Different amino acids at position 57 of the HLA-DQbeta chain associated with susceptibility and resistance to IgA deficiency

Article Abstract:

Many human diseases are preferentially associated with certain genes of the major histocompatibility complex. This is especially true for diseases with a strong immunological component. It has become common for researchers to correlate disease occurrence with the presence of particular human leukocyte antigens, or HLA. The HLA are the products of the major histocompatibility complex genes. An investigation was carried out to explore the relationship between immunoglobulin A deficiency (IgA), the most common form of human immunodeficiency, and the HLA haplotypes. (Since immunoglobulin A is a secretory protein, the deficiency of this antibody is reflected in infections of the mouth, respiratory tract, and gastrointestinal system.) The investigation focused on the class II antigens, which include DP, DQ, and DR antigens. The discussion can be complicated by the fact that each individual inherits a haplotype, that is, half of his or her MHC genes, from each parent, and thus there are always two DP, DQ, and DR haplotypes in each patient. The investigation of 95 patients with IgA deficiency led to the observation that the disease was strongly correlated with the presence of DRw17. In addition, the haplotypes DR7, DQw2 and DR1, DQw5 were found to be positively associated with IgA deficiency. The haplotype DR15, DQw6 had a strong negative association, that is, subjects with this haplotype are very unlikely to have IgA deficiency. Interestingly, the influence of one haplotype could add to the influence of the haplotype from the other parent. They could even be synergistic; for example, the risk associated with having both DRw17, DQw2 and DR1, DQw5 is far greater than the sum of the risks of either set of genes separately. The molecules associated with IgA deficiency were compared for common features. These molecules were found to have either alanine or valine at position 57 of the DQ-beta chain. Both these amino acids are uncharged. DQ-beta chains negatively associated with susceptibility have a charged aspartic acid at position 57. Curiously, this is the same amino acid position in the protein chain which has been found to be altered in patients with insulin-dependent diabetes. The results indicate the far-reaching consequences of alterations in the protein structure of the HLA histocompatibility antigens. (Consumer Summary produced by Reliance Medical Information, Inc.)

Immunoglobulin A

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Cycling of cell-surface MHC glycoproteins through primaquine-sensitive intracellular compartments

Article Abstract:

A key step in the cellular immune response is the processing of antigens. Foreign proteins are endocytosed, or captured, in vesicles formed from cell membrane, and brought into the cell for processing into smaller peptide fragments. These fragments can then associate with class II molecules of the major histocompatibility complex (MHC), which presents these fragments to antigen-specific cells. (MHC molecules in humans are often called HLA, or human leukocyte antigens.) A major question has been whether MHC molecules from the cell surface are also endocytosed, and, if so, whether they can be recycled again to the cell surface. A common method for monitoring proteins and other cellular products has been tagging the proteins to be studied with radioactive labels. However, investigators have found a way to examine protein recycling using reversible labels. Cell surface molecules, which include class I and class II MHC molecules, and another cell surface molecule, transferrin, were labelled using a radioactive compound which could be cleaved by glutathione. Since glutathione cannot penetrate a healthy cell, the application of this substance removes the radiolabel from the molecules on the outside of the cell without affecting the label of the molecules on the inside. If the molecules are actually recycled, then molecules brought back into the cell should be protected from the removal of their radiolabel. The drug primaquine is known to inhibit the recycling of molecules such as transferrin; if the MHC molecules are recycled also, then primaquine should result in an increased accumulation of radiolabeled MHC molecules within the cell. These methods confirmed that the class I and class II molecules are being recycled. The phenomenon probably was previously unnoticed because the recycling occurs so swiftly that the number of MHC molecules undergoing recycling at any one time is actually quite small. The results suggest that the contribution of recycling to the MHC molecules on the cell surface might be as much as 60 times the contribution of newly synthesized MHC molecules. However, it is not yet known if a class II molecule which has bound a peptide for presentation can be recycled to bind other peptides during the molecule's lifetime. (Consumer Summary produced by Reliance Medical Information, Inc.)

Histocompatibility antigens

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The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases

Article Abstract:

A gene belonging to the src group of proto-oncogenes has been associated with X-linked agammaglobulinemia (XLA), a hereditary immunodeficiency disease occurring in males. The gene, which was isolated in yeast artificial chromosome using complementary DNA and which has been designated atk, probably produces the defective development of B cells in the bone marrow that causes XLA. Furthermore, atk also carries the genetic information for a protein-tyrosine kinase.

Research, Abnormalities, Genetic aspects, Protein tyrosine kinase, Protein-tyrosine kinase, Proto-oncogenes, Agammaglobulinemia

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