Denis Wakefield

Acute Anterior Uveitis and HLA-B27

Acute anterior uveitis is the most common form of uveitis. HLA-B27-associated acute anterior uveitis is a distinct clinical entity that has wide-ranging medical significance due to its ocular, systemic, immunologic, and genetic features. The association between HLA-B27 and the spectrum of HLA-B27-associated inflammatory diseases remains one of the strongest HLA-disease associations known to date. This review examines acute anterior uveitis with particular focus on HLA-B27-associated acute anterior uveitis, including the epidemiology, immunopathology, association with HLA-B27 and its subtypes, clinical features, complications, prognosis, and potential new therapies such as anti-TNFalpha therapy and oral HLA-B27-peptide tolerance. There have been substantial recent advances in both clinical and basic scientific research in this field, including studies of the various animal models of acute anterior uveitis and the HLA-B27 transgenic animals, and these are summarized in this review. To the ophthalmologist, HLA-B27-associated acute anterior uveitis is an important clinical entity that is common, afflicts relatively young patients in their most productive years, and is associated with significant ocular morbidity due to its typically recurrent attacks of inflammation and its potentially vision-threatening ocular complications. Furthermore, to the ophthalmologist and the internist, HLA-B27-associated acute anterior uveitis is also of systemic importance due to its significant association with extraocular inflammatory diseases.

Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study.

Abstract Objective To delineate the risk factors, symptom patterns, and longitudinal course of prolonged illnesses after a variety of acute infections. Design Prospective cohort study following patients from the time of acute infection with Epstein-Barr virus (glandular fever), Coxiella burnetii (Q fever), or Ross River virus (epidemic polyarthritis). Setting The region surrounding the township of Dubbo in rural Australia, encompassing a 200 km geographical radius and 104 400 residents. Participants 253 patients enrolled and followed at regular intervals over 12 months by self report, structured interview, and clinical assessment. Outcome measures Detailed medical, psychiatric, and laboratory evaluations at six months to apply diagnostic criteria for chronic fatigue syndrome. Premorbid and intercurrent illness characteristics recorded to define risk factors for chronic fatigue syndrome. Self reported illness phenotypes compared between infective groups. Results Prolonged illness characterised by disabling fatigue, musculoskeletal pain, neurocognitive difficulties, and mood disturbance was evident in 29 (12%) of 253 participants at six months, of whom 28 (11%) met the diagnostic criteria for chronic fatigue syndrome. This post-infective fatigue syndrome phenotype was stereotyped and occurred at a similar incidence after each infection. The syndrome was predicted largely by the severity of the acute illness rather than by demographic, psychological, or microbiological factors. Conclusions A relatively uniform post-infective fatigue syndrome persists in a significant minority of patients for six months or more after clinical infection with several different viral and non-viral micro-organisms. Post-infective fatigue syndrome is a valid illness model for investigating one pathophysiological pathway to chronic fatigue syndrome.

Longitudinal study of outcome of chronic fatigue syndrome

Abstract Objective : To examine the predictors of long term outcome for patients with the chronic fatigue syndrome. Design : Cohort study. Subjects : 139 subjects previously enrolled in two treatment trials; 103 (74%) were reassessed a mean of 3.2 years after start of the trials. Setting : University hospital referral centre. Main outcome measures : Age at onset, duration of illness, psychological and immunological status at initial assessment. Ongoing symptom severity, levels of disability, and immunological function at follow up. Results - 65 subjects had improved but only six reported no current symptoms. An alternative medical diagnosis had been made in two and psychiatric illness diagnosed in 20. The assignment of a primary psychiatric diagnosis at follow up and the strength of the belief that a physical disease process explained all symptoms at entry to the trials both predicted poor outcome. Age at onset of illness, duration of illness, neuroticism, premorbid psychiatric diagnoses, and cell mediated immune function did not predict outcome. Conclusion : Though most patients with the chronic fatigue syndrome improve, a substantial proportion remain functionally impaired. Psychological factors such as illness attitudes and coping style seem more important predictors of long term outcome than immunological or demographic variables.

Uveitis: a global perspective

Purpose: To study the patterns of uveitis in various geographic regions. Methods: A systematic literature review was performed using the MEDLINE database, from 1966 to present. Studies that satisfied our described selection criteria were analyzed to provide a global perspective on uveitis. Results: Twenty-two studies, which were the best available representatives of Australia, North and South America, Europe, Asia, and Africa, were included in the final analysis. The distribution of uveitis cases according to the anatomical site of inflammation in the various regions, and the causes and clinical disease associations of anterior, intermediate, posterior, and pan-uveitis were studied for each of the regions and a comparative analysis was performed. Conclusions: There are similarities and distinct differences in the patterns of uveitis in the various geographic regions. Such patterns of uveitis are influenced by combinations of geographical, environmental, and genetic factors.

The role of cytokines in the pathogenesis of inflammatory eye disease

A coherent view of the role of cytokines in inflammatory eye disease is emerging as a result of studies both in man and experimental animals. Cytokines have been demonstrated in ocular tissue obtained from patients with intraocular inflammation (uveitis) (gamma interferon, IL-2) and have been shown to induce inflammation in experimental animals after intraocular injection [(IL-1, IL-6, IL-8, tumour necrosis factor (TNF), granulocyte macrophage-colony stimulating factor (GM-CSF)]. Several unique features of the immunology of the eye such as the immunosuppression associated with anterior chamber associated immune deviation (ACAID) may be due to the effects of cytokines. Similarly, common complications of ocular inflammation such as glaucoma, keratic precipitates, retinal (macular) oedema and neovascularization may be mediated by cytokines. Understanding of the role of cytokines in inflammatory eye disease has the potential to lead to the development of therapies to abrogate the effects of these important mediators of the inflammatory response.

Pathogenesis of pterygia: role of cytokines, growth factors, and matrix metalloproteinases.

Pterygium is a common ocular surface disease apparently only observed in humans. Chronic UV exposure is a widely accepted aetiological factor in the pathogenesis of this disease and this concept is supported by epidemiological data, ray tracing models and histopathological changes that share common features with UV damaged skin. The mechanism(s) of pterygium formation is incompletely understood. Recent data have provided evidence implicating a genetic component, anti-apoptotic mechanisms, cytokines, growth factors, extracellular matrix remodelling (through the actions of matrix metalloproteinases), immunological mechanisms and viral infections in the pathogenesis of this disease. In this review, the current knowledge on pterygium pathogenesis is summarised, highlighting recent developments. In addition, we provide novel data further demonstrating the complexity of this intriguing disease.

Epidemiology of uveitis.

Uveitis refers to inflammation of the uvea, the middle vascular coat of the eye, and is the most common cause of inflammatory eye disease and an important cause of blindness and visual impairment in most communities. The annual incidence of uveitis is between 17 and 52 per 100,000 population, and the prevalence is 38 to 714 cases per 100,000 population. It has been estimated that uveitis accounts for about 10% of the visual handicap in the Western world, and up to 35% of all uveitis patients have been reported to suffer significant visual impairment or legal blindness. As uveitis often afflicts the young adult population in their most productive years of life, the personal and population burden of this sight threatening disease is significant. Knowledge of the different types and etiology of uveitis in various populations is important in the diagnosis and treatment of inflammatory eye disease. There has been a significant increase in our understanding of the pathogenesis and epidemiology of uveitis in the past decade, and this review will attempt to summarize current understanding of these important features of this common disease.

Virtual microscopy for learning and assessment in pathology.

Virtual slides are high‐magnification digital images of tissue sections, stored in a multi‐resolution file format. Using appropriate software, these slides can be viewed in a web browser in a manner that closely simulates examination of glass slides with a real microscope. We describe the successful implementation of teaching microscopic pathology with virtual slides and, for the first time, their use in summative assessment. Both students and teaching staff readily adapted to the use of virtual microscopy. Questionnaire feedback from students strongly indicated that virtual slides solved a number of problems in their learning, while providing good to excellent image quality. A deliberate policy of allocating two students per workstation promoted collaboration and helped to maintain interest in microscopic pathology. The use of a secure browser facilitated assessment using virtual slides, with no technical or security issues arising despite high peak demand. The new Medicine programme at the University of New South Wales will exclusively utilize virtual microscopy for the study of both histology and histopathology. We believe that the use of high‐quality learning resources such as virtual slides can ensure that microscopic examination of tissues remains both meaningful and interesting. Copyright

Mast cell activation and migration to lymph nodes during induction of an immune response in mice.

The mast cell response in skin and lymph nodes was examined during the sensitization phase of dinitrofluorobenzene (DNFB)-induced contact hypersensitivity in mice. Degranulation of 62% of mast cells in DNFB-exposed skin was evident within 30 min of a dual application of DNFB, reaching a peak of 77% at 24 h, and persisting in 42% after 5 d. Abundant expression of macrophage inflammatory protein (MIP)-1alpha and MIP-1beta mRNAs and proteins was observed in keratinocytes, and mast cell degranulation was significantly inhibited after administration of neutralizing antibodies to MIP-1alpha, but not MIP-1beta. During DNFB sensitization, the mast cell density in the skin decreased by half, concurrent with a fivefold expansion of mast cell numbers in draining lymph nodes. Fluorescent-labeled mast cells injected into the skin appeared in draining lymph nodes after application of DNFB, followed by subsequent migration to the spleen. In lymph nodes, mast cells were an abundant and predominant source of MIP-1beta, neutralization of which partially inhibited T lymphocyte recruitment. These results indicate that mast cells contribute to the induction of this primary immune response by activation at and migration from the site of antigen encounter to draining lymph nodes, wherein they mediate T lymphocyte recruitment by production of MIP-1beta.

Production of pro-inflammatory cytokines correlates with the symptoms of acute sickness behaviour in humans.

BACKGROUND Elaboration of the concept of cytokine-induced sickness behaviour in recent years has opened new avenues for understanding brain involvement in sickness and recovery processes. Additionally, this has led to much speculation about the role of the immune system in neuropsychiatric syndromes, including depression and chronic fatigue. However, few studies have examined this phenomenon as it naturally occurs in sick humans, and none has attempted to document the quantitative relationships between cytokine levels and non-specific symptoms. The aim of this research was to examine human sickness behaviour and its immunological correlates in documented Epstein-Barr virus (EBV), Q fever or Ross River virus (RRV) infections. METHOD We studied two separate samples. The first consisted of 21 patients with acute Q fever. The second included 48 patients with acute RRV or EBV infection. Psychological and somatic symptom profiles were derived from self-report measures completed at enrolment. Quantification of proinflammatory cytokines [interleukin (IL)-1beta and IL-6] in sera and supernatants of peripheral blood mononuclear cell (PBMC) cultures was undertaken by specific ELISAs. RESULTS Levels of IL-1beta and IL-6 spontaneously released from PBMC cultures were consistently correlated with reported manifestations of acute sickness behaviour including fever, malaise, pain, fatigue, mood and poor concentration. CONCLUSIONS IL-1beta and IL-6 produced as part of the host response represent sensitive markers of sickness behaviour in humans with acute infection. Further work is needed to systematically characterize the spectrum and natural history of sickness behaviour in humans and to elucidate its biological basis.