Imidazoquinoline Toll-like receptor 8 agonists activate human newborn monocytes and dendritic cells through adenosine-refractory and caspase-1-dependent pathways.

BACKGROUND: Newborns have frequent infections and manifest impaired vaccine responses, motivating a search for neonatal vaccine adjuvants. Alum is a neonatal adjuvant but might confer a T(H)2 bias. Toll-like receptor (TLR) agonists are candidate adjuvants, but human neonatal cord blood monocytes demonstrate impaired T(H)1-polarizing responses to many TLR agonists caused by plasma adenosine acting through cyclic AMP. TLR8 agonists, including imidazoquinolines (IMQs), such as the small synthetic 3M-002, induce adult-level TNF from neonatal monocytes, but the scope and mechanisms of IMQ-induced activation of neonatal monocytes and monocyte-derived dendritic cells (MoDCs) have not been reported. OBJECTIVE: We sought to characterize IMQ-induced activation of neonatal monocytes and MoDCs. METHODS: Neonatal cord and adult peripheral blood monocytes and MoDCs were cultured in autologous plasma; levels of alum- and TLR agonist-induced cytokines and costimulatory molecules were measured. TLR8 and inflammasome function were assayed by using small interfering RNA and Western blotting/caspase-1 inhibitory peptide, respectively. The ontogeny of TLR8 agonist-induced cytokine responses was defined in rhesus macaque whole blood ex vivo. RESULTS: IMQs were more potent and effective than alum at inducing TNF and IL-1ß from monocytes. 3M-002 induced robust TLR pathway transcriptome activation and T(H)1-polarizing cytokine production in neonatal and adult monocytes and MoDCs, signaling through TLR8 in an adenosine/cyclic AMP-refractory manner. Newborn MoDCs displayed impaired LPS/ATP-induced caspase-1-mediated IL-1ß production but robust 3M-002-induced caspase-1-mediated inflammasome activation independent of exogenous ATP. TLR8 IMQs induced robust TNF and IL-1ß in whole blood of rhesus macaques at birth and infancy. CONCLUSIONS: IMQ TLR8 agonists engage adenosine-refractory TLR8 and inflammasome pathways to induce robust monocyte and MoDC activation and represent promising neonatal adjuvants.

Toll-like receptor-7 tolerizes malignant B cells and enhances killing by cytotoxic agents.

Chronic activation through Toll-like receptors (TLR) occurs in a number of pathologic settings, but has not been studied to the same extent as primary activation. TLR7, expressed by B cells and some dendritic cells, recognizes molecular patterns associated with viruses that can be mimicked by synthetic imidazoquinolines. In response to primary stimulation with the imidazoquinoline, S28690, human mononuclear cells produced tumor necrosis factor-alpha, but were unable to do so upon restimulation with S28690. This state of "tolerization" lasted at least 5 days. Using chronic lymphocytic leukemia B cells as a model to facilitate biochemical analysis, the tolerized state was found to be associated with altered receptor components, including down-regulated expression of TLR7 mRNA and decreased levels of interleukin-1 receptor-associated kinase 1. Tolerization was characterized by a transcriptionally regulated block in stress-activated protein kinase and nuclear factor kappaB activation, with relatively preserved activation of extracellular signal-regulated kinase (ERK). Tolerized chronic lymphocytic leukemia cells were found to be more sensitive to cytotoxic chemotherapeutic agents, in part through altered stress-activated protein kinase signaling pathways. This property of the TLR7-tolerized state may potentially be exploited in the treatment of B cell cancers.

The antiviral activity of Toll-like receptor 7 and 7/8 agonists.

Imiquimod 5% cream is approved for the topical treatment of external anogenital warts caused by human papillomavirus (HPV) and for the skin cancer conditions superficial basal cell carcinoma and actinic keratosis. This drug is the first approved topically active Toll-like receptor (TLR) 7 agonist. Imiquimod activates innate immune cells to produce interferon-a and other cytokines. The induced cytokine cascade, in combination with effects in enhancing antigen presentation, also promotes an antigen-specific T helper type 1 cell-mediated immune response. This immune-based mechanism provides activity against a number of viruses and other intracellular pathogens. Imiquimod was effective topically in clinical studies for HPV but caused mixed results for Molluscum contagiosum, and herpes simplex virus (HSV). Activity against several other viruses were reported in case reports or patient series involving "off-label" usage of imiquimod, while others were evaluated only in preclinical models. Resiquimod, a more potent investigational analogue of imiquimod with mixed TLR7/8 agonist activity, was evaluated in clinical studies topically for the treatment of HSV and systemically for hepatitis C virus also with mixed success. This review focuses on the mechanism of action and antiviral usage reported for the TLR7 agonist imiquimod, the TLR7/8 agonist resiquimod and related imidazoquinoline analogues.

Do collectivists know themselves better than individualists? Cross-cultural studies of the holier than thou phenomenon.

Collectivists know themselves better than individualists do, in that collectivists provide more accurate self-predictions of future behavior in situations with moral or altruistic overtones. In 3 studies, respondents from individualist cultures overestimated the likelihood that they would act generously in situations involving redistributing a reward (Study 1), donating money (Study 2), or avoiding rude behavior (Study 3), whereas collectivists were, in general, more accurate in their self-predictions. Both groups were roughly accurate in predicting the behavior of their peers. Collectivists were more accurate in their self-predictions than were individualists, even when both groups were sampled from the same cultural group (Study 4). Discussion centers on culturally specific motivations that may bias the accuracy of self-insight and social insight.

Immune-mediated changes in actinic keratosis following topical treatment with imiquimod 5% cream.

BACKGROUND: The objective of this study was to identify the molecular processes responsible for the anti-lesional activity of imiquimod in subjects with actinic keratosis using global gene expression profiling. METHODS: A double-blind, placebo-controlled, randomized study was conducted to evaluate gene expression changes in actinic keratosis treated with imiquimod 5% cream. Male subjects (N = 17) with > or = 5 actinic keratosis on the scalp applied placebo cream or imiquimod 3 times a week on nonconsecutive days for 4 weeks. To elucidate the molecular processes involved in actinic keratosis lesion regression by imiquimod, gene expression analysis using oligonucleotide arrays and real time reverse transcriptase polymerase chain reaction were performed on shave biopsies of lesions taken before and after treatment. RESULTS: Imiquimod modulated the expression of a large number of genes important in both the innate and adaptive immune response, including increased expression of interferon-inducible genes with known antiviral, anti-proliferative and immune modulatory activity, as well as various Toll-like receptors. In addition, imiquimod increased the expression of genes associated with activation of macrophages, dendritic cells, cytotoxic T cells, and natural killer cells, as well as activation of apoptotic pathways. CONCLUSION: Data suggest that topical application of imiquimod stimulates cells in the skin to secrete cytokines and chemokines that lead to inflammatory cell influx into the lesions and subsequent apoptotic and immune cell-mediated destruction of lesions.

Administration of a dual toll-like receptor 7 and toll-like receptor 8 agonist protects against influenza in rats.

Toll-like receptors (TLR) detect conserved molecular patterns expressed by pathogens. Detection of the "molecular signature" for RNA viruses including influenza has been attributed to TLR3, TLR7, and TLR8. In the present study, compound 3M-011 was shown to be a synthetic human TLR7/8 agonist and cytokine inducer. 3M-011 was investigated as a stand-alone immune response modifier in a rat model of human influenza. Intranasal (IN) administration of 3M-011 significantly inhibited H3N2 influenza viral replication in the nasal cavity when administered from 72 h before IN viral inoculation to 6h after inoculation. Viral inhibition correlated with the ability of the TLR7/8 agonist to stimulate type I interferon (IFN) and other cytokines such as tumor necrosis factor-alpha, interleukin-12, and IFN-gamma from rat peripheral blood mononuclear cells. Prophylactic administration of TLR7/8 agonist also suppressed influenza viral titers in the lung, which corresponded with local IFN production. The activity of the TLR7/8 agonist resulted in greater inhibition of viral titers compared to rat recombinant IFN-alpha administered in a comparable dosing regimen. These studies indicate that TLR7/8 agonists may have prophylactic and therapeutic benefits in the treatment of respiratory viral infections, such as influenza, when administered prior to or shortly after viral inoculation.

Topical imiquimod treatment prevents UV-light induced loss of contact hypersensitivity and immune tolerance.

Imiquimod (1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine) is a TLR7 agonist that induces cytokine production in TLR7 bearing antigen-presenting cells (APCs), including IL-12, a cytokine that has been demonstrated to be a critical effector molecule for contact hypersensitivity (CHS). To test our hypothesis that topical applications of imiquimod may protect the skin immune system against the deleterious effects of UV light exposures, we treated animals with this agent, or its vehicle or nothing before UV exposures. Although topical imiquimod exposures before UV light did not prevent the depletion of epidermal Langerhans cells, it did prevent the loss of CHS. IL-12 was important in the protective role of imiquimod in preventing UV-induced loss of CHS, as systemic treatment of mice with an anti-IL-12 p70 monoclonal antibody blocked the protective effects of imiquimod. Additionally, only imiquimod-treated mice were resistant to hapten-specific tolerance induction after UV irradiation at the site of the initial sensitization with the hapten 2,4 dinitro-1-fluorobenzene. To model for the effects of TLR7 activation on the UV effect on antigen-APCs, XS52 cell line was used to study this interaction in an in vitro model system. This cell line expressed mRNA for TLR7, downregulated IkappaB, phosphorylated c-Jun N-terminal kinase, and secreted cytokines after exposure to imiquimod or lipopolysaccharide. Activation of the TLR7 signaling pathway on XS52 before UV-light exposures enhanced IL-12p70 secretion by this cell line. Similarly, activation of TLR7 on XS52 before UV-light exposure also prevented the UV-induced loss of IFN-gamma triggering in T cells during an allogeneic mixed lymphocyte reaction. Imiquimod-treated, UV-irradiated XS52 triggered a more vigorous IFN-gamma production than did either imiquimod-treated XS52 or UV-irradiated XS52, again suggesting a synergy between the two treatments. Lastly, enriched lymph node CD11c+ APCs from mice treated with UV irradiation, imiquimod alone or the combination of UV irradiation and imiquimod indicated the same in vivo synergy between imiquimod irradiation and UV irradiation in enhancing IL-12p70 production. These data suggest that topical imiquimod applications may play a role in preventing UV-induced impairment of the skin immune system, which is thought to be one of the critical events that allow the development of UV-induced skin cancers.

Apoptotic responses in squamous carcinoma and epithelial cells to small-molecule toll-like receptor agonists evaluated with automated cytometry.

The authors describe an assay to quantitate DNA fragmentation using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) stain, adapted to a 96-well microplate format for adherent cells, and an automated high-content screening imager. The apoptotic responses to actinomycin D (a known antineoplastic agent) to imiquimod (a small-molecule toll-like receptor [TLR] 7 agonist used in skin cancer treatment) and to several structurally related TLR 7/8 agonists were evaluated in squamous carcinoma SCC15 and SCC25 cells and normal human keratinocytes. Potent proapoptotic and growth-impairing (as determined by reduced cell numbers) actions of actinomycin D (1-300 ng/mL) were discerned with the assay. Consistent with previous reports, imiquimod (at 300 microM; approximately 75 microg/mL) induced TUNEL positivity of malignant cell cultures, but this effect also occurred in normal keratinocytes. Two related TLR agonists induced apoptosis at lower concentrations. However, the concentrations of these and the imiquimod necessary to elicit cancer cell apoptosis were 300 to 1000 times higher relative to their ability to induce the secretion of an antineoplastic protein, interferon-alpha, from human blood monocytes. This TUNEL analysis allows the quantitative comparison of compounds' apoptotic activity toward adherent malignant and normal cells and may be useful for hit characterization after a screen.

Synthesis and structure-activity-relationships of 1H-imidazo[4,5-c]quinolines that induce interferon production.

1H-Imidazo-[4,5-c]quinolines were prepared while investigating novel nucleoside analogues as potential antiviral agents. While these compounds showed no direct antiviral activity when tested in a number of cell culture systems, some demonstrated potent inhibition of virus lesion development in an intravaginal guinea pig herpes simplex virus-2 assay. We have determined that the in vivo antiviral activity can be attributed to the ability of these molecules to induce the production of cytokines, especially interferon (IFN), in this model. Subsequently, we found that the compounds also induce in vitro production of IFN in human peripheral blood mononuclear cells (hPBMCs). The in vitro results reported herein and the in vivo results reported previously led to the discovery of imiquimod, 26, which was developed as a topical agent and has been approved for the treatment of genital warts, actinic keratosis, and superficial basal cell carcinoma.

Ridge preservation with freeze-dried bone allograft and a collagen membrane compared to extraction alone for implant site development: a clinical and histologic study in humans.

BACKGROUND: Tooth extraction typically leads to loss of ridge width and height. The primary aim of this 6-month randomized, controlled, blinded, clinical study was to determine whether ridge preservation would prevent post-extraction resorptive changes as assessed by clinical and histologic parameters. METHODS: Twenty-four patients, 10 males and 14 females, aged 28 to 76 (mean 51.5 +/- 13.6), requiring a non-molar extraction and delayed implant placement were randomly selected to receive either extraction alone (EXT) or ridge preservation (RP) using tetracycline hydrated freeze-dried bone allograft (FDBA) and a collagen membrane. A replaced flap, which did not completely cover the sockets, was used. Following extraction, horizontal and vertical ridge dimensions were determined using a modified digital caliper and an acrylic stent, respectively. Prior to implant placement, a 2.7 x 6.0 mm trephine core was obtained and preserved in formalin for histologic analysis. RESULTS: The width of the RP group decreased from 9.2 +/- 1.2 mm to 8.0 +/- 1.4 mm (P<0.05), while the width of the EXT group decreased from 9.1 +/- 1.0 mm to 6.4 +/- 2.2 mm (P<0.05), a difference of 1.6 mm. Both the EXT and RP groups lost ridge width, although an improved result was obtained in the RP group. Most of the resorption occurred from the buccal; maxillary sites lost more width than mandibular sites. The vertical change for the RP group was a gain of 1.3 +/- 2.0 mm versus a loss of 0.9 +/- 1.6 mm for the EXT group (P<0.05), a height difference of 2.2 mm. Histologic analysis revealed more bone in the RP group: about 65 +/- 10% versus 54 +/- 12% in the EXT group. The RP group included both vital bone (28%) and non-vital (37%) FDBA fragments. CONCLUSIONS: Ridge preservation using FDBA and a collagen membrane improved ridge height and width dimensions when compared to extraction alone. These dimensions may be more suitable for implant placement, especially in areas where loss of ridge height would compromise the esthetic result. The quantity of bone observed on histologic analysis was slightly greater in preservation sites, although these sites included both vital and non-vital bone. The most predictable maintenance of ridge width, height, and position was achieved when a ridge preservation procedure was employed.

Comparison of an allograft in an experimental putty carrier and a bovine-derived xenograft used in ridge preservation: a clinical and histologic study in humans.

PURPOSE: The aim of this randomized, controlled, blinded clinical study was to compare ridge dimensions and histologic characteristics of ridges preserved with 2 different graft materials. MATERIALS AND METHODS: Twenty-four subjects, each requiring a nonmolar extraction and delayed implant placement, were randomly selected to receive ridge preservation treatment with either an allograft in an experimental putty carrier plus a calcium sulfate barrier (PUT) or a bovine-derived xenograft (BDX) plus a collagen membrane. Horizontal and vertical ridge dimensions were determined using a digital caliper and a template. At 4 months postextraction, a trephine core was obtained for histologic analysis. RESULTS: The average ridge width decreased by 0.50 mm for both groups (P < .05). The midbuccal vertical change for the PUT group was a loss of 0.3+/-0.7 mm versus a gain of 0.7+/-1.2 mm for the BDX group, a difference of 1.0 mm (P > .05). Histologic analysis revealed vital bone in the PUT group of about 61%+/-9% versus 26%+/-20% for the BDX group (P < .05). DISCUSSION: Greater vital bone fill in the PUT group may be attributable to earlier and greater vascular invasion of the carrier material. The putty material was characterized by ease of handling, simple placement, and enhanced graft particle containment. CONCLUSIONS: Allograft mixed with an experimental putty carrier produced significantly more vital bone fill than did the use of a xenograft with no carrier material. Ridge width and height dimensions were similarly preserved with both graft materials.

Effect of an immunomodulator on the efficacy of an attenuated vaccine against avian pneumovirus in turkeys.

Since 1997, avian pneumovirus (APV) has caused estimated annual losses of $15 million to the Minnesota turkey industry. In order to develop an attenuated live vaccine against APV, we serially passaged a Minnesota isolate of APV (APV/MN/turkey/1-a/97) in vitro in cell cultures for 41 passages. Laboratory experiments with this high-passage virus (P41) indicated that the attenuated virus provided immunogenic protection to turkeys against challenge with virulent APV, although some birds showed mild to moderate dinical signs after inoculation. To reduce the residual pathogenicity of P41, while maintaining its immunogenicity, we decided to vaccinate turkeys with P41 in the presence of an immunomodulator, S-28828 (1-n-butyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine-hydrochloride), which is a potent cytokine inducer. The combined inoculation of S-28828 (5 mg/kg body weight) and P41 resulted in a significant reduction in the incidence of virus-induced clinical signs in comparison with birds that received P41 without immunomodulator (P < 0.05). Only 17% of birds inoculated with S-28828 + APV P41 showed mild respiratory symptoms at 5 days postinoculation as compared with 46% of the vaccinated turkeys that did not receive S-28828. Vaccination with either P41 or with P41 + S-28828 protected turkeys against dinical signs and viral replication after challenge with virulent APV. These results indicate that immunomodulators, such as S-28828, may act as good vaccine adjuvants that can reduce the pathogenicity but maintain the immunogenicity of partially attenuated vaccines.

Resiquimod and other immune response modifiers as vaccine adjuvants.

Synthetic immune response modifiers, such as resiquimod, are Toll-like receptor 7 and 8 agonists that act as vaccine adjuvants, enhancing antigen-specific antibody production and skewing immunity towards a Th1 response. These compounds stimulate dendritic cells to secrete cytokines, upregulate costimulatory molecule expression and enhance antigen presentation to T cells. The compounds have demonstrated vaccine adjuvant properties in a number of animal models. The adjuvant effects can be enhanced by measures that allow the drug to stay localized with the vaccine without quickly entering the systemic circulation. Clinical studies demonstrate that topical application of resiquimod and analogs is safe and effective at activating the local immune response. For injection, resiquimod or a similar compound may need to be formulated to allow for local immune activation without induction of systemic cytokines.

Bio-optical properties and ocean color algorithms for coastal waters influenced by the Mississippi River during a cold front.

During the passage of a cold front in March 2002, bio-optical properties examined in coastal waters impacted by the Mississippi River indicated that westward advective flows and increasing river discharge containing high concentrations of nonalgal particles contributed significantly to surface optical variability. A comparison of seasonal data from three cruises indicated spectral models of absorption and scattering to be generally consistent with other coastal environments, while their parameterization in terms of chlorophyll (Chl) alpha concentration showed seasonal variability. The exponential slope of the colored dissolved organic matter (CDOM) averaged 0.0161+/-0.00054 nm(-1) and nonalgal absorption averaged 0.011 nm(-1) with deviations from general trends observed due to anomalous water properties. Although the phytoplankton specific absorption coefficients varied over a wide range [0.02 to 0.1 m2 (mg Chl)(-1) at 443 nm] being higher in offshore surface waters, values of phytoplankton absorption spectra at the Sea-Viewing Wide Field-of-View Sensor (SeaWiFS) wave bands were highly correlated to modeled values. Particulate scattering characteristics were similar to observations for other coastal waters, while backscattering ratios were on average lower in phytoplankton-dominated surface waters (0.011+/-0.003) and higher in low Chl near-bottom waters (0.0191+/-0.0045). Average percent differences in remote sensing reflectance Rrs derived from modeled and in-water radiometric measurements were highest in the blue wave bands (52%) and at locations with more stratified water columns. SeaWiFS estimates of Chl and CDOM absorption derived using regional empirical algorithms were highly correlated to in situ data.

Unique efficacy of Toll-like receptor 8 agonists in activating human neonatal antigen-presenting cells.

Newborns are prone to microbial infection and have poor memory responses to multiple antigens. We have previously shown that human neonatal blood monocytes exhibit impaired TNF-alpha responses to most known TLR agonists, including the pure TLR7 agonist imiquimod. Surprisingly, however, neonatal TNF-alpha responses to the imiquimod congener R-848 (TLR 7/8) were fully intact. We now show that TLR8 agonists, including R-848 (TLR7/8), the imidazoquinoline congeners 3M-003 (TLR7/8) and 3M-002 (TLR8), as well as single-stranded viral RNAs (TLR8) induced robust production of the Th1-polarizing cytokines TNF-alpha and IL-12 from neonatal antigen-presenting cells (APCs) that substantially exceeds responses induced by TLR-2, -4, or -7 (alone) agonists. TLR8 agonists also effectively induced up-regulation of the costimulatory molecule CD40 on neonatal and adult myeloid dendritic cells (DCs). The strong activity of TLR8 agonists correlates with their induction of p38 MAP kinase phosphorylation and with degradation of IkappaB-alpha in both neonatal and adult monocytes. We conclude that TLR8 agonists are uniquely efficacious in activating costimulatory responses in neonatal APCs and suggest that these agents are promising candidate adjuvants for enhancing immune responses in human newborns.

Sensitization of IL-2 signaling through TLR-7 enhances B lymphoma cell immunogenicity.

The innate ability of B lymphoma cells to escape control by tumor-reactive T cells must be overcome to develop effective immunotherapies for these diseases. Because signals from both the innate and adaptive immune systems direct the acquisition of strong immunogenicity by professional APCs, the effects of IL-2 and the TLR-7 agonist, S28690, on the immunogenic properties of chronic lymphocytic leukemia (CLL) B cells were studied. IL-2 with S28690 caused CLL cells to proliferate and increased their expression of B7-family members, production of TNF-alpha and IL-10, and levels of tyrosine-phosphorylated STAT-1 and STAT-3 proteins. S28690 increased CD25 expression on CLL cells and sensitized them to IL-2 signaling. However, IL-2 did not change TLR-7 expression or signaling in CLL cells. The ability to stimulate T cell proliferation required additional activation of protein kinase C, which inhibited tumor cell proliferation, "switched off" IL-10 production, and caused essentially all CLL cells (regardless of clinical stage) to acquire a CD83(high)CD80(high)CD86(high)CD54(high) surface phenotype marked by the activation of STAT-1 without STAT-3. These findings suggest that TLR-7 "licenses" human B cells to respond to cytokines of the adaptive immune system (such as IL-2) and provide a strategy to increase the immunogenicity of lymphoma cells for therapeutic purposes.

A fast procedure for the detection of defects in Toll-like receptor signaling.

OBJECTIVES: Inborn defects in Toll-like receptor signaling are recently described primary immunodeficiencies that predispose affected children to life-threatening infections. Patients with interleukin-1 receptor-associated kinase-4 deficiency are prone to invasive pneumococcal disease, and patients with UNC-93B deficiency are prone to herpes simplex virus encephalitis. These genetic disorders are underdiagnosed, partly because diagnosis currently requires expensive and time-consuming techniques available at only a few specialized centers worldwide. We, therefore, aimed to develop a cheap and fast test for the detection of defects in Toll-like receptor signaling. PATIENTS AND METHODS: We used flow cytometry to evaluate the cleavage of membrane-bound L-selectin on granulocytes in 38 healthy controls and in 7 patients with genetically defined Toll-like receptor signaling defects (5 patients with interleukin-1 receptor-associated kinase-4 deficiency and 2 patients with UNC-93B deficiency), on activation with various Toll-like receptor agonists. RESULTS: Impaired L-selectin shedding was observed with granulocytes from all of the interleukin-1 receptor-associated kinase-4-deficient patients on activation with agonists of Toll-like receptors 1/2, 2/6, 4, 7, and 8 and with granulocytes from all of the UNC-93B-deficient patients on activation with agonists of Toll-like receptors 7 and 8. All of the healthy controls responded to these stimuli. CONCLUSIONS: The assessment of membrane-bound L-selectin cleavage on granulocytes by flow cytometry may prove useful for the detection of primary immunodeficiencies in the Toll-like receptor pathway, such as interleukin-1 receptor-associated kinase-4 deficiency and UNC-93B deficiency. This procedure is cheap and rapid. It may, therefore, be suitable for routine testing worldwide in children with invasive pneumococcal disease and in patients with herpes simplex encephalitis.

Herpes simplex virus encephalitis in human UNC-93B deficiency.

Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is the most common form of sporadic viral encephalitis in western countries. Its pathogenesis remains unclear, as it affects otherwise healthy patients and only a small minority of HSV-1-infected individuals. Here, we elucidate a genetic etiology for HSE in two children with autosomal recessive deficiency in the intracellular protein UNC-93B, resulting in impaired cellular interferon-alpha/beta and -lambda antiviral responses. HSE can result from a single-gene immunodeficiency that does not compromise immunity to most pathogens, unlike most known primary immunodeficiencies. Other severe infectious diseases may also reflect monogenic disorders of immunity.

Regression of lymphomatous skin deposits in a chronic lymphocytic leukemia patient treated with the Toll-like receptor-7/8 agonist, imiquimod.

The identification of clinically relevant, active immunomodulatory agents is important for developing immunotherapeutic approaches to chronic lymphocytic leukemia (CLL) and other B-cell lymphomas that are not curable with conventional chemotherapy. In this investigation, the imidazoquinoline Toll-like receptor (TLR)-7/8 agonist, imiquimod, was found to mediate the clearance of a lymphomatous skin lesion in a CLL patient. Imidazoquinolines also activated TLR-7/8 signaling pathways, resulting in increased expression of costimulatory molecules on circulating tumor cells. These observations extend the therapeutic spectrum of imiquimod to cutaneous B-cell lymphomas and suggest the use of TLR-7/8 agonists in CLL immunotherapy.