Fundamental issues remain unresolved regarding the possible contribution of viruses to vascular pathology, as well as the role of the immune system in regulating these processes. Here we demonstrate that infection of mice with gamma-herpesvirus 68 (gammaHV68) provides a novel model for addressing these issues. Interferon-gamma receptor-deficient (IFNgammaR-/-) mice died weeks to months after gammaHV68 infection from a severe large-vessel panarteritis. GammaHV68-infected B cell-deficient and normal weanling mice exhibited milder large-vessel arteritis. Immunohistochemical analyses demonstrated gammaHV68 antigen in arteritic lesions and revealed a striking tropism of gammaHV68 for smooth muscle cells. These studies demonstrate that IFN-gamma is essential for control of chronic vascular pathology induced by gammaHV68 and suggest gamma-herpesviruses as candidate etiologic agents for human vasculitis.
Diffuse oesophageal leiomyomatosis (DL), an inherited smooth muscle proliferation process, has been reported to be associated with Alport syndrome (AS), a familial nephropathy, mainly dominant X-linked inherited, and characterized by ultrastructural changes of the glomerular basement membrane. The COL4A5 gene, encoding the alpha 5 chain of type IV collagen, has been identified as the site of mutations in families with X-linked AS. Recently, a novel alpha 6(IV) collagen chain encoding gene has been mapped closely upstream of COL4A5, and disruption of the 5' end of both genes has been reported in four patients with DL and AS (DL-AS). Here, we report a long-range restriction map around the COL4A6 locus, and show that the COL4A5/COL4A6 deletion observed in seven patients with DL-AS encompasses only the two first exons of COL4A6, with a breakpoint located in the second intron of COL4A6, whose size exceeds 65 kb. Furthermore, we demonstrate that three patients with AS without DL, known to have a deletion of the 5' part of the COL4A5 gene, display a larger deletion in COL4A6. Moreover, a COL4A6 mRNA product was detected by reverse-transcription-polymerase chain reaction in an oesophageal tumour sample of a patient with DL-AS. These results suggest that DL-AS could be caused by an abnormal truncated alpha 6(IV) chain.
Karyotypic abnormalities were studied in multiple myeloma and were correlated with clinical features. Among 115 evaluable patients, 46% had an abnormal karyotype. Trisomy 3, 5, 9, and 15 and monosomy 13 and 16 were the most common clonal abnormalities. Translocations described previously in other B cell malignancies occurred in nine patients, including four with t(8;14)(q24;q32) translocations. The association of all t(8;14) abnormalities with IgA protein type suggested a pathogenetic relationship between a specific karyotypic abnormality and myeloma protein type. Hypodiploidy occurred mainly in patients with only Bence Jones protein, was associated with resistance to therapy, and justified the early consideration of investigational therapies.
Karyotypic abnormalities were studied in multiple myeloma and were correlated with clinical features. Among 115 evaluable patients, 46% had an abnormal karyotype. Trisomy 3, 5, 9, and 15 and monosomy 13 and 16 were the most common clonal abnormalities. Translocations described previously in other B cell malignancies occurred in nine patients, including four with t(8;14)(q24;q32) translocations. The association of all t(8;14) abnormalities with IgA protein type suggested a pathogenetic relationship between a specific karyotypic abnormality and myeloma protein type. Hypodiploidy occurred mainly in patients with only Bence Jones protein, was associated with resistance to therapy, and justified the early consideration of investigational therapies.
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