Antigen Evolution Research Articles

Prostate-Specific Antigen Evolution After Photoselective Vaporization of the Prostate

Prostate-specific antigen (PSA) variations after photoselective vaporization of the prostate are an unsolved question. We included prospectively 323 patients who underwent GreenLight® prostate vaporization for prostatic hyperplasia between 2005 and 2013. We excluded patients with prostate cancer and those with concomitant prostate biopsies. Serum PSA levels were measured before and after the procedure at 1, 6, 12, 24, 36, and 48 months. The median preoperative PSA level was 4.50 ng/mL; it decreased to 2.41 ng/mL at 1 month (47% reduction), 2.17 ng/mL at 6 months (52% reduction), 2.30 ng/mL at 1 year (49% reduction), 2.40 ng/mL at 2 years (47% reduction), 2.31 ng/mL at 3 years (49% reduction), and 2.54 ng/mL at 4 years (44% reduction) (P values were all <0.0001). The median PSA nadir at 6 months was significantly different from the median PSA level at 1, 2, 3, and 4 years (respectively P=0.0046, P=0.0017, P=0.0006, and P=0.01). Patients who received ≤3000 J/cc had a significant trend to a PSA reascension after 6 months. Patients who received ≥4000 J/cc did not show any significant PSA reascension during the 4 years after procedure. Energy was correlated with the PSA reascension in univariate and multivariate analysis. The PSA level significantly decreased by half 1 month after the procedure, reached its nadir at 6 months, and showed a slight progressive reascension during the 4 following years. Applying an energy rate ≥4000 J/cc of prostate induced PSA stability over time whereas energy ≤3000 J/cc induced a reascension of the PSA level after 6 months.

Utility of Cryptococcal Antigen Screening and Evolution of Asymptomatic Cryptococcal Antigenemia among HIV-Infected Women Starting Antiretroviral Therapy in Thailand

Cryptococcal meningitis (CM) remains a significant HIV-associated opportunistic infection in Southeast Asia and Africa, with a high burden of disease and a high mortality rate despite the availability of antiretroviral therapy (ART). We retrospectively examined the utility of cryptococcal antigen screening to identify risk for CM among 211 Thai women initiating ART. Antigenemia prevalence was 11% (n = 9) among 84 women with a CD4 count <100 cells/mm(3). Screening identified all women who later developed CM. Cryptococcal antigen titers decreased over time with ART. Our study confirmed findings from previous studies in Thailand and South Africa and provided novel observational data regarding the course of cryptococcal antigenemia in patients initiating ART and the poor efficacy of low-dose fluconazole prophylaxis in preventing CM among patients with antigenemia.

Score Test for Conditional Independence Between Longitudinal Outcome and Time to Event Given the Classes in the Joint Latent Class Model

Latent class models have been recently developed for the joint analysis of a longitudinal quantitative outcome and a time to event. These models assume that the population is divided in G latent classes characterized by different risk functions for the event, and different profiles of evolution for the markers that are described by a mixed model for each class. However, the key assumption of conditional independence between the marker and the event given the latent classes is difficult to evaluate because the latent classes are not observed. Using a joint model with latent classes and shared random effects, we propose a score test for the null hypothesis of independence between the marker and the outcome given the latent classes versus the alternative hypothesis that the risk of event depends on one or several random effects from the mixed model in addition to the latent classes. A simulation study was performed to compare the behavior of the score test to other previously proposed tests, including situations where the alternative hypothesis or the baseline risk function are misspecified. In all the investigated situations, the score test was the most powerful. The methodology was applied to develop a prognostic model for recurrence of prostate cancer given the evolution of prostate-specific antigen in a cohort of patients treated by radiation therapy.

Sequence Analysis of Major Histocompatibility Complex Class-II DQB1 ( Patr-DQB1) Alleles in Chimpanzees by Polymerase Chain Reaction–Based Methods

The major histocompatibility complex (MHC) class-II genes are described as the genes that encode the antigen-presenting molecule. In particular, functional alleles of MHC class-II genes in nonhuman primates have been analyzed as part of the study of infectious and immune-mediated diseases in animal models and as part of efforts to understand the molecular evolution of human leukocyte antigen. The polymorphisms and sequence analysis of MHC class-II genes in a large number of subjects is necessary for the group management of nonhuman primates. In the present study, we attempted to analyze the DQB1 polymorphism in the common chimpanzee ( Pan troglodytes) by exon 2 sequencing. For exact typing of Patr-DQB1 alleles, we carried out polymerase chain reaction–restriction fragment length polymorphism and sequence analysis. In the genomic DNA of 25 chimpanzees, 6 Patr-DQB1 alleles, including 2 new alleles, were detected. Identification and analysis of Patr-DQB1 alleles using this method may contribute to our understanding of Patr-DQB1 allelic diversity in individual chimpanzees and should be useful in facilitating colony management of chimpanzee groups in Japan.

Evolution of free, complexed, and total serum prostate-specific antigen and their ratios during 1 year of follow-up of men with febrile urinary tract infection

Objectives To determine the serum values of free, complexed, and total prostate-specific antigen (PSA) and their ratios in men with febrile urinary tract infection (UTI) during 1 year of follow-up. Methods A total of 54 men were prospectively enrolled in the study, and serum samples were obtained at the acute stage of the UTI and after 1, 3, 6, and 12 months. Results Most men had a rise (median 3.1, 7.2, and 14.1 ng/mL, respectively) in free PSA (fPSA), complexed PSA (cPSA), and total PSA (tPSA) during the acute phase of the UTI. After 1 month, fPSA rapidly decreased to levels that were maintained during the rest of the follow-up period, and cPSA and tPSA declined more slowly. At 1, 3, and 6 months after the infection the fPSA/tPSA and fPSA/cPSA ratios were abnormal in one half to two thirds of the men (median ratio 11%, 15%, and 16% and 17%, 24%, and 24%, respectively), comparable to findings in patients with prostate cancer. Conclusions These results confirmed that the prostate is involved in men with febrile UTI. The low fPSA/tPSA and fPSA/cPSA ratios in combination with sustained elevations of cPSA and tPSA for up to 6 months after UTI could be falsely interpreted as a sign of prostate cancer. The prolonged elevation of cPSA indicates a long-lasting inflammation of the nonadenomatous parts of the prostate.

Significance of high-grade prostatic intraepithelial neoplasia on prostate biopsy

The early diagnosis of prostate cancer has been facilitated by the development of serum prostate-specific antigen (PSA) testing and evolution in transrectal ultrasound-guided biopsy of the prostate. Over a decade has passed since the initial recommendations for systematic sextant sampling of the prostate to increase the accuracy of cancer detection. Subsequently, variations in the number and location of biopsies have been proposed to maximize prostate cancer detection and obtain more complete information regarding tumor grade, tumor volume, and local stage. Although current biopsy strategies provide a wide sampling of the prostate gland, biopsy histology may not be conclusive for either the presence or absence of adenocarcinoma. High-grade prostatic intraepithelial neoplasia (HGPIN) is found in a significant fraction of patients undergoing transrectal prostate biopsies. In this article, we discuss the significance of high-grade prostatic intraepithelial neoplasia and other abnormal histology findings and current evidence addressing the presence of cancer and need for additional prostate biopsies.

Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients responding to highly active antiretroviral therapy.

Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients responding to highly active antiretroviral therapy.

Antigenic drift of viruses within a host: a finite site model with demographic stochasticity.

We theoretically study the antigenic drift of viruses within an infected host, as observed in human immunodeficiency virus (HIV) and equine infectious anemia virus (EIAV) infections, assuming that a finite number of antigen-determining sites at the viral envelop gene are responsible for the specific immune response. The pattern of antigen evolution becomes more complex than that predicted from the previous one-dimensional antigen space models. If the viral growth rate is sufficiently large, the demographic stochasticity for the fate of a new antigen mutant can be neglected. The high dimensionality in the way a virus escapes the immune defense in genotype space could then causes a rapid increase in the antigenic diversity and the total viral density, until finally the whole antigen genotypes are used up. The viral population is then driven to extinction in a host by the enhanced immune response to all genotypes. In contrast, if the viral growth rate is moderate or small so that only a small fraction of new antigen mutants can survive during the initial endangered period of random extinction, the viral antigenic diversity and the total density remain bounded, thereby enabling them to persist for a prolonged period by shifting the dominant antigen types. The phylogenetic pattern of antigen divergence is well characterized by the mean number of surviving antigen mutants from an antigen genotype. The substitution rate at antigen-determining sites increases as the efficiency of host immune response increases.

Evolutionary pattern of intra–host pathogen antigenic drift: effect of cross–reactivity in immune response

Several viruses are known to change their surface antigen types after infecting a host, thereby escaping the immune defence and ensuring persistent infection. In this paper, we theoretically study the pattern of intra-host micro-evolution of pathogen antigen variants under the antigen specific immune response. We assume that the antigen types of the pathogen can be indexed in one-dimensional space, and that a mutation can produce a new antigen variant that is one step distant from the parental type. We also assume that antibodies directed to a specific antigen can also neutralize similar antigen types with a decreased efficiency (cross-reactivity). The model reveals that the pattern of intra-host antigen evolution critically depends on the width of cross-reactivity. If the width of cross-reactivity is narrower than a certain threshold, antigen variants gradually evolve in antigen space as a travelling wave with a constant wave speed, and the total pathogen density approaches a constant. In contrast, if the width of cross-reactivity exceeds the threshold, the travelling wave loses stability and the distribution of antigen variants fluctuates both in time and in genotype space. In the latter case, the expected episodes after infection are a series of intermittent outbreaks of pathogen density, caused by distantly separated antigen types. The implication of the model to intra-host evolution of equine infectious anaemia virus and human immunodeficiency virus is discussed.

Evolution of Antigen Drift/Switching: Continuously Evading Pathogens

Following infection to a host, some pathogens repeatedly alter their antigen expression, and thereby escape the immune defense (antigen drift/switching). This paper examines the evolutionarily stable mutation rate of pathogens which maximizes the stationary pathogen density in a host. Assumptions are: (i) most mutations are deleterious but a minor fraction, p, of mutations can contribute to the alternation of antigenic property of the pathogen; and (ii) potential antigen types can be indexed in a one-dimensional lattice (the stepping-stone model). The model reveals that: (a) if the mutation rate is higher than a threshold μc = R0/(l - p ), where R0 is the per capita growth rate of pathogen before the immune system is activated, pathogens cannot maintain themselves because too many progeny are lost by lethal mutations; (b) if the mutation rate lies between zero and μc, the system converges to a traveling wave of antigen variants with a constant wave speed; (c) the evolutionarily stable mutation rate μESS is unexpectedly high: more than 0·25 per genome per replication even if most mutations are lethal. Hence more than a fourth of progeny are born defective in the evolutionarily stable state; (d) the μESS is even higher if multiple infections by pathogens are common.The paper also studies the evolutionarily stable mutation rate if every mutant antigen belongs to a different type (the infinite allele model), and the evolution of antigen switching between a finite number of antigen variants stored in the pathogen genome.

Allodeterminants and evolution of a novel HLA-B5 CREG antigen, HLA-B SNA.

A novel HLA-B5 CREG gene, HLA-B SNA was cloned and the primary structure was determined. The sequence data showed that HLA-B SNA was identical to HLA-B51 except the alpha 1 domain in which one amino acid substitution at residue 74 and 5 amino acid substitutions associated with the Bw4/Bw6 epitopes were observed between these Ag. The comparison with other HLA-B locus genes suggested that HLA-B SNA evolved from HLA-B51 by gene exchange or recombination at the exon 2 between HLA-B51 and B8. A total of 10 of 14 HLA-B51-specific CTL clones showed significantly weak or no recognition of HLA-B SNA Ag. They also gave the same degree of a lysis of Hmy2CIR cells expressing the HLA-B35/51 chimeric Ag composed of the alpha 1 domain of HLA-B35 and other domains of HLA-B51 as that of Hmy2CIR cells expressing the HLA-B SNA Ag. These results demonstrated that amino acid substitutions within positions 77-83 associated with the HLA-Bw4/Bw6 epitopes have an influence on recognition of the HLA-B SNA antigen by HLA-B51-specific CTL.

Monoclonal antibodies to breast cancer-associated antigens as potential reagents in the management of breast cancer.

Monoclonal antibodies reactive with the surface of human breast carcinoma cells have been generated and characterized. The immunogens used were membrane-enriched fractions of metastatic carcinoma lesions. The various monoclonals were shown to react with previously known as well as with novel tumor-associated antigens (TAAs). The most specific of the latter group is monoclonal B72.3, which is reactive with a 220,000 to 400,000 high-molecular-weight glycoprotein complex found in 50% of human mammary carcinomas and 80% of human colon carcinomas. Monoclonal antibody B6.2, which recognizes a 90,000-d glycoprotein, was radiolabeled and shown to efficiently localize human carcinoma transplants in athymic mice via gamma imaging without the use of second antibody or background subtraction manipulations. F(ab')2 and Fab' fragments were shown to be more efficient for tumor localization than intact immunoglobulin. Whereas the phenomenon of antigenic heterogeneity of tumor cell populations has long been known to exist, this phenomenon was also shown to manifest itself as antigenic modulation, in which specific TAAs can modulate their expression on the cell surface concurrent with different phases of the cell cycle. A phenomenon known as antigen evolution, in which a specific cloned tumor cell population can gradually drift in antigenic phenotype, has also been demonstrated. Recombinant interferon has been employed to (1) enhance the expression of specific TAAs on the surface of tumor cells already expressing the antigen; and (2) induce the expression of specific TAAs on the surface of carcinoma cells not previously expressing the antigen. The clinical implications of such phenomena in gamma scanning for the detection of tumor masses and for tumor immunotherapy are discussed. Methods for circumvention of problems inherent in the clinical use of monoclonal antibodies are also addressed.

Surface molecules and cell interactions

Many of the cell surface molecules of lymphocytes or their precursors are expressed in an unpredictable way on a limited set of other cell types. This often seems to involve expression on lymphoid and brain cells. The Thy-1 antigen is in this category, being a major glycoprotein of murine neuronal cells, fibroblasts and thymocytes. Structural studies show that this molecule is homologous with immunoglobulin domains which are the structural sub-units of all immunoglobulin polypeptides. Thy-1 is the size of one immunoglobulin domain and its sequence is most homologous with variable regions of immunoglobulins. It is suggested that Thy-1 is one of a set of surface molecules concerned with triggering interactions between cells and that this is the primitive function of the immunoglobulin domain. Cell interactions could be mediated by domain-like structures and receptors for them in a way which parallels the triggering of immunological effector reactions by the interaction of receptors with immunoglobulin constant regions. If this is so then the structure seen in the immunoglobulin domain would have evolved along with the evolution of cell organisation. The genes specifying the cell interaction molecules could then have provided the genetic material for the evolution of antibody and histocompatibility antigen at the time of vertebrate emergence.

Morphologic evolution of the Australia antigen in one case of hepatitis.

We followed the evolution of the Australian antigen (Au ag) in hepatitis in a 36-year-old patient with acute myeloblastic leukemia during a systematic study of Au ag in the serum. The patient suffered two bouts of icterus. The first one occurred during a rifamycin treatment; when the treatment was suspended, the results of liver function tests returned to normal within five days. The second bout was associated with elevated levels of serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase of 110 units. The results of the immunological tests are shown in the Table. Electron microscopy of the serum samples of Dec 23 showed the large particles aggregated in groups of 3 to 22. From 5 to 20 aggregations of Dane particles (Figure) can be counted per grid. The particles are 27 to 30 nm long; they were found in the subsequent serum samples but were no longer aggregated after

Serological Data and Phylogenetic Inference: The Problem of Rates of Change

Kirsch, J. A. W. (Department of Zoology, Univ. Kansas, Lawrence, 66044) 1969. Serological data and phylogenetic inference: the problem of rates of change. Syst. Zool., 18:296–311 [Immunology; cladistics, phylogeny, evolutionary rate; Marsupialia].—Inferences about the evolutionary history of a group based upon studies of its living members can only be made utilizing assumptions about evolutionary rates. One such assumption current among biochemists and serologists is that biochemical evolution has been steady and the same in all lineages. If this were so, cladistic relationships could easily be inferred from phenetics. The assumption of strict time-dependency may be interpreted either as a deterministic or as a stochastic statement. In the former case, the form of phenetic groups is logically determined in ways incompatible with the results of serological studies; this is illustrated by examples from the comparative serology of marsupials. A simple computer model for the evolution of a group of hypothetical taxa of known phylogeny, operating according to the rules of a stochastic interpretation of time-dependency, generates data about those taxa very like empirical data on marsupials. However, the inferred cladistics of the hypothetical group are incorrect in many details, and this is indicated by the incompatibility of phenograms representing the affinities of the taxa with their known cladistics. It is not claimed that the model reproduces the conditions of antigen evolution, but that it does indicate that such evolution, if time-dependent, must be so in a stochastic rather than a deterministic sense; and further, that having introduced chance as a factor in the evolution of biochemical characters, one has only a probability of inferring the correct phylogeny of a group from the resulting data about the similarities of contemporaneous taxa.