Human T Regulatory Cells Can Use the Perforin Pathway to Cause Autologous Target Cell Death

AbstractCytotoxic T lymphocytes and natural killer cells use the perforin/granzyme pathway to kill virally infected cells and tumor cells. Mutations in genes important for this pathway are associated with several human diseases. CD4+ T regulatory (Treg) cells have emerged as important in the control of immunopathological processes. We have previously shown that human adaptive Treg cells preferentially express granzyme B and can kill allogeneic target cells in a perforin-dependent manner. Here, we demonstrate that activated human CD4+CD25+ natural Treg cells express granzyme A but very little granzyme B. Furthermore, both Treg subtypes display perforin-dependent cytotoxicity against autologous target cells, including activated CD4+ and CD8+ T cells, CD14+ monocytes, and both immature and mature dendritic cells. This cytotoxicity is dependent on CD18 adhesive interactions but is independent of Fas/FasL. Our findings suggest that the perforin/granzyme pathway is one of the mechanisms that Treg cells can use to control immune responses

Neutrophils: the forgotten cell in JIA disease pathogenesis

Juvenile idiopathic arthritis (JIA) has long been assumed to be an autoimmune disease, triggered by aberrant recognition of "self" antigens by T-cells. However, systems biology approaches to this family of diseases have suggested complex interactions between innate and adaptive immunity that underlie JIA. In particular, new data suggest an important role for neutrophils in JIA pathogenesis. In this short review, we will discuss the new data that support a role for neutrophils in JIA, discuss regulatory functions that link neutrophils to adaptive immune responses, and discuss future areas of investigation. Above all else, we invite the reader to re-consider the use of the term "autoimmunity" as applied to the family of illnesses we collectively call JIA

Disruption of the mouse inositol 1,3,4,5,6-pentakisphosphate 2-kinase gene, associated lethality, and tissue distribution of 2-kinase expression

Many functions have been suggested for inositol 1,2,3,4,5,6-hexakisphosphate (InsP(6)), including mRNA export, nonhomologous end-joining, endocytosis, and ion channel regulation. However, it remains to be demonstrated that InsP(6) is necessary for in vivo survival. We previously isolated a cDNA encoding the mammalian inositol 1,3,4,5,6-pentakisphosphate (InsP(5)) 2-kinase (2-kinase), the enzyme that converts InsP(5) to InsP(6). We used the sequence to search the BayGenomics databases and identify an ES cell line (XA232) that has a gene trap construct embedded in the 2-kinase gene. We obtained a mouse from this line, produced heterozygotes, and confirmed that the heterozygotes contain the trapping construct and have diminished 2-kinase activity. Breeding the XA232 heterozygotes produced no homozygous offspring; thus, loss of 2-kinase is lethal in mice. Dissections of embryonic day-8.5 uteri yielded no homozygous embryos; thus, the mice die before day 8.5 postcoitum. The gene trap construct contains a β-galactosidase/neomycin reporter gene, allowing us to stain heterozygotes for β-galactosidase to determine tissue-specific expression of 2-kinase protein. 2-kinase is expressed in the hippocampus, the cortex, the Purkinje layer of the cerebellum in the brain, in cardiomyocytes, and in the testes of adult mice. At day 9.5 postcoitum, 2-kinase was expressed in the notochord, the ventricular layer of the neural tube, and the myotome of the somites. Intense staining was also seen in the yolk sac, suggesting that InsP(6) is necessary for yolk sac development or function. Furthermore, failure of yolk sac development or function is consistent with the early lethality of 2-kinase embryos

Randomized, double-blind, placebo-controlled trial of the efficacy and safety of rilonacept in the treatment of systemic juvenile idiopathic arthritis

OBJECTIVE: To assess the efficacy and safety of rilonacept, an interleukin-1 inhibitor, in a randomized, double-blind, placebo-controlled trial. METHODS: An initial 4-week double-blind placebo phase was incorporated into a 24-week randomized multicenter design, followed by an open-label phase. Seventy-one children who had active arthritis in \u3e/=2 joints were randomized (1:1) to the 2 arms of the study. Patients in the rilonacept arm received rilonacept (loading dose 4.4 mg/kg followed by 2.2 mg/kg weekly, subcutaneously) beginning on day 0. Patients in the placebo arm received placebo for 4 weeks followed by a loading dose of rilonacept at week 4 followed by weekly maintenance doses. The primary end point was time to response, using the adapted American College of Rheumatology Pediatric 30 criteria coupled with the absence of fever and taper of the dosage of systemic corticosteroids, using prespecified criteria. RESULTS: The time to response was shorter in the rilonacept arm than in the placebo arm (chi(2) = 7.235, P = 0.007). The secondary analysis, which used the same response criteria, showed that 20 (57%) of 35 patients in the rilonacept arm had a response at week 4 compared with 9 (27%) of 33 patients in the placebo arm (P = 0.016). Exacerbation of systemic juvenile idiopathic arthritis (JIA) was the most common severe adverse event. More patients in the rilonacept arm had elevated liver transaminase levels (including levels more than 3 times the upper limit of normal) compared with those in the placebo arm. Adverse events were similar in the 2 arms of the study. CONCLUSION: Rilonacept was generally well tolerated and demonstrated efficacy in active systemic JIA