Recurrent Episodes Of Inflammation Research Articles

Ageing and recurrent episodes of neuroinflammation promote progressive experimental autoimmune encephalomyelitis in Biozzi ABH mice.

Current therapies for multiple sclerosis (MS) reduce the frequency of relapses by modulating adaptive immune responses but fail to limit the irreversible neurodegeneration driving progressive disability. Experimental autoimmune encephalomyelitis (EAE) in Biozzi ABH mice recapitulates clinical features of MS including relapsing-remitting episodes and secondary-progressive disability. To address the contribution of recurrent inflammatory events and ageing as factors that amplify progressive neurological disease, we examined EAE in 8- to 12-week-old and 12-month-old ABH mice. Compared with the relapsing-remitting (RREAE) and secondary progressive (SPEAE) EAE observed in young mice, old mice developed progressive disease from onset (PEAE) associated with pronounced axonal damage and increased numbers of CD3(+) T cells and microglia/macrophages, but not B cells. Whereas the clinical neurological features of PEAE and SPEAE were comparable, the pathology was distinct. SPEAE was associated with significantly reduced perivascular infiltrates and T-cell numbers in the central nervous system (CNS) compared with PEAE and the acute phase of RREAE. In contrast to perivascular infiltrates that declined during progression from RREAE into SPEAE, the numbers of microglia clusters remained constant. Similar to what is observed during MS, the microglia clusters emerging during EAE were associated with axonal damage and oligodendrocytes expressing heat-shock protein B5, but not lymphocytes. Taken together, our data reveal that the course of EAE is dependent on the age of the mice. Younger mice show a relapsing-remitting phase followed by progressive disease, whereas old mice immediately show progression. This indicates that recurrent episodes of inflammation in the CNS, as well as age, contribute to progressive neurological disease.

Defining chronic pancreatitis with a focus on pathological stress responses

‘Chronic pancreatitis is a disease of the pancreas in which recurrent inflammatory episodes result in replacement of pancreatic parenchyma by fibrous connective tissue. This fibrotic reorganisation of the pancreas leads to a progressive exocrine and endocrine pancreatic insufficiency. In addition, characteristic complications arise, such as pseudocysts, pancreatic duct obstructions, duodenal obstruction, vascular complications, obstruction of the bile ducts, malnutrition and pain syndrome. Pain presents as the main symptom of patients with chronic pancreatitis. Chronic pancreatitis is a risk factor for pancreatic carcinoma. Chronic pancreatitis significantly reduces the quality of life and the life expectancy of affected patients.’ This is the definition adopted for chronic pancreatitis by 74 experts from 11 gastroenterological, surgical, pediatric and radiological societies in Germany, Austria and Switzerland. It was integrated into the only evidence-based guideline so far on chronic pancreatitis [1,2], that complies with the S3 Oxford classification standard for level-of-evidence grades. The authors felt that this definition represents, in a nutshell, how chronic pancreatitis presents clinically, what the underlying mechanism is recurrent inflammation leading to fibrosis [3], the key clinical complications that can be expected and should be looked for, as well as the long

Juvenile Recurrent Parotitis: A Case Report

Chronic Recurrent Parotitis or Juvenile Recurrent Parotitis (JRP) is an uncommon clinical condition that causes episodes of recurrent inflammation of the parotid gland, usually unilaterally. It affects children between 3 and 6 years of age and resolves spontaneously at puberty. Fever and general discomfort occasionally accompany it. In the periods between attacks, the patient is asymptomatic. Its prevalence is higher among men and, even its unknown etiology, it is related to autoimmune phenomena. The true extent of this disease lies in the destruction of parenchyma that is caused by recurrent episodes. This reduces the functionality of the gland 50% to 80%. Treatment options go from conservative treatments with anti-inflammatories, analgesic and antibiotics to invasive surgical treatments. The aim of this article is to address the diagnosis and treatment of this rare disease from a case we deal with in our hospital.

English language version of the S3-consensus guidelines on chronic pancreatitis: Definition, aetiology, diagnostic examinations, medical, endoscopic and surgical management of chronic pancreatitis.

Chronic pancreatitis is a disease of the pancreas in which recurrent inflammatory episodes result in replacement of pancreatic parenchyma by fibrous connective tissue. This fibrotic reorganization of the pancreas leads to a progressive exocrine and endocrine pancreatic insufficiency. In addition, characteristic complications arise, such as pseudocysts, pancreatic duct obstructions, duodenal obstruction, vascular complications, obstruction of the bile ducts, malnutrition and pain syndrome. Pain presents as the main symptom of patients with chronic pancreatitis. Chronic pancreatitis is a risk factor for pancreatic carcinoma. Chronic pancreatitis significantly reduces the quality of life and the life expectancy of affected patients. These guidelines were researched and compiled by 74 representatives from 11 learned societies and their intention is to serve evidence-based professional training as well as continuing education. On this basis they shall improve the medical care of affected patients in both the inpatient and outpatient sector. Chronic pancreatitis requires an adequate diagnostic workup and systematic management, given its severity, frequency, chronicity, and negative impact on the quality of life and life expectancy.

Mouse models of multiple sclerosis: lost in translation?

Multiple sclerosis (MS) is a chronic neurological disorder of the central nervous system (CNS) leading to progressive accumulation of neurological deficits arising from recurrent episodes of inflammation, demyelination and neuronal degeneration. While the aetiology of the disease is unknown MS is widely considered to be the result of aberrant T cell and antibody responses to CNS antigens giving rise to the common concept that MS is an autoimmune disease or that there is an autoimmune component in the pathogenesis. This idea has lead to the development of experimental autoimmune encephalomyelitis (EAE) mouse models of MS in which immunisation with CNS antigens induces neurological and pathological signs of disease in mice. In addition to EAE models, injection with neurotropic viruses has been used to examine how infections are implicated in the disease process and how they may generate autoimmune responses in the CNS. Viral models are also crucial to investigate the impact of blocking trafficking of immune responses into the CNS since an emerging side-effect of current immunotherapeutic approaches in MS is the reactivation of viruses within the CNS. To investigate myelin damage and repair in the absence of the adaptive immune response, toxin-induced demyelination using cuprizone, ethidium bromide and lysolecithin, which rapidly leads to remyelination when the toxins are withdrawn, is also reviewed. Mice also lend themselves to the vast array of transgenic technologies to probe specific pathways as well as the use of humanised transgenic mice to examine the impact of human molecules. Despite the vast array of mouse models EAE is the most frequently exploited paradigm used to develop therapeutic approaches. However, despite over one thousand compounds used in the treatment of EAE few have become licenced for treatment of MS so far. Thus, this review also debates the reasons for these failures in mouse models as well as discusses how mouse models can be better utilised to provide more powerful preclinical tools to develop rational therapies for multiple sclerosis.

FRI0555 Interleukin-1 TargetİNg Drugs in Familial Mediterranean Fever: an Experience in Pediatric Patients

BackgroundFamilial Mediterranean fever (FMF) is the most common auto inflammatory syndrome with recurrent inflammatory episodes. Colchicine is the main treatment of FMF. It is also effective in preventing secondary amyloidosis....

THU0367 Familial Mediterranean Fever (FMF): A Single Center Clinical-Genetic Study

BackgroundFMF is the prototype of autoinflammatory disorder characterized by recurrent self-limited inflammatory episodes.1FMF is an autosomal recessive disease that is prevalent among eastern Mediterranean populations. The responsible gene (MEFV) encodes...

Allergen-specific lung resident CD4+ Th2 cells in asthma (HYP4P.417)

Abstract Asthma is an inflammatory disease of the airways that affects more than 300 million people worldwide. Clinically, asthma is characterized by acute, intermittent and recurrent episodes of inflammation that can be induced by a specific allergen. Allergen-specific CD4 T cells contribute to this process by producing cytokines and inducing B lineage production of IgE. Allergen-specific CD4 memory T cells are also thought to persist after resolution of inflammation to rapidly drive asthma-induced pathology. Due to the challenge of tracking small populations of CD4 T cells that express allergen pMHCII-specific TCRs, little is known about what regulates Th2 memory cell differentiation, migration and maintenance. We have therefore produced a MHCII tetramer containing a peptide from the Derp1 protein of the house dust mite (HDM), the most common cause of atopic asthma, to elucidate the underlying mechanisms of Th2 memory cell differentiation during atopic asthma. Tetramer-based enrichment strategies used to isolate Derp1:I-Ab+ cells from the secondary lymphoid organs and lungs have revealed that heterogenous Th2 memory populations form, including a CD69+ Derp1:I-Ab+ population in the lung thats persists post-contraction. Intravascular staining techniques demonstrate that these cells reside in the lung parenchyma and are driven to the lung by early cytokine exposure. These findings have important implications for novel immunotherapeutics in both asthma and allergy.

Mevalonate kinase deficiency in two sisters with therapeutic response to anakinra: case report and review of the literature

Mevalonate kinase deficiency (MKD) is a rare, hereditary autoinflammatory condition characterized by recurrent inflammatory episodes. Depending on the residual mevalonate kinase activity, the clinical spectrum ranges from a relatively mild periodic fever syndrome to a lethal metabolic disease. Data on therapeutic options for MKD are currently limited and rely generally on case reports and small series. Recent reports show promising results with anakinra and etanercept to treat the attacks. We report two sisters treated with good, but partial response, to continuous daily anakinra (interleukin-1 receptor antagonist).

PW02-013 - The role of IL6 and LPS in pathogenesis of TRAPS

Tumour necrosis factor (TNF) receptor– associated periodic syndrome (TRAPS) is a hereditary autoinflammatory condition resulting from a range of mutations in the TNFRSF1A gene. It is characterised in part by recurrent episodes of inflammation, affecting connective tissues, and manifesting as migratory erysipelas, myalgia and serositis. A number of aberrant inflammatory responses have been described in this condition, including hyperresponsiveness to lipopolysaccharide (LPS). The microRNA mir155 has been implicated in mediating downstream pro-inflammatory response to LPS, and it has has also been implicated in the pathogenesis of rheumatoid arthritis (RA). Tocilizumab (anti-IL6 receptor antibody) has been reported to be an effective treatment in at least one published case of TRAPS.

Th2 differentiation during atopic asthma (P1167)

Abstract Asthma is an inflammatory disease of the airways that affects more than 300 million people worldwide. Clinically, asthma is characterized by acute, intermittent and recurrent episodes of inflammation that can be induced by a specific allergen. CD4+ T cells contribute to this process by producing the Type 2 cytokines IL-4, IL-5, and IL-13 and inducing B cell production of IgE in response to T cell receptor (TCR) recognition of allergen peptides bound to MHCII molecules on host cells. In both murine models of disease and asthmatic patients, quiescent allergen peptide:MHCII (pMHCII)-specific CD4+ memory T cells can persist in lungs and lymphoid organs long after resolution of inflammation. Upon subsequent exposure to allergen, CD4+ memory T cells rapidly drive asthma-induced immunopathology making these cells attractive targets for allergen-specific immune modulation. Little is known, however, about how these cells orchestrate the asthmatic response due to the challenge of tracking small populations of CD4+ T cells that express allergen pMHCII-specific TCRs. To address this lack of knowledge, we have utilized a MHCII tetramer containing a peptide from the Der p1 protein of the house dust mite (HDM), Dermatophagoides pteronyssinus, the most common cause of atopic asthma. Using this tetramer and a novel magnetic bead-based cell enrichment method, we can assess the differentiation and function of Der p1 pMHCII-specific Th2 effector and memory cells in mice responding to HDM.

Arterioesclerosis sistémica precoz y enfermedad autoinflamatoria

Systemic autoinflammatory diseases (SAD) are characterized by the presence of acute, recurrent or persistent inflammatory episodes, in which autoimmune, infectious or neoplastic causes are not evidenced. Systemic inflammation has been linked to development and progression of atherosclerosis. In the case of the Muckle Wells Syndrome (MWS), inflammation would be determined by hyperactivation of interleukin 1β (IL-1β). We present a case report in which vascular complications associated with early atherosclerosis in the MWS are described.

A rare case of endogenous Aspergillus conicus endophthalmitis in an immunocompromised patient

BackgroundThe purpose of this study was to report the case of a patient with bilateral panuveitis who was found to have a rarely reported intraocular fungus, Aspergillus conicus. A 40-year-old man presented with gradual vision loss in both eyes. He had bilateral anterior uveitis, granulomatous vitritis with a preretinal granuloma in the right eye, and nongranulomatous vitritis with two quadrants of chorioretinal scarring in the left.FindingsSerological testing revealed a new diagnosis of human immunodeficiency virus as well as positive rapid plasma reagin and fluorescent treponemal antibody. Polymerase chain reaction (PCR) testing of the aqueous humor from the right eye identified A. conicus. Due to the indolent course of the endogenous fungal infection, the patient was treated with prednisolone acetate 1% eye drops, oral voriconazole, and highly active antiretroviral therapy. More than 1 year later, his vision remained 20/20 in both eyes without any episodes of recurrent inflammation.ConclusionsPCR testing helped identify a rare intraocular infection in an immunocompromised patient. In this case, A. conicus behaved less aggressively than other species of Aspergillus implicated in intraocular infection.

An Update on Autoinflammatory Diseases

Autoinflammatory diseases area group of clinical conditions other than autoimmune diseases, characterized by recurrent inflammatory episodes. From apathogenetic point of view they are determined by a dys regulation of innate immunity, without involvement of specific immunity (auto reactive T cells and auto antibodies). Recently, the increased knowledge in the field of auto inflammation highlighted shared immune mechanisms in the pathogenesis of both classical monogenetic and multifactorial auto inflammatory diseases and a broad spectrum of chronic age-related inflammatory pathologies. The current increase in the prevalence of chronic inflammatory diseases makes this subject of topical interest. In the light of these considerations, we propose an update of auto inflammatory diseases and a new interpretation of auto inflammation with both theoretical and clinical implications.

Bronchial rupture related to endobronchial stenting in relapsing polychondritis

To the Editor: Relapsing polychondritis is a rare multi-systemic disease characterised by recurrent episodes of inflammation and destruction of cartilaginous structures [1]. Airway involvement by relapsing polychondritis, which results in tracheobronchomalacia and airway stenosis, is associated with a poor prognosis. Several reports have suggested that endobronchial intervention can be beneficial in these subjects [2, 3]. Herein, we describe a case of bronchial rupture related to endobronchial intervention in a patient with relapsing polychondritis. A 47-yr-old male nonsmoker was referred for management of progressive dyspnoea, stridor and cough evolving over 12 months. He had been considered to have severe asthma and was treated with a fixed combination of inhaled corticosteroids and long-acting β-agonists, and short courses of oral corticosteroids. Spirometry showed fixed airflow limitation with a post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity of 22% and an FEV1 of 22% predicted. A thoracic computed tomography (CT) scan revealed marked thickening and narrowing of trachea and mainstem bronchi (fig. 1). A diagnosis of relapsing polychondritis was suggested; the patient had no auricular or nasal chondritis and no ocular symptoms. Fluorodeoxyglucose positron emission tomography showed no cartilaginous tracer uptake. Bronchoscopy showed marked thickening and inflammation of airway mucosa. Severe tracheobronchomalacia, …

Autoinflammatory syndromes and cellular responses to stress: pathophysiology, diagnosis and new treatment perspectives

The term 'autoinflammatory disease' was first proposed in 1999 to encompass some of the distinct clinicopathologic features of a group of monogenic conditions, characterised by recurrent episodes of inflammation, without high-titre autoantibodies or antigen-specific T cells. It was subsequently observed that several of these conditions were caused by mutations in proteins involved in the innate immune response, including, among others, components of the NLRP3 inflammasome, cytokine receptors (tumour necrosis factor receptor 1 (TNFR1)) and receptor antagonists (interleukin 1 receptor antagonist (IL-1RA)). More recently, additional mechanisms linking innate immune-mediated inflammation with a variety of cellular processes, including protein misfolding, oxidative stress and mitochondrial dysfunction, have been recognised to play a role in the pathogenesis of some monogenic autoinflammatory conditions, and also in more common diseases such as type 2 diabetes (T2D), previously perceived as a metabolic disorder, but reclassified as a chronic inflammatory condition. NLRP3 inflammasome activation is induced by islet amyloid polypeptides (IAPPs) in T2D and this condition may, in future, be more commonly treated with targeted anti-cytokine therapies. Caspase 1 activation and release of IL-1β/IL-1 family members is central to the pathogenesis of many autoinflammatory syndromes, as evidenced by the effectiveness of anti-IL-1 biologics in treating these disorders. However, many patients continue to experience symptoms of chronic inflammation, and it will be necessary to translate discoveries on the immunopathology of these conditions into more effective therapies. For example, in tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), the pathogenesis may vary with each mutation and therefore future approaches to treatment of individual patients will require a more tailored approach based on genetic and functional studies.

Novel mutations causing hyperimmunoglobulin d and periodic fever syndrome

Hyperimmunoglobulin D and periodic fever syndrome (HIDS) is a rare, hereditary autoinflammatory condition characterized by recurrent inflammatory episodes. We report a 9-year-old boy, diagnosed with HIDS due to two novel mutations, c.62C>T (p.Ala21Val) and c.372-6T>C (probable splicing defect), in the mevalonate kinase (MVK) gene. The pathogenicity of these mutations was confirmed by measurement of low MVK enzyme activity in cultured primary skin fibroblasts of the patient. The symptoms have been refractory to therapy with steroids and non steroidal anti inflammatory drugs. This report expands the genetic and ethnic spectrum of HIDS.

Regulatory Aspects of New Medicines Targeted at Treatment of Autoimmune Diseases

Autoimmune diseases comprise a diverse group of clinical dis orders that result from the body's adaptive immune system reacting against its own tissues.(1) Conversely, autoinflammatory disorders encompass a more limited group of diseases distinguished by recurrent episodes of inflammation but in the absence of high-titer autoantibodies and antigen-specific T cells.(2) The past 15 years have seen a tremendous growth in the development of highly effective treatments for these diseases.

Clinical and genetic features of hereditary periodic fever syndromes in Hispanic patients: the Chilean experience

Hereditary periodic fever syndromes (HPFS) are rare genetic diseases characterized by recurrent episodes of inflammation. Little information is available concerning HPFS in Latin American Hispanic population. The purpose of this study was to determine the clinical and genetic features of HPFS in Chilean population. A multicenter retrospective study of Hispanic Chilean patients with genetically confirmed HPFS was performed. We included 13 patients, 8 with familial Mediterranean fever (FMF) and 5 with TNF receptor-associated periodic syndrome (TRAPS), evaluated at rheumatology or pediatric rheumatology clinics between January 2007 and December 2010. Median age of symptoms onset was 8 years (range 1-35) and 8 years (range 0.3-21) for FMF and TRAPS, respectively. Median duration of fever was 3 days (range 2.5-15) for FMF and 21 days (range 9.5-30) for TRAPS. Genotyping of the MEFV gene in FMF patients revealed a homozygous M694V missense mutation in one patient, and heterozygous missense mutations in seven patients: M694V (n = 3), E148Q, R717H, A744S, and A511V. Sequencing of the TNFRSF1A gene in TRAPS patients revealed heterozygous missense mutations in four patients: T50M, C30R, R92Q, and IVS3+30:G→A, and a two-base pair deletion (IVS2-17_18del2bpCT) in one patient. Mutation in MEFV R717H and mutations in TNFRSF1A IVS2-17_18del2bpCT and IVS3+30:G→A are novel and have not been described previously. This study reports the largest series of genetically confirmed HPFS in Latin America, and adds evidence regarding the clinical and genetic characteristics of patients with FMF and TRAPS in Hispanic population. Mutations identified in MEFV and TNFRSF1A genes include defects reported in other ethnicities and novel mutations.

Airway involvement in relapsing polychondritis

Relapsing Polychondritis (RP) is an uncommon, chronic, and potentially life-threatening multisystem disorder characterized by recurrent inflammatory episodes affecting the cartilaginous tissues of the external ears, nose, peripheral joints, larynx and tracheobronchial tree, sometimes leading to their destruction. RP can also inflame other proteoglycan-rich structures, such as the eye, heart, blood vessels and inner ears. Systemic symptoms are common, and vasculitis affecting skin or internal organs may occur. The etiology of RP is still unknown, but the pathogenetic role of the autoimmunity is suggested by frequent overlaps with various autoimmune diseases, and by the presence of autoantibody against cartilage in the serum of patients with RP. Although several reports have demonstrated the clinicopathologic manifestations and radiologic findings of RP, there are no specific features of RP. Therefore, it is difficult to show the diagnosis of RP. Airway involvements are major causes of morbidity and mortality, and they have accounted for most of the deaths due to RP. To suppress the inflammation of airway mucosa and cartilage is extremely important in the successful treatment for RP. Above all, earlier diagnosis would lead to better outcomes.