Diverse inflammatory cytokines induce selectin ligand expression on murine CD4 T cells via p38α MAPK.

Selectins are glycan-binding adhesion molecules that mediate the initial steps of leukocyte recognition of endothelium. Cytokines control numerous aspects of CD4 Th cell differentiation, but how cytokines control the induction of ligands for E- and P-selectin on Th cell subsets remains poorly understood. Among 20 cytokines that affect Th cell differentiation, we identified six that induce expression of selectin ligands on murine CD4 T cells above the low levels associated with TCR engagement: IL-12, IL-18, IL-27, IL-9, IL-25, and TGF-ß1. Collectively, these six cytokines could potentially account for selectin ligand expression on all of the currently defined nonsessile Th cell lineages, including Th1, Th2, Th9, and Th17 cells, as well as regulatory T cells. Induction of selectin ligand expression by each of these six cytokines was almost completely inhibited by pharmacologic inhibition of p38 MAPK, but not other MAPKs, or by conditional genetic deletion of p38α MAPK. Analysis of the expression of key glycosyltransferase genes revealed that p38α signaling was selectively required for induction of Fut7 and Gcnt1 but not for the induction of St3gal4 or St3gal6. Constitutively active MKK6, an immediate upstream activator of p38 MAPK, induced selectin ligand expression equivalent to that of cytokines, and this induction was completely dependent on the expression of p38α. Our results identify the repertoire of cytokines responsible for selectin ligand induction on CD4 T cells and provide a mechanistic link between Th cell development and T cell migration.

PU.1 Expression in T Follicular Helper Cells Limits CD40L-Dependent Germinal Center B Cell Development.

PU.1 is an ETS family transcription factor that is important for the development of multiple hematopoietic cell lineages. Previous work demonstrated a critical role for PU.1 in promoting Th9 development and in limiting Th2 cytokine production. Whether PU.1 has functions in other Th lineages is not clear. In this study, we examined the effects of ectopic expression of PU.1 in CD4(+) T cells and observed decreased expression of genes involved with the function of T follicular helper (Tfh) cells, including Il21 and Tnfsf5 (encoding CD40L). T cells from conditional mutant mice that lack expression of PU.1 in T cells (Sfpi1(lck-/-)) demonstrated increased production of CD40L and IL-21 in vitro. Following adjuvant-dependent or adjuvant-independent immunization, we observed that Sfpi1(lck-/-) mice had increased numbers of Tfh cells, increased germinal center B cells (GCB cells), and increased Ab production in vivo. This correlated with increased expression of IL-21 and CD40L in Tfh cells from Sfpi1(lck-/-) mice compared with control mice. Finally, although blockade of IL-21 did not affect GCB cells in Sfpi1(lck-/-) mice, anti-CD40L treatment of immunized Sfpi1(lck-/-) mice decreased GCB cell numbers and Ag-specific Ig concentrations. Together, these data indicate an inhibitory role for PU.1 in the function of Tfh cells, germinal centers, and Tfh-dependent humoral immunity.

Th17 cells demonstrate stable cytokine production in a proallergic environment.

Th17 cells are critical for the clearance of extracellular bacteria and fungi, but also contribute to the pathology of autoimmune diseases and allergic inflammation. After exposure to an appropriate cytokine environment, Th17 cells can acquire a Th1-like phenotype, but less is known about their ability to adopt Th2 and Th9 effector programs. To explore this in more detail, we used an IL-17F lineage tracer mouse strain that allows tracking of cells that formerly expressed IL-17F. In vitro-derived Th17 cells adopted signature cytokine and transcription factor expression when cultured under Th1-, Th2-, or Th9-polarizing conditions. In contrast, using two models of allergic airway disease, Th17 cells from the lungs of diseased mice did not adopt Th1, Th2, or Th9 effector programs, but remained stable IL-17 secretors. Although in vitro-derived Th17 cells expressed IL-4Rα, those induced in vivo during allergic airway disease did not, possibly rendering them unresponsive to IL-4-induced signals. However, in vitro-derived, Ag-specific Th17 cells transferred in vivo to OVA and aluminum hydroxide-sensitized mice also maintained IL-17 secretion and did not produce alternative cytokines upon subsequent OVA challenge. Thus, although Th17 cells can adopt new phenotypes in response to some inflammatory environments, our data suggest that in allergic inflammation, Th17 cells are comparatively stable and retain the potential to produce IL-17. This might reflect a cytokine environment that promotes Th17 stability, and allow a broader immune response at tissue barriers that are susceptible to allergic inflammation.

Drug-induced Grover's disease: a case report and review of the literature.

BACKGROUND: Grover's disease (GD) is a relatively rare transient dermatosis that can be idiopathic or acquired. Acquired GD may occur secondary to internal triggers such as medications and malignancies and external factors such as friction. OBJECTIVE: The purpose of this report is to describe the clinical and histological presentation of drug-induced Grover's disease (DIGD) and discuss potential pathogenic mechanisms. METHODS: A systemic review of the literature was performed to identify medications implicated in DIGD. RESULTS: We identified 13 reports of patients with DIGD. Most patients presented with a papular or papulovesicular morphology involving the trunk and extremities. Pruritus was the most common symptom. The majority of the offending agents were cancer therapeutics. Discontinuation of the culprit medication was sufficient for rash clearance and symptom resolution in most cases. CONCLUSION: The overlap in morphology and associated symptoms in DIGD and GD makes the diagnosis of DIGD challenging and has potentially led to underdiagnosis. However, in cases of more extensive involvement and treatment recalcitrance, a drug-induced eruption should be considered.

Ultrasound Is Not Useful in Monitoring Lipedematous Alopecia: A Clinical, Trichoscopic, Histologic, and Ultrasound Analysis of 2 Cases.

Introduction: Lipedematous scalp (LS) is a rare condition characterized by thickened adipose tissue in the subcutaneous layer of the scalp resulting in a soft, spongy, or thick consistency of the scalp. When associated with hair loss, this condition is called lipedematous alopecia (LA). Various imaging modalities have been used to diagnose LS and LA along with histopathology. Case Presentation: We present 2 cases of LS: a 56-year-old female with a 1-year history of hair thinning, pain, and tenderness at the vertex scalp and a 60-year-old female with a 5-year history of lichen planopilaris presenting with a 1-year history of itching and soreness on the crown of her head. Ultrasound (US) was used for diagnosis, treatment response surveillance, routine clinical examination, and symptom assessment. Follow-up US revealed no improvement in scalp thickness in either case despite symptom improvement and visual improvement in hair growth. Discussion/Conclusion: US has been reported as a helpful tool in the diagnosis of LS; however, treatment response was better approximated by hair growth and symptom alleviation. We found that once the diagnosis with made with US, clinical monitoring is adequate as symptom improvement and hair growth may not correlate with a change in scalp thickness.

Th9 cell development requires a BATF-regulated transcriptional network.

T helper 9 (Th9) cells are specialized for the production of IL-9, promote allergic inflammation in mice, and are associated with allergic disease in humans. It has not been determined whether Th9 cells express a characteristic transcriptional signature. In this study, we performed microarray analysis to identify genes enriched in Th9 cells compared with other Th subsets. This analysis defined a transcriptional regulatory network required for the expression of a subset of Th9-enriched genes. The activator protein 1 (AP1) family transcription factor BATF (B cell, activating transcription factor­like) was among the genes enriched in Th9 cells and was required for the expression of IL-9 and other Th9-associated genes in both human and mouse T cells. The expression of BATF was increased in Th9 cultures derived from atopic infants compared with Th9 cultures from control infants. T cells deficient in BATF expression had a diminished capacity to promote allergic inflammation compared with wild-type controls. Moreover, mouse Th9 cells ectopically expressing BATF were more efficient at promoting allergic inflammation than control transduced cells. These data indicate that BATF is a central regulator of the Th9 phenotype and contributes to the development of allergic inflammation.