophage cell surface mediating a change in transcription or, less likely, a change in stability of C4 mRNA. Regulation of C4 synthesis in the mouse macrophage is accomplished by mechanisms that are independent of this feedback control but the murine cells also display separate mechanisms for regulation of C4 and factor B-specific mRNA levels. Resident and elicited macrophages from either mouse or guinea-pig differ with respect to expression of the class III MHC gene products. These studies form the basis for evaluating the molecular regulation of inflammation, maturation of mononuclear phagocytes and the genetic variants and deficiencies of complement proteins.

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cis and trans elements differ among mouse strains with high and low extrahepatic complement factor B gene expression.

Journal of Experimental Medicine ◽

10.1084/jem.175.2.471 ◽

1992 ◽

Vol 175 (2) ◽

pp. 471-479 ◽

Cited By ~ 14

Author(s):

G Garnier ◽

B Ault ◽

M Kramer ◽

H R Colten

Keyword(s):

Gene Expression ◽

Dna Binding ◽

Alternative Pathway ◽

Constitutive Expression ◽

Mouse Strains ◽

Complement Factor ◽

Class Iii ◽

Factor B ◽

Tissue Specific ◽

Mhc Class Iii

Factor B (Bf), an enzyme of the alternative pathway of complement activation, is one of four major histocompatibility complex (MHC) class III genes. To ascertain the genetic mechanism for tissue-specific constitutive and regulated expression of Bf, we sequenced the regulatory regions 5' of the gene from mice of different H-2 MHC haplotypes and assessed trans-acting factors, specific DNA binding nucleoproteins, in liver and kidney. Striking tissue-specific differences in constitutive expression of Bf were demonstrated in mice of H-2f or H-2z haplotypes when compared with H-2d or H-2u (kidney and intestinal Bf in H-2d or H-2u much greater than H-2f or H-2z). These differences correlated with a point nucleotide substitution 3 bp downstream of the upstream Bf initiation site that affects interaction with a DNA binding protein. This and additional cis differences localize the sequence substitutions responsible for previously identified restriction fragment length polymorphisms among inbred mouse strains and also reveal two previously unrecognized polymorphisms generated by SmaI and HinfI digestion. Evidence for differences in trans was found in a comparison of DNA binding nucleoproteins from kidney, but not liver, of B10.PL when compared with B10.M. These data, together with the high degree of sequence homology between human and mouse Bf 5' flanking regions, should prompt a search for polymorphic restriction sites and cis binding elements in the Bf promoter that could serve as markers of human MHC-associated renal pathology and variants in local MHC class III gene expression.

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