- Email: [email protected]
Breaking down immunity to the fungal wall
The
testis differentiation and, again, Sex9 was switched off in both gonads in the fema!e, only one of which becomes a mature ovaq¢. The latter suggests the presence of an independent ovadan-detem)inant. Gender determination is a complex and important dinicaB issue. The primary criteria for assignation to male vs. female are hotly debated: chromosomal vs. gene (SRY positive/negative) gender, external genitalia, gonads or gender identity, This issue is not on~yof centra~ importance to the individual but has come to the fore in competitive sports. With time, the molecular process of sex determination will become more clearly understood; it is certain~y not as simple as we thought.
Mich~le RamsayPhi) Reader, Departmentof HumanGenetics, SouthAfrican institute for Medica0Researchand School of Pathology, UniversityoftheW~lwatersrand,Johannesburg,SouthAtdca.
inibrain genes and cdtica loci for Down syndrome
abnormalities in the regulation of the number of particular types of neuronal ceDls. Expression of mnb RNA has also been examined ~n s/tu in mouse brains, using a probe designed from the human eDNA sequence. The expression pattern of rnnb in mice was broadSyconsistent with the areas of the brain affected in bS, where a reduction in neuronaB number and cretan brain size :s a0so observed. The MNB genes each encode a serinelthreonine protein kinase, consistent with a role in the regulation of cellular proliferation. This work re-emphasizes the important role of model organisms in the study of human genetics. The mnb Drosophila mutant provided an important insight in,to the probable function of the human MNB gene. it seems likely that complex interactions between this and the otl~er chromosome 21 genes that are expressed during neuronal development, and whose expression levels are altered by the presence of a third generate copy, will be responsible for the characteristic mental handicap seen in DS. The identification of such genes and the study of interactions between them, for exampie in trar~sgenic mice, should ~ead to a greater understanding of the DS phenotype ard of normal brain development.
Katllnjn L. Evans PhD A huma~ homologue of Drosophila
minibrain (MNB) is expressed in the neuronal regions affected in Down syndrome and maps to the critical region
ResearchAssociate, MRC HumanGenetics Unit, Western General Hospital, Crewe Road, Edinburgh, UK EH4 2XU.
Guimer, J. et al. (1996) Hum. Mot. Goner, 5,1305=1310
With a frequency of 1 in 600 live birlhs, Down syndrome (DS) is the most common genetic cause
of mental handicap. In additionto mental handicap, there are a seriesof othercharacteristicsthatexhibit variable penetrance. The majority of cases of DS are caused by trisomy (a third complete copy) of chromosome 21 although ~5% of DS individuals have only partialtrisomies.Analysisof these partial trisomies has resulted in a proposed minimum region that has to be present in three copies to resuit in DS: the DS criticalregion(DSCR). The ability to infer a DSCR remains controversial, mainly because even when the trisomy is complete the expressionof the associatedtraits is stillvariable. Guimer and co-workers isolated genes, by exon trapping and eDNA selection, from cosmids that spanned the DSCR. A number of the partial cDNAs were homologous to a Drosophila melanogasterminibrain (mnb) gene. The complete human cDNA for this homologous region (MNB) was then isolated. Drosophilawith mutant mnb show a reduction in specificbrain structures,apparentlyarisingfrom Copyright©i996
Mn,q down imrnun to fungaJwall ................................................ ::.....................................................
Fungal ~-glucan interacts with vitronectin and stimulates turnout n~rosis factor ~ release from macrophages Olson, E.J. et a/. (1996)
~iterature
(TNFo{~),which then coordinates the host's inflam matory defence to ~he fungus. Other studies, however, show that in contrast to the ~nduction of TNF-c~, ~-gtucan suppresses TNF-~-induced septic shock. This paper attempts to explain thcse paradoxica8 findings. OBsen and co-workers examined the complex effects of f3-glucan on TNF-~ production by rabbit macrophages. Bn response to #-glucan, a~veolar macrophages produced TNF-~ in a biphasic, dose-dependent manner. At the highest concentrations, TNF-a production was inhibited to a level below spontaneous release in the absence of pglucan, by absorption of TNF-~ from the culture supematant by ~°glucan. Adhesive g~ycoproteins present in the p~asma and aNeoRarspaces were found to enhance both the recognition of fungi and their attachment to macrophages. One of these adhesive proteins, vitronectin, was shown to bind to 13-glucan. When complexes of 13-glucan and vitronectin were used to stimulate macrophages, TNF-a secretion was enhanced compared wilh the level of TNF-e elicited by I~-glucan alone. These experiments contribute a new ootentiat mechanism for the biphasic TNF.a response of macrophages to 13-glucan and suggest how host factors could amplify and enhance the sensitivity of the inflammatory response to fungi. In addition to a role in resistance to infection, these mechanisms could be relevant to the understanding of SBS - a condition that is thougl~t to be linked to low-level exposure to inhaled fungal products. Although ~his paper doesn't address tt~e issue of increased nest su~c~plibiNy ~.oi0~fectionwilh fungi, identitication of a pro-inflammatory component of fungi and dissection of the mechanism by which it activates inflammation in the lung could be of importance ~n monitoring ihe toxicity of the indoor environment, Furthermore, an increased understanding of the absorption of pro-inflammatory cytokines might be of importance in the development of therapies in which these cytokines are involved.
Infect. lmmun. 64, 35483554
Colin R.A. Hewitt PhD ResearchFellow, ImmunotoxicologyLaboratory,Centre
Every breath taken contains particles derived from living organisms. Some fungal and bacterial particles cause infection, whereas others provoke allergies or might be involved in ill-defined illnesses such a~ sick building syndrome (SBS). I]-Glucans are present in the cell walls of most fungi; they are implicated in the inflammatory responses seen in both (ungal infection and SBS [Rylander, R. et al. (1992) Indoor Environ. 1, 263-267]. They are recognized by receptors on macrophages and promote the adI~esionof fungi to the phagocytesurfacemembrane. Many studies
for Mechanismsof HumanToxicity,Universityof Le=cester. PO Box 138, LancasterRoad, Leicester,UK LE1 9HN
show that on binding ~-glucan, macrophages produce the cytokine tumour necrosis factor
Elsevier Science Ltd. All rights reserved. 1357 - 4310/96/$15.00
,~9~
testis differentiation and, again, Sex9 was switched off in both gonads in the fema!e, only one of which becomes a mature ovaq¢. The latter suggests the presence of an independent ovadan-detem)inant. Gender determination is a complex and important dinicaB issue. The primary criteria for assignation to male vs. female are hotly debated: chromosomal vs. gene (SRY positive/negative) gender, external genitalia, gonads or gender identity, This issue is not on~yof centra~ importance to the individual but has come to the fore in competitive sports. With time, the molecular process of sex determination will become more clearly understood; it is certain~y not as simple as we thought.
Mich~le RamsayPhi) Reader, Departmentof HumanGenetics, SouthAfrican institute for Medica0Researchand School of Pathology, UniversityoftheW~lwatersrand,Johannesburg,SouthAtdca.
inibrain genes and cdtica loci for Down syndrome
abnormalities in the regulation of the number of particular types of neuronal ceDls. Expression of mnb RNA has also been examined ~n s/tu in mouse brains, using a probe designed from the human eDNA sequence. The expression pattern of rnnb in mice was broadSyconsistent with the areas of the brain affected in bS, where a reduction in neuronaB number and cretan brain size :s a0so observed. The MNB genes each encode a serinelthreonine protein kinase, consistent with a role in the regulation of cellular proliferation. This work re-emphasizes the important role of model organisms in the study of human genetics. The mnb Drosophila mutant provided an important insight in,to the probable function of the human MNB gene. it seems likely that complex interactions between this and the otl~er chromosome 21 genes that are expressed during neuronal development, and whose expression levels are altered by the presence of a third generate copy, will be responsible for the characteristic mental handicap seen in DS. The identification of such genes and the study of interactions between them, for exampie in trar~sgenic mice, should ~ead to a greater understanding of the DS phenotype ard of normal brain development.
Katllnjn L. Evans PhD A huma~ homologue of Drosophila
minibrain (MNB) is expressed in the neuronal regions affected in Down syndrome and maps to the critical region
ResearchAssociate, MRC HumanGenetics Unit, Western General Hospital, Crewe Road, Edinburgh, UK EH4 2XU.
Guimer, J. et al. (1996) Hum. Mot. Goner, 5,1305=1310
With a frequency of 1 in 600 live birlhs, Down syndrome (DS) is the most common genetic cause
of mental handicap. In additionto mental handicap, there are a seriesof othercharacteristicsthatexhibit variable penetrance. The majority of cases of DS are caused by trisomy (a third complete copy) of chromosome 21 although ~5% of DS individuals have only partialtrisomies.Analysisof these partial trisomies has resulted in a proposed minimum region that has to be present in three copies to resuit in DS: the DS criticalregion(DSCR). The ability to infer a DSCR remains controversial, mainly because even when the trisomy is complete the expressionof the associatedtraits is stillvariable. Guimer and co-workers isolated genes, by exon trapping and eDNA selection, from cosmids that spanned the DSCR. A number of the partial cDNAs were homologous to a Drosophila melanogasterminibrain (mnb) gene. The complete human cDNA for this homologous region (MNB) was then isolated. Drosophilawith mutant mnb show a reduction in specificbrain structures,apparentlyarisingfrom Copyright©i996
Mn,q down imrnun to fungaJwall ................................................ ::.....................................................
Fungal ~-glucan interacts with vitronectin and stimulates turnout n~rosis factor ~ release from macrophages Olson, E.J. et a/. (1996)
~iterature
(TNFo{~),which then coordinates the host's inflam matory defence to ~he fungus. Other studies, however, show that in contrast to the ~nduction of TNF-c~, ~-gtucan suppresses TNF-~-induced septic shock. This paper attempts to explain thcse paradoxica8 findings. OBsen and co-workers examined the complex effects of f3-glucan on TNF-~ production by rabbit macrophages. Bn response to #-glucan, a~veolar macrophages produced TNF-~ in a biphasic, dose-dependent manner. At the highest concentrations, TNF-a production was inhibited to a level below spontaneous release in the absence of pglucan, by absorption of TNF-~ from the culture supematant by ~°glucan. Adhesive g~ycoproteins present in the p~asma and aNeoRarspaces were found to enhance both the recognition of fungi and their attachment to macrophages. One of these adhesive proteins, vitronectin, was shown to bind to 13-glucan. When complexes of 13-glucan and vitronectin were used to stimulate macrophages, TNF-a secretion was enhanced compared wilh the level of TNF-e elicited by I~-glucan alone. These experiments contribute a new ootentiat mechanism for the biphasic TNF.a response of macrophages to 13-glucan and suggest how host factors could amplify and enhance the sensitivity of the inflammatory response to fungi. In addition to a role in resistance to infection, these mechanisms could be relevant to the understanding of SBS - a condition that is thougl~t to be linked to low-level exposure to inhaled fungal products. Although ~his paper doesn't address tt~e issue of increased nest su~c~plibiNy ~.oi0~fectionwilh fungi, identitication of a pro-inflammatory component of fungi and dissection of the mechanism by which it activates inflammation in the lung could be of importance ~n monitoring ihe toxicity of the indoor environment, Furthermore, an increased understanding of the absorption of pro-inflammatory cytokines might be of importance in the development of therapies in which these cytokines are involved.
Infect. lmmun. 64, 35483554
Colin R.A. Hewitt PhD ResearchFellow, ImmunotoxicologyLaboratory,Centre
Every breath taken contains particles derived from living organisms. Some fungal and bacterial particles cause infection, whereas others provoke allergies or might be involved in ill-defined illnesses such a~ sick building syndrome (SBS). I]-Glucans are present in the cell walls of most fungi; they are implicated in the inflammatory responses seen in both (ungal infection and SBS [Rylander, R. et al. (1992) Indoor Environ. 1, 263-267]. They are recognized by receptors on macrophages and promote the adI~esionof fungi to the phagocytesurfacemembrane. Many studies
for Mechanismsof HumanToxicity,Universityof Le=cester. PO Box 138, LancasterRoad, Leicester,UK LE1 9HN
show that on binding ~-glucan, macrophages produce the cytokine tumour necrosis factor
Elsevier Science Ltd. All rights reserved. 1357 - 4310/96/$15.00
,~9~