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HIV-1 Inhibition of TNF

Subtypes of HIV-1 differ with regard to their geographical prevalence and viral gene sequences. To date, no definitive relationship between subtype and pathogenic potential has established. Ranjbar et al. (p. 4182 ) found several amino acid differences within the transactivator of transcription (Tat) protein between viral subtypes B and C compared with subtype E based on nucleotide sequences. Tryptophan at aa 32 was found only in subtype E isolates. In stimulated CD4⁺ T cells or monocytes, vector-expressed subtype B or C, but not E, Tat enhanced activity of a cotransfected luciferase reporter gene controlled by the region of the TNF gene that binds Tat. A subtype E variant in which tryptophan at aa 32 of the wild-type subtype E isolate was replaced with glycine had partial TNF reporter activity. TNF gene DNase I hypersensitivity patterns of stimulated CD4⁺ T cells differed between cells stably transfected with subtype B and subtype E Tat. Intracellular TNF protein levels were repressed in stimulated subtype E Tat-transfected cells but elevated in stimulated subtype B Tat-transfected cells; levels in cells transfected with the subtype E Tat variant were 30% of subtype B Tat-transfected cell levels. Chromatin immunoprecipitation assays revealed decreased inducible recruitment to the TNF promoter of histone acetyltransferase p300/CBP-associating factor (P/CAF) and another enhanceosome protein and lower H3 acetylation only in cells transfected with subtype E Tat. Increased TNF reporter activity occurred in cells cotransfected with subtype E Tat plus a P/CAF expression plasmid. The authors present structural models of Tat and P/CAF interactions to support their interpretation that the aa 32 mutation in HIV-1 subtype E Tat inhibits chromatin remodeling and TNF expression in stimulated cells.

Thymic NK1.1⁺ NKT Cells

Most mature thymic T cells are exported to the periphery. A notable exception to this pattern is the mature NK1.1⁺ NKT cell. Although NKT cells contribute to resistance to many autoimmune diseases and cancers, it is not known why only immature NKT cells are exported from the adult thymus. Berzins et al. (p. 4059 ) confirmed retention of mature NKT cells in the thymus using transplanted CD45.2⁺ thymic lobes in CD45.1⁺ congenic mice. By 4–6 wk, only 1% of donor thymocytes remained in the graft, and more than half of those cells were NKT. Additionally, >20% of NKT cells in thymii of radiation chimeras that received bone marrow from congenic mice were of host origin even 1 year later. In both experiments, retained NKT cells were predominantly NK1.1⁺ and had higher levels of the NK receptor NKG2D than adjacent NKT cells of host origin. Long-lived donor NK1.1⁺ thymocytes sorted from harvested grafts produced considerably higher levels of IFN- after in vitro stimulation than host thymocytes from the same graft. In general, NKT cell numbers in the thymus decreased with increasing age, but the frequency of NKT cells as a proportion of all lymphocytes in all organs was constant. However, there was a shift toward an NK1.1⁺ phenotype in the thymus and an increase in export of NK1.1⁺ NKT cells with age. The authors speculate that these long-term thymic resident NK1.1⁺ NKT cells suppress damaging immune responses within the thymus by releasing high levels of IFN-.

Increasing Pregnancy Tolerance

One way of studying pregnancy tolerance is to measure embryo resorption rates. Lin and colleagues established that the resorption rate in normal BALB/c mice is 4–5% but is increased 4-fold after injection of dsRNA at gestational days 6.5 and 7.5. In their follow-up to that work, Lin et al. (p. 4147 ) found that the normal resorption rate of NOD/SCID mice also was 4–5%. However, the dramatic dsRNA-induced increase in resorption rate measured at gestational day 12.5 in BALB/c mice did not occur in NOD/SCID mice or in BALB/c mice injected with anti-TLR3 mAb at gestational days 4.5, 5.5, and 6.5. Higher basal levels of expression of TLR3 were detected on CD45⁺ placental cells collected at gestational day 12.5 from BALB/c mice compared with those from NOD/SCID mice. Only BALB/c mice had increases in the percentage of CD45⁺TLR3⁺ cells and the CD45⁺CD80⁺:CD45⁺ cell ratio after dsRNA stimulation. The increases were abrogated by pretreatment of BALB/c mice with anti-TLR3 mAb. In addition, only BALB/c mice had an increased CD8⁺CD80⁺:CD8⁺ cell ratio after dsRNA stimulation. CD45⁺ placental cells from dsRNA-stimulated BALB/c mice had higher levels of intracellular IL-2 and lower levels of IL-10 compared with control BALB/c mice. NOD/SCID mice injected with dsRNA had no change in the percentage of CD45⁺IL-2⁺ cells and a modest decrease in CD45⁺IL-10⁺ cells. The authors propose that increased embryo resorption rates in immune competent mice result from interaction of dsRNA with TLR3 on placental cells, as can occur during viral infection.

Triggering Autoimmunity

The break in self-tolerance characteristic of autoimmune disorders can occur by a variety of mechanisms, including exposure of self Ags that are normally hidden from the immune system or by a change in immunogenicity of a self-protein due to secondary modifications. Niederkorn et al. (p. 3950 ) examined the development of chronic dry eye syndrome. Increased corneal permeability as measured by dye uptake occurred in mice exposed to desiccating stress induced by s.c. injection of scopolamine hydrobromide vs nonstressed controls. The stressed animals had reduced numbers of conjunctival goblet cells, decreased tear production, and greater CD4⁺ T cell infiltration of the conjunctival basal epithelium. Anti-CD25-treated animals developed keratoconjunctivitis (LKC) and had fewer conjunctival goblet cells after stress than controls. Draining cervical lymph node cells from stressed animals transferred LKC to nonstressed nude mice. Inflammation in recipients occurred only in the eyes and was accompanied by infiltration of CD4⁺ T cells in the lachrymal glands and accumulation of transferred CFSE-labeled CD4⁺ T cells from stressed animals in the conjunctival epithelium. Cotransfer of CD4⁺CD25⁺ T cells from nonstressed animals prevented LKC. Li and Carayanniotis (p. 4479 ) looked at the impact of iodination of tyrosine residues in thyroglobulin and thyroiditis development. Three thyroglobulin peptides containing I-A^k-binding motifs flanked by tyrosine residues (at aa 130, 306, and 1942) induced T cells from mice immunized with the iodinated peptides, but not with the noniodinated peptides, to produce IL-2 and IFN- in vitro after peptide challenge. Two of the iodinated peptides inhibited activation of A^k-restricted T cells by a thyroglobulin epitope presented by A^k-expressing APCs, whereas both iodinated and noniodinated forms of the third peptide inhibited activation. Two of the iodinated peptides induced thyroiditis in naive animals by immunization in CFA or by adoptive transfer of peptide primed lymph node cells; one peptide induced the disease only by the adoptive transfer method. These two approaches demonstrate that environmental triggers such as desiccating stress or iodination expose mice to normally hidden self Ags or altered self Ags, respectively, that result in reactive T cells and autoimmune disease.

Leukotrienes and Asthma

Both groups of leukotrienes (LTs), dihydroxy (LTB₄) and cysteinyl (cys-LTs), are involved in Th2 cell-dependent pulmonary inflammation in response to Ag. Although cys-LTs constrict bronchus smooth muscle, their role in pulmonary inflammatory responses is not defined. Kim et al. (p. 4440 ) detected lymphocyte and eosinophil infiltrates, basement membrane thickening, increased mucus production, and hyperplasia of goblet and intraepithelial mast cells in lungs of OVA-sensitized and -challenged wild-type mice that were reduced significantly in lungs of mice lacking LTC₄ synthase (LTC₄S), the terminal enzyme for cys-LT generation. Immunized and challenged LTC₄S null mice had lower serum levels of OVA-specific IgE and IgG1 and reduced expression of IL-5, IL-13, eotaxin, and IL-10 in lung tissue compared with wild-type controls. Levels of IL-4, IL-5, IL-13, and IFN- produced by parabronchial lymph node cells stimulated in vitro were lower from sensitized and challenged mutant vs wild-type animals. In contrast, the two groups of mice did not differ in their delayed-type or contact hypersensitivity responses to OVA challenge after OVA plus CFA immunization or FITC challenge after FITC sensitization, respectively. OVA-sensitized and -challenged LTC₄S null mice were less responsive to aerosolized methacholine than wild-type mice. The experiments demonstrate that LTC₄S participates with LTB₄ in the initiation of a Th2 cell-dependent pulmonary inflammatory response to OVA challenge in sensitized mice.

A Novel C Regulator Protein

Although the primary function of the C system is to defend an organism against invading pathogens, it also has the capacity to damage tissues and cause inflammation. Regulators of complement activation (RCA) protect the host against deleterious effects of complement. Kraus et al. (p. 4419 ) searched genomic databases for sequences homologous to highly conserved domains within RCA genes. A cDNA clone from a rat pituitary library contained C receptor-like short consensus repeat (SCR) sequences and was found to be the homologue of human CSMD1 (C subcomponent C1r/s (CUB) and sushi multiple domains 1) protein. The rat protein sequence derived from the nucleotide sequence predicted a 388-kDa protein with 14 CUB domains each separated by SCR domains followed by 15 C-terminal RCA-like SCR domains. A recombinant CSMD1 protein inhibited deposition of rat serum C3 on human lymphoma cells, but not on zymosan, and partially inhibited hemolysis of Ab-sensitized sheep erythrocytes incubated with rat serum. In situ hybridization of antisense CSMD1 mRNA was most prominent in neurons of the CNS, especially in the hippocampus, and in bipolar cells of the retina in the adult rat; low expression was detected in dividing epithelial cells of other organs. High CSMD1 mRNA expression was seen in the amoeboid distal tip of the growing axon in the developing brain of 15- or 17-day-old rat embryos. The authors suggest that CSMD1, a rat RCA protein, protects fetal neural growth cones via its C inhibitory activity and is involved in regenerative growth of epithelial cells in several organs.

Summaries written by Dorothy L. Buchhagen, Ph.D.

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