The germless theory of allergic disease: revisiting the hygiene hypothesis.

Rising rates of allergic disease accompany the healthier benefits of a contemporary westernized lifestyle, such as low infant mortality. It is likely that these twinned phenomena are causally related. The hygiene hypothesis states that allergy and increased longevity are both consequences of reducing infectious stressors during early childhood for millennia. Mechanistic explanations for the hygiene hypothesis have typically invoked the T-helper-type 1/2 (T(H)1/T(H)2) model. Here, we discuss why we favour a broader 'counter-regulatory' model--one that might also explain the increasing incidence of autoimmune disease in westernized countries.

Interleukin-13: central mediator of allergic asthma.

The worldwide incidence, morbidity, and mortality of allergic asthma are increasing. The pathophysiological features of allergic asthma are thought to result from the aberrant expansion of CD4(+) T cells producing the type 2 cytokines interleukin-4 (IL-4) and IL-5, although a necessary role for these cytokines in allergic asthma has not been demonstrable. The type 2 cytokine IL-13, which shares a receptor component and signaling pathways with IL-4, was found to be necessary and sufficient for the expression of allergic asthma. IL-13 induces the pathophysiological features of asthma in a manner that is independent of immunoglobulin E and eosinophils. Thus, IL-13 is critical to allergen-induced asthma but operates through mechanisms other than those that are classically implicated in allergic responses.

Mechanism of suppression of cell-mediated immunity by measles virus.

The mechanisms underlying the profound suppression of cell-mediated immunity (CMI) accompanying measles are unclear. Interleukin-12 (IL-12), derived principally from monocytes and macrophages, is critical for the generation of CMI. Measles virus (MV) infection of primary human monocytes specifically down-regulated IL-12 production. Cross-linking of CD46, a complement regulatory protein that is the cellular receptor for MV, with antibody or with the complement activation product C3b similarly inhibited monocyte IL-12 production, providing a plausible mechanism for MV-induced immunosuppression. CD46 provides a regulatory link between the complement system and cellular immune responses.

In vivo cytokine profiles in patients with kala-azar. Marked elevation of both interleukin-10 and interferon-gamma.

The immunological mechanisms underlying the susceptibility to disseminated visceral parasitism of mononuclear phagocytes in patients with kala-azar remain undefined. Resistance and susceptibility are correlated with distinct patterns of cytokine production in murine models of disseminated leishmanial disease. To assess lesional cytokine profiles in patients with kala-azar, bone marrow aspirates were analyzed using a quantitative reverse transcriptase PCR technique to amplify specific mRNA sequences of multiple Th1-, Th2-, and/or macrophage-associated cytokines. Transcript levels of IL-10 as well as IFN-gamma were significantly elevated in patients with active visceral leishmaniasis; IL-10 levels decreased markedly with resolution of disease. These findings suggest that IL-10, a potent, pleiotropic suppressor of all known microbicidal effector functions of macrophages, may contribute to the pathogenesis of kala-azar by inhibiting the cytokine-mediated activation of host macrophages that is necessary for the control of leishmanial infection.

Receptor mediated subversion of macrophage cytokine production by intracellular pathogens.

Appropriately regulated immune responses depend on the controlled production of cytokines from antigen presenting cells. IL-12 synthesis is tightly regulated by several redundant mechanisms. One mechanism of IL-12 regulation involves the cross-linking of surface receptors on macrophages. This pathway may be exploited by intracellular pathogens of macrophages to inhibit IL-12 production and delay or prevent the development of cell mediated immunity.

Distinct Tlr4-expressing cell compartments control neutrophilic and eosinophilic airway inflammation.

Allergic asthma is a chronic, inflammatory lung disease. Some forms of allergic asthma are characterized by T helper type 2 (Th2)-driven eosinophilia, whereas others are distinguished by Th17-driven neutrophilia. Stimulation of Toll-like receptor 4 (TLR4) on hematopoietic and airway epithelial cells (AECs) contributes to the inflammatory response to lipopolysaccharide (LPS) and allergens, but the specific contribution of TLR4 in these cell compartments to airway inflammatory responses remains poorly understood. We used novel, conditionally mutant Tlr4(fl/fl) mice to define the relative contributions of AEC and hematopoietic cell Tlr4 expression to LPS- and allergen-induced airway inflammation. We found that Tlr4 expression by hematopoietic cells is critical for neutrophilic airway inflammation following LPS exposure and for Th17-driven neutrophilic responses to the house dust mite (HDM) lysates and ovalbumin (OVA). Conversely, Tlr4 expression by AECs was found to be important for robust eosinophilic airway inflammation following sensitization and challenge with these same allergens. Thus, Tlr4 expression by hematopoietic and airway epithelial cells controls distinct arms of the immune response to inhaled allergens.

Complement and IL-12: yin and yang.

Interleukin 12 (IL-12) is central to the orchestration of cell-mediated immune responses in the innate as well as the adaptive immune system. Recent studies of the pathogenesis of diseases as disparate as measles and asthma have suggested that the complement system, itself at the interface of innate and adaptive immunity, is a biologically relevant regulator of IL-12 production. These data are reviewed here.

Central cloudy corneal dystrophy of Francois. A clinicopathologic study.

Central cloudy corneal dystrophy of Francois was first described in 1955 by J. Francois; its pathophysiology remains unknown. An 80-year-old woman with bilateral central cloudy corneal dystrophy of Francois was examined after having undergone a combined penetrating keratoplasty and cataract extraction. The corneal button was obtained. Light microscopy revealed stromal staining for acid mucopolysaccharide. Transmission electron microscopy revealed extracellular vacuoles, some of which had fibrillogranular material and electron-dense deposits. Fibrillogranular material was present in and around some keratocytes. Numerous endothelial vacuoles contained light-staining fibrillogranular material and round electron-dense granules. Our findings suggest that the opacities in patients with central cloudy corneal dystrophy of Francois are due to the extracellular accumulation of mucopolysaccharide and lipidlike material. Further studies are needed to elucidate the nature of these deposits.

True exfoliation of the lens capsule.

True exfoliation or lamellar delamination of the lens capsule is a rare disorder in which the lens capsule is thickened and the superficial portion of the lens capsule splits from the deeper layer and extends into the anterior chamber. The pathogenesis of this disorder is not clear, but intense infrared radiation has been thought to be the main causative factor. We describe a patient with a history of heat exposure who had a cataract and was found to have bilateral delamination of the anterior lens capsule. Findings from light microscopy and scanning and transmission electron microscopy demonstrated a lamellar separation of the anterior portion of the lens capsule, confirming the diagnosis of true exfoliation.

Conjunctival intraepithelial neoplasia. A possible marker for human immunodeficiency virus infection?

BACKGROUND: Conjunctival intraepithelial neoplasia has traditionally been found at the limbus in elderly individuals. Recently, this ocular tumor has been observed in younger patients. OBJECTIVE: To investigate the potential association of human immunodeficiency virus infection with the emergence of this atypical presentation of conjunctival intraepithelial neoplasia. DESIGN, SETTING, AND PARTICIPANTS: Records of patients at the Bascom Palmer Eye Institute (Miami, Fla) in whom conjunctival intraepithelial neoplasia was diagnosed between January 1, 1991, and December 31, 1993, were reviewed. Attempts were made to contact those patients younger than 50 years for clinical evaluation and human immunodeficiency virus serologic testing. RESULTS: Conjunctival intraepithelial neoplasia was diagnosed in 73 patients during the study period. Of the nine patients younger than 50 years, six were available for serologic testing. Three (50%) of these individuals were found to be positive for human immunodeficiency virus. CONCLUSION: Human immunodeficiency virus testing and counseling should be considered in patients younger than 50 years in whom conjunctival intraepithelial neoplasia is diagnosed.

Euphorbia sap keratopathy: four cases and a possible pathogenic mechanism.

AIMS: To report four cases of Euphorbia sap causing anterior segment toxicity. METHODS: Medical records of four patients who presented with Euphorbia sap keratoconjunctivitis were reviewed. Clinical findings were compared with previously published reports. RESULTS: All of these patients experienced a similar clinical course. Initial contact with Euphorbia sap caused punctate epitheliopathy; patients noted immediate burning and photophobia, but no visual loss. In all cases, patients experienced epithelial slough with delayed healing, requiring approximately 9 days to heal the epithelial defect. Patients were treated with topical antibiotics, pressure patching or a bandage contact lens, and final visual acuities were excellent in all cases. A review of the literature revealed that Euphorbia sap contains a diterpenoid diester which exhibits antineoplastic activity in rodents. CONCLUSIONS: Individuals who work with Euphorbia plants should be cautioned to wear eye protection. Patients with Euphorbia sap anterior segment toxicity should be informed that their condition may worsen initially, but that visual outcome is generally excellent. The progressive corneal epithelial sloughing and delayed corneal epithelial healing may be secondary to the antineoplastic effects of Euphorbia sap.

Traumatic cataract presenting with unilateral nasal hemianopsia.

A 56-year-old man developed a nasal field defect in his left eye 3 months after a traumatic accident. An examination showed a posterior subcapsular cataract in the left eye with no neurologic deficits. Humphrey 24-2 visual field testing revealed a nasal hemianopsia in the left eye. After cataract extraction and intraocular lens implantation, the patient's visual field returned to normal. This case shows that a cataract can present with a localized visual field deficit, which may be corrected by cataract extraction.

Effects of methylprednisolone and cyclosporine A on fungal growth in vitro.

PURPOSE: The management of corneal transplants after mycotic keratitis often poses a therapeutic dilemma. Clinicians are hesitant to use topical steroids because of their potential enhancement of fungal growth. This study seeks to evaluate the in vitro effects of methylprednisolone and cyclosporine A on the growth of various molds that often are responsible for keratomycoses. METHODS: Fusarium oxysporum, Fusarium solani, and Aspergillus fumigatus were grown in the presence of varying concentrations of methylprednisolone, cyclosporine A, and vehicle controls. Fungal growth was evaluated in a masked fashion based on the number of colonies and their morphologies. RESULTS: All tested concentrations of cyclosporine A (1%, 2%, 4%) had a statistically significant suppressive effect on the growth of F. oxysporum (p<0.001) and F. solani (p<0.001) compared with methylprednisolone and vehicle control solutions. A dose-dependent decrease in the number of colonies grown also was noted for F. oxysporum (p<0.001) and F. solani (p<0.001). In the case of A. fumigatus, cyclosporine A significantly decreased the colony size (p<0.015) in a dose-dependent fashion. CONCLUSIONS: Cyclosporine A appears to have an inhibitory effect on fungal growth in vitro. Cyclosporine A may be an important alternative to topical steroids for management of corneal transplants after mycotic keratitis.

Comparative Efficacy of the SLT versus LASAG Nd: YAG Delivery Systems in Rabbits.

PURPOSE: The efficacy of two types of contact transscleral Nd:YAG laser delivery systems, a synthetic sapphire-tipped laser probe connected to a Surgical Laser Technologies (SLT) laser and a quartz fiberoptic tip connected to a LASAG Microrupter III, was compared. METHOD: A total of nine pigmented rabbits underwent transscleral LASAG cycloablation in one eye (3.2 W, 0.5 s); an additional eight rabbits underwent Surgical Laser Technologies cycloablation (3.0 W, 0.5 s). RESULTS: The maximum difference in intraocular pressure between the experimental versus fellow eyes was - 15.09 mm Hg (+/-0.25) with the LASAG and -13.16 mm Hg (+/-3.12) with the SLT laser; in both delivery systems, this difference was achieved 4 days postoperatively. The differences between the two groups in duration of pressure reduction was not statistically significant (p = 0.83). CONCLUSION: These data suggest that these delivery systems are equally effective in lowering intraocular pressure in rabbits. Histological changes of the ciliary processes and adjacent ocular tissue are presented.

Role of the lipoxygenase pathway in RSV-induced alternatively activated macrophages leading to resolution of lung pathology.

Resolution of severe Respiratory Syncytial Virus (RSV)-induced bronchiolitis is mediated by alternatively activated macrophages (AA-Mφ) that counteract cyclooxygenase (COX)-2-induced lung pathology. Herein, we report that RSV infection of 5-lipoxygenase (LO)(-/-) and 15-LO(-/-) macrophages or mice failed to elicit AA-Mφ differentiation and concomitantly exhibited increased COX-2 expression. Further, RSV infection of 5-LO(-/-) mice resulted in enhanced lung pathology. Pharmacologic inhibition of 5-LO or 15-LO also blocked differentiation of RSV-induced AA-Mφ in vitro and, conversely, treatment of 5-LO(-/-) macrophages with downstream products, lipoxin A4 and resolvin E1, but not leukotriene B4 or leukotriene D4, partially restored expression of AA-Mφ markers. Indomethacin blockade of COX activity in RSV-infected macrophages increased 5-LO and 15-LO, as well as arginase-1 mRNA expression. Treatment of RSV-infected mice with indomethacin also resulted not only in enhanced lung arginase-1 mRNA expression and decreased COX-2, but also decreased lung pathology in RSV-infected 5-LO(-/-) mice. Treatment of RSV-infected cotton rats with a COX-2-specific inhibitor resulted in enhanced lung 5-LO mRNA and AA-Mφ marker expression. Together, these data suggest a novel therapeutic approach for RSV that promotes AA-Mφ differentiation by activating the 5-LO pathway.

New insights into innate immune mechanisms underlying allergenicity.

Allergic diseases, which have reached epidemic proportions, are caused by inappropriate immune responses to a relatively small number of environmental proteins. The molecular basis for the propensity of specific proteins to promote maladaptive, allergic responses has been difficult to define. Recent data suggest that the ability of such proteins to promote allergic responses in susceptible hosts is a function of their ability to interact with diverse pathways of innate immune recognition and activation at mucosal surfaces. This review highlights recent insights into innate immune activation by allergens--through proteolytic activity, engagement of pattern recognition receptors, molecular mimicry of TLR signaling complex molecules, lipid-binding activity, and oxidant potential--and the role of such activation in inducing allergic disease. A greater understanding of the fundamental origins of allergenicity should help define new preventive and therapeutic targets in allergic disease.

Topical interferon alpha 2b eye-drops for treatment of ocular surface squamous neoplasia: a dose comparison study.

BACKGROUND/AIMS To compare the effectiveness and side-effect profile of two doses of interferon alpha2b (IFNalpha2b) eye-drops (1 million international units (IU)/ml versus 3 million IU/ml) in the treatment of ocular surface squamous neoplasia (OSSN). METHODS Retrospective case series. RESULTS Thirty-five eyes were identified over an 11-year period (1996-2007). Twenty-one eyes (19 patients) with conjunctival intraepithelial neoplasia (CIN) were treated with 1 million IU/ml of topical IFN-alpha2b; 12 eyes (nine patients) with CIN were treated with 3 million IU/ml. Two patients with squamous cell carcinoma (SCC) were treated with topical interferon, one with 1 million IU/ml and one with 3 million IU/ml. Baseline demographic information was not statistically different between the two groups. In patients with CIN, topical therapy eliminated disease in 81% of eyes in the 1 million IU/ml group versus 92%, in the 3 million IU/ml group, p=0.41. The median time to OSSN resolution was 2.8 months in the 1 million IU/ml group and 1.9 months in the 3 million IU/ml group, p=0.55. Neither eye with SCC responded to interferon therapy. Topical therapy was well tolerated. After a median follow-up of 24 months, three recurrences were seen in eyes successfully treated with topical therapy. CONCLUSION In our study, there were no significant differences between the 1 million IU/ml group and the 3 million IU/ml group for the treatment of CIN.

Measles: immunosuppression, interleukin-12, and complement receptors.

Measles virus, the first pathogen recognized to cause immunosuppression, induces profound and prolonged abnormalities in cellular immune responses in infected hosts. The ability of measles virus to specifically ablate monocyte/macrophage and dendritic cell production of interleukin (IL)-12 provides a potentially unifying mechanism for many of these in vivo and in vitro abnormalities. Cross-linking of the cellular receptor for measles virus, the complement regulatory protein CD46, is sufficient to inhibit IL-12 production. CD46-mediated downregulation of IL-12 has turned out to be a specific instance of a more general pattern of tight inhibitory control over IL-12 production effected by complement and phagocytic receptors on antigen-presenting cells. Exploitation of these pathways by other intracellular pathogens is likely.