Histocompatibility Types Research Articles

Signature for Long-Term Vaccine-Mediated Control of a Simian and Human Immunodeficiency Virus 89.6P Challenge: Stable Low-Breadth and Low-Frequency T-Cell Response Capable of Coproducing Gamma Interferon and Interleukin-2

In 2001, we reported 20 weeks of control of challenge with the virulent 89.6P chimera of simian and human immunodeficiency viruses (SHIV-89.6P) by a Gag-Pol-Env vaccine consisting of DNA priming and modified vaccinia virus Ankara boosting. Here we report that 22 out of 23 of these animals successfully controlled their viremia until their time of euthanasia at 200 weeks postchallenge. At euthanasia, all animals had low to undetectable viral loads and normal CD4 counts. During the long period of viral control, gamma interferon (IFN-gamma)-producing antiviral T cells were present at unexpectedly low breadths and frequencies. Most animals recognized two CD8 and one CD4 epitope and had frequencies of IFN-gamma-responding T cells from 0.01 to 0.3% of total CD8 or CD4 T cells. T-cell responses were remarkably stable over time and, unlike responses in most immunodeficiency virus infections, maintained good functional characteristics, as evidenced by coproduction of IFN-gamma and interleukin-2. Overall, high titers of binding and neutralizing antibody persisted throughout the postchallenge period. Encouragingly, long-term control was effective in macaques of diverse histocompatibility types.

Juvenile rheumatoid arthritis.

1. Jane G. Schaller, MD* 1. 2. *David and Leona Karp Professor of Pediatrics; Chair, Department of Pediatrics, Tufts University School of Medicine, Boston, MA. 1. There are several recognizable subgroups of juvenile rheumatoid arthritis (JRA): systemic-onset, polyarticular, pauciarticular, and late childhood onset. 2. Rheumatoid factor usually is negative in JRA. 3. Systemic-onset JRA is characterized by high intermittent fevers and other extra-articular manifestations: lymphadenopathy, rash, pleuritis, and pericarditis. 4. Iridocyclitis is absent in acute-onset disease but common in patients who have pauciarticular disease. 5. Nonsteroidal anti-inflammatory drugs (NSAIDs) remain the front-line and important agents in the therapy of patients who have JRA. 6. Controlled studies show that d-penicillamine, hydroxychloroquine, and oral gold are no more effective than placebo in the treatment of JRA. Juvenile rheumatoid arthritis (JRA) is a term used to describe the condition of chronic synovitis in children of which there are several distinct subgroups. Chronic synovitis in children was first described well in the English literature in 1897 by George Frederick Still, an English pediatrician and pathologist, who reported on 23 children who had chronic arthritis and came to his attention while he was training at the Hospital for Sick Children, Great Ormond Street. Still postulated that several separate conditions were responsible for chronic arthritis in children. Little subsequent work in this area was pursued until the late 1940s. Most modern observers have come to agree with Still that chronic arthritis in children encompasses several distinct disease subgroups (Table 1⇓ ). The relationship of JRA to adult rheumatoid arthritis was uncertain for many years. Now it seems clear that the classic adult-type rheumatoid arthritis does occur in children but is quite rare, the JRA subgroups seronegative 1 polyarthritis and systemic-onset disease also occur in adults but not frequently, the pauciarthritis of early childhood has not been recognized in adults, and the pauciarthritis of older children usually is classified as spondyloarthropathy in adults. The nomenclature for chronic childhood arthritis remains confusing (Table 2⇓), but …

Cervical cancer and human papillomavirus: epidemiological evidence and perspectives for prevention.

Cervical cancer is a major public health problem, as it is the second most common cancer in women world-wide after breast cancer. About 80% of the half a million cases estimated to occur annually in the world, occur in developing countries. The epidemiological evidence linking human papillomavirus (HPV) to cervical cancer is reviewed. It is concluded that over 90% of cervical cancers can be attributed to certain HPV types. HPV 16 accounts for the highest proportion (50%) followed by HPV 18 (12%), HPV 45 (8%) and HPV 31 (5%). The association with these HPV types are very strong and consistent with odds ratios over 15 in all case-control studies in high- and low-risk countries for cervical cancer. However, HPV is not a sufficient cause of this malignancy; certain cofactors are necessary for a proportion of HPV persistent infections to eventually progress to cancer. These include host factors such as histocompatibility types and immunological response, hormonal influences and infections with other sexually transmitted agents such as Chlamydia trachomatis. In addition, results from our studies carried out in Spain and Colombia support the hypothesis that male carriers of HPV play an important role in the development of cervical cancer in their wives. The recognition of the central role of HPV in cervical cancer has far-reaching implications for the primary and secondary prevention of this malignancy. Prophylactic and therapeutic HPV vaccines are now under development and HPV typing is being integrated into screening programmes in pilot studies in a few developed countries. In developing countries, well conducted conventional screening programmes remain the best approach for the control of cervical cancer until a safe and efficient HPV vaccine can be used in the general population.

Predictors for live birth after unexplained spontaneous abortions: Correlations between immunologic test results, obstetric histories, and outcome of next pregnancy without treatment

Our objective was to determine whether results from tests for maternal serum antinuclear antibodies, cytotoxic antibodies to paternal lymphocytes, parental histocompatibility types, and blocking factors for maternal-paternal mixed lymphocyte reactions were predictive of pregnancy outcome without immunologic treatment. Pregnancy outcome data from 95 women with a history of unexplained recurrent spontaneous abortions who underwent immunologic tests at Jefferson Medical College were evaluated with multiple logistic regression analyses. The number of prior spontaneous abortions, history of another relevant diagnosis, parental sharing of one histocompatibility antigen, and maternal age were related to the outcome of the next pregnancy in women given no immunologic treatment ( p = 0.05). No significant correlation was found between results from the immunologic tests or other history characteristics evaluated and outcome of the next pregnancy. The immunologic tests evaluated were not clinically useful predictors of pregnancy outcome.

Growth and egg production traits in chickens as influenced by major histocompatibility types and background genomes

SummaryAn experiment was conducted with populations of White Leghorn chickens that had been selected for high (HA) or low (LA) antibody response to sheep erythrocytes and were segregating at the major histocompatibility complex (MHC) for B‐system alloantigens B13 and B21. Results were quantified in terms of body weights, age and body weight at sexual maturity, egg production, egg weights, egg components and incidence of avian leukosis shedders. In many cases, background genome (HA or LA) by MHC type (B13 or B21) interactions were present, suggesting that both particular alleles and the genetic environment in which they exist may alter physiological performance.ZusammenfassungEinfluß von Histokompatibilitätstypen und Rest‐Genotypen auf Wachstum und Legeleistung von GeflügelDie zwei verwendeten Weiße Leghorn Populationen waren für hoch (HA) oder niedrigen (LA) Antikörperreaktion auf Schafe Erythrozyten selektiert worden und hatten im Histokompatibilitätsbereich (MHC) die B‐System Alloantigene B13 und B21. Die Wirkung dieser Genotypen sowie des Restgenoms auf Körpergewicht, Alter und Gewicht bei Geschlechtsreife, Legeleistung, Eigewicht, Eizusammenset‐zung und Ausmaß von Ausscheidung von Geflügelleukoseantigen wurden untersucht. In vielen Fällen waren Interaktionen zwischen Restgenom (HA) oder (LA) mit MHC‐Typ (B13) oder (B21) vorhanden, so daß der Eindruck entsteht, daß sowohl bestimmte Allele wie auch das genetische Umfeld, in dem sie existieren, physiologische Leistungen beeinflußt.

Olfactory discrimination of mouse strains (Mus musculus) and major histocompatibility types by humans (Homo sapiens).

A series of experiments revealed that humans can use olfaction to discriminate closely related strains of mice, differing genetically only at the major histocompatibility gene complex (H-2). In Experiment 1, subjects were asked to distinguish between the whole-body odors of live mice. In Experiments 2 and 3, the odor source was mouse fecal pellets, and in Experiments 4 and 5, the odor source was mouse urine.

Olfactory discrimination of mouse strains (Mus musculus) and major histocompatibility types by humans (Homo sapiens).

Olfactory discrimination of mouse strains (Mus musculus) and major histocompatibility types by humans (Homo sapiens).

The hematopoietic system is a source of odorants that distinguish major histocompatibility types.

Radiation chimeras were made by restoring lethally irradiated inbred mice with bone marrow cells of F1 hybrid mice of crosses between that inbred strain and an H-2-congenic strain. The urine of these chimeras was tested by the Y maze method, and shown to have acquired a scent indicative of the reconstituting donors' H-2 type. Thus, cells of the hematopoietic system contribute to the H-2-related odorant properties that enable mice to distinguish one another according to their H-2 types.

Chemosensory recognition of mouse major histocompatibility types by another species.

Mice can recognize one another by individually characteristic body scents that reflect their genetic constitution at the extremely polymorphic major histocompatibility complex (MHC) of genes on chromosome 17. Reproductive behavioral manifestations of this sensory communication system include MHC-related mating preferences and neuroendocrine responses that affect preimplantation pregnancy and arise from the MHC-related scent of alien males. We have shown previously that mice can be trained in a Y maze to distinguish the scents of urine of congeneic mice that differ genetically only at the MHC. By means of an automated olfactometer, we now show that rats also can similarly distinguish the urinary scents of MHC congeneic mice. Thus, the mode of individual recognition that depends on scents determined by MHC genes can operate across species barriers.

Genetic and anthropologic factors in gluten-sensitive enteropathy.

AbstractGluten‐sensitive enteropathy (GSE), a disease characterized by intestinal villous atrophy and malabsorption, is due to a sensitivity to wheat protein, gliadin, and probably has its basis in an underlying immunologic defect. GSE has a genetic basis in that some 70–80% of north American and northern European patients bear the HLA‐B8 histocompatibility type and about 90% bear the HLA‐DRw3 histocompatibility type. These histocompatibility types are both increased because they are in linkage disequilibrium in normal populations. This suggests that HLA‐B8 and HLA‐DRw3 genes are in linkage disequilibrium with a GSE disease gene, accounting for the association of the disease with certain histocompatibility antigens.A gene coding for a lymphoid surface antigen has been identified which is not HLA‐linked. This gene is distributed at a low frequency in the general population; it has been proposed that both the HLA and non‐HLA genes important to GSE code for different domains of the single surface receptor molecule that somehow predisposes to a heightened immune reaction to gliadin, thus causing the disease.GSE is most prevalent where HLA‐B8 occurs at the highest frequency in the general population and is not seen in populations where HLA‐B8 is not found. One explanation for this is that the gene complex containing HLA‐B8 (and HLA‐DRw3) evolved in response to infectious agents: Individuals bearing this complex were capable of more vigorous antibody response. However, such individuals were also more likely to be hypersensitive to wheat protein; as wheat became domesticated these individuals may have been at a disadvantage. It is only in regions such as northern Europe where wheat domestication occurred relatively late that one finds both a high frequency of HLA‐B8 and a high incidence of GSE.

CLONAL DIVERSITY AND POPULATION STRUCTURE IN A REEF‐BUILDING CORAL, ACROPORA CERVICORNIS : SELF‐RECOGNITION ANALYSIS AND DEMOGRAPHIC INTERPRETATION

Description of genetic variation in a population, recognized by Hubby and Lewontin (1966) as providing fundamental datum of evolutionary studies, is now routinely accomplished by electrophoretic characterization of allozyme variation and by other molecular techniques. These studies have revealed considerable variation at the molecular level, as well as the structure of this variation within and among populations. Although the value of the molecular approach in population genetics is beyond dispute, there remain interesting aspects of population variation not directly assayable by these methods. Biological self-recognition phenomena, exemplified by self-sterility in flowering plants and immune systems in animals, have been utilized in a population genetic context for only a few species. An analysis of genetic population structure based upon a self-recognition phenomenon requires a relatively straightforward assay incorporating the phenomenon, and an established relationship between the detectable polymorphisms and a more general aspect of population structure. Harberd used a combination of morphological characters and self-sterility relationships to deduce clonal structure in populations of the grasses, Festuca rubra and F. ovina (Harberd, 1961, 1962a) and the clover, Trifolium repens (Harberd, 1962b). In most vertebrate populations nearly every individual possesses a unique histocompatibility type, but some vertebrate population structures have been characterized by a departure from this condition of complete diversification. Kallman (1964) interpreted the occurrence of duplicated histocompatibility types within isolated populations of platyfish as an indication of inbreeding. For populations in which asexual reproduction occurs, some authors (Maslin, 1967; Cuellar, 1976, 1977; Angus and Schultz, 1979; Angus, 1980) have assumed that each clone is distinguished by a unique histocompatibility type, thus equating the diversity of incompatible strains with clonal diversity. In one such study (Angus and Schultz, 1979), a tissue graft analysis applied to populations of the unisexual fish, Poeciliopsis monacha-lucida, resolved more clones than had been detected in an earlier electrophoretic survey (Vrijenhoek et al.,

1 The definition and classification of diabetes mellitus

Diabetes earned its name from an uncommon combination of dramatic symptoms and lethal outcome, distinctive enough to have made it one of the earliest 'clinical syndromes' to be recognized and recorded by ancient observers of human disease (Frank, 1957; Papaspyros, 1964). Recognition of the central importance of surfeit of glucose in the urine and, later, in the blood have led to a progressive expansion of the concept of diabetes mellitus to the point where it is now considered a common and widespread biochemical disorder of which the original descriptive, clinical entity occupies only a small part. The concept of diabetes broadened first to include patients with marked glycosuria and lesser symptoms and then, with the application of automated biochemistry to population groups, large numbers of totally asymptomatic persons found to transgress arbitrary blood glucose norms. It is this conceptual expansion that has led to current re-evaluations of diagnostic criteria and classification for the disease. The search for satisfactory diagnostic blood glucose values recapitulates the history of this conceptual expansion; the clinical origins of diabetes remain indelibly stamped upon the terminology of classification. In essence, recent reviews have set boundaries to the diagnostic expansion, resulting in some withdrawal from the limits which biochemical 'diagnosis' had reached. This is signified by the upward revision of diagnostic blood glucose criteria for 'diabetes mellitus' (DM) and the introduction of the new intermediate class of 'impaired glucose tolerance' (IGT). Recognition of the variety of genetic and environmental factors that may give rise to the diabetic state and its sequelae (Fajans, Cloutier and Crowther, 1978) has prompted attempts to introduce aetiological mechanisms into an essentially clinical classification. This creates problems,for individual aetiological mechanisms may express themselves in several clinical forms, and a given clinical form may owe its origin to a number of pathogenic mechanisms. Thus, although the diabetogenic process associated with particular histocompatibility (HLA) types and certain autoimmune phenomena (Madsbad et al, 1980; Nerup and Lernmark, 1981) usually expresses itself as the severely symptomatic 'classical' syndrome, it

Histocompatibility types and antiviral antibodies in a diverse group of individuals

A study was made of the possible relationship between histocompatibility (HLA) antigens of the A and B loci and antibodies to cytomegalovirus, influenza A (victoria strain), measles, rotavirus, vaccinia, and varicella/zoster. A large and diverse group of unselected individuals was studied. A possible relationship was detected between the presence of the antigen B15 and a lack of circulating measles antibodies. The study group was divided into three sections: (a) healthy individuals, (b) “renal disease” patients awaiting renal transplantation, and (c) patients with various types of “other disease.” mainly of an immunological nature. Significantly elevated titers to cytomegalovirus and raricella/zoster were found in the two diseased groups, but these elevated titers could not be linked with the presence or absence of any particular HLA A or B antigen.

EVIDENCE FOR A FOOD ADDITIVE AS A CAUSE OF KETOSIS-PRONE DIABETES

A comprehensive survey of ketosis-prone diabetes showed a 29% preponderance of males and a trend for the time of diagnosis to coincide with epidemics of viral diseases. There was a significantly increased incidence between July and January in the age group diagnosed at 0-14 years but this seasonal trend was not shown in a group of boys diagnosed at this age who were all born in the month of October. The incidence of diabetes in this group of boys was very much higher than would be expected (p<0·00001). HLA histocompatibility types and virus infections were considered as possible causes of this striking finding but there seemed to be at least one additional seasonal factor acting prenatally. Circumstantial evidence suggested that this additional factor is the N-nitrosocompound content of processed mutton traditionally consumed in Iceland in the two weeks from December 23. Recently produced Icelandic smoked/ cured mutton contains considerable concentrations of N-nitroso-compounds. This work implies that a common food additive contributes to the production of ketosis-prone diabetes, not in the consumer but in the progeny.

Histocompatibility types in Parkinson's disease

HLA-A, B, and C antigens were determined in 52 patients with idiopathic Parkinson's disease and HLA-D antigens in 29 patients. In comparison with a representative sample of the Finnish general population, no significant deviations in HLA types of patients with Parkinson's disease were found. The patients with a slowly progressing disease had Cw3 antigen more often than the patients with a rapid progression.

Histocompatibility antigens and humoral immunity to Epstein-Barr virus.

To explore possible genetic determinants of immunity to Epstein-Barr (EB) virus infection, prevalence rates and geometric mean titers (GMT) of antibody against EB viral capsid antigen (VCA) were measured in 422 adults of known HLA and ABO histocompatibility types. Deviation from the overall prevalence (87%) of anti-VCA titers > 10 was limited to subjects with HLA-A10 (95%) and those with a "blank" HLA-A locus (78%). The latter deviation was largely accounted for by the 13 subjects of HLA-A1/blank constitution (46%). Deviations from the overall mean anti-VCA titer (GMT 131.5) were found in seropositive subjects with blood group 0 (GMT 153.3) and tissue antigens HLA-A3 (GMT 150.8), HLA-B7 (GMT 152.1), HA-Bw15 (GMT 97.0), and HLA-B27 (GMT 86.4). Separate reanalysis of the data for male and female subjects verified the association of blood group 0 with elevated and HLA-B27 with reduced mean levels of anti-VCA antibody.

Genetic susceptibility to multiple sclerosis.

Previous studies of histocompatibility (HLA) types in multiple sclerosis (MS) families did not provide convincing proof of an HLA-linked susceptibility factor. In 12 families we studied, all MS cases in each family shared at least one chromosome. The probability of this occurring in the absence of genetic linkage is approximately 0.001. The estimated penetrance is 5 percent, implying that the genetic susceptibility factor may be a necessary but not a sufficient cause of MS. Additional studies are needed to identify other differences between affected and unaffected susceptible individuals.

Recognition among mice. Evidence from the use of a Y-maze differentially scented by congenic mice of different major histocompatibility types.

Previous studies of mating preference signified that mice can sense one another's major histocompatibility complex (MHC) types, probably by olfaction. This conclusion has now been substantiated by the use of a Y-maze whose two arms were differentially scented with currents of air conducted through boxes occupied by B6 (H-2b) males and by B6-H-2k congenic males. Four B6 mice, two males and two females, were successfully trained, by water deprivation and reward, to enter the arm scented by B6 or B6-H-2k males. One of the males and one of the females were trained to select the B6-scented arm; the other male and female were trained to select the B6-H-2k-scented arm. Untrained mice showed no MHC discrimination in the maze. The performance of the trained mice in distinguishing between MHC congenic homozygous F2 segregants derived from a cross of B6-H-2k with B6 was as good as their performance in distinguishing the respective inbred strains, thus essentially eliminating alternative and significant additional explanations of MHC-associated sensory discrimination. The data further indicate that chemosensory discrimination of MHC types can be entirely dissociated from sex differences and from the circumstances of mating.

Measles antibodies and histocompatibility types in multiple sclerosis

Measles antibody titres and HLA antigens were determined in 71 White and 11 Coloured multiple sclerosis (MS) patients and 71 White and 11 Coloured age and sex-matched controls. Measles antibody titres were determined by the hemagglutination inhibition test and HLA antigens were determined serologically by a micro-lymphocytotoxicity test. Measles antibody titres were significantly higher in MS than in control cases and this was true for both female and male patients. No association was observed between the HLA antigens, especially HLA-A3 or HLA-B7 and measles antibody titres in the sera of MS patients or controls.

Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains.

MRL/1 and BXSB male mice have a systemic lupus erythematosus (SLE)-like disease similar to but more acute than that occurring in NZB X W mice. The common elements of lymphoid hyperplasia, B-cell hyperactivity, autoantibodies, circulating immune complex (IC), complement consumption, IC glomerulonephritis with gp70 deposition, and thymic atrophy were found in all three kinds of SLE mice. On the basis of these common elements, SLE seen in these mice can be considered a single disease in the same sense that human SLE is one disease. The differences in the SLE expressed in the different mice are no greater than those found in an unselected series of humans with SLE. However, the significant quantitative and qualitative variations in abnormal immunologic expression suggest that different constellations of factors, genetic and/or pathophysiologic, may operate in the three murine strains and that each constellation is capable of leading, via its particular abnormal immunologic consequences, to the activation of common immunopathologic effector mechanisms that cause quite similar SLE-like syndromes. From an experimental point of view, the availability of several inbred murine strains of commonplace histocompatibility types that express an SLE-like syndrome makes possible innumerable manipulations which should help to elucidate the nature and cause(s) of this disorder.