A subset of dendritic cells induces CD4+ T cells to produce IFN-gamma by an IL-12-independent but CD70-dependent mechanism in vivo

Interferon (IFN)-gamma, a cytokine critical for resistance to infection and tumors, is produced by CD4(+) helper T lymphocytes after stimulation by cultured dendritic cells (DCs) that secrete a cofactor, interleukin (IL)-12. We have identified a major IL-12-independent pathway whereby DCs induce IFN-gamma-secreting T helper (Th)1 CD4(+) T cells in vivo. This pathway requires the membrane-associated tumor necrosis family member CD70 and was identified by targeting the LACK antigen from Leishmania major within an antibody to CD205 (DEC-205), an uptake receptor on a subset of DCs. Another major DC subset, targeted with 33D1 anti-DCIR2 antibody, also induced IFN-gamma in vivo but required IL-12, not CD70. Isolated CD205(+) DCs expressed cell surface CD70 when presenting antigen to T cell receptor transgenic T cells, and this distinction was independent of maturation stimuli. CD70 was also essential for CD205(+) DC function in vivo. Detection of the IL-12-independent IFN-gamma pathway was obscured with nontargeted LACK, which was presented by both DC subsets. This in situ analysis points to CD70 as a decision maker for Th1 differentiation by CD205(+) DCs, even in Th2-prone BALB/c animals and potentially in vaccine design. The results indicate that two DC subsets have innate propensities to differentially affect the Th1/Th2 balance in vivo and by distinct mechanisms.     

One or Several Types of Triptan Overuse Headaches?

Background.— Whereas the clinical features of pure triptan overuse headache (TOH) are well known, there are insufficient data regarding the semiological pattern of headaches when triptan overuse is associated with other types of medication overuse.
Objective.— To investigate and compare the clinical characteristics of patients with pure TOH and those with medication overuse headaches associating triptan and other medication overuses (combined TOH).
Methods.— This cross-sectional, observational study was conducted in 7 tertiary-care headache centers participating in the French Observatory of Migraine and Headaches. From 2004 to 2006, data from 163 patients with TOH were collected in face-to-face structured interviews (according to the International Classification of Headache Disorders, 2nd edition criteria).
Results.— Eighty-two patients fulfilled criteria for pure TOH (pTOH patients) and 81 for combined TOH (cTOH) patients. Continuous headaches were reported in 76% of cTOH patients compared with 32% of pTOH patients. Significantly more frequent and severe headaches and more intense phono-/photophobia between attacks were noted in cTOH patients. More cTOH than pTOH patients reported a history of tension-type headaches and a long-standing history of chronic headaches. Finally, compared with pTOH patients, cTOH patients were characterized by stronger dependence on acute treatments of headaches according to the DSM-IV criteria.
Conclusions.— Combined therapy with analgesics and/or the total number of drug units taken per day may cause a shift from a pattern of clear-cut headache attacks in patients with pTOH toward more severe clinical presentation in patients with cTOH. These patients should receive more intensive prophylactic therapy and specific behavioral management.     

Increasing incidence of melanoma after solid organ transplantation: a retrospective epidemiological study

The risk of melanoma in organ transplant recipients (OTR) is increased compared with the general population. This retrospective study registered all cases of post‐transplant melanoma in kidney, heart, lung, and liver transplant recipients followed in our specialized post‐transplant Dermatology Clinic since 1991. The yearly prevalence of melanoma and skin carcinoma between 2000 and 2015 was computed and compared in this population. Based on another cohort of kidney transplant recipients grafted since 2005, adjusted age‐ and sex‐standardized incidence ratio (SIR) was calculated using a renal transplantation registry. In our overall OTR cohort, between 1991 and 2000, five melanomas occurred in 1800 OTRs (0.28%), whereas between 1991 and 2015, 53 melanomas were diagnosed in 49 of 4510 OTR (1.09%), representing a 3.9‐fold increase in prevalence after 2000. Remarkably, the prevalence of nonmelanoma skin cancers remained unchanged over this period. Two deaths related to melanoma were recorded with an overall follow‐up of 62 months. In our cohort of 1102 renal transplant recipients, the SIR of melanoma was 4.52. Our data suggest that contrasting with nonmelanoma skin cancer, the risk of post‐transplant melanoma has considerably increased over the last decade.     

Frequency of the AGT Pro11Leu Polymorphism in Humans: does Diet Matter?

The Pro11Leu substitution in the AGXT gene, which causes primary hyperoxaluria type 1, is found with high frequency in some human populations (e.g., 5–20% in Caucasians). It has been suggested that this detrimental mutation could have been positively selected in populations with a meat-rich diet. In order to test this hypothesis, we investigated the occurrence of Pro11Leu in both herder and agriculturalist populations from Central Asia. We found a lower frequency of this detrimental mutation in herders, whose diet is more meat-rich, as compared to agriculturalists, which therefore challenges the universality of the previous claim. Furthermore, when combining our original data with previously published results, we could show that the worldwide genetic differentiation measured at the Pro11Leu polymorphism does not depart from neutrality. Hence, the distribution of the variation observed in the AGXT gene could be due to demographic history, rather than local adaptation to diet.     

Elevated antibody titers to Epstein-Barr virus prior to the diagnosis of Epstein-Barr-virus-associated gastric adenocarcinoma

Epstein-Barr virus (EBV) has recently been identified in the tumor cells of patients with gastric carcinoma. We tested pre-morbid serum samples from a carefully monitored cohort of Japanese men in order to investigate the possibility that patients with EBV-associated gastric cancer represent a sub-set of individuals with long-standing difficulties in appropriately managing EBV infection. From a serum bank, we obtained 108 samples derived from 54 patients destined to develop gastric adenocarcinoma and 54 controls. Samples were tested under code for antibodies to EBV-capsid antigen, early antigen and nuclear antigen. Individuals who were positive for IgA antibodies against EBV viral-capsid antigen (VCA) and IgG antibodies against the R component of EBV early antigen were at a 3.9-fold and 1.9-fold excess risk of disease, respectively. Antibody titers to EBV VCA were significantly higher in those destined to get EBV-associated gastric cancer than those subsequently developing non-EBV-associated gastric cancer or age-and-gender-matched controls. These findings suggest that the inability to control EBV infection on a long-term basis exists many years prior to the development of EBV-associated gastric cancer, and that EBV may play an etiologic role in this sub-set of malignancies.     

Detection of two epstein-barr-virus (EBV)-carrying leukemic cell clones in a patient with chronic lymphocytic leukemia (CLL)

The leukemic-cell population of one CLL patient, PG, was found to contain a sub-set of EBV-genome-carrying cells. It was detected directly by the expression of EBNA (EBV-encoded nuclear antigen) and by its capacity to grow in vitro. The proportion of EBNA-positive cells (0.1%) was maintained constantly during the period of this study, the final 3 years of the patient's life. EBV-carrying clonal sibling B-cell lines were established on 5 occasions. They had identically rearranged JH bands and chromosomal markers corresponding to the ex vivo CLL cells. Analysis of the viral episomes in the lines proved that they were the descendants of one cell. On the last occasion of blood sampling, 8 B-cell lines were established; 4 of these contained the same clonal markers as the previous lines, while 4 other lines belonged to another clone with identical JH rearrangement. Their abnormal karyotypes were different from the first clone. The chromosomal markers were only partly identical, suggesting secondary diversifications. The EBV sub-strain carried by this group of lines was different from the sub-strain of the first clone, as judged by the EBNA size distributions (EBNOtype) and EBV-DNA analysis. Analysis of the terminal repeat in the viral episomes also showed that the first and the second set of clones represented 2 independent EBV-infection events in vivo. © 1995 Wiley-Liss, Inc.