免疫细胞衰老表现及免疫功能变化的研究进展

机体衰老的本质是细胞衰老不断累积的过程。免疫系统的衰老既是机体衰老的必然结果,也是导致机体衰老的重要原因。免疫系统作为衰老变化的主要系统之一受到越来越多的学者重视。本文将从适应性免疫系统的T、B细胞及固有免疫系统的自然杀伤(NK)细胞、巨噬细胞、中性粒细胞、树突状细胞(DC)和骨髓源性抑制细胞等免疫细胞的亚群、衰老指标和功能等方面在衰老过程中的改变进行总结,进一步明确免疫系统衰老在机体衰老过程中扮演的重要角色。     

An anomalous haplotype distribution of the arrestin domain-containing 4 gene (ARRDC4) haplotypes in Caucasians

Little was known about the sequence variability of the human Arrestin domain-containing 4 gene (ARRDC4). We sequenced its DNA from exon 2 to exon 8 in a sample of 92 Russians. Seven variants were identified; one of them has not been described yet. It causes an amino acid change from Thr to Met. Identified variants were genotyped in the complete sample of 253 unrelated men and women to analyze haplotype distribution. Fifteen haplotypes were inferred. Nine haplotypes had estimated frequencies > 1%. Ninety-five percent of all haplotypes were determined by five haplotype-tagging single nucleotide polymorphisms. Haplotypes form two clades. The two most common haplotypes cover 76% of all haplotypes. The certainty of the haplotype reconstruction does not depend on the haplotype-inferring algorithms, but is a result of the anomalous haplotype distribution of ARRDC4, which makes this gene a suitable candidate gene for haplotype association studies. Interestingly, there is a great evolutionary distance between the two most common haplotypes, which could suggest a more complicated coalescent process with either past gene flow, selections, or bottlenecks.     

An alternative method for isolating homozygotes of autosomal translocations in the mosquito Culex tarsalis.

An alternative pseudolinkage procedure for isolating homozygotes of autosomal translocations has been developed with the mosquito Culex tarsalis (Coquillet). The first step was to induce a translocation heterozygote in a population that was marked with recessive mutants. Interbred translocation heterozygotes produced translocation homozygotes that were phenotypically different from their translocation heterozygote and normal siblings. Thus, a translocation homozygote line of this species was selected and established in shorter time and with less effort than by prior pseudolinkage procedure.     

Crossmatch difficulties following the prophylactic use of Rh immune globulin.

With increasing demand for platelet transfusion the need to use platelets from Rh-positive persons for Rh-negative individuals often arises. The administration of Rho(D) immune globulin (human) in this situation has been recommended, but may cause serologic difficulties owing to the recipient''s passive acquisition of antibodies other than anti-D.     

Molecular and immunological significance of chimpanzee major histocompatibility complex haplotypes for hepatitis C virus immune response and vaccination studies

The chimpanzee is a critical animal model for studying cellular immune responses to infectious pathogens such as hepatitis B and C viruses, human immunodeficiency virus, and malaria. Several candidate vaccines and immunotherapies for these infections aim at the induction or enhancement of cellular immune responses against viral epitopes presented by common human major histocompatibility complex (MHC) alleles. To identify and characterize chimpanzee MHC class I molecules that are functionally related to human alleles, we sequenced 18 different Pan troglodytes (Patr) alleles of 14 chimpanzees, 2 of them previously unknown and 3 with only partially reported sequences. Comparative analysis of Patr binding pockets and binding assays with biotinylated peptides demonstrated a molecular homology between the binding grooves of individual Patr alleles and the common human alleles HLA-A1, -A2, -A3, and -B7. Using cytotoxic T cells isolated from the blood of hepatitis C virus (HCV)-infected chimpanzees, we then mapped the Patr restriction of these HCV peptides and demonstrated functional homology between the Patr-HLA orthologues in cytotoxicity and gamma interferon (IFN-gamma) release assays. Based on these results, 21 HCV epitopes were selected to characterize the chimpanzees' cellular immune response to HCV. In each case, IFN-gamma-producing T cells were detectable in the blood after but not prior to HCV infection and were specifically targeted against those HCV peptides predicted by Patr-HLA homology. This study demonstrates a close functional homology between individual Patr and HLA alleles and shows that HCV infection generates HCV peptides that are recognized by both chimpanzees and humans with Patr and HLA orthologues. These results are relevant for the design and evaluation of vaccines in chimpanzees that can now be selected according to the most frequent human MHC haplotypes.     

A mathematical model for the investigation of the Th1 immune response to Chlamydia trachomatis

Chlamydia are bacterial pathogens of humans and animals causing the important human diseases trachoma, sexually transmitted chlamydial disease and pneumonia. Of the human chlamydial diseases, sexually transmitted disease caused by Chlamydia trachomatis is a major public health concern. Chlamydia trachomatis replicates intracellularly and is characterised by a complex developmental cycle. Chlamydia is susceptible to humoral and cell-mediated immunity. Here we investigate the Th1 cell-mediated immune response against Chlamydia-infected cells as the response changes over the chlamydial developmental cycle. We suggest a form for the immune response over one developmental cycle by modelling the change in the number of intracellular chlamydial particles and assume peptides are presented in proportion to the number of replicating forms of chlamydial particles. We predict, perhaps non-intuitively, that persistent Chlamydia should be induced and forced not to return to the lytic cycle. We also suggest that extending the length of the time of the lytic cycle will effectively decrease the required efficacy of the Th1 response to eliminate the pathogen. We produce plots of active disease progression, control and clearance for varying levels of Th1 effectiveness.     

Specific, transient suppression of the immune response by HGG tolerant spleen cells. II. Effector cells and target cells.

In a previous report, it was shown that spleen cells from mice made tolerant to human gamma-globulin (HGG)5 could specifically inhibit the immune response of normal spleen cells after adoptive transfer to lethally irradiated recipients. However, that report also showed that the suppressive activity was only transiently associated with tolerant spleen cell populations. It was concluded from those experiments that while suppressive activity could be demonstrated in tolerant spleen cells under certain conditions, such activity was not obligatory for the maintainance of the tolerant state. The experiments presented here were performed to determine the nature of the effector cell(s) and the target cell(s) involved in this system of suppression of the immune response. Treatment of cells from tolerant animals with anti-thymocyte serum and complement to remove thymus-derived (T) cells completely abrogated suppresive activity. Removal of adherent cells from tolerant spleen cells by passage over glass wool columns resulted in partial loss of the suppression. The inhibitory activity of the suppressor cells was resistant to 900 R irradiation regardless of whether the tolerant spleen cells were irradiated before or after adoptive transfer. The cellular target(s) for the supprssor cells was examined by using lipopolysaccharide (LPS) as an alternative source of helper activity for the response to HGG. LPS, injected at the time of the initial antigenic challenge of mice that had been reconstituted with tolerant and normal spleen cells, prevented the expression of suppression against bone marrow-derived (B) cells. However, when LPS was presented only at the time of secondary antigenic challenge, it was unable to overcome suppression of the immune response of reconstituted recipients. Thus, LPS could produce a state where the B cells were resistant to suppression, but LPS could not rescue the responsiveness of B cells once the cells in the reconstituted recipient had been suppressed. In addition, the immune response to both the hapten dinitrophenol (DNP) and the carrier (HGG) were suppressed when recipients of tolerant and normal spleen cells were challenged with DNP6HGG. This indicates that T helper cells are also a target for suppression. The results presented in this paper are discussed in relation to a possible mechanism of suppression which proposes that suppressive activity represents the induction of tolerance in immunologically competent cells by HCG which is closely associated with the tolerant spleen cells.     

The chicken's femoral-lymph nodules: T and B cells and the immune response.

Femoral lymph nodules (FLN), which are barely perceptible in normal birds, after a footpad injection of sheep red blood cells (SRBC) may either significantly enlarge (responder) or remain reduced in size (nonresponder). There were approximately 38% T cells and 53% B cells in the FLN of responder chickens. Significantly more plaque-forming cells (PFC) developed in the FLN than in the spleen after a footpad injection of SRBC. Total antibody, mercaptoethanol- (ME) resistant, and ME-sensitive fractions were significantly higher in birds given i.v. than in those given footpad injections. There were no differences in PFC and agglutinin titers between FLN-responders and nonresponders. The number of PFC in FLN exceeded the number of splenic PFC previously reported. The high PFC response of the FLN may reflect the large percentage of B cells in this lymphomyeloid tissue or the presence of antigen-experienced B cells in the FLN. Although FLN may influence a systemic immune response its major role appears to be restricted to a local response.     

VNTR alleles associated with the alpha-globin locus are haplotype and population related.

The human alpha-globin complex contains several polymorphic restriction-enzyme sites (i.e., RFLPs) linked to form haplotypes and is flanked by two hypervariable VNTR loci, the 5' hypervariable region (HVR) and the more highly polymorphic 3'HVR. Using a combination of RFLP analysis and PCR, we have characterized the 5'HVR and 3'HVR alleles associated with the alpha-globin haplotypes of 133 chromosomes, and we here show that specific alpha-globin haplotypes are each associated with discrete subsets of the alleles observed at these two VNTR loci. This statistically highly significant association is observed over a region spanning approximately 100 kb. With the exception of closely related haplotypes, different haplotypes do not share identically sized 3'HVR alleles. Earlier studies have shown that alpha-globin haplotype distributions differ between populations; our current findings also reveal extensive population substructure in the repertoire of alpha-globin VNTRs. If similar features are characteristic of other VNTR loci, this will have important implications for forensic and anthropological studies.     

Persistent activity of suppressor cells in T cell-mediated immune response.

Tolerance to dinitrochlorobenzene contact sensitivity induced i.v. injection of dinitrobenzenesulfonic acid in guinea pigs is a long-lasting phenomenon (up to 1 year). The tolerogen, however, was traceable in the circulation only up to 3 months after its application. In spite of that, tolerance was adoptively transferred by parabiosis 6 months after being induced. Moreover, active suppressor cells eliminated by cyclophosphamide treatment are able to regenerate in those adoptively tolerized animals. These results indicate that the tolerogenic injection stimulates precursors of suppressor cells to generate active suppressor cells and memory cells of suppression. The further formation of active suppressor cells from memory cells seems to be tolerogen independent, but the existence of specific stimulator cells for suppression may be considered. These cells may bind undetectable small amounts of tolerogen. The recovery of suppression might, however, be also due to recovery of suppressor cells which were temporarily inactivated but not destroyed by cyclophosphamide treatment.