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PubMed2003

MHC class II-mediated apoptosis in dendritic cells: a role for membrane-associated and mitochondrial signaling pathways.

Cytotoxic elimination of dendritic cells (DC) in lymphoid tissue represents an important pathway of immune regulation. However, the mechanism of DC removal is still controversial since mature DC are insensitive to death receptor-mediated killing and other surface or soluble molecules mediating DC death in vivo have yet to be characterized. Class II ligation is the only known signal that induces rapid cell death in mature DC, thus our studies have now focused on the requirements for this cell death using the advantages of tools available for both the mouse and human systems. Anti-class II mAb could be grouped into (i) mAb that both bound to class II and caused class II-mediated cell death as well as (ii) those that bound to class II, but did not cause apoptosis. mAb binding stable class II dimers as well as those mAb recognizing either the alpha or beta chains of class II were found in both groups. Whereas class II-mediated death was enhanced by DC-DC homotypic interactions, DC clustering itself was insufficient to induce apoptosis. Although DC death could be inhibited by uncoupling actin filament bundling, the inhibition of various proteases, including the caspases, and protein transport mediators failed to inhibit class II-mediated cell death. Neither Bid, poly-ADP-ribose polymerase, caspases-3, -7 and -8 nor FLICE-inhibitory protein were found to be cleaved during class II apoptosis. Lastly, although class II mAb induced a rapid mitochondrial membrane depolarization in DC, cell death was not inhibited by Bcl-2 over-expression in DC. The independence of this form of apoptosis from protein or RNA synthesis, coupled to the rapidity of the mitochondrial depolarization and the lack of protection by Bcl-2, suggests that mature DC express pre-formed pro-apoptotic molecules that are involved in class II-mediated death.

Amino Acid Chloromethyl Ketones↗

PubMed1995

Origin and evolution of HLA class I pseudogenes.

The HLA (human major histocompatibility complex, or MHC) region includes three types of class I MHC genes: (1) class Ia loci (HLA-A, -B, and -C), which are highly expressed and polymorphic; (2) class Ib loci, which have much reduced expression and polymorphism; and (3) unexpressed class I pseudogenes. Phylogenetic analysis suggests that both class Ib loci and class I pseudogenes arose by duplication of class Ia loci. 5' regulatory elements conserved in class Ia genes are not conserved in either class Ib or class I pseudogenes, but the former show evidence of purifying selection at nonsynonymous sites in coding regions that is lacking in the latter. In the HLA class I region, there is little correspondence between map distance and phylogenetic distance, suggesting a complex history of tandem gene duplications. Furthermore, separate phylogenetic analysis of different gene regions suggests that several class I genes are evolutionary chaemeras, which presumably have arisen as a result of a process of interlocus recombination. For example, the 5' flanking region of the HLA-92 pseudogene was donated by a gene related to HLA-B and -C; and the HLA-A gene arose when exons 1-3 (and intervening introns) were donated to a gene related to the HLA-70 pseudogene by a gene related to HLA-B and -C.

Animals↗

PubMed2000

'They might as well brand us': working-class resistance to compulsory vaccination in Victorian England.

From its origins in resistance to the 1853 Compulsory Vaccination Act, the Victorian anti-vaccination movement successfully challenged the public health policies of an increasingly interventionist state. Anti-vaccinationists were not only middle-class reformers, but were also drawn from a politically active working class. These campaigners saw compulsory vaccination as an extreme example of class legislation, for its policy and administration implicitly targeted working-class infants and inflicted multiple penalties on a public who considered themselves 'conscientious objectors'. Anti-vaccinationism was quickly absorbed into English working-class culture. Indeed, it helped to reorganize working-class identities around the site of the vulnerable body thereby absorbing many people into a working class who interpreted the violation of their bodies as a form of political tyranny. Participation in this movement was, however, also an exclusive exercise for anti-vaccinators, as respectable working-class citizens distinguished themselves from members of the 'undeserving' classes. This paper explores the class nature of the Vaccination Acts, their relationship to the New Poor Law, and the political implications of their administration. It also imbeds anti-vaccinationism firmly within working-class culture, illustrating the campaign's relationship to popular protest and entertainment, and this legislation's impact upon working-class bodies.

England↗

PubMed1996

Expression of HLA class I genes in meiotic and post-meiotic human spermatogenic cells.

In human spermatogenic cells, in contrast to somatic cells, expression of major histocompatibility complex (MHC) class I molecules is undetectable. This lack of expression may contribute to the absence of female immune reaction against spermatozoa and may be necessary for gamete fusion. Among the molecular repressor mechanisms that may be used at the DNA level, we investigated 5' CpG methylation of the different class Ia and class Ib loci in meiotic pachytene spermatocytes and postmeiotic round spermatids, which had been purified from human testes by centrifugal elutriation. These results were compared with those obtained with mature spermatozoa and peripheral blood mononuclear cells. Using methylation-sensitive restriction enzymes and DNA locus-specific probes, we found that HLA-A, HLA-B/C, and HLA-E loci were similarly unmethylated in the germ and somatic cells tested, whereas HLA-F and HLA-G were even less methylated in the former cells. Together with the observation that spermatozoon DNA contains class I genes that are transfectable and able to direct transcription and protein synthesis in murine L cells, these data suggest that HLA class I genes are in an active conformation in male germ cells. We indeed found that both spermatocytes and spermatids contained low levels of class Ia and class Ib mRNA. Using reverse transcriptase-polymerase chain reaction, followed by DNA sequencing, we also detected three HLA-G transcriptional isoforms, resulting from alternative splicings, which suggested that this class Ib gene may have a potential function in these germ cells. Although intracellular expression of beta2-microglobulin (the light chain that associates with HLA class I heavy chains) was found in spermatocytes but not in round spermatids, no membrane-bound nor intracellular translated HLA class I heavy chain was detected in either germ cell type, when monomorphic anti-HLA class I monoclonal antibodies were used. Thus, lack of expression of HLA class I proteins in the male germ line is likely to involve post-transcriptional mechanisms of regulation.

Alternative Splicing↗

PubMed1989

The effect of steroids on the regulation of major histocompatibility complex-class II expression on nonlymphoid tissue.

The induction of MHC-class II antigens on human nonlymphoid tissues plays an essential role during the inhibition and augmentation of the immune response. Steroids have long been shown to possess strong immunosuppressive properties and successful steroid treatment has been associated with the absence of MHC-class II antigens on grated tissues. In this study we more specifically investigated the effect of steroids on the regulation of MHC-class II expression on nonlymphoid tissue. First, the influence of prednisolone on the induction process of the MHC-class II antigens on nonlymphoid tissue was determined. For this purpose vascular endothelial cells, kidney epithelial cells, fibroblasts, and a human colon tumor cell line were incubated with rIFN-gamma or primary MLC supernatant in the absence or presence of different concentrations of prednisolone. It was demonstrated that the induction process of MHC-class II antigens on these cell types was not affected by the drug at the different concentrations tested (1, 10, and 100 micrograms/ml). Next, the effect of prednisolone on the production of MHC-class II inducing factors was investigated. The drug was added at initiation of culture to primary MLC and the MHC-class II-inducing capacity of the supernatants was determined on day 7. Prednisolone at concentrations of 0.5-100 micrograms/ml clearly inhibited the overall production of factors responsible for MHC-class II induction on nonimmunological cells. The drug inhibited the production of IFN-gamma as well as non-IFN-gamma MHC-class II-inducing mediators. At a concentration of 1 microgram/ml the production of IFN-gamma and non-IFN-gamma MHC-class II-inducing mediators was reduced by, respectively, 85 per cent and 75 per cent. At a concentration of 10 micrograms/ml the production of both IFN-gamma and non-IFN-gamma mediators was almost completely inhibited. It is concluded that steroids downregulate the expression of MHC-class II antigens on nonlymphoid tissue by the inhibition of the production of MHC-class II-inducing mediators. However, once these mediators are present, the induction process itself is not affected by the drug.

Glucocorticoids↗

PubMed1998

MHC class I molecules are enriched in caveolae but do not enter with simian virus 40.

Simian virus 40 (SV40) binds to MHC class I molecules anywhere on the cell surface and then enters through caveolae. The fate of class I molecules after SV40 binding is not known. Sensitivity of 125I-surface-labelled class I molecules to papain cleavage was used to distinguish internalized class I molecules from class I molecules remaining at the cell surface. Whereas the caveolae-enriched membrane microdomain was found to also be enriched for class I molecules, no internalized papain-resistant 125I-surface-labelled class I molecules could be detected at any time in either control cells or in cells preadsorbed with saturating amounts of SV40. Instead, 125I-surface-labelled class I molecules, as well as preadsorbed 125I-labelled anti-class I antibodies, accumulated in the medium, coincident with the turnover of class I molecules at the cell surface. The class I heavy chains that accumulated in the medium were truncated and their release was specifically prevented by the metalloprotease inhibitor 1,10-phenanthroline. Thus, whereas class I molecules mediate SV40 binding, they do not appear to mediate SV40 entry.

Animals↗

PubMed1991

Involvement of major histocompatibility complex class I compatibility between dam and calf in the aetiology of bovine retained placenta.

The possibility was examined that in cattle compatibility of major histocompatibility complex (MHC) products between dam and calf might negatively influence the placental maturation and expulsion, and therefore increase the risk of retained placenta in healthy, normally calving cattle. Fifteen combinations of a single dam and two offspring were selected; the placenta of the first offspring was normally expelled (control) and the placenta of the second one was retained (case). The MHC class I and class II antigens of the animals were typed by immunoprecipitation and by one-dimensional isoelectric focusing (1D-IEF). Compatibility or incompatibility of class I or class II antigens was established by comparison of the IEF banding patterns of dam and calves. Analysis revealed that MHC class I compatibility between dam and calf increased the risk of retained placenta. In this study, the effect of class II compatibility was not significant, nor was the effect of the interaction of class I and class II. In a subsequent, additional sample the experimental design was extended: induction of tolerance against non-inherited maternal antigens (NIMA) might be implicated in the occurrence of the disorder within the group of class I incompatible cases. In three out of the five class I incompatible retained placenta cases, the banding pattern of the incompatible haplotype of the calf was identical to that of the haplotype of the granddam that was not inherited by the dam (NIMA). Notably, within the nine class I incompatible controls, there were none in which the offspring shared a paternal class I type with the granddam. This might suggest a tolerance-inducing effect of NIMA in cattle in relation to retained placenta.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2005

Impact of MHC class II incompatibility on localization of mononuclear cell infiltrates to the bronchiolar compartment of orthotopic lung allografts.

Chronic pathological changes in transplanted lungs are unique because they center on the airways. We examined the relative role of MHC class I and II antigens in causing bronchial pathology in orthotopic lung transplants to rats maintained on cyclosporin A (CsA). Transplants mismatched for MHC class II antigens had significantly more peri-bronchiolar infiltrates than MHC class I incompatible transplants. No significant increase in infiltrates was found in lung transplants incompatible for MHC class I plus II antigens compared to MHC class II antigens alone. Immunohistochemistry demonstrated that MHC class II antigen expression was confined to macrophages in MHC class I incompatible transplants, but was upregulated on bronchial epithelium in transplants with MHC class II incompatibilities. Vascular endothelium was notably devoid of MHC class II antigen expression in all transplants. However, both peri-bronchial and peri-vascular infiltrates were frequently cuffed by alveolar macrophages and type II pneumocytes that expressed MHC class II antigens. PCR analysis demonstrated that IFN-gamma and regulated on activation, normal T cells expressed and secreted (RANTES) were upregulated in MHC class II incompatible transplants. Thus, MHC class II incompatible orthotopic lung transplants in rats maintained on CsA immunosuppression undergo a bronchiolcentric upregulation of alloantigens.

Animals↗

PubMed2004

Is there a north-south divide in social class inequalities in health in Great Britain? Cross sectional study using data from the 2001 census.

OBJECTIVE: To examine individual social class inequalities in self rated general health within and between the constituent countries of Great Britain and the regions of England. DESIGN: Cross sectional study using data from the 2001 national census. SETTING: Great Britain. PARTICIPANTS: Adults aged between 25 and 64 in Great Britain and enumerated in the 2001 population census (n = 25.6 million). MAIN OUTCOME MEASURES: European age standardised rates of self rated general health, for men and women classified by the government social class scheme. RESULTS: In each of the seven social classes, Wales and the North East and North West regions of England had high rates of poor health. There were large social class inequalities in self rated health, with rates of poor health generally increasing from class 1 (higher professional occupations) to class 7 (routine occupations). The size of the health divide varied between regions: the largest rate ratios for routine versus higher professional classes were for Scotland (2.9 for men; 2.8 for women) and London (2.9 for men; 2.4 for women). Women had higher rates of poor health compared to men in the same social class, except in class 6 (semi-routine occupations). CONCLUSIONS: A northwest-southeast divide in social class inequalities existed in Great Britain at the start of the 21st century, with each of the seven social classes having higher rates of poor health in Wales, the North East and North West regions of England than elsewhere. The widest health gap between social classes, however, was in Scotland and London, adding another dimension to the policy debate on resource allocation and targets to tackle the health divide.

Adult↗

PubMed1998

Education and occupational social class: which is the more important indicator of mortality risk?

STUDY OBJECTIVES: In the UK, studies of socioeconomic differentials in mortality have generally relied upon occupational social class as the index of socioeconomic position, while in the US, measures based upon education have been widely used. These two measures have different characteristics; for example, social class can change throughout adult life, while education is unlikely to alter after early adulthood. Therefore different interpretations can be given to the mortality differentials that are seen. The objective of this analysis is to demonstrate the profile of mortality differentials, and the factors underlying these differentials, which are associated with the two socioeconomic measures. DESIGN: Prospective observational study. SETTING: 27 work places in the west of Scotland. PARTICIPANTS: 5749 men aged 35-64 who completed questionnaires and were examined between 1970 and 1973. FINDINGS: At baseline, similar gradients between socioeconomic position and blood pressure, height, lung function, and smoking behaviour were seen, regardless of whether the education or social class measure was used. Manual social class and early termination of full time education were associated with higher blood pressure, shorter height, poorer lung function, and a higher prevalence of smoking. Within education strata, the graded association between smoking and social class remains strong, whereas within social class groups the relation between education and smoking is attenuated. Over 21 years of follow up, 1639 of the men died. Mortality from all causes and from three broad cause of death groups (cardiovascular disease, malignant disease, and other causes) showed similar associations with social class and education. For all cause of death groups, men in manual social classes and men who terminated full time education at an early age had higher death rates. Cardiovascular disease was the cause of death group most strongly associated with education, while the non-cardiovascular non-cancer category was the cause of death group most strongly associated with adulthood social class. The graded association between social class and all cause mortality remains strong and significant within education strata, whereas within social class strata the relation between education and mortality is less clear. CONCLUSIONS: As a single indicator of socioeconomic position occupational social class in adulthood is a better discriminator of socioeconomic differentials in mortality and smoking behaviour than is education. This argues against interpretations that see cultural--rather than material--resources as being the key determinants of socioeconomic differentials in health. The stronger association of education with death from cardiovascular causes than with other causes of death may reflect the function of education as an index of socioeconomic circumstances in early life, which appear to have a particular influence on the risk of cardiovascular disease.

Adult↗

PubMed2002

Social class gradients in health during adolescence.

STUDY OBJECTIVE: To review existing data on social class gradients in adolescent health and to examine whether such gradients exist in new data concerning US adolescents. DESIGN: Review of relevant publications and unpublished data; regression analyses using adolescent self reported health status data to determine whether there are gradients by social class, using three classes categorised by adolescent reported parental work status and education. PARTICIPANTS: Adolescents of ages 11-17. MAIN RESULTS: Findings from the literature indicate the presence of social class gradients in some but not all aspects of adolescent health. Results from new data showed social class gradients in several domains of health and in profiles of health. The likelihood of being satisfied with one's health, of being more resilient (better family involvement, better problem solving, more physical activity, better home safety), having higher school achievement, and of being in the best health profiles were significantly and progressively greater as social class rose. Moreover, the probability of being in the poorest health profile type group was progressively higher as social class declined. CONCLUSIONS: The review of existing data and the new findings support the existence of social class gradients in satisfaction with one's health, in resilience to health threats, in school achievement, and in being in the best health overall (as manifested by the health profiles composed of four major domains of health). The study had two especially notable findings: (1) the paucity of studies using the same or similar indicators, and (2) the consistent existence of social class gradients in characteristics related to subsequent health, particularly intake of nutritional foods and physical activity. The sparseness of existing data and the different aspects of health investigated in the relatively few studies underscore the need for (1) the development of conceptual models specifically focused on adolescent health and social class; (2) additional inquiry into the measurement of social class and adolescent perceptions of class; (3) inclusion of contextual variables in study design; and (4) longitudinal cohort studies to better understand the specific determinants of health during adolescence.

Adolescent↗

PubMed1996

Major histocompatibility complex class I molecule expression is normal on peripheral blood lymphocytes from patients with insulin-dependent diabetes mellitus.

Recent work from one laboratory has shown, in both nonobese diabetic mice and humans, an association between insulin-dependent diabetes mellitus (IDDM) and quantitative difference in MHC class I molecule expression. This reported decrease in MHC class I molecule expression is very controversial in the nonobese diabetic mouse model of IDDM, but to our knowledge, it has not been evaluated by another group in human IDDM. To evaluate this question, we studied 30 patients with IDDM and 30 age- and sex-matched normal controls. MHC class I molecule expression was measured by flow cytometry with conformational-dependent MHC class I mAbs. The mean antigen density of MHC class I molecule expression in IDDM vs. normal control is 454+/-34 vs. 440+/-28 for lymphocytes and 1,440+/-117 vs. 1,494+/- 117 for monocytes, both P > 0.05. Three conformational-dependent MHC class I antibodies showed consistent results. To estimate the biological variation of MHC class I molecule expression in normal controls, we also studied 10 age- and sex-matched normal control pairs. Using X +/-SD of the percentage difference of mean antigen density in the normal control pairs as our definition of normal, we found that 70% (21/30) of IDDM patients had normal, 13% (4/30) of IDDM patients had decreased, and 17% (5/30) of IDDM patients had increased MHC class I molecule expression on lymphocytes. All IDDM patients showed normal MHC class I expression on monocytes. In conclusion, we find that there is no consistent decrease in MHC class I molecule expression on either lymphocytes or monocytes from patients with IDDM. The MHC class I molecule expression observed in IDDM patients is largely within the expected biological variation of MHC class I molecule expression that has been observed in normal controls.

Adult↗

PubMed1986

The relation of social class to risk factors, rehabilitation, compliance and mortality in survivors of acute coronary heart disease.

We studied 299 consecutive male 28-day survivors of unstable angina or myocardial infarction aged under 60 years to examine the relationship between social class and initial risk factors, change in risk-factors at one year follow-up, return to work, and 3-year mortality. There was a significant correlation between smoking on admission and social class, with 80% of lower and 31% of upper classes being current smokers. Daily cigarette consumption among smokers was significantly higher in lower-class patients. Lower-class patients also had a significantly higher weekly alcohol intake. Although the proportion of hypertensives did not vary with social class, mean in-hospital blood pressure was higher in lower-class patients. Social class bore no relationship to amount of leisure exercise, serum cholesterol or degree of overweight. There was a 90% 1-year return to work overall, and while there was no relationship between social class and eventual re-employment, lower-class patients took significantly longer to return to work. There were highly significant associations between social class and successful smoking cessation, increase in leisure exercise and weight reduction over the first year after discharge. There was no significant association between social class and 3-year mortality.

Angina, Unstable↗

PubMed1995

Elimination of self-peptide major histocompatibility complex class I reactivity in NOD and beta 2-microglobulin-negative mice.

Nonobese diabetic (NOD) mice and beta 2-microglobulin-gene-ablated mice (beta 2M -/-) show impaired presentation of major histocompatibility complex (MHC) class I and self-peptides, structures now recognized as critical for T-cell education to endogenous peptides. The naturally occurring NOD class I presentation abnormality appears to be attributable to, in part, a quantitative defect in the production of Tap-1 mRNA; Tap-1 with Tap-2 normally functions as a transporter for stable self-peptide and class I assembly. This study attempts to reverse NOD and beta 2-M -/- mouse autoreactivity by introduced or reestablished syngeneic class I presentation. Introduction of MHC class I and self-peptides on syngeneic MHC class I-matched cells specifically prevented diabetes in NOD mice and eliminated in vitro class I-directed T-cell autoreactivity in NOD and beta 2M -/- mice. Reestablishment of endogenous class I and self-peptide presentation in NOD mice was achieved with two well-described cures for the NOD mouse, complete Freund's adjuvant and mouse hepatitis virus. Both treatments induced Tap-1 mRNA, reestablished class I presentation of endogenous antigens, and eliminated in vitro and in vivo T-cell autoreactivity of self-peptides in the class I groove. These results substantiate a therapeutic role of self-peptide complexed with class I for T-cell education and suggest that some well-described NOD treatments may work, in part, through reestablishment of tolerance through class I and self-peptide.

Aging↗

PubMed1988

Molecular analysis of deficient class I H-2 antigen expression by mouse lung carcinoma cells.

We have continued our investigations of line lung carcinoma cells to understand the molecular basis of decreased expression of class I H-2 Ag and class I Ag induction with DMSO. We show that line 1, a murine lung carcinoma cell line, has low levels of class I Ag (H-2K, D, and L) because it is deficient in both class I and beta 2-microglobulin (B2M) RNA, and that these mRNA can be coordinately induced with DMSO. Evidence presented herein also shows that IFN-gamma can induce surface expression of class I Ag and suggests that it may act through a different mechanism than DMSO in inducing class I Ag. To further evaluate the regulation of class I expression, H-2Dp genes were transfected into line 1 cells. The transfected H-2 genes appear to be constitutively expressed at much higher levels than are the endogenous class I genes because surface expression of the foreign Dp Ag on the transfectants is elevated relative to the endogenous H-2d haplotype class I Ag. Both Dp surface expression and Dp mRNA are induced after treatment with DMSO. In all the Dp transfectants, we observed higher constitutive levels of class I mRNA as well as increased constitutive levels of endogenous B2M mRNA when compared to control or untransfected line 1 cells, however, we could not correlate these constitutive levels with Dp copy number. These results suggest that the regulation of class I and B2M genes is linked and that expression of class I genes can affect the expression of B2M genes.

Animals↗

PubMed1989

Combined immunodeficiency with defective expression in MHC class II genes.

MHC class II deficiency is an inherited immunodeficiency disease characterized by the presence of a normal number of T and B lymphocytes and profound anomaly of cellular and humoral responses to foreign antigens. All bone-marrow-derived cells (including B lymphocytes, monocytes and activated T lymphocytes) and also enterocytes and endothelial cells do not express all HLA class II (DR, DQ and DP) molecules on their membrane. It is known that the proper recognition of foreign antigens depends on their presentation, together with HLA class II molecules, on the membrane of antigen-presenting cells. MHC class II deficient combined immunodeficiency confirms the important role of MHC gene products in immune-defence mechanisms. Patients suffer from repeated and severe infections that are frequently the cause of death. The defect in HLA class II expression is the consequence of a lack of synthesis of HLA class II alpha and beta chains in patients' cells. Studies performed at DNA and RNA levels showed that there was no gross abnormality of MHC class II genes and that mRNA for all HLA molecules was not detected in patients' cells. These results, together with segregation studies performed in several families, suggested that the defect in HLA class II gene expression involves a transacting regulatory factor. Direct transcription assays showed that the disease is characterized by an absence of HLA class II gene transcription. An analysis of the specific binding of nuclear proteins from patients' cell lines to HLA class II promotor showed that a specific protein, RF-X, which normally binds to a regulatory sequence common to HLA class II promotors, is affected in MHC class II combined immunodeficiency.

Gene Expression Regulation↗

PubMed1995

Cross-linking cell surface class II molecules stimulates Ig-mediated B cell antigen processing.

Th cells bind to peptide-class II complexes presented on B cell surfaces. Recent evidence indicates that upon cross-linking, class II molecules transduce signals that modulate a variety of B cell functions. One possible function of class II signaling is to regulate the assembly of processed Ag-class II complexes. Here we show that cross-linking B cell surface class II molecules augments the processing and presentation of an Ek-restricted Ag to a specific T cell hybrid. Significantly, class II cross-linking only affects processing initiated by Ag binding to the surface Ig. The processing of Ag taken up by fluid phase pinocytosis is not affected by class II cross-linking, nor is the presentation of an antigenic peptide that does not require processing. Augmentation of Ag processing is enhanced by treatment of B cells with dibutyryl cAMP, a second messenger in the class II signaling pathway. The cross-linking of class II molecules does not alter the rate or number of Ig molecules internalized or the biosynthesis or expression of Ek molecules. Moreover, changes in the expression of the B7 family of costimulatory molecules or the adhesion molecule LFA-1 (CD11a/CD18) induced by class II cross-linking do not appear to account for the augmentation of processing observed here. Thus, the cross-linking of class II molecules on B cell surfaces selectively stimulates Ig-mediated Ag processing, indicating that a step in this pathway is a target of class II-mediated signaling events.

Animals↗

PubMed1994

Major histocompatibility complex class II expression is required for posttransplant immunological but not hemopoietic reconstitution in mice.

We had previously shown in a canine model that the administration of anti-MHC class II monoclonal antibody (MAB) immediately after autologous marrow transplantation prevented hemopoietic reconstitution. Since MHC class II expression in mice differs from that in dogs we were interested in determining the effect of MHC class II manipulation on posttransplant hemopoietic and immunological recovery in mice. Three murine models including MHC class II knock-out mice were studied. BALB/c mice (I-E+, I-A+) given anti-MHC class II MAB H81.9 (anti-I-E; 1 mg/kg/day, days 0-4) after TBI and infusion of syngeneic marrow or infused with anti-I-E purged marrow both showed normal hemopoietic reconstitution. Similarly, C57B1/6 mice (I-E-, I-A+) transplanted with M5/114 (anti-I-A) purged marrow recovered normal hemopoiesis. MHC class II knock-out (C2D) mice, which lack class II completely, also recovered normal hemopoiesis after TBI and transplantation with either normal or class II-deficient (C2D) marrow, although the kinetics of platelet recovery as determined by megakaryocytopoiesis and platelet counts on day 14 were slightly delayed. C57B1/6 mice transplanted with C2D marrow recovered normally. Immunologic recovery, however, was abnormal both in C2D recipients and in normal mice transplanted with C2D marrow: While CD8+ T lymphocytes recovered normally, no (or only very few) CD4+ T cells were identified posttransplant. Treatment of normal mice with anti-MHC class II MAB in vivo or transplantation of MHC class II-purged marrow, however, did not interfere with complete immunological recovery, although T cell maturation was slightly delayed. Thus, complete immunological reconstitution requires the expression of MHC class II on marrow-derived precursor cells, while the expression of MHC class II antigens is not a requirement for hemopoietic reconstitution in mice.

Animals↗