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This month in J Lab Clin Med
Copyright © 2006 by Mosby, Inc.
VOLUME 147
JUNE 2006
NUMBER 6
THIS MONTH IN J Lab Clin Med Issue Highlights for June 2006
Mesangial matrix in IgA nephropathy: a role for IgG antibodies IgA nephropathy is a chronic nephritis that is characterized by mesangial deposits of immunoglobulin A. Although IgA lends its name to the syndrome, one may demonstrate that other immunoglobulin subtypes and complement components are also deposited in the glomerular matrix; in experimental models, these other immunoproteins may be present before glomerular scarring is seen. Some patients with IgA nephropathy have in their serum anti-mesangial-cell antibodies of immunoglobulin type IgG; it’s not quite clear just where they fit in to the pathophysiology of the syndrome. An article in this month’s issue of the Journal addresses this question. As described beginning on page 301, Drs. Angela Darvill and Francis W Ballardie of the University and Royal Infirmary of Manchester (UK) cultured human mesangial cells in a complement-free system. They added IgG from patients who had IgA nephropathy, and observed a dose-dependent increase in matrix production. If they then compared the strength of this effect with the level of anti-mesangial-cell antibodies in the test sera, they found a strong correlation. The authors conclude that the presence of IgG anti-mesangial-cell antibodies may be an important part of the glomerular scarring seen in IgA nephropathy, rather than just being a marker for the disease.
Microparticles and the microvasculature: preëclampsia is not where the action is Microparticles are small fragments of cells that may be shed when the cells are damaged or activated; they have interesting biological properties that may help explain some otherwiseenigmatic clinical observations. For example, the microparticles shed by platelets are often in a favorable configuration to serve as a surface for assembly of clotting protease complexes; this may be part of the explanation for the mildness of bleeding in immune thrombocytopenia (and indeed for
J Lab Clin Med 2006;147:271–273. 0022-2143/$ – see front matter © 2006 Mosby, Inc. All rights reserved. doi:10.1016/j.lab.2006.05.002
271
272
In this Issue
J Lab Clin Med June 2006
the occasional ITP patient who develops thrombotic as well as hemorrhagic complications). Preëclampsia is a syndrome usually seen in late pregnancy, which may involve activation of the coagulation system, activation of platelets, disordered blood pressure control and other evidence of endothelial dysfunction. It seems a likely context for microparticles to be serving as culprits; that notion was put to the test by Dr. C.A.R. Lok and colleagues from the Academic Medical Center of Amsterdam. In their study, human umbilical vein endothelial cells were incubated for various time periods in the absence or presence of isolated microparticle fractions from preëclamptic patients, normotensive pregnant women, and non-pregnant controls. As a positive control, interleukin (IL)-1␣ was used. As expected, IL-1␣ enhanced the expression of IL-1␣, IL-2, IL-6, IL-8, nuclear factor– kappa-B (NFB)-1, NFB-2, NFB-inhibitor, cyclin-dependent kinase inhibitor and monocyte chemotactic protein-1; it also transiently increased tissue factor expression. None of these effects, however, was seen when microparticles from preëclamptic patients were added. Attractive though it might be to implicate microparticles in the pathophysiology of eclampsia and preëclampsia, this study does not support the notion. It is of course possible that the experimental model is too simple or that the endothelial cell is not the site of action of microparticles, or indeed that they may be important in only a subset of patients. But given the readiness with which the effects of IL-1␣ were demonstrable, the authors concluded that it was unlikely that microparticles from preëclamptic patients induce endothelial dysfunction by directly affecting the expression of inflammation-related genes in these cells. Their paper may be found on page 310.
Leukocytes and coronary reperfusion: an old story revisited Although it has spent little if any time at center stage, the role of leukocytes in atherosclerotic disease has always been interesting. Some of the earliest studies of coronary risk prediction identified the white blood cell count as a strong independent predictor, a finding that was largely ignored until the importance of white cells in both acute and chronic vascular injury was recognized. More recently, an association between coronary risk and markers of inflammation (such as CRP) has become clear; it seems likely that leukocytosis may be a less specific marker of risk as well as one of its determinants. In ischemia and reperfusion, the ability of activated neutrophils (adhering to endothelium, adhering to each other and releasing mediators) to contribute to flow limitation may be particularly important. Indeed, the degree of leukocytosis accompanying a myocardial infarction is one of the predictors of outcome—a higher white count is associated with higher morbidity. A study in this month’s issue asks whether the white blood cell count correlates with successful reëstablishment of blood flow in the setting of an acute coronary event (see page 321). Dr. Jaap Jan J. Smit, MD and several associates from the Isala Klinieken, Zwolle, the Netherlands, examined the white blood cell counts of 364 patients undergoing percutaneous coronary interventions (such as angioplasty and/or stenting) for myocardial infarction. The white count was measured on admission and 6 and 24 hours after primary intervention. Angiographic measurements of reperfusion were compared to changes in the count. If coronary flow was successfully reëstablished, the white count fell modestly over 24 hours: from a median of 11,500/L to 9,900/L. If flow was not successfully restored, the white count stayed up (and it was a bit higher at baseline in these patients). It remains to be seen whether following the white count will be useful in directing care of patients with coronary insufficiency; in the meanwhile, the notion that white cells are important in the process gains some support.
Integrins and the health of podocytes Integrins are the major adhesion molecules governing attachment of podocytes to the glomerular basement membrane, and integrins have been shown to play a role in the regulation of cell survival. Because podocytes are important to the maintenance of perm-selectivity in the glomerulus, it becomes interesting to know what triggers apoptosis or loss of function in these cells; the role of integrins in the regulation of apoptosis was explored by researchers from Taiwan’s Kaohsiung Medical University.
J Lab Clin Med Volume 147, Number 6
In this Issue
In cultured rat podocyte, apoptosis was detected by conventional means, such as the TUNEL assay, and Fas, Fas ligand, Bax, Bcl-2, and ERK activation were analyzed by Western blot. When an integrin antagonist, Gly-Arg-Gly-Asp (GRGD), was added to the cell cultures, the percentage of cells with apoptosis increased sharply. A similar increase in apoptosis was seen with inhibition of protein tyrosine kinase by the addition of genistein. In GRGD-treated cells, cytochrome C was released into the cytoplasm and the expression of Bax was up-regulated, while Bcl-2 expression was not changed. Fas was not expressed in either control or GRGR-treated podocytes although Fas ligand was up-regulated in GRGD-treated cells. ERK activation was also found to be increased in GRGD-treated cells. In this model, interfering with the function of ␣31-integrin markedly increased apoptosis, indicating that said integrin is necessary for continued well-being of cultured rat podocytes; and the signaling involves Bax, Bcl-2, and cytochrome C.
That’s all, folks!! This is the last issue of this “Browser’s Index.” My term as Editor ends July 1, 2006 and the baton passes to my successor, Dr. Jeffrey Laurence of the Weil Medical College at Cornell University. It has been my privilege to serve the Central Society as an editor for fifteen years, equally divided between a term as Senior Editor under my predecessor, Dr. Harry Jacob, and my own tenure as Editor-in-Chief. It has been a richly rewarding fifteen years, and I thank the many people who have helped make it so. I owe a special debt to our many manuscript referees and to the Associate Editors and Editorial Advisors with whom I have worked over the years. With the change in Editor will come some changes in the Journal that readers will surely notice and that I hope they will find exciting. The Journal’s recent focus on translational medicine will be made more explicit and will be given a higher profile; I will leave it to Dr. Laurence to tell you more about that as he begins his service. The encroaching deadline has always been a powerful muse for me, but she has not always been a kind and gentle muse. I leave my position with mixed feelings: there is a sense of liberation from a strict task-mistress, but there will also be nostalgia for the time I spent as her servant. The Journal will be in good hands, and I encourage Society members to give Dr. Laurence their enthusiastic support. For the Editors Dale E. Hammerschmidt, MD Editor-in-Chief
273
VOLUME 147
JUNE 2006
NUMBER 6
THIS MONTH IN J Lab Clin Med Issue Highlights for June 2006
Mesangial matrix in IgA nephropathy: a role for IgG antibodies IgA nephropathy is a chronic nephritis that is characterized by mesangial deposits of immunoglobulin A. Although IgA lends its name to the syndrome, one may demonstrate that other immunoglobulin subtypes and complement components are also deposited in the glomerular matrix; in experimental models, these other immunoproteins may be present before glomerular scarring is seen. Some patients with IgA nephropathy have in their serum anti-mesangial-cell antibodies of immunoglobulin type IgG; it’s not quite clear just where they fit in to the pathophysiology of the syndrome. An article in this month’s issue of the Journal addresses this question. As described beginning on page 301, Drs. Angela Darvill and Francis W Ballardie of the University and Royal Infirmary of Manchester (UK) cultured human mesangial cells in a complement-free system. They added IgG from patients who had IgA nephropathy, and observed a dose-dependent increase in matrix production. If they then compared the strength of this effect with the level of anti-mesangial-cell antibodies in the test sera, they found a strong correlation. The authors conclude that the presence of IgG anti-mesangial-cell antibodies may be an important part of the glomerular scarring seen in IgA nephropathy, rather than just being a marker for the disease.
Microparticles and the microvasculature: preëclampsia is not where the action is Microparticles are small fragments of cells that may be shed when the cells are damaged or activated; they have interesting biological properties that may help explain some otherwiseenigmatic clinical observations. For example, the microparticles shed by platelets are often in a favorable configuration to serve as a surface for assembly of clotting protease complexes; this may be part of the explanation for the mildness of bleeding in immune thrombocytopenia (and indeed for
J Lab Clin Med 2006;147:271–273. 0022-2143/$ – see front matter © 2006 Mosby, Inc. All rights reserved. doi:10.1016/j.lab.2006.05.002
271
272
In this Issue
J Lab Clin Med June 2006
the occasional ITP patient who develops thrombotic as well as hemorrhagic complications). Preëclampsia is a syndrome usually seen in late pregnancy, which may involve activation of the coagulation system, activation of platelets, disordered blood pressure control and other evidence of endothelial dysfunction. It seems a likely context for microparticles to be serving as culprits; that notion was put to the test by Dr. C.A.R. Lok and colleagues from the Academic Medical Center of Amsterdam. In their study, human umbilical vein endothelial cells were incubated for various time periods in the absence or presence of isolated microparticle fractions from preëclamptic patients, normotensive pregnant women, and non-pregnant controls. As a positive control, interleukin (IL)-1␣ was used. As expected, IL-1␣ enhanced the expression of IL-1␣, IL-2, IL-6, IL-8, nuclear factor– kappa-B (NFB)-1, NFB-2, NFB-inhibitor, cyclin-dependent kinase inhibitor and monocyte chemotactic protein-1; it also transiently increased tissue factor expression. None of these effects, however, was seen when microparticles from preëclamptic patients were added. Attractive though it might be to implicate microparticles in the pathophysiology of eclampsia and preëclampsia, this study does not support the notion. It is of course possible that the experimental model is too simple or that the endothelial cell is not the site of action of microparticles, or indeed that they may be important in only a subset of patients. But given the readiness with which the effects of IL-1␣ were demonstrable, the authors concluded that it was unlikely that microparticles from preëclamptic patients induce endothelial dysfunction by directly affecting the expression of inflammation-related genes in these cells. Their paper may be found on page 310.
Leukocytes and coronary reperfusion: an old story revisited Although it has spent little if any time at center stage, the role of leukocytes in atherosclerotic disease has always been interesting. Some of the earliest studies of coronary risk prediction identified the white blood cell count as a strong independent predictor, a finding that was largely ignored until the importance of white cells in both acute and chronic vascular injury was recognized. More recently, an association between coronary risk and markers of inflammation (such as CRP) has become clear; it seems likely that leukocytosis may be a less specific marker of risk as well as one of its determinants. In ischemia and reperfusion, the ability of activated neutrophils (adhering to endothelium, adhering to each other and releasing mediators) to contribute to flow limitation may be particularly important. Indeed, the degree of leukocytosis accompanying a myocardial infarction is one of the predictors of outcome—a higher white count is associated with higher morbidity. A study in this month’s issue asks whether the white blood cell count correlates with successful reëstablishment of blood flow in the setting of an acute coronary event (see page 321). Dr. Jaap Jan J. Smit, MD and several associates from the Isala Klinieken, Zwolle, the Netherlands, examined the white blood cell counts of 364 patients undergoing percutaneous coronary interventions (such as angioplasty and/or stenting) for myocardial infarction. The white count was measured on admission and 6 and 24 hours after primary intervention. Angiographic measurements of reperfusion were compared to changes in the count. If coronary flow was successfully reëstablished, the white count fell modestly over 24 hours: from a median of 11,500/L to 9,900/L. If flow was not successfully restored, the white count stayed up (and it was a bit higher at baseline in these patients). It remains to be seen whether following the white count will be useful in directing care of patients with coronary insufficiency; in the meanwhile, the notion that white cells are important in the process gains some support.
Integrins and the health of podocytes Integrins are the major adhesion molecules governing attachment of podocytes to the glomerular basement membrane, and integrins have been shown to play a role in the regulation of cell survival. Because podocytes are important to the maintenance of perm-selectivity in the glomerulus, it becomes interesting to know what triggers apoptosis or loss of function in these cells; the role of integrins in the regulation of apoptosis was explored by researchers from Taiwan’s Kaohsiung Medical University.
J Lab Clin Med Volume 147, Number 6
In this Issue
In cultured rat podocyte, apoptosis was detected by conventional means, such as the TUNEL assay, and Fas, Fas ligand, Bax, Bcl-2, and ERK activation were analyzed by Western blot. When an integrin antagonist, Gly-Arg-Gly-Asp (GRGD), was added to the cell cultures, the percentage of cells with apoptosis increased sharply. A similar increase in apoptosis was seen with inhibition of protein tyrosine kinase by the addition of genistein. In GRGD-treated cells, cytochrome C was released into the cytoplasm and the expression of Bax was up-regulated, while Bcl-2 expression was not changed. Fas was not expressed in either control or GRGR-treated podocytes although Fas ligand was up-regulated in GRGD-treated cells. ERK activation was also found to be increased in GRGD-treated cells. In this model, interfering with the function of ␣31-integrin markedly increased apoptosis, indicating that said integrin is necessary for continued well-being of cultured rat podocytes; and the signaling involves Bax, Bcl-2, and cytochrome C.
That’s all, folks!! This is the last issue of this “Browser’s Index.” My term as Editor ends July 1, 2006 and the baton passes to my successor, Dr. Jeffrey Laurence of the Weil Medical College at Cornell University. It has been my privilege to serve the Central Society as an editor for fifteen years, equally divided between a term as Senior Editor under my predecessor, Dr. Harry Jacob, and my own tenure as Editor-in-Chief. It has been a richly rewarding fifteen years, and I thank the many people who have helped make it so. I owe a special debt to our many manuscript referees and to the Associate Editors and Editorial Advisors with whom I have worked over the years. With the change in Editor will come some changes in the Journal that readers will surely notice and that I hope they will find exciting. The Journal’s recent focus on translational medicine will be made more explicit and will be given a higher profile; I will leave it to Dr. Laurence to tell you more about that as he begins his service. The encroaching deadline has always been a powerful muse for me, but she has not always been a kind and gentle muse. I leave my position with mixed feelings: there is a sense of liberation from a strict task-mistress, but there will also be nostalgia for the time I spent as her servant. The Journal will be in good hands, and I encourage Society members to give Dr. Laurence their enthusiastic support. For the Editors Dale E. Hammerschmidt, MD Editor-in-Chief
273