The intestinal microbiome in human disease and how it relates to arthritis and spondyloarthritis

Humans and microbes have developed a symbiotic relationship over time, and alterations in this symbiotic relationship have been linked to several immune mediated diseases such as inflammatory bowel disease, type 1 diabetes and spondyloarthropathies. Improvements in sequencing technologies, coupled with a renaissance in 16S rRNA gene based community profiling, have enabled the characterization of microbiomes throughout the body including the gut. Improved characterization and understanding of the human gut microbiome means the gut flora is progressively being explored as a target for novel therapies including probiotics and faecal microbiota transplants. These innovative therapies are increasingly used for patients with debilitating conditions where conventional treatments have failed. This review discusses the current understanding of the interplay between host genetics and the gut microbiome in the pathogenesis of spondyloarthropathies, and how this may relate to potential therapies for these conditions.

Clinical factors associated with the humoral immune response to influenza vaccination in chronic obstructive pulmonary disease

Background and objective Individuals with chronic obstructive pulmonary disease (COPD) are at a high risk of developing significant complications from infection with the influenza virus. It is therefore vital to ensure that prophylaxis with the influenza vaccine is effective in COPD. The aim of this study was to assess the immunogenicity of the 2010 trivalent influenza vaccine in persons with COPD compared to healthy subjects without lung disease, and to examine clinical factors associated with the serological response to the vaccine. Methods In this observational study, 34 subjects (20 COPD, 14 healthy) received the 2010 influenza vaccine. Antibody titers at baseline and 28 days post-vaccination were measured using the hemagglutination inhibition assay (HAI) assay. Primary endpoints included seroconversion (≥4-fold increase in antibody titers from baseline) and the fold increase in antibody titer after vaccination. Results Persons with COPD mounted a significantly lower humoral immune response to the influenza vaccine compared to healthy participants. Seroconversion occurred in 90% of healthy participants, but only in 43% of COPD patients (P=0.036). Increasing age and previous influenza vaccination were associated with lower antibody responses. Antibody titers did not vary significantly with cigarette smoking, presence of other comorbid diseases, or COPD severity. Conclusion The humoral immune response to the 2010 influenza vaccine was lower in persons with COPD compared to non-COPD controls. The antibody response also declined with increasing age and in those with a history of prior vaccination.

Evaluation of immune responses to influenza vaccination in chronic obstructive pulmonary disease

Background: Given that viral infections are common triggers for exacerbations of Chronic Obstructive Pulmonary Disease (COPD), current clinical guidelines recommend that all patients receive annual influenza vaccinations. A detailed examination of the immune response to vaccination in COPD has not previously been undertaken, so this study aimed to compare immune responses to influenza vaccination between COPD patients and healthy subjects. Methods: Twenty one COPD patients and fourteen healthy subjects were recruited and cellular immune function was assessed pre- and post- vaccination with trivalent inactivated influenza vaccine. Results: One month after vaccination, H1N1 specific antibody titres were significantly lower in COPD patients than in healthy controls (p=0.02). Multivariate analysis demonstrated that post vaccination antibody titres were independently associated with COPD, but not with age or smoking status. Innate immune responses to the vaccine preparation did not differ between the two populations. Serum concentrations of IL-21, a cytokine that is important for B cell development and antibody synthesis, were also lower in COPD patients than in healthy subjects (p<0.01). In vitro functional differences were also observed, with fewer proliferating B cells expressing CD27 (p=0.04) and reduced T-cell IFN-γ synthesis (p<0.01) in COPD patients, relative to healthy subjects. Conclusions: In conclusion, COPD was associated with altered immune responses to influenza vaccination compared to healthy controls with reductions in both T-cell and B-cell function. These findings provide a foundation for future research aimed at optimising the effectiveness of influenza vaccination in COPD.

Immunogenetic characteristics of immunoglobulin E in allergic disease

Patients with allergic diseases produce an excess of allergen-specific IgE, the specific effector molecule that triggers allergic reactions. The provocation for this excess IgE production is still uncertain. Current ideas include oligoclonal expansion of allergen-specific B cells emanating from germinal centres, activation by superantigen of a subset of B cells, or polyclonal B cells class switching to IgE due to an IL-4 predominance. Additionally, genetic elements contribute to a propensity for increased allergen-specific IgE production. The procedure of RT-PCR allows for amplification of infrequent IgE mRNA transcripts from B cells of atopic individuals, and so facilitates examination of expressed Ig cDNA sequences. Better knowledge of the molecular characteristics of IgE produced by patients with allergic diseases would elucidate the immunogenetic basis for elevated allergen-specific IgE levels. The 'immunogenetic footprint' of IgE transcripts may elucidate the origin and activation of IgE-producing B cells in allergic disease. Here we review studies of the immunogenetic features of IgE in allergic diseases, highlighting the major advances and the experimental limitations.

Introduction: Epitope mimicry as a component cause of autoimmune disease

The causes of autoimmune diseases have yet to be fully elucidated. Autoantibodies, autoreactive T cell responses, the presence of a predisposing major histocompatibility complex (MHC) haplotype and responsiveness to corticosteroids are features, and some are possibly contributory causes of autoimmune disease. The most challenging question is how autoimmune diseases are triggered. Molecular mimicry of host cell determinants by epitopes of infectious agents with ensuing cross-reactivity is one of the most popular yet still controversial theories for the initiation of autoimmune diseases [1]. Throughout the 1990s, hundreds of research articles focusing to various extents on epitope mimicry, as it is more accurately described in an immunological context, were published annually. Many of these articles presented data that were consistent with the hypothesis of mimicry but that did not actually prove the theory. Other equally convincing reports indicated that epitope mimicry was not the cause of the autoimmune disease despite sequence similarity between molecules of infectious agents and the host. Some 20 years ago, Rothman [2] proposed a model for disease causation and I have used this as a framework to examine the role of epitope mimicry in the development of autoimmune disease. The thesis of Rothman’s model is that an effect, in this instance autoimmune disease, arises as a result of a cause. In most cases, multiple-component causes contribute synergistically to yield the effect, and each of these components alone is insufficient as a cause. Logically, some component causes, such as the presence of a particular autoimmune response, are also necessary causes.

Towards the pathogenesis of autoimmune liver disease

There have been recent improvements in the clinical understanding and definition of the major types of autoimmune liver disease. However, still lacking is knowledge of their prevalence and pathogenesis. Three areas of study are in progress in our laboratory. First, in type 1 autoimmune hepatitis, the search continues to identify a liver/disease-specific autoantigenic reactant. Using hepatocyte membrane preparations, immunoblotting has underlined the problem of distinguishing, among multiple reactants, those that may be causally rather than consequentially related to hepatocellular damage. Second, in primary biliary cirrhosis (PBC), the need for population screening to ascertain prevalence and detect preclinical cases can be met by a rapid automated procedure for detection, by specific enzyme inhibition in microtitre wells, of antibody (anti-M2) to the pyruvate dehydrogenase complex E2 subunit (PDC-E2). Third, the structure of the conformational epitope within the inner lipoyl domain of PDC-E2 is being investigated by screening random phage-displayed peptide libraries using PBC sera. This has yielded phage clones in which the sequence of the peptide insert portrays the structure of this epitope, as judged by clustering of PBC-derived sequences to particular branches of a guide-tree that shows relatedness of peptides, and by reactivity of selected phage clones with anti-PDC-E2. Thus phage display identifies a peptide 'mimotope' of the antibody epitope in the inner lipoyl domain of PDC-E2.

Molecular mimicry: Can epitope mimicry induce autoimmune disease?

Mimicry of host antigens by infectious agents may induce cross-reactive autoimmune responses to epitopes within host proteins which, in susceptible individuals, may tip the balance of immunological response versus tolerance toward response and subsequently lead to autoimmune disease. Epitope mimicry may indeed be involved in the pathogenesis of several diseases such as post-viral myocarditis or Chagas disease, but for many other diseases in which it has been implicated, such as insulin-dependent diabetes mellitis or rheumatoid arthritis, convincing evidence is still lacking. Even if an epitope mimic can support a cross-reactive T or B cell response in vitro, its ability to induce an autoimmune disease in vivo will depend upon the appropriate presentation of the mimicked host antigen in the target tissue and, in the case of T cell mimics, the ability of the mimicking epitope to induce a proliferative rather than anergizing response upon engagement of the MHC-peptide complex with the T cell receptor. B cell presentation of mimicking foreign antigen to T cells is a possible mechanism for instigating an autoimmune response to self antigens that in turn can lead to autoimmune disease under particular conditions of antigen presentation, secondary signalling and effector cell repertoire. In this review evidence in support of epitope mimicry is examined in the light of the necessary immunological considerations of the theory.

Kits and methods for diagnosis, screening, treatment and disease monitoring [WO 2015048852 A1]

Disclosed are methods for detecting the presence of a carcinoma or an increased likelihood that a carcinoma is present in a subject. More particularly, the present invention discloses methods for diagnosis, screening, treatment and monitoring of carcinomas associated with aberrant DNA methylation of the MED15 promoter region

Systematic review: Unmet supportive care needs in people diagnosed with chronic liver disease

Objective People with chronic liver disease, particularly those with decompensated cirrhosis, experience several potentially debilitating complications that can have a significant impact on activities of daily living and quality of life. These impairments combined with the associated complex treatment mean that they are faced with specific and high levels of supportive care needs. We aimed to review reported perspectives, experiences and concerns of people with chronic liver disease worldwide. This information is necessary to guide development of policies around supportive needs screening tools and to enable prioritisation of support services for these patients. Design Systematic searches of PubMed, MEDLINE, CINAHL and PsycINFO from the earliest records until 19 September 2014. Data were extracted using standardised forms. A qualitative, descriptive approach was utilised to analyse and synthesise data. Results The initial search yielded 2598 reports: 26 studies reporting supportive care needs among patients with chronic liver disease were included, but few of them were patient-reported needs, none used a validated liver disease-specific supportive care need assessment instrument, and only three included patients with cirrhosis. Five key domains of supportive care needs were identified: informational or educational (eg, educational material, educational sessions), practical (eg, daily living), physical (eg, controlling pruritus and fatigue), patient care and support (eg, support groups), and psychological (eg, anxiety, sadness). Conclusions While several key domains of supportive care needs were identified, most studies included hepatitis patients. There is a paucity of literature describing the supportive care needs of the chronic liver disease population likely to have the most needs—namely those with cirrhosis. Assessing the supportive care needs of people with chronic liver disease have potential utility in clinical practice for facilitating timely referrals to support services.

Genetic factors in the pathogenesis of CPPD crystal deposition disease

Crystal deposition is a very complex process ruled by numerous factors. A small but important proportion of cases of chondrocalcinosis are monogenic, and many of the genes involved have been identified. These genetic findings strongly point to control of the level of extracellular inorganic pyrophosphate as the primary mechanism for their association with either calcium pyrophosphate dihydrate or hydroxyapatite deposition. However, effects on extracellular inorganic pyrophosphate levels do not explain the mechanism of association in all of these monogenic diseases. Further, there are likely to be several as yet unidentified genes that are important in this common condition. This review highlights what genetic studies have demonstrated about the processes involved in these diverse but related disorders.

Respiratory Exacerbations in Indigenous Children From Two Countries With Non-Cystic Fibrosis Chronic Suppurative Lung Disease/Bronchiectasis

BACKGROUND: Acute respiratory exacerbations (AREs) cause morbidity and lung function decline in children with chronic suppurative lung disease (CSLD) and bronchiectasis. In a prospective longitudinal cohort study, we determined the patterns of AREs and factors related to increased risks for AREs in children with CSLD/bronchiectasis. METHODS: Ninety-three indigenous children aged 0.5 to 8 years with CSLD/bronchiectasis in Australia (n = 57) and Alaska (n = 36) during 2004 to 2009 were followed for > 3 years. Standardized parent interviews, physical examinations, and medical record reviews were undertaken at enrollment and every 3 to 6 months thereafter. RESULTS: Ninety-three children experienced 280 AREs (median = 2, range = 0-11 per child) during the 3-year period; 91 (32%) were associated with pneumonia, and 43 (15%) resulted in hospitalization. Of the 93 children, 69 (74%) experienced more than two AREs over the 3-year period, and 28 (30%) had more than one ARE in each study year. The frequency of AREs declined significantly over each year of follow-up. Factors associated with recurrent (two or more) AREs included age < 3 years, ARE-related hospitalization in the first year of life, and pneumonia or hospitalization for ARE in the year preceding enrollment. Factors associated with hospitalizations for AREs in the first year of study included age < 3 years, female caregiver education, and regular use of bronchodilators. CONCLUSIONS: AREs are common in children with CSLD/bronchiectasis, but with clinical care and time AREs occur less frequently. All children with CSLD/bronchiectasis require comprehensive care; however, treatment strategies may differ for these patients based on their changing risks for AREs during each year of care.

Prevalence and risk factors for foot and ankle musculoskeletal disorders experienced by nurses

Background Nurses are at high risk of musculoskeletal disorders (MSDs). Although the prevalence of MSDs of the lower back, upper limbs, neck and shoulders have been reported previously in nursing, few studies have evaluated MSDs of the foot and ankle. This study evaluated the prevalence of foot and ankle MSDs in nurses and their relation to individual and workplace risk factors. Methods A self-administered survey incorporating the Nordic Musculoskeletal Questionnaire (NMQ) was distributed, over a nine-week period, to all eligible nurses (n = 416) working in a paediatric hospital in Brisbane, Australia. The prevalence of MSDs for each of the NMQ body regions was determined. Bivariate and multivariable logistic regression analyses were conducted to examine the relationships between activity-limiting foot/ankle MSDs and risk factors related to the individual (age, body mass index, number of existing foot conditions, smoking history, general physical health [SF36 Physical Component Scale], footwear features) or the workplace (level of nursing position, work location, average hours worked, hours worked in previous week, time since last break from work). Results A 73% response rate was achieved with 304 nurses completing surveys, of whom 276 were females (91%). Mean age of the nurses was 37 years (±10), younger than the state average of 43 years. Foot/ankle MSDs were the most prevalent conditions experienced by nurses during the preceding seven days (43.8%, 95% CI 38.2-49.4%), the second most prevalent MSDs to impair physical activity (16.7%, 95% CI 13.0-21.3%), and the third most prevalent MSD, after lower-back and neck problems, during the preceding 12 months (55.3%, 95% CI 49.6-60.7%). Of the nurse and work characteristics investigated, obesity, poor general physical health, existing foot conditions and working in the intensive care unit emerged as statistically significant (p < 0.05) independent risk factors for activity-limiting foot/ankle MSDs. Conclusions Foot/ankle MSDs are common in paediatric hospital nurses and resulted in physical activity limitations in one out of every six nurses. We recommend targeted education programs regarding the prevention, self-management and treatment strategies for foot/ankle MSDs. Further research is needed into the impact of work location and extended shift durations on foot/ankle MSDs.

Spanish version of the screening Orebro Musculoskeletal Pain Questionnaire: A cross-cultural adaptation and validation

Background Spanish is one of the five most spoken languages in the world. There is currently no published Spanish version of the Örebro Musculoskeletal Pain Questionnaire (OMPQ). The aim of the present study is to describe the process of translating the OMPQ into Spanish and to perform an analysis of reliability, internal structure, internal consistency and concurrent criterion-related validity. Methods Design: Translation and psychometric testing. Procedure: Two independent translators translated the OMPQ into Spanish. From both translations a consensus version was achieved. A backward translation was made to verify and resolve any semantic or conceptual problems. A total of 104 patients (67 men/37 women) with a mean age of 53.48 (±11.63), suffering from chronic musculoskeletal disorders, twice completed a Spanish version of the OMPQ. Statistical analysis was performed to evaluate the reliability, the internal structure, internal consistency and concurrent criterion-related validity with reference to the gold standard questionnaire SF-12v2. Results All variables except “Coping” showed a rate above 0.85 on reliability. The internal structure calculation through exploratory factor analysis indicated that 75.2% of the variance can be explained with six components with an eigenvalue higher than 1 and 52.1% with only three components higher than 10% of variance explained. In the concurrent criterion-related validity, several significant correlations were seen close to 0.6, exceeding that value in the correlation between general health and total value of the OMPQ. Conclusions The Spanish version of the screening questionnaire OMPQ can be used to identify Spanish patients with musculoskeletal pain at risk of developing a chronic disability.

Interleukin 17A is an immune marker for chlamydial disease severity and pathogenesis in the koala (Phascolarctos cinereus)

The koala (Phascolarctos cinereus) is an iconic Australian marsupial species that is facing many threats to its survival. Chlamydia pecorum infections are a significant contributor to this ongoing decline. A major limiting factor in our ability to manage and control chlamydial disease in koalas is a limited understanding of the koala’s cell-mediated immune response to infections by this bacterial pathogen. To identify immunological markers associated with chlamydial infection and disease in koalas, we used koala-specific Quantitative Real Time PCR (qrtPCR) assays to profile the cytokine responses of Peripheral Blood Mononuclear Cells (PBMCs) collected from 41 koalas with different stages of chlamydial disease. Target cytokines included the principal Th1 (Interferon gamma; IFNγ), Th2 (Interleukin 10; IL10), and pro-inflammatory cytokines (Tumor Necrosis Factor alpha; TNFα). A novel koala-specific IL17A qrtPCR assay was also developed as part of this study to quantitate the gene expression of this Th17 cytokine in koalas. A statistically significant higher IL17A gene expression was observed in animals with current chlamydial disease compared to animals with asymptomatic chlamydial infection. A modest up-regulation of pro-inflammatory cytokines, such as TNFα and IFNγ, was also observed in these animals with signs of current chlamydial disease. IL10 gene expression was not evident in the majority of animals from both groups. Future longitudinal studies are now required to confirm the role played by cytokines in pathology and/or protection against C. pecorum infection in the koala.