The humoral immune response to heat shock proteins.

Humoral immune reactions to heat shock proteins (hsp) from microorganisms are one aspect of microbial infections in humans. The production of antibodies which are specific to epitopes present on procaryotic hsp leads also to the appearance of cross-reactive serum antibodies in the host organism that react with human hsp. This article discusses the consequences of such autoreactive antibodies for the host in context with the development of immune tolerance and autoimmune diseases, especially rheumatoid arthritis (RA), and in experimental animal models for arthritis such as adjuvant arthritis in rats. On the basis of epitope cross-reactivity between hsp and other host proteins, a hypothesis is presented for the development of autoimmune disease following the production of hsp-specific antibodies.     

Annexins: what are they good for?

Annexins comprise a unique family of calcium- and phospholipid-binding proteins. At least one of the twenty members thus far described from this family can be found expressed in nearly every eukaryotic cell type. As common as these proteins may be, no one clear function for all has been established. Historically, individual members of this family have been given various names describing their ability to associate with a host of intra- and extracellular proteins and with cellular lipid membranes. The collection of reviews in this issue of CMLS represents an effort to offer a coordinated view of the research activities in the field and to extract structural and functional commonalities.     

Eastern Pacific cooling and Atlantic overturning circulation during the last deglaciation

Surface ocean conditions in the equatorial Pacific Ocean could hold the clue to whether millennial-scale global climate change during glacial times was initiated through tropical ocean-atmosphere feedbacks or by changes in the Atlantic thermohaline circulation. North Atlantic cold periods during Heinrich events and millennial-scale cold events (stadials) have been linked with climatic changes in the tropical Atlantic Ocean and South America, as well as the Indian and East Asian monsoon systems, but not with tropical Pacific sea surface temperatures. Here we present a high-resolution record of sea surface temperatures in the eastern tropical Pacific derived from alkenone unsaturation measurements. Our data show a temperature drop of approximately 1 degrees C, synchronous (within dating uncertainties) with the shutdown of the Atlantic meridional overturning circulation during Heinrich event 1, and a smaller temperature drop of approximately 0.5 degrees C synchronous with the smaller reduction in the overturning circulation during the Younger Dryas event. Both cold events coincide with maxima in surface ocean productivity as inferred from 230Th-normalized carbon burial fluxes, suggesting increased upwelling at the time. From the concurrence of equatorial Pacific cooling with the two North Atlantic cold periods during deglaciation, we conclude that these millennial-scale climate changes were probably driven by a reorganization of the oceans' thermohaline circulation, although possibly amplified by tropical ocean-atmosphere interaction as suggested before.     

Forcing of wet phases in southeast Africa over the past 17,000 years

Intense debate persists about the climatic mechanisms governing hydrologic changes in tropical and subtropical southeast Africa since the Last Glacial Maximum, about 20,000?years ago. In particular, the relative importance of atmospheric and oceanic processes is not firmly established. Southward shifts of the intertropical convergence zone (ITCZ) driven by high-latitude climate changes have been suggested as a primary forcing, whereas other studies infer a predominant influence of Indian Ocean sea surface temperatures on regional rainfall changes. To address this question, a continuous record representing an integrated signal of regional climate variability is required, but has until now been missing. Here we show that remote atmospheric forcing by cold events in the northern high latitudes appears to have been the main driver of hydro-climatology in southeast Africa during rapid climate changes over the past 17,000 years. Our results are based on a reconstruction of precipitation and river discharge changes, as recorded in a marine sediment core off the mouth of the Zambezi River, near the southern boundary of the modern seasonal ITCZ migration. Indian Ocean sea surface temperatures did not exert a primary control over southeast African hydrologic variability. Instead, phases of high precipitation and terrestrial discharge occurred when the ITCZ was forced southwards during Northern Hemisphere cold events, such as Heinrich stadial 1 (around 16,000?years ago) and the Younger Dryas (around 12,000?years ago), or when local summer insolation was high in the late Holocene, that is, during the past 4,000?years.     

Introduction: molecular and biomechanical basis of osteoarthritis

Osteoarthritis has developed into the most common chronic disease in the highly industrialized nations. Moreover, because of the prevalence of the disease in the elderly, this trend occurs worldwide as a consequence of increasing longevity due to the overall improvement in living conditions and health status. In contrast, research on osteoarthritis is still financially marginalized within biomedical research, so that the molecular and biophysical bases for disease initiation and progression are largely unmapped. The following sequence of five reviews highlights a remarkable change in that body of knowledge taking place at the beginning of the World Health Organization (WHO) 'Bone and Joint Decade 2001-2010'. The data and ideas presented in these articles reflect to some extent the guidelines set up by the WHO and by the National Institutes of Health of the USA and therefore allow a glimpse into the directions that research in osteoarthritis will take in the future.     

A molecular basis for the two locus model of human complement component C4

The major histocompatibility complex(MHC)-linked fourth component of complement (C4) shows a high degree of polymorphism in several animal species. In man C4 polymorphism was detected by distinct charge differences of the variants. O'Neill et al. showed that this C4 polymorphism was controlled by two closely linked genetic loci, F (C4A) and S (C4B) and these results were extended by Awdeh et al. with an improved typing method. Biochemical analysis of human C4 has revealed that it consists of three polypeptide chains, alpha, beta and gamma. In all reports so far on the molecular analysis of human C4, no molecular weight differences between the A and B locus-encoded molecules have been noticed. Here we demonstrate that the C4A and C4B locus-encoded alpha-chains have a molecular weight (MW) of 96,000 and 94,000, respectively, presenting for the first time a molecular basis for the difference between all C4A and C4B variants tested. Even rare variants that are difficult to allocate to the A or B locus on the basis of charge differences could be identified as C4A or C4B variants in this way, thereby providing new insights into the relationships between the C4A and C4B loci.     

The humoral immune response to heat shock proteins

Humoral immune reactions to heat shock proteins (hsp) from microorganisms are one aspect of microbial infections in humans. The production of antibodies which are specific to epitopes present on procaryotic hsp leads also to the appearance of cross-reactive serum antibodies in the host organism that react with human hsp. This article discusses the consequences of such autoreactive antibodies for the host in context with the development of immune tolerance and autoimmune diseases, especially rheumatoid arthritis (RA), and in experimental animal models for arthritis such as adjuvant arthritis in rats. On the basis of epitope cross-reactivity between hsp and other host proteins, a hypothesis is presented for the development of autoimmune disease following the production of hsp-specific antibodies.     

Annexin V interactions with collagen

Annexin V was originally identified as a collagen-binding protein called anchorin CII and was isolated from chondrocyte membranes by affinity chromatography on native type II collagen. The binding of annexin V to native collagen type II is stable at physiological ionic strength when annexin V is reconstituted in liposomes. The binding to native collagen types II and X, and to some extent to type I as well, was confirmed using recombinant annexin V. A physiological role for annexin V interactions with extracellular collagen is consistent with the localization of annexin V on the outer cell surface of chondrocytes, microvilli of hypertrophic chondrocytes, fibroblasts and osteoblasts. A breakthrough in our understanding of the function of annexin V was made with the discovery of its calcium channel activity. At least one of several putative functions of annexin V became obvious from studies on matrix vesicles derived from calcifying cartilage. It was found that calcium uptake by matrix vesicles depend on collagen type II and type X binding to annexin V in the vesicles and was lost when collagens were digested with collagenase; calcium influx was reconstituted after adding back native collagen II or V. These findings indicate that annexin V plays a major role in matrix vesicle-initiated cartilage calcification as a collagen-regulated calcium channel.