Noninfectious Triggers Research Articles

Guillain-Barre syndrome and link with COVID-19 infection and vaccination: a review of literature.

Guillain-Barré syndrome (GBS) is an autoimmune disease associated with significant morbidity. A wide variety of infectious and non-infectious triggers have been identified to be associated with GBS. COVID-19 has gained attention in recent years for its role in GBS pathogenesis. Our study aims to review the literature on GBS and its epidemiological and pathophysiological association with COVID-19. Recent literature on GBS associated with COVID-19 infections, such as case reports, case series, systematic reviews, and large-scale epidemiological studies, were reviewed. We also reviewed studies that included vaccines against COVID-19 in association with GBS. Studies that focused on understanding the pathobiology of GBS and its association with infectious agents including COVID-19 were reviewed. Despite a lack of consensus, GBS is strongly associated with COVID-19 infection. The exact pathophysiological mechanism regarding COVID-19 as a causative agent of GBS is unknown. Mechanisms, such as the proinflammatory state, triggering of autoimmunity, and direct viral invasion, are postulated and remain to be investigated. Adenovirus vector vaccines are most likely associated with GBS, and the consensual reports clearly suggest mRNA vaccines are associated with low risk and may be protective against GBS by reducing the risk of COVID-19 infection.

Acute myocarditis: an overview of pathogenesis, diagnosis and management.

Acute myocarditis encompasses a diverse presentation of inflammatory cardiomyopathies with infectious and non-infectious triggers. The clinical presentation is heterogeneous, from subtle symptoms like mild chest pain to life-threatening fulminant heart failure requiring urgent advanced hemodynamic support. This review provides a comprehensive overview of the current state of knowledge regarding the pathogenesis, diagnostic approach, management strategies, and directions for future research in acute myocarditis. The pathogenesis of myocarditis involves interplay between the inciting factors and the subsequent host immune response. Infectious causes, especially cardiotropic viruses, are the most frequently identified precipitants. However, autoimmune processes independent of microbial triggers, as well as toxic myocardial injury from drugs, chemicals or metabolic derangements also contribute to the development of myocarditis through diverse mechanisms. Furthermore, medications like immune checkpoint inhibitor therapies are increasingly recognized as causes of myocarditis. Elucidating the nuances of viral, autoimmune, hypersensitivity, and toxic subtypes of myocarditis is key to guiding appropriate therapy. The heterogeneous clinical presentation coupled with non-specific symptoms creates diagnostic challenges. A multifaceted approach is required, incorporating clinical evaluation, electrocardiography, biomarkers, imaging studies, and endomyocardial biopsy. Cardiovascular magnetic resonance imaging has become pivotal for non-invasive assessment of myocardial inflammation and fibrosis. However, biopsy remains the gold standard for histological classification and definitively establishing the underlying etiology. Management relies on supportive care, while disease-specific therapies are limited. Although some patients recover well with conservative measures, severe or fulminant myocarditis necessitates aggressive interventions such as mechanical circulatory support devices and transplantation. While immunosuppression is beneficial in certain histological subtypes, clear evidence supporting antiviral or immunomodulatory therapies for the majority of acute viral myocarditis cases remains insufficient. Substantial knowledge gaps persist regarding validated diagnostic biomarkers, optimal imaging surveillance strategies, evidence-based medical therapies, and risk stratification schema. A deeper understanding of the immunopathological mechanisms, rigorous clinical trials of targeted therapies, and longitudinal outcome studies are imperative to advance management and improve the prognosis across the myocarditis spectrum.

A Review on Myocarditis and Cardiomyopathy

Myocarditis presents a complex challenge with diverse causes, including infectious agents and non-infectious factors. Despite advancements, it remains associated with poor prognosis, especially when complicated by heart dysfunction. This review discusses its pathogenesis, diagnosis, treatment, and prognosis, covering various infectious and non-infectious triggers. Diagnosis involves electrocardiography, imaging, and sometimes biopsy. Treatment focuses on managing heart failure and arrhythmias, with ongoing research aiming to improve outcomes. Collaborative efforts are crucial for advancing understanding and care for this condition.

Increase in pediatric recurrent fever evaluations during the first year of the COVID-19 pandemic in North America.

The impact of the COVID-19 pandemic on new diagnoses of recurrent fevers and autoinflammatory diseases is largely unknown. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) PFAPA/AID Working Group aimed to investigate the impact of the COVID-19 pandemic on the number of pediatric patients evaluated for recurrent fevers and autoinflammatory diseases in North America. The absolute number of new outpatient visits and the proportion of these visits attributed to recurrent fever diagnoses during the pre-pandemic period (1 March 2019-29 February 2020) and the first year of the COVID-19 pandemic (1 March 2020-28 February 2021) were examined. Data were collected from 27 sites in the United States and Canada. Our results showed an increase in the absolute number of new visits for recurrent fever evaluations in 21 of 27 sites during the COVID-19 pandemic compared to the pre-pandemic period. The increase was observed across different geographic regions in North America. Additionally, the proportion of new visits to these centers for recurrent fever in relation to all new patient evaluations was significantly higher during the first year of the pandemic, increasing from 7.8% before the pandemic to 10.9% during the pandemic year (p < 0.001). Our findings showed that the first year of the COVID-19 pandemic was associated with a higher number of evaluations by pediatric subspecialists for recurrent fevers. Further research is needed to understand the reasons behind these findings and to explore non-infectious triggers for recurrent fevers in children.

Short-term air pollution exposure and exacerbation events in mild to moderate COPD: a case-crossover study within the CanCOLD cohort

BackgroundInfections are considered as leading causes of acute exacerbations of chronic obstructive pulmonary disease (COPD). Non-infectious risk factors such as short-term air pollution exposure may play a clinically important role....

Porcine Circovirus 2 Activates the PERK-Reactive Oxygen Species Axis To Induce p53 Phosphorylation with Subsequent Cell Cycle Arrest at S Phase in Favor of Its Replication.

Porcine circovirus type 2 (PCV2), the causative agent of porcine circovirus-associated diseases (PCVAD), is known to induce oxidative stress, activate p53 with induction of cell cycle arrest, and trigger the PERK (protein kinase R-like endoplasmic reticulum kinase) branch of the endoplasmic reticulum (ER) stress pathway. All these cellular responses could enhance PCV2 replication. However, it remains unknown whether PERK activation by PCV2 is involved in p53 signaling with subsequent changes of cell cycle. Here, we demonstrate that PCV2 infection induced cell cycle arrest at S phase to favor its replication via the PERK-reactive oxygen species (ROS)-p53 nexus. PCV2 infection promoted phosphorylation of p53 (p-p53) at Ser15 in porcine alveolar macrophages. Inhibition of PERK by RNA silencing downregulated total p53 (t-p53) and p-p53. Treatment with the MDM2 inhibitor nutlin-3 led to partial recovery of t-p53 in perk-silenced and PCV2-infected cells. perk silencing markedly downregulated ROS production. Scavenging of ROS with N-acetylcysteine (NAC) of PCV2-infected cells downregulated t-p53 and p-p53. Increased accumulation of p-p53 in the nuclei during PCV2 infection could be downregulated by silencing of perk or NAC treatment. Further studies showed that perk silencing or NAC treatment alleviated S phase accumulation and downregulated cyclins E1 and A2 in PCV2-infected cells. These findings indicate that the PCV2-activated PERK-ROS axis promotes p-p53 and contributes to cell cycle accumulation at S phase when more cellular enzymes are available to favor viral DNA synthesis. Overall, our study provides a novel insight into the mechanism how PCV2 manipulates the host PERK-ROS-p53 signaling nexus to benefit its own replication via cell cycle arrest. IMPORTANCE Coinfections or noninfectious triggers have long been considered to potentiate PCV2 infection, leading to manifestation of PCVAD. The triggering mechanisms remain largely unknown. Recent studies have revealed that PERK-mediated ER stress, oxidative stress, and cell cycle arrest during PCV2 infection are conducive to viral replication. However, how PCV2 employs such host cell responses requires further research. Here, we provide a novel mechanism of PCV2-induced ER stress and enhanced viral replication: the PCV2-activated PERK-ROS-p53 nexus increases S phase cell population, a cell cycle period of DNA synthesis favorable for PCV2 replication. The fact that PCV2 deploys the simple ROS molecules to activate p53 to benefit its replication provides novel insights into the triggering factors, that is, certain stimuli or management measures that induce ER stress with subsequent generation of ROS would exacerbate PCVAD. Use of antioxidants is justified on farms where PCVAD is severe.

Allergy Diagnostics 2021

Allergic diseases are among the most common diseases worldwide. For appropriate management knowledge of the allergy trigger is crucial. The clinical picture of allergic diseases is diverse and correct diagnosis is often a challenge. The allergist needs to distinguish intolerances from allergies and infectious diseases from non-infectious triggers. Test results have to be interpreted accordingly to differentiate sensitizations from allergies. In this review current state of the art diagnostic measures to diagnose type I and type IV allergies are described and discussed.Immediate type allergies such as allergic rhinoconjunctivitis, asthma and anaphylaxis are mediated by allergen-specific IgE antibodies detectable both in serum and tissue. Typical triggers are pollen, mites, animal epithelia, food, insect toxins and pharmaceuticals. In everyday practice, diagnostics are based on three complementary pillars: the allergy-specific anamnesis as a prerequisite of correct interpretation of subsequent diagnostic tests like skin testing and serological immunoglobulin detection. These can be supplemented as required and available by provocation tests to prove clinical reactivity and cellular assays to demonstrate the cellular immune response.Type IV allergic reactions are mediated by T cells causing contact allergy with a local eczematous reaction with a latency of several hours to days. Some 3,500 triggers, often from occupational environment, are known; e. g., nickel, chromium, cobalt, fragrances, rubber, plastics, preservatives, dyes, neomycin, benzocaine, sulfonamides, quinidine, wool wax, perubalsam, eye therapeutics, light filter substances, disinfectants, pesticides, technical oils or plants. Diagnosis of contact allergy combines the history of cutaneous exposure with associated symptoms and patch testing, with detection of a late phase clinical reaction after 6 to 48, up to a maximum of 96 hours after antigen contact.

A study on vaginitis among pregnant and non-pregnant females in Alexandria, Egypt: An unexpected high rate of mixed vaginal infection.

BackgroundMany infectious and noninfectious triggers lead to inflammation of the vagina.AimWe investigated the prevalence of causative vaginitis microorganisms in 516 pregnant and nonpregnant female volunteers. Vaginal samples were examined microscopically, cultured and tested for different pathogens.ResultsOf the participants, 310 (60.1%) were pregnant, whereas 206 (39.9%) were nonpregnant. Using Amsel's criteria and Nugent's scores, bacterial vaginosis (BV) was diagnosed in 59.1%, and the prevalence of vulvovaginal candidiasis (VVC) was 50.2% in the population. Candida infections were significantly higher in nonpregnant females (p value ≤ 0.01), and 24% of females had mixed infections. The most common mixed infection was BV and Candida spp., detected in 21% of the cases.ConclusionsBacterial vaginosis is the most common cause of vaginitis. We observed that 24% of females experienced mixed infections, and Candida albicans was the most common fungal species causing VVC. Trichomonas vaginalis prevalence was underestimated using wet mounts.

Inflammatory Episodes of Desmoplakin Cardiomyopathy Masquerading as Myocarditis: Unique Features on Cardiac Magnetic Resonance Imaging

Myocarditis is associated with numerous infectious and noninfectious triggers; cardiovascular magnetic resonance imaging during and after the episode may inform prognosis ([1][1]). Criteria for myocarditis include abnormal T1 and T2 findings, the latter identifying active inflammation or edema ([2][

Myocarditis in Humans and in Experimental Animal Models.

Myocarditis is defined as an inflammation of the cardiac muscle. In humans, various infectious and non-infectious triggers induce myocarditis with a broad spectrum of histological presentations and clinical symptoms of the disease. Myocarditis often resolves spontaneously, but some patients develop heart failure and require organ transplantation. The need to understand cellular and molecular mechanisms of inflammatory heart diseases led to the development of mouse models for experimental myocarditis. It has been shown that pathogenic agents inducing myocarditis in humans can often trigger the disease in mice. Due to multiple etiologies of inflammatory heart diseases in humans, a number of different experimental approaches have been developed to induce myocarditis in mice. Accordingly, experimental myocarditis in mice can be induced by infection with cardiotropic agents, such as coxsackievirus B3 and protozoan parasite Trypanosoma cruzi or by activating autoimmune responses against heart-specific antigens. In certain models, myocarditis is followed by the phenotype of dilated cardiomyopathy and the end stage of heart failure. This review describes the most commonly used mouse models of experimental myocarditis with a focus on the role of the innate and adaptive immune systems in induction and progression of the disease. The review discusses also advantages and limitations of individual mouse models in the context of the clinical manifestation and the course of the disease in humans. Finally, animal-free alternatives in myocarditis research are outlined.

A host gene expression approach for identifying triggers of asthma exacerbations.

RationaleAsthma exacerbations often occur due to infectious triggers, but determining whether infection is present and whether it is bacterial or viral remains clinically challenging. A diagnostic strategy that clarifies these uncertainties could enable personalized asthma treatment and mitigate antibiotic overuse.ObjectivesTo explore the performance of validated peripheral blood gene expression signatures in discriminating bacterial, viral, and noninfectious triggers in subjects with asthma exacerbations.MethodsSubjects with suspected asthma exacerbations of various etiologies were retrospectively selected for peripheral blood gene expression analysis from a pool of subjects previously enrolled in emergency departments with acute respiratory illness. RT-PCR quantified 87 gene targets, selected from microarray-based studies, followed by logistic regression modeling to define bacterial, viral, or noninfectious class. The model-predicted class was compared to clinical adjudication and procalcitonin.ResultsOf 46 subjects enrolled, 7 were clinically adjudicated as bacterial, 18 as viral, and 21 as noninfectious. Model prediction was congruent with clinical adjudication in 15/18 viral and 13/21 noninfectious cases, but only 1/7 bacterial cases. None of the adjudicated bacterial cases had confirmatory microbiology; the precise etiology in this group was uncertain. Procalcitonin classified only one subject in the cohort as bacterial. 47.8% of subjects received antibiotics.ConclusionsOur model classified asthma exacerbations by the underlying bacterial, viral, and noninfectious host response. Compared to clinical adjudication, the majority of discordances occurred in the bacterial group, due to either imperfect adjudication or model misclassification. Bacterial infection was identified infrequently by all classification schemes, but nearly half of subjects were prescribed antibiotics. A gene expression-based approach may offer useful diagnostic information in this population and guide appropriate antibiotic use.

Treating pediatric acute-onset neuropsychiatric syndrome.

Pediatric acute-onset neuropsychiatric syndrome (PANS) can be caused by infectious and noninfectious triggers. NPs can help children with PANS recover from their symptoms and prevent future recurrences by appropriately screening, recognizing, and diagnosing the clinical presentation of PANS. PANS treatment includes pharmacologic therapies as well as cognitive behavioral therapy.

Allergic Proctocolitis Is a Risk Factor for Functional Gastrointestinal Disorders in Children

To prospectively evaluate the long-term effect of allergic proctocolitis on the development of functional gastrointestinal disorders (FGIDs), defined as gastrointestinal symptoms that cannot be attributed to another medical condition.The study included 80 Italian children consecutively diagnosed with allergic proctocolitis, in addition to 80 matched controls.Patients presenting to the Pediatric Gastroenterology Unit of Sapienza, University of Rome, with newly diagnosed allergic proctocolitis were recruited for participation in the study. Each subject underwent an anal inspection, stool culture, fecal calprotectin, and rectosigmoidoscopy with mucosal biopsies obtained from the left colon and rectum. Serum-specific immunoglobulin E and skin-prick testing (cow’s milk, soy, rice, wheat, and egg) were also performed. Subjects were managed with a stepwise protocol progressing from cow’s milk protein maternal avoidance, then extensively hydrolyzed formula, and then amino acid–based formula. For the control group, each subject was matched with either a sibling <6 years of age without a history of cow’s milk allergy or with another child of similar age and sex who presented to the hospital emergency department for mild trauma in the absence of previous chronic gastrointestinal symptoms. Subjects had monthly clinic follow-up until remission of symptoms, followed by telephone interview every 12 months until the age of 4 years. After subjects turned 4 years old, parents were mailed the parental Questionnaire on Pediatric Gastrointestinal Symptoms, Rome III version, a validated questionnaire for the diagnosis of FGIDs.There were 80 subjects in each of the allergic proctocolitis and control groups, with no significant differences in demographics of the 2 groups. Throughout the course of the study, none of the allergic proctocolitis patients had a change in their diagnosis, and none in the control group developed an organic disorder. In the allergic proctocolitis group, 12 subjects (15%) met FGID criteria compared with 4 subjects in the control group (5%) (P = .035). For the allergic proctocolitis group, adjusting for age and sex, the odds for developing an FGID was odds ratio 4.39 (95% confidence interval, 1.03–18.68). There was no correlation between FGIDs and family history of atopy, positive allergy testing results, fecal calprotectin, endoscopic score, histologic score, or eosinophil score. In the allergic proctocolitis group, the only variable that was statistically significant for development of an FGID was duration of hematochezia (odds ratio 3.14; 95% confidence interval, 1.72–5.74)Allergic proctocolitis is a risk factor for the development of FGID in children, further supporting that both transient infectious and noninfectious inflammatory triggers can contribute to the development of FGIDs.The authors of this study prospectively identify allergic proctocolitis as a risk factor for the development of FGIDs, describing long-term morbidity with what is considered a self-limiting, relatively mild disease. This supports the idea that prolonged inflammation, in the absence of infection, can lead to the development of FGIDs. Interestingly, the duration of hematochezia was associated with an increasing rate of developing FGIDs, which suggests that prompt treatment could have an impact on this associated morbidity.

Acute-on-Chronic Liver Failure: A Portuguese Single-Center Reference Review

Acute-on-chronic liver failure (ACLF) is a syndrome characterized by an acute deterioration of a patient with cirrhosis, frequently associated with multi-organ failure and a high short-term mortality rate. We present a retrospective study that aims to characterize the presentation, evolution, and outcome of patients diagnosed with ACLF at our center over the last 3 years, with a comparative analysis between the group of patients that had ACLF precipitated by infectious insults of bacterial origin and the group of those with ACLF triggered by a nonbacterial infectious insult; the incidence of acute kidney injury and its impact on the prognosis of ACLF was also analyzed. Twenty-nine patients were enrolled, the majority of them being male (89.6%), and the mean age was 53 years. Fourteen patients (48.3%) developed ACLF due to a bacterial infectious event, and 9 of them died (64.2%, overall mortality rate 31%); however, no statistical significance was found (p < 0.7). Of the remaining 15 patients (51.7%) with noninfectious triggers, 11 died (73.3%, overall mortality rate 37.9%); again there was no statistical significance (p < 0.7). Twenty-four patients (83%) developed acute kidney injury (overall mortality rate 65.5%; p < 0.022) at the 28-day and 90-day follow-up. Twelve patients had acute kidney injury requiring renal replacement therapy (41.37%; overall mortality rate 37.9%; p < 0.043). Hepatic transplant was performed in 3 patients, with a 100% survival at the 28-day and 90-day follow-up (p < 0.023). Higher grades of ACLF were associated with increased mortality (p < 0.02; overall mortality 69%). Conclusions: ACLF is a heterogeneous syndrome with a variety of precipitant factors and different grades of extrahepatic involvement. Most cases will have some degree of renal dysfunction, with an increased risk of mortality. Hepatic transplant is an efficient form of therapy for this syndrome.

Procalcitonin as a Diagnostic and Prognostic Marker of Sepsis in Critically Ill Patients in Intensive Care Unit

Background: Sepsis is a leading cause of mortality in critically ill patients. However, differentiating sepsis from non-infectious triggers of the systemic inflammatory response syndrome (SIRS) is difficult. Procalcitonin is useful biomarker of systemic inflammatory response to infection. Its level rises in response to a proinflammatory stimulus, especially of bacterial origin and not rise significantly with viral or non infectious inflammation. Objectives: The aim of this study was to determine the relation of procalcitonin (PCT) level with the development of organ failure and mortality in critically ill septic ICU patients Patients and Methods: The current study was conducted on 60critically ill adult septic patients aged between 18-60 years old of both sex with anticipated stay of >48 hours. All patients were assessed clinically with haemodynamic and full laboratory monitoring, CRP, a PCT level and SOFA score were calculated in the1st and the 4th day of admission.Results: There was significant increase in PCT level between three groups and no significant difference between groups as regard CRP. According to SOFA score there was significant difference between three groups. There was a positive correlation between PCT level and SOFA Score (r = 0.924, P = 0.001) while there was no correlation between CRP and SOFA score (r = -0.233, P = 0.091). Conclusion: PCT is a good diagnostic and prognostic marker of sepsis. PCT shows a closer correlation than that of CRP with the severity of infection and organ dysfunction.

Toxoplasmosis-associated IRIS involving the CNS: a case report with longitudinal analysis of T cell subsets

BackgroundHIV-infected patients may present an unforeseen clinical worsening after initiating antiretroviral therapy known as immune reconstitution inflammatory syndrome (IRIS). This syndrome is characterized by a heightened inflammatory response toward infectious or non-infectious triggers, and it may affect different organs. Diagnosis of IRIS involving the central nervous system (CNS-IRIS) is challenging due to heterogeneous manifestations, absence of biomarkers to identify this condition, risk of long-term sequelae and high mortality. Hence, a deeper knowledge of CNS-IRIS pathogenesis is needed.Case presentationA 37-year-old man was diagnosed with AIDS and cerebral toxoplasmosis. Anti-toxoplasma treatment was initiated immediately, followed by active antiretroviral therapy (HAART) 1 month later. At 2 months of HAART, he presented with progressive hyposensitivity of the right lower limb associated with brain and dorsal spinal cord lesions, compatible with paradoxical toxoplasmosis-associated CNS-IRIS, a condition with very few reported cases. A stereotactic biopsy was planned but was postponed based on its inherent risks. Patient showed clinical improvement with no requirement of corticosteroid therapy. Routine laboratorial analysis was complemented with longitudinal evaluation of blood T cell subsets at 0, 1, 2, 3 and 6 months upon HAART initiation. A control group composed by 9 HIV-infected patients from the same hospital but with no IRIS was analysed for comparison. The CNS-IRIS patient showed lower percentage of memory CD4+ T cells and higher percentage of activated CD4+ T cells at HAART initiation. The percentage of memory CD4+ T cells drastically increased at 1 month after HAART initiation and became higher in comparison to the control group until clinical recovery onset; the percentage of memory CD8+ T cells was consistently lower throughout follow-up. Interestingly, the percentage of regulatory T cells (Treg) on the CNS-IRIS patient reached a minimum around 1 month before symptoms onset.ConclusionAlthough both stereotactic biopsies and steroid therapy might be of use in CNS-IRIS cases and should be considered for these patients, they might be unnecessary to achieve clinical improvement as shown in this case. Immunological characterization of more CNS-IRIS cases is essential to shed some light on the pathogenesis of this condition.

Procalcitonin: present and future.

Critically ill patients are frequently at risk of sepsis or inflammatory conditions. Procalcitonin (PCT) is a biomarker for critically ill patients to differentiate sepsis from non-infectious triggers of the systemic inflammatory response syndrome. It has been recently shown that PCT is a valuable tool to guide antibiotic treatment in patients with bacteria infections. However, PCT is also less than a universal and perfect biomarker, and its physiologic role remains unknown. An increase in PCT is associated not only with localized bacterial infection, but also with non-infectious disease or other microbial infections. Numerous studies have suggested that use of PCT would reduce patients' exposure to antibiotics; however, the use of PCT-guided management of antibiotics strategy needs further study to validate their safety in daily practice in ICU settings. Data supporting this concept from randomized trials are still required. Future studies should focus on PCT kinetics. On the other hand, the need for biologic role of PCT shall be highlighted. Immunoneutralization of PCT will likely be a therapeutic approach for human sepsis only if its physiologic effects are elaborated. The aim of this review is to summarize and discuss the current evidence for PCT in a series of clinical settings.

Life-Threatening Acute Fulminant Myocarditis Following a Coffee Diet Program

Myocarditis is an inflammatory disease of the myocardium caused by various infectious or noninfectious triggers. Although viral infections are important causes of myocarditis, some drugs or toxins can also cause myocarditis. We report a case of life-threatening fulminant myocarditis which followed an extensive coffee diet program. Despite medical treatment, the patient was not able to maintain hemodynamic stability. She was supported by extracorporeal membrane oxygenation and completely recovered 3 months later.

Infectious and noninfectious triggers in Guillain–Barré syndrome

Guillain–Barré syndrome (GBS) is the commonest cause of acquired flaccid paralysis in the world and regarded by many as the prototype for postinfectious autoimmunity. Here the authors consider both infectious and noninfectious triggers of GBS and determine where possible what immunological mechanisms may account for this association. In approximately two-thirds of cases, an infectious trigger is reported in the weeks that lead up to disease onset, indicating that the host’s response to infection must play an important role in disease pathogenesis. The most frequently identified bacteria, Campylobacter jejuni, through a process known as molecular mimicry, has been shown to induce cross-reactive anti-ganglioside antibodies, which can lead to the development of axonal-type GBS in some patients. Whether this paradigm can be extended to other infectious organisms or vaccines remains an important area of research and has public health implications. GBS has also been reported rarely in patients with underlying systemic diseases and immunocompromised states and although the exact mechanism is yet to be established, increased susceptibility to known infectious triggers should be considered most likely.

Role of the Functional Toll-Like Receptor-9 Promoter Polymorphism (-1237T/C) in Increased Risk of End-Stage Renal Disease: A Case-Control Study

Inflammation induced by infectious and noninfectious triggers in the kidney may lead to end stage renal disease (ESRD). Toll-like receptor 9 (TLR-9) a receptor for CpG DNA is involved in activation of immune cells in renal disease and may contribute to chronic inflammatory disease progression through an interleukin-6 (IL-6) dependent pathway. Previous studies indicate that -1237T/C confers regulatory effects on TLR-9 transcription. To date the effect of TLR-9 polymorphisms on ESRD remains unknown. We performed a case-control study and genotyped 630 ESRD patients and 415 controls for -1237T/C, -1486T/C and 1635G/A by real-time PCR assays and assessed plasma concentration of IL-6 by ELISA. Haplotype association analysis was performed using the Haploview package. A luciferase reporter assay and real-time PCR were used to test the function of the -1237T/C promoter polymorphism. A significant association between -1237T/C in TLR-9 and ESRD was identified. The TCA, TTA and CCA haplotype of TLR-9 were associated with ESRD. ESRD patients carrying -1237TC had a higher mean plasma IL-6 level when compared with -1237TT. The TLR-9 transcriptional activity of the variant -1237CC allele is higher than the -1237TT allele. The results indicate that in a Han Chinese population the presence of the C allele of -1237T/C in the TLR-9 gene increases susceptibility towards development of ESRD. In vitro studies demonstrate that -1237T/C may be involved in the development of ESRD through transcriptional modulation of TLR-9.