The causal relationships among CD4 cell depletion, HIV replication, and immune activation are not well understood. HIV-2 infection, “nature’s experiment” with inherently attenuated HIV disease, provides additional insights into this issue. We report the finding that in HIV-2 and HIV-1 patients with a comparable degree of CD4 depletion the imbalance in the relative sizes of the naive and memory T cell populations and the up-regulation of CD4 and CD8 cell activation markers (HLA-DR, CD38, CD69, Fas molecules) are similar, even though the viral load in the plasma of HIV-2-infected patients is two orders of magnitude lower than in HIV-1 patients and HIV-2 patients are known to have slower rates of CD4 T cell decline and a better clinical prognosis. Moreover, we found a similar increase in the frequency of cycling CD4 T cells (Ki67+), which was in strong correlation with the expression of activation markers. Finally, the level of T cell anergy, as assessed by the proliferative responses to CD3 stimulation and to a panel of microbial Ags, proved to be comparable in HIV-1 and HIV-2 patients with a similar degree of CD4 depletion despite large differences in viral load. Our data are consistent with a direct causal relationship between immune activation and CD4 cell depletion in HIV disease and an only indirect relation of these parameters to the virus replication rate. Invoking the concept of proximal immune activation and virus transmission, which links efficient transmission of virus to local cell activation and proliferation in response to Ags and inflammation, we propose an integrative interpretation of the data and suggest that strongly elevated immune activation induces CD4 cell depletion and not vice versa, with potential implications for the choice of treatment strategies.
to more severe or chronic forms of the disease 5,6 and avoid The objective of this study is to present and validate a the occurrence of new episodes, including some cases of clinical scale for the diagnosis of drug-induced liver injury fulminant hepatic failure. 7 (DILI). Five components were selected to be included in the Because there are no specific markers or tests for DILI, the scale: temporal relationship between drug intake and the ondiagnosis is usually based on circumstantial evidence. 8 It set of clinical picture, exclusion of alternative causes, extraherelies on a great deal of speculation by the clinician, the patic manifestations, rechallenge or accidental re-exposure, collection of a detailed pharmacological history, the estaband previous report in medical literature. The relative imporlishment of a consistent relationship between drug intake tance of each component was weighed, and arbitrary scores and the onset of the clinical picture, and the exclusion of were attributed. The probability of the diagnosis of DILI was alternative causes. Clinical improvement following drug expressed as a final score, which could vary from 06 to 20.withdrawal is another element that may indicate a drugContent validity, criterion validity, construct validity, and inrelated cause, although there is an increased recognition of ter-rater reliability were studied. To analyze validity and reliaprolonged cholestatic hepatitis, sometimes lasting for more bility, a random sample of 50 cases of suspected DILI was than 6 months, after drug withdrawal. 9 Rechallenge is fredrawn from a series of 120 cases reported to our unit. The quently considered to be the most reliable test in the diagnoclassification of the 50 cases by three experts in DILI was sis of suspected cases of DILI, 10 but it is clearly dangerous used as the external standard in the study of criterion validity.and is best avoidable. 7 Agreement between the scale and the standard, and agreement This complex process of diagnosis usually requires an exbetween two independent raters (inter-rater reliability) was perienced clinician who is deeply aware of the critical compoanalyzed by weighted k coefficient. There was agreement benents to be weighed for an accurate diagnosis, including a tween the scale and the standard in 42 cases (84%) with a good knowledge of the published literature. The translation weighted k coefficient of 0.90. A good discriminatory capacity of such experience and subjective clinical judgment into a of the scale was found when construct validity was studied.quantitative measurement to define, by more objective criteAgreement between raters was observed in 86% of the cases, ria, the probability of an adverse event being related to a corresponding to the weighted k of 0.93. In conclusion, the drug, is of major importance. The complexity of the clinical clinical scale was shown to have a high-level of validity and diagnosis has led to attempts to improve in vitro diagnostic inter-rater reliability as well as a good discriminatory capacity tests to...
FOXN1 deficiency is a primary immunodeficiency characterized by athymia, alopecia totalis, and nail dystrophy. Two infants with FOXN1 deficiency were transplanted with cultured postnatal thymus tissue. Subject 1 presented with disseminated Bacillus Calmette-Guérin infection and oligoclonal T cells with no naive markers. Subject 2 had respiratory failure, human herpes virus 6 infection, cytopenias, and no circulating T cells. The subjects were given thymus transplants at 14 and 9 months of life, respectively. Subject 1 received immunosuppression before and for 10 months after transplantation. With follow up of 4.9 and 2.9 years, subjects 1 and 2 are well without infectious complications. The pretransplantation mycobacterial disease in subject 1 and cytopenias in subject 2 resolved. Subject 2 developed autoimmune thyroid disease 1.6 years after transplantation. Both subjects developed functional immunity. Subjects 1 and 2 have 1053/mm3 and 1232/mm3 CD3+ cells, 647/mm3 and 868/mm3 CD4+ T cells, 213/mm3 and 425/mm3 naive CD4+ T cells, and 10 200 and 5700 T-cell receptor rearrangement excision circles per 100 000 CD3+ cells, respectively. They have normal CD4 T-cell receptor β variable repertoires. Both subjects developed antigen-specific proliferative responses and have discon-tinued immunoglobulin replacement. In summary, thymus transplantation led to T-cell reconstitution and function in these FOXN1 deficient infants.
The CD31 ؉ subset of human naive CD4 ؉ T cells is thought to contain the population of cells that have recently emigrated from the thymus, while their CD31 ؊ counterparts have been proposed to originate from CD31 ؉ cells after homeostatic cell division. Naive T-cell maintenance is known to involve homeostatic cytokines such as interleukin-7 (IL-7). It remains to be investigated what role this cytokine has in the homeostasis of naive CD4 ؉ T-cell subsets defined by CD31 expression. We provide evidence that IL-7 exerts a preferential proliferative effect on CD31 ؉ naive CD4 ؉ T cells from adult peripheral blood compared with the CD31 ؊ subset. IL-7-driven proliferation did not result in loss of CD31 expression, suggesting that CD31 ؉ naive CD4 ؉ T cells can undergo cytokine-driven homeostatic proliferation while preserving CD31. Furthermore, IL-7 sustained or increased CD31 expression even in nonproliferating cells. Both proliferation and CD31 maintenance were dependent on the activation of phosphoinositide 3-kinase (PI3K) signaling. Taken together, our data suggest that during adulthood CD31 ؉ naive CD4 ؉ T cells are maintained by IL-7 and that IL-7-based therapies may exert a preferential effect on this population. (Blood. 2009;113: 2999-3007) IntroductionHuman naive CD4 ϩ T cells have recently been shown to contain 2 subpopulations distinguished by the expression of CD31 (platelet endothelial cell adhesion molecule-1, PECAM-1). The CD31 ϩ subset is thought to incorporate the population of cells recently emigrated from the thymus, whereas the CD31 Ϫ subset has been proposed to derive from CD31 ϩ after homeostatic cell division. 1 During T-cell development in the thymus, rearrangement of the T-cell receptor (TCR) genes generates stable episomal DNA excision circles (TRECs) that are progressively diluted with cell division. 2-4 Accordingly, CD31 ϩ naive CD4 ϩ T cells have higher TREC content compared with the CD31 Ϫ naive subset. 1 Moreover, the progressive age-associated decline in naive CD4 ϩ T cells is mainly due to a reduction in the CD31 ϩ naive subset while the CD31 Ϫ subset persists, 5,6 further supporting the contribution of thymic output to the maintenance of CD31 ϩ cells. However, the decrease in TREC levels observed during aging is disproportionally greater compared with the decline in CD31 ϩ naive T cells, implicating other mechanisms, in addition to thymic output, in the persistence of these cells into old age. 4 Cytokine-driven expansion has been proposed to significantly contribute to a low level of homeostatic proliferation that maintains naive T-cell numbers. 7 Besides its established importance in thymopoiesis, interleukin-7 (IL-7) is considered to play a key role in naive T-cell survival and proliferation in the periphery. 2,7 In vitro studies of human naive CD4 ϩ T cells cultured in the presence of IL-7 revealed, alongside with its antiapoptotic properties, an ability to induce proliferative responses without a switch to a memory phenotype. 8 IL-7 seems to exert a preferential effect on umbilic...
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