The I region of the major histocompatibility complex (MHC) of the mouse (H-2) contains a tightly-linked cluster of highly polymorphic genes (class II MHC genes) which control immune responsiveness. Speculation on the origin of this polymorphism, which is believed to be essential for the function of the class II proteins in immune responses to disease, has given rise to two hypotheses. The first is that hypermutational mechanisms (gene conversion or segmental exchange) promote the rapid generation of diversity in MHC genes. The alternative is that polymorphism has arisen from the steady accumulation of mutations over long evolutionary periods, and multiple specific alleles have survived speciation (trans-species evolution). We have looked for evidence of 'segmental exchange' and/or 'trans-species evolution' in the class II genes of the genus Mus by molecular genetic analysis of I-A beta alleles. The results indicate that greater than 90% (28 out of 31) of the alleles examined can be organized into two evolutionary groups both on the basis of restriction site polymorphisms and by the presence or absence of a short interspersed nucleotide element (SINE). Using this SINE sequence as an evolutionary tag, we demonstrate that I-A beta alleles in these two evolutionary groups diverged at least three million years ago and have survived the speciation events leading to several modern Mus species. Nucleotide sequence comparisons of eight Mus m. domesticus I-A beta alleles representing all three evolutionary groups indicate that most of the divergence in exon sequences is due to the steady accumulation of mutations that are maintained independently in the different alleles. But segmental exchanges between alleles from different evolutionary groups have also played a role in the diversification of beta 1 exons.
A panel of dendritic epidermal T cell (DETC) lines, and hybridomas derived from them, has been shown to spontaneously secrete lymphokines in the absence of added stimuli, which suggests that these cells are autoreactive. These cell lines are characterized by the expression of a V gamma 1.1C gamma 4/V delta 6 type T cell receptor (TcR), but several of the DETC lines also express a second TcR. Sequence analyses of these gamma/delta TcR revealed that the gamma chains were identical and that the delta chains, while not identical, were quite restricted in diversity, indicating that these receptors may recognize a common or closely related group of antigens. Analysis of hybridomas derived from newborn thymocytes identified six hybridomas that spontaneously secrete lymphokines. Five hybrids expressed a V gamma 1.1C gamma 4/V delta 6 receptor and one hybrid a V gamma 1.1C gamma 4/V delta 4 receptor that had a close structural relationship to the DETC gamma/delta TcR associated with spontaneous lymphokine secretion. gamma/delta TcR of the C gamma 4 type expressed by splenic hybridomas that did not spontaneously secrete lymphokines revealed no such relationship. Curiously, like the DETC, several of the thymocyte hybridomas that spontaneously secreted lymphokines expressed a second TcR, V gamma 2C gamma 1 or V gamma 3C gamma 1, apparently in association with the same delta chain that paired with the C gamma 4 chain. The presence of spontaneous lymphokine-secreting gamma/delta T cells with such highly homologous TcR in both the thymus and skin suggests a thymic origin for the autoreactive DETC and that these cells recognize a common or closely related group of self-antigens.
A longitudinal study of circulating autoantibodies in the sera of 48 BB rats was performed by indirect immunofluorescence. No pancreatic islet cell, adrenocortical, or thyroid microsomal autoantibodies were found. However, autoantibodies reactive to gastric parietal cells (PCA), smooth muscle, and thyroid colloidal antigens were identified, PCA were not detected in Wistar-Furth or BB x Wistar-Furth F1 hybrid rats. The range of ages at the time of first appearance of PCA was the same as that of onset of insulin-dependent diabetes (IDD) in the BB rats, suggesting that the processes leading to PCA and IDD were occurring at the same time of life in these animals. The presence of PCA was associated with degrees of lymphocytic gastritis and with squamous metaplasia of the gastric mucosa in the oldest BB rats (9 mo of age). Levels of serum iron and vitamin B12 did not differ between PCA-positive and PCA-negative BB rats, nor was achiorhydria found in any rat studied. The identification of PCA (and chronic gastritis) and other autoantibodies in the BB rat suggests that these animals have an underlying autoimmune diathesis. These findings thus provide indirect support for an autoimmune pathogenesis for IDD in the BB rat.
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