Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The induction of immunological self-tolerance begins in the thymus during fetal life. The random recombination of gene segments coding for TCR is followed by the negative selection of T cells bearing a TCR directed against self-antigens presented by thymic MHC. Insulin-like growth factor type 2 (IGF-2) is the dominant gene of the insulin family that is transcribed and translated in the thymus of different species. Contrary to the other members of the insulin gene family, IGF-2 gene (IGF2) is not transcribed in the thymus of diabetes-prone BB rats. The absence of thymic IGF2 expression is associated with the diabetogenic autoimmune process in BB rats. This defect could not only contribute to the lymphopenia of BB rats, but also to the absence of central self-tolerance of the insulin family in this animal.
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PMID:[Role of the thymus in the pathophysiology of autoimmune diabetes type 1]. 1130 59

The size of the T lymphocyte pool is maintained by regulation of T cell production, proliferation, and survival. Under the pressure of a T lymphopenic environment, mature naive T cells begin to proliferate in the absence of Ag, a process called homeostatic expansion. Homeostatic expansion involves TCR recognition of self peptide/MHC ligands, but less is known about the soluble factors that regulate this process. Here we show that IL-12 dramatically enhanced the homeostatic proliferation of CD8 T cells. In contrast, IL-2 had no beneficial effect on homeostatic expansion and, in fact, inhibited T cell expansion induced by IL-12. Using gene-targeted mice, we showed that IL-12 acted directly on the T cells to enhance homeostatic expansion, but that IL-12 cannot override the requirement for TCR interaction with self peptide/MHC ligands in homeostatic expansion. These data indicate that inflammatory cytokines may modulate T cell homeostasis after lymphopenia and have implications for regulation of the T cell repertoire and autoimmunity.
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PMID:Il-12 enhances CD8 T cell homeostatic expansion. 1131 90

Ag-specific proliferation of CD4+ T cells is regulated, in part, by costimulatory signals through CD28. The proliferative response during primary activation is an important determinant of the ability of the T cell to respond to Ag re-encounter. Proliferation of mature CD4+ T cells during lymphopenia (homeostatic proliferation) requires interaction with endogenous peptide MHC. However, the role of costimulation during homeostatic proliferation is unclear, as is the ability of homeostatic proliferation to regulate secondary T cell responses. Using a TCR transgenic system and serial adoptive transfers we find that homeostatic proliferation of CD4+ T cells occurs for at least 5 wk after adoptive transfer into recombination-activating gene (RAG)-/- recipients. Two discrete populations of proliferating T cells can be resolved, one that is highly proliferative and dependent on CD28 signaling, and the other that contains cells undergoing low levels of CD28-independent proliferation. Importantly, naive CD4+ T cells that have undergone homeostatic proliferation acquire both phenotypic and functional characteristics of true memory cells. These studies indicate that functional memory T cells can be generated by encounters with endogenous Ags only. This mechanism of T cell regeneration is possibly active during lymphopenia due to viral infections, such as HIV, transplantation, or cancer therapy, and may explain selected autoimmune diseases.
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PMID:A closer look at homeostatic proliferation of CD4+ T cells: costimulatory requirements and role in memory formation. 1156 85

We report a case of a combined immunodeficiency (CID) in a child affected by trichothiodystrophy (TTD) characterized by an altered response to ultraviolet (UV) light due to a defect in the XPD gene. The XPD gene encodes a subunit of the transcription factor II H (TFIIH), a complex involved in nucleotide-excision repair (NER) and basal transcription. Our patient showed neurological and immune system abnormalities, including CD4 + lymphopenia never previously reported in TTD patients. In vitro immunological studies revealed a marked reduction in T-cell proliferation in response to mitogens and CD3 cross-linking which was partially recovered by the addition of anti-CD28 antibody or exogenous interleukin-2. The patient's T cells displayed alterations in T-cell receptor (TCR/CD3) proximal signalling characterized by marked reduction in Lck kinase activity coupled with a constitutive hyperactivation of Fyn kinase. Despite these alterations, normal levels of Lck and Fyn proteins were detected. The role of antigen-presenting cells (APCs) in the pathogenesis of the T-cell defect was investigated by analysing dendritic cells (DCs) generated from the patient's blood monocytes. In these cells, flow cytometry revealed significantly reduced expression of the CD86 co-stimulatory molecules and HLA glycoproteins. In addition, the patient's DCs showed a decreased ability to stimulate naive T lymphocytes. Overall, the results of our study suggest that a defective TFIIH complex might result in alterations in T cells and DC functions leading to a severe immunodeficiency.
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PMID:Defective dendritic cell maturation in a child with nucleotide excision repair deficiency and CD4 lymphopenia. 1173 70

Thymectomy of BALB/c mice on day 3 of life results in the development of autoimmune gastritis (AIG) due to the absence of CD4(+)CD25(+) regulatory T cells. However, depletion of CD4(+)CD25(+) T cells by treatment with anti-CD25 rarely resulted in AIG. Depletion was efficient, as transfer of splenocytes from depleted mice induced AIG in nu/nu mice. One explanation for this result is that CD4(+)CD25(-) T cells upon transfer to nude recipients undergo lymphopenia-induced proliferation, providing a signal for T cell activation. Cotransfer of CD25(+) T cells did not inhibit initial proliferation but did suppress AIG. Surprisingly, immunization with the AIG target Ag, H/K ATPase, in IFA failed to induce disease in normal animals but induced severe AIG in CD25-depleted mice. These results demonstrate that second signals (nonspecific proliferation, TCR activation, or inflammation) are needed for induction of autoimmunity in the absence of CD25(+) regulatory T cells.
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PMID:Cutting edge: depletion of CD4+CD25+ regulatory T cells is necessary, but not sufficient, for induction of organ-specific autoimmune disease. 1205 2

TCR and cytokine signals induce naive T cells to undergo spontaneous divisions as part of a homeostatic response to conditions of T cell deficiency. The conditions under which these signals evoke the homeostatic response and their interaction with each other are poorly understood, and yet are very important clinically in considering strategies for immune reconstitution. Here, we show that p56(lck) (lck)-mediated TCR signals and IL-7R signals are each able to stimulate T cell proliferation in lymphopenic hosts independently of one another, but can also synergize to facilitate proliferation. Furthermore, the relative contribution to the homeostatic response by TCR and cytokine signals is not fixed and critically depends on both the degree of lymphopenia and specific characteristics of individual T cell clones. Finally, we show that only lck and not fyn can mediate the TCR-driven proliferation, while neither lck nor fyn is required for IL-7R-induced proliferation.
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PMID:TCR and IL-7 receptor signals can operate independently or synergize to promote lymphopenia-induced expansion of naive T cells. 1224 69

T cells expand without intentional antigen stimulation when transferred into adult lymphopenic environments. In this study, we show that the physiologic lymphopenic environment existing in neonatal mice also supports CD4 T cell proliferation. Strikingly, naive CD4 T cells that proliferate within neonates acquire the phenotypic and functional characteristics of memory cells. Such proliferation is inhibited by the presence of both memory and naive CD4 T cells, is enhanced by 3-day thymectomy, is independent of IL-7, and requires a class II MHC-TCR interaction and a CD28-mediated signal. CD44(bright) CD4 T cells in neonates have a wide repertoire as judged by the distribution of Vbeta expression. Thus, lymphopenia-induced T cell proliferation is a physiologic process that occurs during the early postnatal period.
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PMID:Neonates support lymphopenia-induced proliferation. 1253 Sep 82

The composition of peripheral blood leukocyte populations was studied following experimental PCV2-infection in 3-week-old piglets. Four of 10 PCV2-infected piglets developed clinical and pathological symptoms consistent with postweaning multisystemic wasting syndrome (PMWS) between 14 and 21 days post-inoculation (p.i.), and were characterised as PMWS-affected. Only these four PMWS-affected piglets, but neither the non-symptomatic infected nor control animals, developed a clear leukopenia. Kinetic analysis demonstrated a clear loss of both CD21(+) B and CD3(+) T lymphocytes in the PMWS-affected piglets. By CD3/CD4/CD8 triple labelling, the influence of PCV2 infection on all T cell sub-populations was discernible. A loss of CD3(+)CD4(+)CD8(+) memory/activated Th lymphocytes was particularly notable. However, all T lymphocyte sub-populations-CD3(+)CD4(+)CD8(+) memory Th, CD3(+)CD4(+)CD8(-) nai;ve Th, CD3(+)CD4(-)CD8(+) Tc and CD3(+)CD4(-)CD8(-) gammadelta TCR(+) lymphocytes-were susceptible to PCV2 infection-induced lymphopenia. CD3(-)CD4(-)CD8(+) NK cells were also depleted in the PMWS-affected animals, but granulocytes and monocytes were less affected. In conclusion, PCV2 infection induces primarily a lymphopenia, but only in animals which subsequently develop PMWS. The lymphopenia can be identified early p.i., particularly with the B lymphocytes. Memory/activated Th lymphocytes might be affected more than the other T cell sub-populations, but as time progressed a collapse of both T and B cell populations was clear.
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PMID:Association of lymphopenia with porcine circovirus type 2 induced postweaning multisystemic wasting syndrome (PMWS). 1273 11

Data from experimental and human cryptosporidiosis have established a major role of specific immunity in the control of Cryptosporidium parvum infection. In this work, alterations in spleen and Peyer's patch (Pp) lymphocytes were investigated in the course of a spontaneously resolutive gut cryptosporidiosis in four-day-old suckling NMRI mice infected with either 4 x 10(5) or 30 viable oocysts. Oocysts from entire small intestines, and spleen and Pp lymphocytes were examined using flow cytometry from day 7 to day 27 post-infection. Compared to uninfected animals, a 3-5 fold increase in the numbers of spleen TCR alphabeta+, CD4+, CD8+, TCR gammadelta+ and CD45R/B220+ lymphocytes was observed on day 17 post-infection in heavily infected animals. In Pp, more than ten-fold increases were observed, except for TCR gammadelta+ lymphocytes. At termination of infection, i.e. on days 21-23 after ingestion of 4 x 105 oocysts, T and B lymphocytes decreased rapidly in both organs, and remained lower than in uninfected animals on days 19-23 post-infection. In mice infected with 30 oocysts, similar alterations were observed in Pp, but not in spleen. Data suggest that in normally developing mice, clearance of gut C. parvum infection is associated with an initial increase in systemic and local lymphocyte numbers, followed by their decrease to below control levels during the recovery phase.
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PMID:Kinetics of spleen and Peyer's patch lymphocyte populations during gut parasite clearing in Cryptosporidium parvum infected suckling mice. 1519 40

The Biobreeding diabetes-prone rat suffers from a profound peripheral lymphopenia and yet succumbs to a T cell-dependent autoimmune disease. Lymphopenia segregates with a mutated chromosomal locus, termed lyp, recently identified as a frameshift mutation in IAN4. Others have correlated loss of IAN4 function with decreased mitochondrial integrity resulting in T cell apoptosis. Here we report that IAN4-/- T cells enter a state similar to that of partial activation wherein they down-regulate CD62L and undergo incomplete blasting yet do not progress through mitosis. When given a strong stimulus, this partial activation phenotype can be overcome. This phenotype can be recapitulated in wild-type T cells through suboptimal stimulation. The phenotype is not simply a reaction to the lymphopenic environment, as spontaneous CD62L down-regulation occurs in mature single-positive medullary thymocytes that develop within a non-lymphopenic environment, and normal T cells do not undergo similar blasting when parked in a lymphopenic environment. Finally, we show that IAN4-/- T cells are more readily triggered via TCR stimulation. Thus, in addition to their role in apoptosis, IAN family members may also play a role in regulating the T cell activation state through modulation of TCR signaling strength.
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PMID:Partial activation precedes apoptotic death in T cells harboring an IAN gene mutation. 1530 72


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