From HLA-B27 to spondyloarthritis: a journey through the ER

Summary: Almost four decades of research into the role of human leukocyte antigen-B27 (HLA-B27) in susceptibility to spondyloarthritis has yet to yield a convincing answer. New results from an HLA-B27 transgenic rat model now demonstrate quite convincingly that CD8⁺ T cells are not required for the inflammatory phenotype. Discoveries that the HLA-B27 heavy chain has a tendency to misfold during the assembly of class I complexes in the endoplasmic reticulum (ER) and to form aberrant disulfide-linked dimers after transport to the cell surface have forced the generation of new ideas about its role in disease pathogenesis. In transgenic rats, HLA-B27 misfolding generates ER stress and leads to activation of the unfolded protein response, which dramatically enhances the production of interleukin-23 (IL-23) in response to pattern recognition receptor agonists. These findings have led to the discovery of striking T-helper 17 cell activation and expansion in this animal model, consistent with results emerging from humans with spondyloarthritis and the discovery of IL23R as an additional susceptibility gene for ankylosing spondylitis. Together, these results suggest a novel link between HLA-B27 and the T-helper 17 axis through the consequences of protein misfolding and open new avenues of investigation as well as identifying new targets for therapeutic intervention in this group of diseases.     

Tuberculin Reaction Trends And BCG Vaccination

The problems of refining metallic mercury as they relate to the health of the worker are described. The reliability of several methods for assessing the work environment is shown and a relationship between high mercury environment, increased body load of mercury (as evidenced by urinary excretion), and symptoms of mercurialism in exposed mill workers is demonstrated. Because of the poor reliability of urine mercury levels in determining impending or early mercury poisoning, several biochemical analyses on blood of mill workers were performed. Support is given to the current threshold limit value (TLV) for mercury. However, the data show that this level contains no more than a safety factor of 2.     

Fibrillin‐1 staining anomalies are associated with increased staining for TGF‐β and elastic fibre degradation; new clues to the pathogenesis of emphysema

We recently demonstrated aberrant staining of fibrillin‐1 in lung tissue specimens with emphysematous lesions. In this study, we have extended this observation by an elaborate analysis of the elastic fibre. Using domain‐specific antibodies to fibrillin‐1, and to other elastin fibre‐associated molecules, lung tissue derived from patients without obvious clinical emphysema, but harbouring various degrees of microscopical emphysematous lesions, was analysed. In addition, the fibrillin‐regulated growth factor TGF‐β was studied. Electron microscopy and biochemical analysis of desmosine (a marker for elastin) were also performed. Results were compared with lung tissue derived from patients with clinical emphysema. Domain‐specific antibodies recognizing the C‐terminal, N‐terminal, and middle part of fibrillin‐1 showed aberrant staining patterns associated with increasing degrees of microscopical emphysema. Staining for elastin, emilin‐1, and fibulin‐2 was, however, not aberrant. TGF‐β staining was markedly increased. On the electron microscopic, but not light microscopical, level, initial elastic fibre degradation was noticed in specimens with microscopical emphysema. Lung specimens from patients with clinical emphysema also displayed fragmented fibrillin‐1 staining and, in addition, displayed extensive degradation of the elastic fibre. The results suggest that fibrillin‐1 anomalies and TGF‐β overexpression are associated with initial events occurring during the emphysematous process. Based on these and other data, a mechanism for emphysematogenesis is proposed. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Physical activity during pregnancy and age at menarche of the daughter

In utero exposures have been proposed as possible determinants of later disease risk. Given that a later age at menarche is a breast cancer risk factor, and that higher childhood physical activity has been associated with a later menarcheal age, it is possible that a pregnant mother's activity may also influence this outcome. The purpose of this study was to determine if a mother's physical activity during pregnancy is related to their daughter's menarcheal age. Participants of the Nurses' Health Study II reported their age at menarche to the nearest year, whereas their mothers (n=33,016) completed surveys regarding their health and lifestyle habits during their pregnancy with their daughters. Mothers reported their home, occupational, and leisure-time physical activities, as well as the activity of their daughters at ages 5 to 10 years. Using multiple linear regression analysis with adjustment for specific covariates including daughter's childhood body size, neither home nor occupational activity alone were associated with age at menarche of the daughter, but there was a direct association with leisure-time physical activity (P(trend)<0.001). Compared with women inactive in their leisure-time, women who were highly active had daughters with menarche 1.1 (95% confidence interval, 0.3-1.9) months later. Using a composite variable of both home and leisure-time activity, daughters of women who were highly active at home and in their leisure-time had daughters with menarche 3.1 (95% confidence interval, 0.4-5.9) months later than those who were highly inactive in both. Physical activity during pregnancy may be associated with a modest delay in menarcheal age in offspring.     

Enhanced myocyte contractility and Ca2+ handling in a calcineurin transgenic model of heart failure

OBJECTIVE: Impaired myocyte Ca2+ handling is a common characteristic of failing hearts and increases in calcineurin activity, a Ca2+-sensitive phosphatase, have been implicated in heart failure phenotype. Transgenic mice with cardiac-specific expression of an active form of calcineurin display depressed function, hypertrophy and heart failure. We examined whether defects in cardiomyocyte Ca2+ handling properties contribute to the impaired cardiac function in calcineurin transgenic mice. METHODS: The levels of SR Ca2+ handling proteins, SR Ca2+ transport function and cardiomyocyte mechanics, as well as Ca2+ kinetics were examined in mice overexpressing a constitutively active form of calcineurin. RESULTS: Transgenic expression of activated calcineurin catalytic subunit resulted in significant protein increases (66%) in SERCA2 and decreases (35%) in phospholamban, as well as enhanced (approximately 80%) phospholamban phosphorylation. These alterations in the SR Ca2+-transport proteins resulted in increased V(max) and Ca2+-affinity of SERCA2. The myofibrillar Mg-ATPase activity was also significantly increased at pCa>6.0. The enhanced SR Ca2+ handling and Mg-ATPase activity reflected significant elevation in myocyte contractile parameters (3-fold), Ca2+ transient amplitude (1.5-fold) and the rate of Ca2+ signal decay (2-fold). In contrast, in vivo cardiac function assessed by echocardiography, indicated severely depressed contractility in calcineurin hearts. The apparent disparity in contractile properties between the cellular and multicellular preparations may be partially due to tissue remodeling, including interstitial fibrosis and a marked reduction (45%), dephosphorylation (81%) and redistribution of the gap junctional protein connexin-43, which could compromise intercellular communication. CONCLUSION: Despite enhanced SR Ca2+ handling and contractility in myocytes, pathological remodeling and defects in intercellular coupling may underlie contractile dysfunction of the calcineurin hearts.     

Three germline mutations in the TP53 gene

Three germline mutations in the TP53 tumor-suppressor gene are reported, two of which are not reported previously. A missense mutation at codon 265 of TP53 was found in three patients of a family that complied with the definition of the Li-Fraumeni syndrome. A nonsense mutation in codon 306 was found in a woman who had had a rhabdomyosarcoma at age 4 and a subsequent breast cancer at age 22. She was part of a Li-Fraumeni-like family, but the parental origin of the mutation could not be traced. Finally, while screening for somatic alterations in TP53 in a series of 141 sporadic breast tumors, we detected a constitutional missense mutation in codon 235 in a woman diagnosed with breast cancer at age 26 and a recurrence 4 years later. The recurrence, but not the primary tumor, showed an additional missense mutation at codon 245 as well as loss of the wild-type allele. This suggests that the 245 mutation was particularly important for tumor progression and that there might exist heterogeneity in terms of cancer predisposition potential among the various germline TP53 mutations. Hum Mutat 9:157–163, 1997. © 1997 Wiley-Liss, Inc.