Lipoprotein
Cholesterol and Atherosclerosis Pp.633-653
Howard
S. Kruth
In
Search of Pathogenic Mechanisms in Endometriosis: The Challenge for Molecular
Cell Biology Pp.655-664
A.
Starzinski-Powitz, A. Zeitvogel, A. Schreiner and R. Baumann
The
Role of the Ubiquitin-proteasome Pathway in MHC Class I Antigen Processing:
Implications for Vaccine
Design
Pp.665-676
A.
Sijts, D. Zaiss and P-M. Kloetzel
Molecular
Mechanisms of Neuronal Migration Disorders, Quo Vadis? Pp.677-688
S.
Couillard-Despres, J. Winkler, G. Uyanik and L. Aigner
The
Molecular Basis of Lymphoid Architecture and B cell Responses: Implications for
Immunodeficiency and
Immunopathology
Pp.689-725
Carola
G. Vinuesa and Matthew C. Cook
The
Role of Pancreatic Chromogranins in Islet Physiology Pp.727-732
E.
Karlsson
b-Amyloid, Neuronal Death and Alzheimer’s DiseasePp.733-737
J.
Carter and C.F. Lippa
Mammalian
Secreted Phospholipases A2 and Their Pathophysiological Significance
in Inflammatory Diseases Pp.739-754
Lhousseine
Touqui and Mounia Alaoui-El-Azher
[Back to top]
Lipoprotein Cholesterol and Atherosclerosis
Howard
S. Kruth
Progressive accumulation of cholesterol in the arterial wall causes
atherosclerosis, the pathologic process underlying most heart attacks and
strokes. Low density lipoprotein (LDL), the major carrier of blood cholesterol,
has been implicated in the buildup of cholesterol in atherosclerotic plaques.
Endothelial cells that line arteries function to transport LDL into the vessel
wall. Models for the mechanism of cholesterol accumulation in atherosclerotic
plaques emphasize increased LDL uptake into the vessel wall or increased
retention of LDL that has entered the vessel wall. This article reviews the
pathways of cholesterol entry and removal, the metabolism, and the physical
changes of cholesterol in the vessel wall. How these processes are believed to
contribute to cholesterol buildup in atherosclerotic plaques is discussed.
[Back to top] In Search of Pathogenic Mechanisms in Endometriosis: The
Challenge for Molecular Cell Biology
A.
Starzinski-Powitz, A. Zeitvogel, A. Schreiner and R. Baumann
Endometriosis,
defined histologically as the presence of endometrium-like glands and stroma
outside the uterus, is a chronic, invasive and metastasising disease. It shares
features with malignant tumours (invasion and metastasis) but is not
neoplastic. Despite the fact that endometriosis is one of the most frequent
gynaecological diseases, it is under researched, puzzling and highly debated.
The aetiology and pathogenesis is little understood although it is agreed that
implantation, at least in many cases, is responsible for endometriosis. This
theory advocates retrograde menstruation as the underlying phenomenon, where
cells of the menstrual efflux provide the cellular source for endometriotic
lesion formation. Causative therapy and non-invasive diagnostics of
endometriosis do not exist. Thus, there is a substantial but unmet need for
molecular and cellular research to unravel the pathogenic mechanisms of
endometriosis as a basis for developing novel diagnostic and therapeutic
concepts. In this review, we specifically focus on the cellular basis of lesion
formation, the possible modulation of this by cytokines and other factors and
the characteristics of endometriotic cells in terms of invasion and metastasis.
Considering available experimental information, we concentrate on arguments and
ideas in favour of an endometriotic founder cell population exhibiting
substantial plasticity for differentiation and self-renewal. Perhaps present in
the menstrual efflux or arising by metaplasia (a complementary theory to
implantation), this cell type might respond to stimuli present in the ectopic
host environment and establish the endometriotic phenotype.
[Back to top] The Role of the Ubiquitin-proteasome Pathway in MHC Class I
Antigen Processing: Implications for Vaccine Design
A.Sijts*, D. Zaiss and P-M. Kloetzel
Proteasomes are multisubunit enzyme complexes that reside in the cytoplasm and nucleus of eukaryotic cells. By selective protein degradation, proteasomes regulate many cellular processes including MHC class I antigen processing. Three constitutively expressed catalytic subunits are responsible for proteasome mediated proteolysis. These subunits are exchanged for three homologous subunits, the immunosubunits, in IFNg-exposed cells and in cells with specialized antigen presenting function. Both constitutive and immunoproteasomes degrade endogenous proteins into small peptide fragments that can bind to MHC class I molecules for presentation on the cell surface to cytotoxic T lymphocytes. However, immunoproteasomes seem to fulfill this function more efficiently. IFNg further induces the expression of a proteasome activator, PA28, which can also enhance antigenic peptide production by proteasomes.
In this review, we will introduce the ubiquitin-proteasome system and summarize recent findings regarding the role of the IFNg-inducible proteasome subunits and proteasome regulators in antigen processing. We review the different ways by which tumors and viruses have been found to target the proteasome system to avoid MHC class I presentation of their antigens, and discuss recent progressions in the development of computer assisted approaches to predict CTL epitopes within larger protein sequences, based on proteasome cleavage specificity. The availability of such programs as well as a general insight into the proteasome mediated steps in MHC class I antigen processing provides us with a rational basis for the design of new antiviral and anticancer T cell vaccines.
[Back to top] Molecular Mechanisms of Neuronal Migration Disorders,
Quo Vadis?
S.
Couillard-Despres, J. Winkler, G. Uyanik and L. Aigner
Following
terminal mitosis, neuronal precursor cells leave their site of origin and
migrate towards their definitive site of residency. In order to establish the
intricate cytoarchitecture described in the adult human brain, neuronal
migration must be finely regulated. In humans, brain malformations can result
from neuronal migration defects. The spectrum of migration disorder severity
extends from few heterotopic neurons, as observed in periventricular
heterotopia, to a complete cortical disorganization, as observed in cases of
lissencephaly. Recently, specific migration disorders have been linked to
mutations/deletions in the doublecortin, filamin-1, LIS1 and reelin genes.
These proteins act at different levels of the signaling cascades transducing
extracellular guiding cues into cytoskeletal reorganization. Here, we summarize
the data concerning these four molecules and speculate on their functions and
interaction partners during neuronal development.
[Back to top]
The
Molecular Basis of Lymphoid Architecture and B cell Responses: Implications for
Immunodeficiency and
Immunopathology
Carola
G. Vinuesa and Matthew C. Cook
Immune responses usually take place in secondary lymphoid organs such as spleen and lymph nodes. Most lymphocytes within these organs are in transit, yet lymphoid organ structure is highly organized; T and B cells segregate into separate regions. B cell compartments include naïve cells within follicles, marginal zones and B-1 cells. Interactions between TNF family molecules on hematopoietic cells and their receptors on mesenchymal cells guide the initial phase of lymphoid organogenesis, and regulate chemokine secretion that mediates subsequent T-B cell segregation. Recruitment of B cells into different compartments depends on both the milieu established during organogenesis, and the threshold for B cell receptor signaling, which is modulated by numerous coreceptors.
Novel intrafollicular (germinal center) and extrafollicular (plasma cell) compartments are established when B cells respond to antigen. These divergent B cell responses are mediated by different patterns of gene expression, and influenced again by BCR signaling threshold and cellular interactions that depend on normal lymphoid architecture.
Aberrant
B cell responses are reviewed in the light of these principles taking into
account the molecular and architectural aspects of immunopathology.
Histological features of immunodeficiency reflect defects of B cell recruitment
or differentiation. B cell hyper-reactivity may arise from altered BCR
signaling thresholds (autoimmunity), defects in stimuli that guide
differentiation in response to antigen (follicular hyperplasia vs
plasmacytosis), or defective B cell gene expression. Interestingly, in diseases
such as rheumatoid arthritis, Sjögren’s syndrome and Hashimoto’s thyroiditis
lymphoid organogenesis may be recapitulated in non-lymphoid parenchyma, under
the influence of molecular interactions similar to those that operate during
embryogenesis.
[Back to top] The Role of Pancreatic
Chromogranins in Islet Physiology
E.
Karlsson
Chromogranins are acidic secretory glycoproteins with a widespread but specific distribution in neuroendocrine tissues. The chromogranin family is heterogenous, consisting of propeptides such as chromogranin-A, chromogranin-B and secretogranin II, which can either elicit an effect themselves, or serve as precursors to a large number of peptides, which are biologically more active. Chromogranin processing varies in different neuroendocrine tissues. Furthermore, it is more marked in pancreatic islets than in many other tissues. Chromogranin-A and chromogranin-B are expressed in all types of pancreatic islet cells, whereas secretogranin II has not been found in pancreatic tissue. The aim of the present mini review is to focus on chromogranin-A, chromogranin-B and their derived peptides, in the function of pancreatic islets.
[Back to top] b-Amyloid, Neuronal Death and
Alzheimer’s Disease
J.
Carter and C.F. Lippa
Alzheimer’s
disease (AD) is a common neurodegenerative disease that affects cognitive
function in the elderly. Large extracellular beta-amyloid (Ab) plaques and tau-containing intraneuronal
neurofibrillary tangles characterize AD from a histopathologic perspective.
However, the severity of dementia in AD is more closely related to the degree
of the associated neuronal and synaptic loss. It is not known how neurons die
and synapses are lost in AD; the current review summarizes what is known about
this issue. Most evidence indicates that amyloid precursor protein (APP)
processing is central to the AD process. The Ab
in plaques is a metabolite of the APP that forms when an alternative (b-secretase and then g-secretase) enzymatic pathway is utilized for processing.
Mutations of the APP gene lead to AD by influencing APP metabolism. One leading
theory is that the Ab in plaques leads
to AD because Ab is directly toxic to
the adjacent neurons. Other theories advance the notion that neuronal death is
triggered by intracellular events that occur during APP processing or by
extraneuronal preplaque Ab oligomers.
Some investigators speculate that in many cases there is a more general
disorder of protein processing in neurons that leads to cell death. In the
later models, Ab plaques are a
byproduct of the disease process, rather than the direct cause of neuronal
death. A direct correlation between Ab
plaque burden and neuronal (or synaptic) loss should occur in AD if Ab plaques cause AD through a direct toxic
effect. However, histopathologic studies indicate that the correlation between
Ab plaque burden and neuronal (or
synaptic) loss is poor. We conclude that APP processing and Ab formation is important to the AD process,
but that neuronal alterations that underlie symptoms of AD are not due
exclusively to a direct toxic effect of the Ab
deposits that occur in plaques. A more general problem with protein processing,
damage due to the neuron from accumulation of intraneuronal Ab or extracellular, preplaque Ab may also be important as underlying factors
in the dementia of AD.
[Back to top] Mammalian Secreted Phospholipases A2 and Their
Pathophysiological Significance in Inflammatory Diseases
Lhousseine Touqui and Mounia
Alaoui-El-Azher
Phospholipases A2 (PLA2s) represent a growing family of enzymes that catalyze the hydrolysis of phospholipids at the sn-2 position leading to the generation of free fatty acids and lysophospholipids. Mammalian PLA2s are divided into two major classes according to their molecular mass and location: intracellular PLA2 and secreted PLA2 (sPLA2). Type-IIA sPLA2 (sPLA2-IIA), the best studied enzyme of sPLA2, plays a role in the pathogenesis of various inflammatory diseases. Conversely, sPLA2-IIA can exert beneficial action in the context of infectious diseases since recent studies have shown that this enzyme exhibits potent bactericidal effects. Induction of the synthesis of sPLA2-IIA is generally initiated by endotoxin and a limited number of cytokines via paracrine and/or autocrine processes. If the mechanisms involved in the regulation of sPLA2-IIA gene expression have been relatively clarified, little is known on the mechanisms that regulate the expression of other sPLA2. There have been substantial progresses in understanding the transcriptional regulation of sPLA2-IIA expression. Recently, transcription factors including NF-kB, PPAR, C/EBP have been identified to play a prominent role in the regulation of sPLA2-IIA gene expression. The activation of these transcription factors is under the control of distinct signaling pathways (PKC, cAMP …). Accumulating evidences in the literature suggest that cytosolic PLA2 together with two sPLA2 isozymes (sPLA2-IIA and sPLA2-V) are functionally coupled with cyclooxygenase-1 and 2 pathways, respectively, for immediate and delayed PG biosynthesis. This spatio-temporal coupling of cyclooxygenase enzymes with PLA2s may represent a key mechanism in the propagation of inflammatory reaction. Unraveling the mechanisms involved in the regulation of the expression of sPLA2s is important for understanding their pathophysiological roles in inflammatory diseases.