Long chikungunya?An overview to immunopathology of persistent arthralgia

Chikungunya fever(CF)is caused by an arbovirus whose manifestations are extremely diverse,and it has evolved with significant severity in recent years.The clinical signs triggered by the Chikungunya virus are similar to those of other arboviruses.Generally,fever starts abruptly and reaches high levels,followed by severe polyarthralgia and myalgia,as well as an erythematous or petechial maculopapular rash,varying in severity and extent.Around 40%to 60%of affected individuals report persistent arthralgia,which can last from months to years.The symptoms of CF mainly represent the tissue tropism of the virus rather than the immunopathogenesis triggered by the host's immune system.The main mechanisms associated with arthralgia have been linked to an increase in T helper type 17 cells and a consequent increase in receptor activator of nuclear factor kappa-Βligand and bone resorption.This review suggests that persistent arthralgia results from the presence of viral antigens post-infection and the constant activation of signaling lymphocytic activation molecule family member 7 in synovial macrophages,leading to local infiltration of CD4+T cells,which sustains the inflammatory process in the joints through the secretion of pro-inflammatory cytokines.The term"long chikungunya"was used in this review to refer to persistent arthralgia since,due to its manifestation over long periods after the end of the viral infection,this clinical condition seems to be characterized more as a sequel than as a symptom,given that there is no active infection involved.

Reciprocal crosstalk between dendritic cells and natural killer cells under the effects of PGE2 in immunity and immunopathology

The reciprocal activating crosstalk between dendritic cells （DCs） and natural killer （NK） cells plays a pivotal role in regulating immune defense against viruses and tumors. The cytokine-producing capacity, Th-cell polarizing ability and chemokine expression, migration and stimulatory functions of DCs are regulated by activated NK cells. Conversely, the innate and effector functions of NK cells require close interactions with activated DCs. Cell membrane-associated molecules and soluble mediators, including cytokines and prostaglandins （PGs）, contribute to the bidirectional crosstalk between DCs and NK cells. One of the most well-known and well-studied PGs is PGE2. Produced by many cell types, PG E2 has been shown to affect various aspects of the immune and inflammatory responses by acting on all components of the immune system. There is emerging evidence that PGE2 plays crucial roles in DC and NK cell biology. Several studies have shown that DCs are not only a source of PGE2, but also a target of its immunomodulatory action in normal immune response and during immune disorders. Although NK cells appear to be unable to produce PGE2, they are described as powerful PGE2-responding cells, as they express all PGE2 E-prostanoid （EP） receptors. Several NK cell functions （lysis, migration, proliferation, cytokine production） are influenced by PGE2. This review highlights the effects of PGE2 on DC- NK cell crosstalk and its subsequent impact on immune regulations in normal and immunopathological processes.

Childhood Henoch-Schnlein Purpura Nephritis and IgA Nephropathy: One Disease Entity?——A Clinico-pathologically Comparative Study

Summary： In order to characterize their relationship through clinicopathological comparison between IgA nephropathy and Henoch-Schoenlein purpura nephritis （HSPN）, 31 children with IgA nephrop- athy aged between 3 to 15 years and 120 children with HSPN aged between 4 to 15 years were compared with each other in clinical manifestation, blood biochemistry, serum immunology and followup study. Renal pathological findings under light microscope, immunofluorescence and electronic microscope were analyzed and also compared between 31 children with IgA nephropathy and 32 biopsied children with HSPN. The results showed that the onset age was over 12 years in 25.8 % children with IgA nephropathy, but only 10 % in HSPN （P〈0.05）. The clinical patterns of IgA nephropathy and HSPN were similar, but extra-renal manifestations were more often in HSPN, all of them had skin purpura, 59 % had gastrointestinal symptoms and 47 % suffered from arthralgia, compared with only abdominal pain in 3.2 % children with IgA nephropathy. The renal pathological investigation showed global sclerosis in 35.5 % of IgA nephropathy and 3.1% of HSPN, mesangial sclerosis in 41.9 % of IgA nephropathy and 6.3 % of HSPN, but endothelial proliferation in 65.6 % of HSPN and 29 % of IgA nephropathy （all P〈0.01）. Thin basement membrane nephropathy was only found in 6. 5 % children with IgA nephropathy, no in HSPN. The electronic dense deposits in HSPN were sparse, lodse and wildly spread in glomerular mesangium, subendothelial area and even intra basement membrane, but it was dense, lumpy and mostly limited in mesangium and paramesangium in IgA nephropathy. Predominant IgA deposits were found in 81.2% of HSPN, and overwhelming IgG deposits in 12.5 % of HSPN with relatively weak IgA deposits, moreover 6.3 % of HSPN showed linear IgG deposits in glomerular capillary. Totally 71. 9 G of HSPN had IgG deposits in glomeruli and only 19.4% of IgA nephropathy showed glomerular IgG deposits （P〈0. 01）. No IgG deposit was observed in 81. 6 % of IgA nephropathy, among them most showed IgA and IgM and/or C3 deposits, moreover overwhelming IgG deposits and linear IgG deposits couldn＇t be found in IgA nephropathy. Mean 20 months follow-up showed complete remission in 72.5% of HSPN, but only 19.4% in IgA nephropathy after 34 months follow-up. Moreover, 64.5 % of IgA nephropathy had consistent hematuria and proteinuria and 16. 1% had active nephritides （P〈0.05）. It was concluded that significant clinico-pathological difference was found between HSPN and IgA nephropathy, which didn＇t support the one disease entity hypothesis. HSPN and IgA nephropathy are probably two diseases with similar immune abnormalities.

COVID-19,liver dysfunction and pathophysiology:A conceptual discussion

The intra and extracellular pathways of hepatic injury by coronavirus disease 2019(COVID-19)are still being studied.Understanding them is important to treat this viral disease and other liver and biliary tract disorders.Thus,this paper aims to present three hypotheses about liver injury caused by COVID-19:(1)The interactions between severe acute respiratory syndrome coronavirus 2 spike protein and membrane receptors in the hepatocyte;(2)The dysbiosis and"gutliver axis"disruption in patients with serious clinical presentations of COVID-19;and(3)The inflammatory response exacerbated through the production of interleukins such as interleukin-6.However,despite these new perspectives,the pathophysiological process of liver injury caused by COVID-19 is still complex and multifactorial.Thus,understanding all these variables is a challenge to science but also the key to propose individualized and effective patient therapies.

DYNAMIC OBSERVATION ON THE CHANGES OF PLASMA SOMATOSTATIN AND GLUCAGON DURING THE DEVELOPMENT OF CIRRHOSIS AND AFTER PORTACAVAL SHUNTING IN THE CIRRHOTIC RATS

In the present study we observed dynamically and systemically the changes of plasma somatostatin and glucagon in the peripheral and portal vein, and the changes of pancreatic immunopathology in the course of development of cirrhosis induced by CCl4 and after portacaval shunt （PCS） in the cirrhotic rats as well as investigated their causes and correlationship. The results showed that hyperglucagonemia was caused by spontaneous portosystemic shunting and surgically induced portacaval anastomosis. Moreover, there was much higher level of glucagon in the portal vein with corresponding increase of A cells in PCS rats than those in the controls, indicating that another cause for elevation of glucagon was hypersecretion of pancreatic A cells. Our data demonstrated that both deterioration of liver function and portosystemic shunting might not be responsible for the elevated level of somatostatin in the cirrhotic rats with PCS. However, there was a closed positive correlation between plasma glucagon and somatostatin. Thus it was concluded that hyperglucagonemia stimulated the release of somatostatin. In view of the fact the elevated level of glucagon was much higher than that of somatostatin, there was probably a relative lack of somatostatin in cirrhosis with portal hypertension.

THE CLINICAL AND PATHOLOGICAL FEATURES ANDTREATMENT OF RAPIDLY PROGRESSIVEGLOMERULONEPHRITIS

Objectivs For better understanding the incidence, clinical and pathological features of rapidlyprogressive glomerulonephritis and improving the level of diagnosis and treatent. Methods Records Of 19 biopsyproved RPGN were reviewed. Results Nephrotic syndrome and acute renal failure were common. The incidenceof this disease is about 2% of all renal biopsies of the same period. Conclusion 1. Renal biopsy should beperformed as soon as possible if RPGN is suspected. 2. The detection of antineutrophil cytoplasmic autoantibody isvery important. 3. The indication of pulse therapy should be strictly justified according to the pathologicalfindings. 4. Dialysis and plasma exchange should be given to ARF patients in the early stage.

Immunopathological observation of lumbar disc herniation and discogenic pain

Objective To evaluate and compare the immunopathological changes of lumbar disc herniation and discogenic pain.Methods Seventy-one lumbar disc nucleuses were collected intra-operation,and they were divided into four groups.Group A:30 cases

Physiological strategies in wild rodents:immune defenses of commensal rats

The importance of issues associated with urban/commensal rats and mice(property damage,management costs,and health risks)press upon research on these animals.While the demography of commensal rodents is mostly studied,the need for understanding factors influencing their natural morbidity/mortality is also stressed.In this respect,more attention is expected to be paid to immunity,the physiological mechanism of defense against host survival threats(pathogens,parasites,diseases).Commensal rats and mice carry numerous pathogens that evoke diverse immune responses.The state of immunity in commensal house mice is studied in great detail,owing to the use of laboratory strains in biomedical research.Because commensal rats are,compared to mice,carriers of more zoonotic agents,rats’immunity is studied mainly in that context.Some of these zoonotic agents cause chronic,asymptomatic infections,which justified studies of immunological mechanisms of pathogen tolerance versus clearance regulation in rats.Occurrence of some infections in specific tissues/organs pressed upon analysis of local/regional immune responses and/or immunopathology.A survey of immunological activity/responses in commensal rats is given in this review,with mention of existing data in commensal mice.It should throw some light on the factors relevant to their morbidity and lifespan,supplementing the knowledge of commensal rodent ecology.

The cytokine storm of severe influenza and development of immunomodulatory therapy

Severe influenza remains unusual in its virulence for humans. Complications or ultimately death arising from these infections are often associated with hyperinduction of proinflammatory cytokine production, which is also known as ＇cytokine storm＇. For this disease, it has been proposed that immunomodulatory therapy may improve the outcome, with or without the combination of antiviral agents. Here, we review the current literature on how various effectors of the immune system initiate the cytokine storm and exacerbate pathological damage in hosts. We also review some of the current immunomodulatory strategies for the treatment of cytokine storms in severe influenza, including corticosteroids, peroxisome proliferator-activated receptor agonists, sphingosine-l-phosphate receptor 1 agonists, cyclooxygenase-2 inhibitors, antioxidants, anti-tumour-necrosis factor therapy, intravenous immunoglobulin therapy, statins, arbidol, herbs, and other potential therapeutic strategies.

Clinical and immunopathological features of patients with lupus hepatitis

Background Lupus hepatitis is yet to be characterized based on its clinical features and is often difficult to differentially diagnose from other liver diseases. We aimed to elucidate clinical, histopathological and immunopathological features of lupus hepatitis and to evaluate primarily the effectiveness of liver immunopathological manifestations on differential diagnosis of lupus hepatitis from other liver diseases. Methods A retrospective study was performed to analyze clinical features of lupus hepatitis in 47 patients out of 504 inpatients with systemic lupus erythematosus （SLE） in First Affiliated Hospital of Sun Yat-sen University, China from May 2006 to July 2009, and to evaluate the association between lupus hepatitis and SLE activity. Additionally, liver histopathological changes by hematoxylin and eosin （HE） staining and immunopathological changes by direct immunofluorescence test in 10 lupus hepatitis cases were analyzed and compared to those in 16 patients with other liver diseases in a prospective study. Results Of 504 SLE patients, 47 patients （9.3%） were diagnosed to have lupus hepatitis. The prevalence of lupus hepatitis in patients with active SLE was higher than that in those with inactive SLE （11.8% vs. 3.2%, P 〈0.05）. The incidence of hematological abnormalities in patients with lupus hepatitis was higher than that in those without lupus hepatitis （40.4% vs. 21.7%, P 〈0.05）, such as leucocytes count （2.92x109/L vs. 5.48x109/L）, platelets count （151x109/L vs. 190x109/L）, serum C3 and C4 （0.34 g/L vs. 0.53 g/L; 0.06 g/L vs. 0.09 g/L） （P 〈0.05）; 45 of 47 （95.7%） lupus hepatitis patients showed 1 upper limit of normal （ULN） 〈serum ALT level 〈5 ULN. The liver histopathological features in patients with lupus hepatitis were miscellaneous and non-specific, similar to those in other liver diseases, but liver immunopathological features showed positive intense deposits of complement lq in 7/10 patients with lupus hepatitis and negative complement lq deposits in all patients with other liver diseases （Fisher＇s exact test, P=-0.011）. Conclusions Lupus hepatitis was not infrequent in active SLE patients which would be one of the indices indicating SLE activity. Positive intense deposit of complement lq in liver may be a characteristic immunopathological feature of lupus hepatitis, which provides a new way to differentially dia qnose lupus hepatitis from other liver diseases.

Hepatic effector CD8＋ T-cell dynamics

CD8＋ T cells play a critical role in hepatitis B virus （HBV） pathogenesis. During acute, self-limited infections, these cells are instrumental to viral clearance; in chronic settings, they sustain repetitive cycles of hepatocellular necrosis that promote hepatocellular carcinoma development. Both CD8＋ T-cell defensive and destructive functions are mediated by antigen-experienced effector cells and depend on the ability of these cells to migrate to the liver, recognize hepatocellular antigens and perform effector functions. Understanding the signals that modulate the spatiotemporal dynamics of CD8＋ T cells in the liver, particularly in the context of antigen recognition, is therefore critical to gaining insight into the pathogenesis of acute and chronic HBV infection. Here, we highlight recent data on how effector CD8＋ T cells traffic within the liver, and we discuss the potential for novel imaging techniques to shed light on this important aspect of HBV pathogenesis.

Current progress and challenges in the design and development of a successful COVID-19 vaccine

The coronavirus disease 2019(COVID-19)pandemic,caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),is still a worldwide concern,with little to no sign of a decreasing trend.There is a general consensus that normal life will be hampered until a safe and effective vaccine strategy is available and globally administered.Numerous countries have accelerated the clinical trials process for the development of a successful COVID-19 treatment,with over 200 candidates presently available for testing against SARS-CoV-2.Here,we provide an overview of the COVID-19 vaccine candidates currently in development,discuss the scientific and practical challenges associated with COVID-19 vaccine design,and share the potential strategies that could be exploited for vaccine design success.

Immunostimulation in the era of the metagenome

Microbes are increasingly being implicated in autoimmune disease.This calls for a re-evaluation of how these chronic inflammatory illnesses are routinely treated.The standard of care for autoimmune disease remains the use of medications that slow the immune response,while treatments aimed at eradicating microbes seek the exact opposite-stimulation of the innate immune response.Immunostimulation is complicated by a cascade of sequelae,including exacerbated inflammation,which occurs in response to microbial death.Over the past 8 years,we have collaborated with American and international clinical professionals to research a model-based treatment for inflammatory disease.This intervention,designed to stimulate the innate immune response,has required a reevaluation of disease progression and amelioration.Paramount is the inherent conflict between palliation and microbicidal efficacy.Increased microbicidal activity was experienced as immunopathology-a temporary worsening of symptoms.Further studies are needed,but they will require careful planning to manage this immunopathology.