Enhanced dissociation of HLA-DR-bound peptides in the presence of HLA-DM

Human leukocyte antigen (HLA)-DM is a critical participant in antigen presentation that catalyzes the release of class II-associated invariant chain-derived peptides (CLIP) from newly synthesized class II histocompatibility molecules, freeing the peptide-binding site for acquisition of antigenic peptides. The mechanism for the selective release of CLIP but not other peptides is unknown. DM was found to enhance the rate of peptide dissociation to an extent directly proportional to the intrinsic rate of peptide dissociation from HLA-DR, regardless of peptide sequence. Thus, CLIP is rapidly released in the presence of DM, because its intrinsic rate of dissociation is relatively high. In antigen presentation, DM has the potential to markedly enhance the rate of peptide exchange, favoring the presentation of peptides with slower intrinsic rates of dissociation.     

HLA-DM is expressed on the cell surface and colocalizes with HLA-DR and invariant chain in human Langerhans cells

The subcellular distribution patterns of molecules involved in the process of antigen loading [HLA-DR, HLA-DM, and the cytoplasmic and luminal parts of the invariant chain (Ii, CD74)] were investigated in Langerhans cells (LC), both qualitatively and quantitatively. The analysis was performed by immunofluorescence labelling of acetone-fixed vertical cryostat sections from normal human skin specimens and subsequent examination using confocal laser scanning microscopy (CSLM). The intensity-modulated multiple-wavelength scanning (IMS) technique was used to enhance channel separation when scanning dual-labelled specimens. The mean (n = 9) relative epidermal volumes of reactivity were: HLA-DR 8%+/-3%, HLA-DM 6%+/-2%, luminal Ii 6%+/-2%, and cytoplasmic Ii 4%+/-1%. The difference between HLA-DR and the other epitopes was significant at the P<0.001 level. All molecule combinations, except the combination of HLA-DM and luminal Ii (which was not studied), were to various extents colocalized. Experiments performed on unfixed epidermal sheets showed that HLA-DM is present on the cell surface of LC, suggesting that HLA-DM may interact with HLA-DR on the surface to induce peptide loading.     

The role of superantigens in infectious diseases

Exogenous antigens are presented to T lymphocytes through mechanisms that ensure high recognition specificity. Recently described superantigens in contrast to conventional antigens are particles that follow a different processing and presentation route not binding to a specific region of T lymphocyte receptors. These particles bind to a large number of T lymphocytes, generating a disproportionate and non-specific immune response. Two types of superantigens have been described. Endogenous superantigens, transported in the host genoma, have been involved in clonal depletion and immunological tolerance phenomena. Exogenous superantigens, mainly bacterial toxins, have been involved in several diseases. There is evidence that these antigens participate in diseases such as Kawasaki disease, toxic shock caused by Staphylococcus aureus, rheumatoid arthritis, HIV infection and Streptococcus pyogenes infections.     

Travel and the emergence of infectious diseases

Travel is a potent force in the emergence of disease. Migration of humans has been the pathway for disseminating infectious diseases throughout recorded history and will continue to shape the emergence, frequency, and spread of infections in geographic areas and populations. The current volume, speed, and reach of travel are unprecedented. The consequences of travel extend beyond the traveler to the population visited and the ecosystem. When they travel, humans carry their genetic makeup, immunologic sequelae of past infections, cultural preferences, customs, and behavioral patterns. Microbes, animals, and other biologic life also accompany them. Today's massive movement of humans and materials sets the stage for mixing diverse genetic pools at rates and in combinations previously unknown. Concomitant changes in the environment, climate, technology, land use, human behavior, and demographics converge to favor the emergence of infectious diseases caused by a broad range of organisms in humans, as well as in plants and animals.     

Several cooperating binding sites mediate the interaction of a lysosomal enzyme with phosphotransferase

Lysosomal targeting of soluble lysosomal hydrolases is mediated by mannose 6-phosphate receptors, which recognize and bind mannose 6-phosphate residues in the oligosaccharide chains of proteins destined for delivery to lysosomes. This recognition marker is generated by the sequential action of two enzymes, the first of which, UDP-N-acetylglucosamine phosphotransferase, recognizes lysosomal enzymes on the basis of a structural determinant in their polypeptide chains. This recognition event is a key step in lysosomal targeting of soluble proteins, but the exact nature of the recognition determinant is not well understood. In this study we have characterized the phosphotransferase recognition signals of human lysosomal aspartylglucosaminidase (AGA) using transient expression of polypeptides carrying targeted amino acid substitutions. We found that three lysine residues and a tyrosine residing in three spatially distinct regions of the AGA polypeptide are necessary for phosphorylation of the oligosaccharides. Two of the lysines are especially important for the lysosomal targeting efficiency of AGA, which seems to be mostly dictated by the degree of phosphorylation of the alpha subunit oligosaccharide. On the basis of the results of this and previous studies we suggest a general model for recognition of lysosomal enzymes by the phosphotransferase.     

Progress in prevention and therapy of infectious complications in children and adolescents with neoplastic diseases

Due to the high dose-intensity of most current treatment protocols, the growing number of marrow transplantations, the routine use of aggressive supportive care and certain pathogen-related problems, infections remain an important cause for morbidity and mortality in children and adolescents with cancer. Over the last decade, however, considerable progress has been made in diagnosis, prevention and treatment of infectious complications in the immunocompromised host. This article first delineates both clinical approach and current treatment strategies in the pediatric cancer patient presenting with neutropenia and fever of unknown origin. It then reviews diagnosis and treatment of the most common specific infections and concludes with a discussion of preventive measures in the setting of anticancer treatment.     

Bone and joint manifestations of systemic infectious diseases

Bone and joint infections can occur as the consequence of a wide variety of systemic diseases. Disseminated fungal and mycobacterial infections, hepatitis, syphilis, gonorrhea, Lyme disease, and AIDS can all have osteoarticular manifestations. A thorough knowledge of the wide range of potential pathogens is key to establishing a correct diagnosis and instituting appropriate treatment.     

Incorporating gender in the anthropology of infectious diseases

The paper focuses on key issues in research and control of infectious diseases and demonstrates the utility of combining a gender perspective with anthropological investigation both for understanding disease and for designing and evaluating interventions for its control. Based on a definition of gender as opposed to sex, it illustrates, with the help of a gender framework for tropical diseases, how this concept is applied. It argues that gender-sensitive research is essential to the understanding of the nature of the disease, its prevalence, distribution, determinants and consequences. Examples are taken from anthropological studies on infectious diseases, including research on urinary schistosomiasis, malaria, leprosy, leishmaniasis and onchocerciasis. How gender-sensitive qualitative research can guide the design and evaluation of appropriate interventions for the prevention and control of infectious diseases is also discussed.     

Automated sentinel system of infectious diseases in Cuba

We state that the creation of the Automated System of Epidemiological Surveillance should become an integral part of the Service of Hygiene and Epidemiology of the Republic of Cuba, which allows for the operative evaluation of the epidemiological situation in the country in order to take timely anti-epidemiological and prophylactic steps.     

Fellowship training in infectious diseases: a report from the regional and national meetings of infectious diseases division chiefs and program directors

During the 2-year period April 1995 to April 1997, six regional meetings and one national meeting of division chiefs and program directors of adult infectious diseases programs in the United States were held to review fellowship training. Herein, we report data on job availability and job selection for recently graduated fellows. We summarize discussions on decreasing the number of fellows in training, and we outline suggested components of a core clinical curriculum and of three training tracks--clinician track, clinical investigator track, and basic investigator track.     

Implications of bacterial protein toxins in infectious and food-borne diseases

Among the 315 protein toxins elicited by gram positive and gram negative bacteria so far characterized, about 50 toxins are currently considered as totally or partially, responsible of the pathological manifestations and/or lethality resulting from host infection or intoxication (contaminated food) by relevant toxinogenic bacteria. A certain number of criteria are required for the assessment of indisputable involvement of a toxin or an array of toxins (from the same bacteria) in infectious diseases: 1) The bacterial microorganism clearly identified as the pathogenic agent of the disease produces component(s) considered as toxin(s); 2) The administration to appropriate animal(s) of the toxin(s) separated from the relevant bacteria or produced by genetic engineering from a heterologous tox+ recombinant bacterial strain produces symptoms and pathophysiological disorders that mimic those observed in the natural disease or at least those elicited in experimental animals by the cognate toxin-producing bacteria; 3) The in vitro incubation of the isolated toxin(s) with appropriate animal organs, tissues or cells elicits certain pathophysiological, biochemical or metabolic manifestions observed in the host infected with the relevant toxinogenic bacteria; 4) Toxin concentration in the organism of the host infected by the toxinogenic bacteria should be compatible with the characteristics of the relevant disease. The toxins of pathogenic interest exhibit a variety of effects in bacterial diseases. Bacteria that colonize a wound or mucosal surface but do not invade target cells can produce toxins that act locally or enter the bloodstream and attack internal organs (e.g. Corynebacterium diphtheriae, Vibrio cholerae, ...). Bacteria growing in a wound can produce toxins that destroy host tissue and kill phagocytes in the immediate vicinity of the bacteria, thus facilitating bacterial growth and spread. On the basis of the above mentioned criteria, the following bacterial diseases among many others are toxin-associated (toxinoses): diphtheria, tetanus, botulism, whooping cough, diarrhea, bloody diarrhea, hemolytic uremic syndrome, cholera, scarlet fever, toxic shock syndrome, gas gangrene, B. fragilis diarrhea, anthrax, pseudomembranous colitis.     

Epidemiology of infectious inflammatory diseases and role of Candida in newborns

The results of a 20-year microbiological monitoring of full-term newborns with infectious inflammatory diseases hospitalized from maternity homes of Moscow are presented. The incidence of candidiasis within that period was shown to increase 7 times at the account of the events of cutaneous and mucocutaneous candidiasis, gastrointestinal candidiasis and candidiasis of the central nervous system. One of the sources of the endogenic contamination of the newborns and infants was their intestinal microflora. In 4.6 per cent of the patients the meconium contamination by Candida was stated during the first days after the birth.