The case of the wonky mouse

Article Abstract:

The cause of multiple sclerosis (MS) is not known, and there is no effective treatment for this neurological disorder. Most researchers believe that MS is an autoimmune disease that results when cells from the patient's own immune system mistakenly attack the fatty myelin sheaths that insulate nerve fibers within the brain and spinal cord. The change in the physiological properties of nerve conduction, as these sheaths are slowly destroyed, accounts for the symptoms of the disease. The supposition that MS is an autoimmune disorder is based primarily on two lines of evidence: the indications of immune reaction in MS lesions; and the characteristics of the experimental allergic encephalomyelitis (EAE), which is clearly autoimmune in laboratory animals and resembles MS closely. In the October 10, 1991 issue of Nature, researchers report results that shed doubt on the validity of the autoimmune model of MS. Using techniques of molecular biology, the researchers developed strains of mice with genetic abnormalities in the expression of a class I H-2 gene; H-2 genes in mice are the equivalent of the histocompatibility (HLA) genes in humans. The mice were genetically engineered so that there would be an abnormally large expression of H-2 antigen on the oligodendrocytes, the cells that make the myelin sheaths. Some of the resulting transgenic mice developed neurological symptoms resembling EAE. However, in these mice, which have been dubbed 'wonky', there is no indication of an autoimmune process in their brains and spinal cords. This may indicate that the immune responses seen in MS lesions may be merely a result of the destruction of the myelin and not the cause of it. However, the results of this experiment must also be interpreted with caution. In the process of preparing the genetically engineered mice, the expression of myelin basic protein (MBP) appears to have been altered. The neurological symptoms of the mice may be unrelated to changes in the H-2 antigens on the brain cells, and may be the result of the disruption of the normal processes by which myelin is built. The 'wonky mouse' may develop its neurological symptoms by a process that has nothing in common with the processes involved in MS. (Consumer Summary produced by Reliance Medical Information, Inc.)

Editorial, Multiple sclerosis, Genetically modified mice, Histocompatibility antigens

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Antigen presentation: peptide feeding and cellular cookery

Article Abstract:

A clear picture of the role of the histocompatibility antigens in the cellular immune response is beginning to emerge. The histocompatibility antigens were originally discovered as a consequence of, and derived their name from, their mediation of transplant rejection. However, it has become clear that the natural role of these cell surface molecules is to present antigen to T cells. The major histocompatibility complex, or MHC, genetically codes the H-2 antigens in mice, which are directly analogous to the human leucocyte antigen molecules in man. Research on the class I H-2 molecules has now revealed a striking relationship between the molecules themselves and the peptide fragments of the antigen they are to present. The histocompatibility molecules on the cell surface exist in a complex consisting of class I heavy chains, a molecule called beta-2 microglobulin, and the antigen fragment to be presented. An important question for immunologists was what happened to the histocompatibility molecules without antigens to present. Research has now demonstrated that the heavy chains-beta-2 complex is not stable at normal body temperature. Many of the molecules simply do not make it to the cell surface, and those that do quickly fall apart and are degraded. This can be demonstrated by cooling the cells below normal body temperature. At the lower temperature, the molecules are more stable and are readily detected. In addition, it can be shown that adding antigen fragments to the medium containing the cells increases the amount of detectable H-2 molecules. Presumably, the antigen fragments bind to the unstable molecules, preventing them from becoming degraded; as more molecules become stabilized, more are detectable at the cell surface. It would seem that the turnover of these molecules might guarantee that, if a fragment of antigen were to become available, a histocompatibility molecule would be there to bind it and present it to the T cells. (Consumer Summary produced by Reliance Medical Information, Inc.)

HLA histocompatibility antigens

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The box and the rod

Article Abstract:

T-cell coreceptors CD4 and CD8 have been found to have similar crystal structures but are different in their major histocompatibility complex (MHC) binding sites. CD8 uses complementarity determining regions (CDR) to bind to class I MHC molecules, a strategy analogous to antibodies' binding. In contrast, CD4 does not use its CDR-like regions in this manner. Moreover, the mutagenesis of CD4's MHC-binding site indicates that CD4 is more extensively bound to MHC than is CD8.

T cell antigen receptors, T cells, Binding sites (Biochemistry), Active sites (Biochemistry)

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