Radiation-induced lung injury in vivo: Expression of transforming growth factor—Beta precedes fibrosis

Cytokine release from irradiated cells has been postulated to start soon after irradiation preceding detectable clinical and pathological manifestation of lung injury. The expression of transforming growth factor beta (TGF), a fibrogenic and radiation-inducible cytokine, was studied from 1–16 weeks after the 15 and 30 Gray (Gy) of thoracic irradiation to rats. Thoracic irradiation caused an increase in TGF protein in bronchoalveolar lavage (BAL) fluid peaking at 3–6 weeks as compared to sham-irradiated control rats. Steady state TGF mRNA expression as shown by whole lung northern blot assay paralleled the TGF protein expression in BAL fluid. The peak of TGF protein increase in BAL fluid between 3 and 6 weeks coincided with the initial influx of inflammatory cells in BAL fluid, but preceded histologically discernable pulmonary fibrosis that was not apparent until 8–10 weeks after irradiation. In conclusion, TGF and mRNA and protein upregulation preceded the radiation-induced pulmonary fibrosis, suggesting a pathogenetic role in the development of radiation fibrosis.     

Identification of non-amplifying CYP21 genes when using PCR-based diagnosis of 21-hydroxylase deficiency in congenital adrenal hyperplasia (CAH) affected pedigrees

Steroid 21-hydroxylase deficiency is among the most common inborn errors of metabolism in man. Characterization of mutations in the 21- hydroxylase gene (CYP21) has permitted genetic diagnosis, facilitated by the polymerase chain reaction (PCR). The most common mutation is conversion of an A or C at nt656 to a G in the second intron causing aberrant splicing of mRNA. Homozygosity for nt656G is associated with profoundly deficient adrenal cortisol and aldosterone synthesis, secondary hypersecretion of adrenal androgens, and a severe form of congenital adrenal hyperplasia (CAH) characterized by ambiguous genitalia and/or sodium wasting in newborns. During the course of genetic analysis of CYP21 mutations in CAH families, we and others have noticed a number of relatives genotyped as nt656G homozygotes, yet showing no clinical signs of disease. A number of lines of evidence have led us to propose that the putative asymptomatic nt656G/G individuals are incorrectly typed due to dropout of one haplotype during PCR amplification of CYP21. For prenatal diagnosis, we recommend that microsatellite typing be used as a supplement to CYP21 genotyping in order to resolve ambiguities at nt656.      

Signaling via LTbetaR on the lamina propria stromal cells of the gut is required for IgA production

Peyer's patches (PPs) and/or mesenteric lymph nodes (MLNs) are thought to be essential for immunoglobulin A (IgA) production. We found that the severe IgA deficiency in lymphotoxin-deficient (LT(-/-)) mice could be fully reversed by reconstitution with LT-expressing bone marrow, despite the absence of both LNs and PPs. The number of IgA precursors from LT(-/-) mice was not reduced, and they were able to migrate into the lamina propria (LP) of wild-type mice but not of LTbetaR(-/-) mice. Consistently, lymphoid tissue chemokines and adhesion molecules were reduced within the LP of LTalpha(-/-) and LTbetaR(-/-) mice. IgA deficiency in LTalpha(-/-) mice was reversed by the transplantation of a segment of RAG-1 (recombination-activating gene 1) deficient intestine, which confirmed the dispensability of the MLNs and PPs and the sufficiency of the LT-mediated gut microenvironment for IgA production.     

Coeliac disease, adenocarcinoma of jejunum and in situ squamous carcinoma of oesophagus

The development of both adenocarcinoma of the jejunum and in situ squamous carcinoma of the oesophagus in an adult coeliac patient is described. Good evidence that adenocarcinoma of jejunum occurs more frequently in patients with coeliac disease has recently become available though this association has been suggested for some time. While oesophageal carcinoma has long been associated with coeliac disease, in situ carcinoma of oesophagus has not been previously described in these circumstances. We feel that the risk of this complication, as calculated from published series, warrants a screening programme for oesophageal malignancy in adult coeliacs.     

Creutzfeldt-Jakob disease (CJD) with a mutation at codon 148 of prion protein gene: relationship with sporadic CJD

Creutzfeldt-Jakob disease (CJD), the most common human prion disease, includes sporadic (s) and familial (f) forms. Regardless of etiology, both forms are thought to share the pathogenic mechanism whereby the cellular prion protein (PrP(C)) converts into its pathogenic isoform (PrP(Sc)). While PrP(C) conversion is thought to be random in sCJD, conversion in fCJD is facilitated by the congenital presence of mutated PrP. Differences in PrP genotype (PRNP) and in conversion circumstances lead to PrP(Sc) with distinct characteristics that elicit different disease phenotypes. Here, we describe a case of fCJD with a substitution of histidine (H) for arginine (R) at codon 148 (R148H) and heterozygosity of the methionine/valine (M/V) polymorphic codon 129, with the 129M allele coupled with the mutation. The disease phenotype and all major characteristics of PrP(Sc) of fCJD(R148H) were virtually indistinguishable from those of sCJDMV2, which has features different from those of any other sCJD. Therefore, despite the differences in etiology, PRNP, and conversion process, the two forms of PrP(Sc) had similar characteristics. Furthermore, comparison of fCJD(R148H) with a recently reported case carrying R148H and homozygosity at codon 129 suggests that codon 129 coupled with the mutation as well as that located on the normal allele can modify major phenotypic and PrP(Sc) features of fCJD(R148H).     

Sensitization of Mice by Inhalation of Antigen After Infection with Bordetella pertussis

Intranasal infection of mice with Bordetella pertussis or injection of pertussis vaccine previous to administration of an albumin aerosol augments sensitivity toward albumin. Sensitization was demonstrated by provocation of anaphylactic reactions following intravenous injection of antigen.     

Tissue-specific homing receptor mediates lymphocyte adhesion to cytokine-stimulated lymph node high endothelial venule cells.

Lymphocytes bind to high endothelial venule (HEV) cells as the first step in the migration of these cells into lymph nodes (LN) and Peyer's patches (PP). In this study we isolated and cultured HEV cells from rat LN and investigated the effects of cytokines on the adhesiveness of these cells for lymphocytes. The results showed that lymphocytes from thoracic duct, spleen and LN adhered preferentially to the cultured LN HEV cells compared to cells isolated from the thymus and bone marrow. The adhesiveness of LN HEV cells for thoracic duct lymphocytes (TDL) was significantly increased in a dose- and time-dependent manner by pretreatment of the HEV cells with tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) or interleukin-4 (IL-4). In contrast, pretreatment of HEV cells with IL-1, IL-6 or IL-7 did not alter the capacity of LN HEV cells to adhere lymphocytes. Furthermore, incubation of LN HEV cells with suboptimal doses of TNF and IL-4, IFN-gamma and IL-4, or TNF-alpha and IFN-gamma increased significantly the endothelial adhesiveness. Interestingly, although IL-1 alone did not promote the adhesiveness of HEV cells, the cytokine synergized with suboptimal doses of IL-4 and TNF-alpha to increase the adhesiveness. The adhesion of TDL to non-stimulated and IL-4-stimulated LN HEV cells could be blocked specifically by treatment of lymphocytes with the LN homing-receptor-specific A.11.5 monoclonal antibody (mAb). In contrast, lymphocytes pretreated with the PP-homing receptor-specific 1B.2.6 mAb or the antileucocyte common antigen (OX1) mAb adhered normally to the HEV cells. Taken together, these results indicate that the baseline and cytokine-stimulated bindings between lymphocytes and LN HEV cells are mediated by adhesive mechanisms that regulate lymphocyte migration into LN in vivo and provide strong evidence that cytokines are central mediators of organ-specific lymphocyte migration.