transforming-growth-factor-beta and Hypergammaglobulinemia

Hyper-IgM immunodeficiency is an immunologic disorder characterized by normal or increased serum IgM levels and reduced serum IgG and IgA levels caused by the disruption of Ig class switching in B cells. The gene encoding activation-induced cytidine deaminase (AID) is responsible for the autosomal recessive form of hyper-IgM syndrome.. To investigate the relationship between the AID gene mutation and the clinical phenotype, we analyzed the AID gene in a female Japanese patient with the autosomal recessive form of hyper-IgM syndrome.. Genomic DNA and cDNA were extracted from neutrophils and analyzed by means of PCR. The AID gene was expressed as a glutathione S-transferase fusion protein. RT-PCR was performed after stimulation of the patient's PBMCs with phorbol myristate acetate and TGF-beta.. Despite significantly low serum IgG levels, our patient had not shown a predisposition to any severe infections, even without Ig replacement therapy. We identified a point mutation resulting in the stop codon in exon 5 of the AID gene (R190X) in the patient. No other mutations of the AID gene were detected in the patient. The same mutation was not detected in other members of her family. The mutant allele fused with the glutathione S-transferase protein was expressed stably at the same level as the normal allele. The AID gene expression in the patient was induced by phorbol myristate acetate and TGF-beta.. The mutation of the AID gene is assumed to be of the dominant negative form. This is the first report of a dominant negative form of the mutation in vivo.

Topics: Alleles; Base Sequence; Child; Cytidine Deaminase; Female; Gene Expression; Genes, Dominant; Humans; Hypergammaglobulinemia; Immunoglobulin M; Molecular Sequence Data; Monocytes; Point Mutation; Tetradecanoylphorbol Acetate; Transforming Growth Factor beta

The glomerulopathy of monoclonal immunoglobulin light chain deposition disease is a progressive disorder characterized by accumulation of monoclonal light chains and matrix proteins in the mesangium. To define the role of light chains in this process, cultured rat mesangial cells were exposed to different light chains and human albumin. Two light chains were purified from the urine of patients who had biopsy-proven light chain deposition disease. These proteins inhibited mesangial cell proliferation and increased production of matrix proteins, including type IV collagen, laminin, and fibronectin. By immunocytochemistry and bioassay, transforming growth factor-beta (TGF-beta) production and activity increased when mesangial cells were exposed to these proteins. Furthermore, anti-TGF-beta antibody abolished the inhibition of cell proliferation and the increase of extracellular matrix protein production caused by these light chains. These findings were not observed in mesangial cells exposed to human albumin and two other light chains previously characterized to be tubulopathic. We concluded that the glomerulopathic light chains increased TGF-beta, which inhibited mesangial cell proliferation and increased matrix protein production. Together with overexpression of TGF-beta in affected glomeruli of light chain deposition disease, light chain-mediated stimulation of mesangial cells to produce TGF-beta appears to be a key pathological mechanism of this disease.

Topics: Animals; Cell Division; Cells, Cultured; Extracellular Matrix Proteins; Glomerular Mesangium; Glomerulosclerosis, Focal Segmental; Humans; Hypergammaglobulinemia; Immunoglobulin Light Chains; Kidney Diseases; Male; Microscopy, Electron; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta