High Serum IgG4 Levels Research Articles

The association of different serum IgG4 levels with distinct clinical characteristics and treatment efficacy in patients with IgG4-related disease

To explore the clinical characteristics and treatment efficacy of IgG4-related disease (IgG4-RD) patients with different levels of serum IgG4. A total of 299 patients newly diagnosed with IgG4-RD were enrolled in this study. Patients were classified into four groups according to baseline serum IgG4 levels: Group A: normal concentration; Group B: > normal but <2× the upper reference limit (URL); Group C: between 2× and 5× the URL; Group D: >5× the URL. All patients were followed up for 12 months. The patients' clinical characteristics, laboratory parameters, plasmablasts/plasma cells and treatment efficacy were analysed. IgG4-RD patients with higher serum IgG4 levels had higher percentages of dacryoadenitis, sialadenitis, and autoimmune pancreatitis and a higher prevalence of allergy history, whereas patients with retroperitoneum and mediastinum lesions usually had lower serum IgG4 levels. In addition, the serum IgG4 re-elevation rate in Group D (19.4%) was higher than those in Group B (4.9%) and Group C (7.7%) (p=0.003 and p=0.020, respectively). Patients suffered fewer clinical relapses with a serum IgG4 reduction ≥50% of baseline serum IgG4 in Group B and ≥40% of baseline serum IgG4 in Group D (p=0.019 and p=0.043, respectively). In addition, the rate of clinical relapse in patients who received combination therapy with glucocorticoids and mycophenolate mofetil was 18.75% in Group D, which was higher than the rates in Groups B and C (0) (p=0.027). IgG4-RD patients with different levels of serum IgG4 exhibit different clinical characteristics and treatment responses.

High Levels of Serum IgG for Opisthorchis viverrini and CD44 Expression Predict Worse Prognosis for Cholangiocarcinoma Patients after Curative Resection.

BackgroundOpisthorchis viverrini (OV)-associated cholangiocarcinoma (CCA) has a high immune response with chronic inflammation and oxidative stress. CD44 and Nestin, two cancer stem cell (CSC) markers, play major roles in cancer cell survival. Effects of immune response and expression CSC markers on survival of patients with CCA remain unclear.ObjectiveTo investigate the effects of level of OV IgG together with CSC marker expression and also the combination of these markers on survival of CCA patients after curative resection.MethodsAll serum specimens from CCA patients who underwent curative surgery from 2005 to 2015 were examined for IgG for OV antigen by ELISA. Tissue specimens were studied for CD44 and Nestin expression. Survival analysis by Cox proportional hazard model was used for estimating hazard ratio (HR) with a 95% confidence interval (CI).ResultsIn this study, 122 (69.3%) of 176 were positive for OV IgG, and 35 (19.9%) were considered to have high-positive OV IgG. CD44s positive expression was found in 54 (40%), CD44v6 high expression in 96 (69.6%), CD44v8-10 high expression in 87 (63.5%) and Nestin high expression in 21 (16.1%). Multivariate survival analysis found that high-positive OV IgG and late stage tumor were independent prognostic factors with the adjusted HR of 2.24 (95% CI 1.27–3.93) and 2.78 (95% CI 1.46–5.29), respectively. Subgroup analysis in early and late stage CCA showed that a combined positive OV IgG and CD44s expression with the high expression of CD44v8-10 had the significantly poorest prognosis with HR of 3.75 (95% CI 1.61–8.72) and HR of 1.76 (95% CI 1.02–3.03), respectively.ConclusionA high level of OV IgG as well as a high level of CSC markers resulted in an aggressive CCA. OV IgG level together with CSC markers can be used as the prognostic markers for CCA patients’ survival. The study of the CD44 pathway is promising for adjuvant treatment.

IgG4-related Disease of the Nervous Systems

IgG4-related disease is a unique fibroinflammatory disorder with organ system involvement, which was first described in Japan. It is characterized by high serum IgG4 levels and infiltration of IgG4-positive plasma cells in several organs. IgG4-related disease can involve the central and peripheral nervous systems, resulting in hypertrophic pachymeningitis, orbital diseases, hypophysitis, and peripheral nerve disease. Sufficient pathological findings are important for diagnosing IgG4-related disease and distinguishing it from mimics. The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria and the 2020 Revised Comprehensive Diagnostic Criteria have recently been published. Herein, we describe a current update of the clinicopathological features, approach to diagnosis, and management of IgG4-related neurological diseases.

Clinical features and relapse risks of IgG4-related ophthalmic disease: a single-center experience in China

BackgroundIgG4-related ophthalmic disease (IgG4-ROD) is one of the phenotypes of IgG4-related disease (IgG4-RD), and its lesions are mainly located in the ocular. Currently, there are few studies on IgG4-ROD and no study has compared the phenotypic differences between IgG4-ROD and non IgG4-ROD (nIgG4-ROD). Thus, it is difficult to establish the optimal treatment strategy for IgG4-ROD. The aim of this study was to identify the disparities between the two groups and to clarify the risk factors for IgG4-ROD relapse.Methods434 IgG4-RD patients met comprehensive diagnostic criteria and diagnosed at Peking University People’s Hospital between January 2009 and January 2020 were recruited in this study. Patients were divided into IgG4-ROD and nIgG4-ROD group according to the ophthalmic involvement. Demographic, clinical, and laboratory data of two groups were collected and compared. Cox regression analysis was used to identify the independent risk factors for IgG4-ROD relapse.Results255 IgG4-ROD patients were identified in this study. IgG4-ROD group had almost equal sex ratio, younger age of disease onset and diagnosis comparing with nIgG4-ROD patients. As compared to nIgG4-ROD group, higher percentage of IgG4-ROD patients met the 2019 American College of Rheumatology/European League Against Rheumatism classification criteria (AECC) for IgG4-RD; moreover, IgG4-ROD patients had higher AECC scores and IgG4-RD responder index (RI). Allergic diseases and multiorgan involvement were more common in IgG4-ROD group. IgG4-ROD was frequently associated with salivary gland, paranasal sinus, lung, and lymph node involvement, while retroperitoneal fibrosis and biliary system lesions were more common in nIgG4-ROD. IgG4-ROD patients had higher serum IgG4 levels, IgG4/IgG ratio, IgE levels, and lower CRP levels. The initial glucocorticoid plus immunosuppressant was a protective factor for IgG4-ROD relapse. IgG4-ROD patients treated with initial glucocorticoid plus immunosuppressant had longer relapse-free survival time than patients treated with initial glucocorticoid monotherapy.ConclusionsIgG4-ROD patients had distinctive clinical features compared with nIgG4-ROD patients. The initial glucocorticoid plus immunosuppressant was a protective factor for IgG4-ROD relapse, which could prolong the relapse-free survival time of IgG4-ROD patients. These findings may have important implications for understanding and management of IgG4-ROD.

T-B cell epitope peptides induce protective immunity against Mycoplasma pneumoniae respiratory tract infection in BALB/c mice

Mycoplasma pneumoniae is the most common pathogen of community-acquired pneumonia in humans. Due to its high rates of antibiotic resistance, vaccination has become the best method to control the dissemination of M. pneumoniae. The recombinant carboxyl terminus of the P1 (P1C) protein is an immunodominant antigen, but it has negative effects such as poor stability and lower purity. In the current study, T-B epitopes of the P1C protein were predicted according to bioinformatics analysis and assessed for efficacy in peptide vaccination. BALB/c mice were subcutaneously inoculated with the T-B epitope peptides four times and then infected with M. pneumoniae through the respiratory tract. The results showed that the T-B epitope peptides of the P1C protein (P1C103-117, P1C155-169, P1C224-238 and P1C244-258) induced strong antigen-specific serum antibody responses and cellular immune responses with high levels of serum IgG, IgA antibodies and Th1-biased (IFN-γ and IL-2) cytokines. Immunization with T-B epitope peptides significantly reduced the M. pneumoniae burden and the degree of inflammation in the challenged mice. Furthermore, the levels of IFN-γ and TNF-α in the supernatants of lung homogenates were observably reduced compared to those in the PBS group. Overall, our findings demonstrate that T-B epitopes (P1C103-117, P1C155-169, P1C224-238 and P1C244-258) play significant roles in the P1C protein and can be used to induce powerful humoral and cellular immune responses to provide significant protection against M. pneumoniae pulmonary infection, which provides new insight into the design of potential multiepitope vaccines to prevent host infection by M. pneumoniae.

IgG4-related gastric disease with plasma cell-rich obliterative arteritis accompanied by early-stage gastric cancer: a case report

BackgroundImmunoglobulin G4-related disease (IgG4-RD) is an immune-mediated inflammatory disorder that can involve multiple organs. It is characterized by IgG4-positive plasma cell-rich storiform fibrosis and obliterative phlebitis associated with a high serum IgG4 level. There are few reports of gastric IgG4-RD, especially those detected prior to systemic or other organ involvement.Case presentation: A 70-year-old man was diagnosed with type 0–IIc gastric cancer at the anterior wall of the gastric corpus by upper gastrointestinal endoscopy. In addition, a submucosal tumor (SMT) 7 mm in diameter was found at the greater curvature of the angulus. Laparoscopic distal gastrectomy with regional lymph node dissection was performed. Pathology revealed a poorly differentiated adenocarcinoma in the type 0–IIc lesion and storiform fibrosis with infiltration of a large number of IgG4-positive plasma cells in the SMT. Postoperative laboratory testing showed elevation of serum IgG4 levels; thus, we diagnosed the SMT as IgG4-RD. Intriguingly, the gastric IgG4-RD lesion demonstrated IgG4-positive plasma cell-rich arteritis as well as typical obstructive phlebitis. The patient has been followed for 2 years after surgery without recurrence of cancer, but skin lesions of IgG4-RD have appeared.ConclusionWe report a rare case of IgG4-RD presenting as a gastric SMT, accompanied by early-stage gastric cancer. Our case may support a newly proposed relationship between IgG4-RD and malignancies. The gastric IgG4-RD lesion showed arteritis as well as obliterative phlebitis, potentially providing novel insight into IgG4-related vascular lesions.

Evaluation of controlled attenuation parameter in assessing hepatic steatosis in patients with autoimmune liver diseases.

BACKGROUNDHepatic steatosis commonly occurs in some chronic liver diseases and may affect disease progression.AIMTo investigate the performance of controlled attenuation parameter (CAP) for the diagnosis of hepatic steatosis in patients with autoimmune liver diseases (AILDs).METHODSPatients who were suspected of having AILDs and underwent liver biopsy were consistently enrolled. Liver stiffness measurement (LSM) and CAP were performed by transient elastography. The area under the receiver operating characteristic (AUROC) curve was used to evaluate the performance of CAP for diagnosing hepatic steatosis compared with biopsy.RESULTSAmong 190 patients with biopsy-proven hepatic steatosis, 69 were diagnosed with autoimmune hepatitis (AIH), 18 with primary biliary cholangitis (PBC), and 27 with AIH-PBC overlap syndrome. The AUROCs of CAP for the diagnosis of steatosis in AILDS were 0.878 (0.791-0.965) for S1, 0.764 (0.676-0.853) for S2, and 0.821 (0.716-0.926) for S3. The CAP value was significantly related to hepatic steatosis grade (P < 0.001). Among 69 patients with AIH, the median CAP score was 205.63 ± 47.36 dB/m for S0, 258.41 ± 42.83 dB/m for S1, 293.00 ± 37.18 dB/m for S2, and 313.60 ± 27.89 dB/m for S3. Compared with patients with nonalcoholic fatty liver disease (NAFLD) presenting with autoimmune markers, patients with AIH concomitant with NAFLD were much older and had higher serum IgG levels and LSM values.CONCLUSIONCAP can be used as a noninvasive diagnostic method to evaluate hepatic steatosis in patients with AILDs. Determination of LSM combined with CAP may help to identify patients with AIH concomitant with NAFLD from those with NAFLD with autoimmune phenomena.

Autoimmune pancreatitis: Current perspectives.

Over the last two decades, our knowledge and understanding regarding the pathogenesis and biology of autoimmune pancreatitis (AIP) have improved tremendously. Type 1 AIP or IgG4-related pancreatitis (IgG4-RP) is now believed to be the prototype of the multisystemic IgG4-related disease. In view of clinical features like obstructive jaundice and mass-forming lesions in the pancreas in elderly men, type 1 AIP often mimics pancreatic cancer. IgG4-related sclerosing cholangitis concomitantly involving the extrahepatic and intrahepatic biliary tree is the most common extrapancreatic involvement seen in up to 80% of these patients, which needs to distinguish from cholangiocarcinoma. Histology is characterised by lymphoplasmacytic inflammation, abundant IgG4 positive plasma cell infiltration, storiform fibrosis and obliterative phlebitis. Apart from histology, high serum IgG4 levels, pancreatic parenchymal and duct imaging findings and other organ involvement aid in diagnosis especially in cases where definitive histology is not evident. Also, these parameters lay the foundation of various diagnostic criteria proposed over last few years. On the contrary, histology alone is the mainstay for establishing diagnosis of idiopathic duct-centric pancreatitis (IDCP) as it lacks any specific serological marker or imaging. Since both types of AIP respond dramatically to corticosteroid treatment, a biopsy is crucial to establish the preoperative diagnosis and to exclude malignancy so as to avoid unnecessary surgery. This review discusses the morphologic spectrum, treatment and prognosis of IgG4-RP and IDCP with an emphasis on approach to diagnosis with relevant histologic features, differential diagnoses and the challenges faced during biopsy interpretation.

Safety, Efficiency and Treatment Satisfaction in Children with Primary Immunodeficiency Receiving Subcutaneous Immunoglobulin Treatment

OBJECTIVEPatients with Inborn Errors of Immunity, also known as Primary Immunodeficiency (PID), are prone to recurrent bacterial infections and these patients often require lifelong IgG replacement therapy. The aim of this presentation is to evaluate the efficacy, safety, and patient satisfaction in PID patients receiving subcutaneous immunoglobulin (SCIG) treatment and to share our expe-riences.METHODSTwenty-one patients who were followed up with the diagnosis of PID by our Pediatric Allergy and Immunology Clinic and received regular intravenous immunoglobulin therapy (IVIG) befo-re starting SCIG treatment were included in the study.RESULTSA total of 21 patients were included in the study. 10 of the patients (47.6%) were female, 11 (52.4%) were male, and the mean age was 8.8±4.42 years. Five of the patients were Syrian patients living in the refugee camp. Threshold IgG levels of the patients were evaluated every 3 months. IgG levels were significantly higher than baseline IVIG levels at weeks 3, 6, and 12 of SCIG treatment, respectively. There was no significant difference between 3rd, 6th and 12th months of SCIG treatment. A statistically significant decrease was observed in the frequency of infections in patients who received SCIG treatment (p=0.003). During SCIG treatment, the total infection rate was 4.1/person/year. According to the TSQM-9 satisfaction questionnaire, the annual hospitalization rate was 0.9/patient/year for IVIG and 0.4/patient/year for SCIG (p>0.005), and 61.9% of patients were moderately satisfied, 14.2%. 19% were very satisfied and 4.7% were not satisfied with the treatment. When the satisfaction criteria were evaluated, it was observed that the patients mostly (71%) were satisfied with the absence of vascular access prob-lems and the comfort of self-application at home.CONCLUSIONSCIG therapy causes high serum IgG levels and a reduced frequency of infections and can be a safe, effective, and well-tolerated treatment alternative in patients with PID with high patient satisfaction.

Follow-up with serum IgG4-monitoring in 8 patients with IgG4-related disease diagnosed by a lacrimal gland mass.

The diagnostic criteria for IgG4-related disease were previously published and serum IgG4 measurement has been reimbursed by national health insurance in Japan since 2012. Eight patients diagnosed with IgG4-related disease based on lacrimal gland masses were retrospectively reviewed. The 8 patients were 3 men and 5 women ranging in age from 52 to 77 (median, 63) years at the initial visit and their follow-up period ranged from 0.25 to 11 (median, 7) years. Bilateral and unilateral involvement were noted in 4 patients each; 2 on the right side and 2 on the left side in those with unilateral involvement. Serum IgG4 was high in 5 of 8 patients at the initial visit. Five patients with no systemic signs were followed without treatment, whereas oral steroids were administered and tapered in the other 3 patients who exhibited systemic signs. One patient with a history of radiation for MALT lymphoma in bilateral lacrimal glands developed IgG4-related disease in the left lacrimal gland 10 years later and was followed without treatment. Nine years later, her serum IgG4 level increased to 1500 mg/dL and paracardiac lesions, found on positron emission tomography, were confirmed to be MALT lymphoma by needle biopsy, leading to systemic chemotherapy. The other 7 patients had neither local recurrence nor additional systemic signs. Serum IgG4 monitoring may be useful to detect systemic complications in IgG4-related ophthalmic disease and markedly high serum IgG4 levels may indicate new lymphoma at other sites.

Intranasal Delivery of Inactivated Influenza Virus and Poly(I:C) Adsorbed Corn-Based Nanoparticle Vaccine Elicited Robust Antigen-Specific Cell-Mediated Immune Responses in Maternal Antibody Positive Nursery Pigs.

We designed the killed swine influenza A virus (SwIAV) H1N2 antigen (KAg) with polyriboinosinic:polyribocytidylic acid [(Poly(I:C)] adsorbed corn-derived Nano-11 particle based nanovaccine called Nano-11-KAg+Poly(I:C), and evaluated its immune correlates in maternally derived antibody (MDA)-positive pigs against a heterologous H1N1 SwIAV infection. Immunologically, in tracheobronchial lymph nodes (TBLN) detected enhanced H1N2-specific cytotoxic T-lymphocytes (CTLs) in Nano-11-KAg+Poly(I:C) vaccinates, and in commercial vaccinates detected CTLs with mainly IL-17A+ and early effector phenotypes specific to both H1N2 and H1N1 SwAIV. In commercial vaccinates, activated H1N2- and H1N1-specific IFNγ+&TNFα+, IL-17A+ and central memory T-helper/Memory cells, and in Nano-11-KAg+Poly(I:C) vaccinates H1N2-specific central memory, IFNγ+ and IFNγ+&TNFα+, and H1N1-specific IL-17A+ T-helper/Memory cells were observed. Systemically, Nano-11-KAg+Poly(I:C) vaccine augmented H1N2-specific IFNγ+ CTLs and H1N1-specific IFNγ+ T-helper/Memory cells, and commercial vaccine boosted H1N2- specific early effector CTLs and H1N1-specific IFNγ+&TNFα+ CTLs, as well as H1N2- and H1N1-specific T-helper/Memory cells with central memory, IFNγ+&TNFα+, and IL-17A+ phenotypes. Remarkably, commercial vaccine induced an increase in H1N1-specific T-helper cells in TBLN and naive T-helper cells in both TBLN and peripheral blood mononuclear cells (PBMCs), while H1N1- and H1N2-specific only T-helper cells were augmented in Nano-11-KAg+Poly(I:C) vaccinates in both TBLN and PBMCs. Furthermore, the Nano-11-KAg+Poly(I:C) vaccine stimulated robust cross-reactive IgG and secretory IgA (SIgA) responses in lungs, while the commercial vaccine elicited high levels of serum and lung IgG and serum hemagglutination inhibition (HI) titers. In conclusion, despite vast genetic difference (77% in HA gene identity) between the vaccine H1N2 and H1N1 challenge viruses in Nano-11-KAg+Poly(I:C) vaccinates, compared to over 95% identity between H1N1 of commercial vaccine and challenge viruses, the virus load and macroscopic lesions in the lungs of both types of vaccinates were comparable, but the Nano-11-KAg+Poly(I:C) vaccine cleared the virus from the nasal passage better. These data suggested the important role played by Nano-11 and Poly(I:C) in the induction of polyfunctional, cross-protective cell-mediated immunity against SwIAV in MDA-positive pigs.

IgG4-related disease: a contemporary review

Background/aimImmunoglobulin G4-related disease (IgG4-RD), is an immune-mediated fibroinflammatory condition, which may involve multiple organs and mostly presents with high serum IgG4 levels and specific histopathological characteristics. As IgG4-RD is a relatively new entity the etiology, prevalence and epidemiologic knowledge is quite limited. Although involvement of almost all anatomical regions has been reported, the most commonly affected regions are pancreas, lacrimal glands, salivary glands, retroperitoneum, orbita, lymph nodes, kidney and lungs. Diagnosis is made with combined evaluation of clinical, radiological and histopathological findings. Typical histopathological features include storiform fibrosis, dense lymphoplasmacytic infiltrates and obliterative phlebitis. Its course is typically marked by remission and relapsing attacks and it may lead to fibrosis, destructive lesions in tissues and organ failure unless promptly treated. In the treatment of IgG4-RD, many approaches including surgical resection of tissues, systemic glucocorticoids, steroid-sparing immunosuppressive drugs, and biological agents are employed. Although association is not clear, malignancies are frequently reported in IgG4-RD patients. Therefore, it is prudent to monitor patients for the symptoms of malignant diseases.ConclusionIn this review, recent advances in clinico-pathological characteristics, diagnosis, and treatment of IgG4–RD are discussed.

Immune responses in mice vaccinated with a DNA vaccine expressing a new elastase from Trichinella spiralis

The elastase, which belongs to the serine protease family, hydrolyses various proteins and may be involved in the parasite invasion. In this study, complete sequence of elastase-1 (TsE) the nematode Trichinella spiralis (Owen, 1835) was cloned into the plasmid pcDNA3.1 as TsE DNA vaccine. After intramuscular vaccination, serum anti-Trichinella antibodies (IgG and subclass IgG1/IgG2a, and IgA), total and specific intestinal mucosal sIgA in mice vaccinated with pcDNA3.1/TsE were measured by ELISA. The results showed that vaccination with pcDNA3.1/TsE induced a systemic humoral immune response (high levels of serum IgG and subclass IgG1/IgG2a and IgA) and local intestinal mucosal immune responses (high levels of TsE-specific sIgA). Vaccination of mice with TsE DNA vaccine also triggered a systemic and local concomitant Th1/Th2 response, as demonstrated by significant elevation of Th1 (IFN-γ and IL-2) / Th2 (IL-4 and IL-10) cytokine levels after the spleen, mesenteric lymph node and Peyer's patch cells from vaccinated mice were stimulated with recombinant TsE (rTsE). The vaccination of mice with pcDNA3.1/TsE displayed a 17% reduction of intestinal adult worms and a 39% reduction of muscle larvae. Our results indicated that TsE DNA vaccine elicited a systemic concomitant Th1/Th2 response and an enteral local sIgA response, and produced a partial protection against infection with T. spiralis. The TsE may be regarded as a potential candidate vaccine target against Trichinella infection. The oral polyvalent vaccines should be developed to improve the protective efficacy of anti-Trichinella vaccines.

S1782 IgG4 Colitis and Infliximab Therapy

INTRODUCTION: Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition. It is characterized by increased serum levels of IgG4 and tissue infiltration by IgG4 cells. It can involve multiple organs and if untreated the disease can lead to fibrosis and irreversible organ damage. IgG4-RD has mostly been described in adults and it's exact prevalence in pediatrics is unknown. We report a pediatric case of IgG4-positive sclerosing colitis who had dramatic response to Infliximab therapy. CASE DESCRIPTION/METHODS: 6 year old adopted male who was previously healthy presented to ER with acute onset of severe abdominal pain and fever. He was febrile with severe RLQ tenderness, guarding and minimal bowel sounds. Labs showed elevated WBC and CRP. US abdomen study did not visualize appendix. Subsequent MRI abdomen showed descending colitis with no evidence of obstruction, abscess or acute appendicitis. He soon developed abdominal distension and multiple episodes of bilious emesis. AXR obtained showed dilated loops of small bowel concerning for partial SBO, requiring NGT decompression. Stool studies including C. Diff returned negative. As he developed a SIRS picture with worsening abdominal distension, stat CT abdomen obtained showed bowel dilation without an obvious transition zone or pneumatosis but thickening of terminal ileum and left colon. Due to patient's worsening clinical picture, there was concern for possible compromised bowel or distal bowel obstruction not diagnosed by imaging, hence he underwent diagnostic ex-laparoscopy which showed thickening and inflammation of the left colon leading to segmental left colon resection and descending colostomy. Biopsies were taken and immunostaining was concerning for an IgG4 sclerosis colitis. Serum IgG4 level was elevated at 202. Patient was started on steroids followed by Infliximab as maintenance therapy. Repeat EGD/Colonoscopy prior to colostomy reversal showed normal biopsies and immunostaining. He responded well to Infliximab therapy with subsequent normal serum IgG4 levels. DISCUSSION: The pathogenesis of IgG4-RD remains incompletely understood. Study shows that small subset of patients with IBD can be characterized by high levels of serum and mucosal IgG4. These patients are generally prone to more severe and extensive lesions suggesting that high level of IgG4 may be a biomarker for a new subtype of IBD. The current literature in this area is sparse. Our case showed positive response to Infliximab therapy in IgG4 positive colitis.

Molecular characterization of a Trichinella spiralis serine proteinase

The aim of this study was to investigate the biological characteristics and functions of a Trichinella spiralis serine proteinase (TsSerp) during larval invasion and development in the host. The full-length TsSerp cDNA sequence was cloned and expressed in Escherichia coli BL21. The results of RT-PCR, IFA and western blotting analyses showed that TsSerp was a secretory protein that was highly expressed at the T. spiralis intestinal infective larva and muscle larva stages and primarily located at the cuticle, stichosome and intrauterine embryos of the parasite. rTsSerp promoted the larval invasion of intestinal epithelial cells (IECs) and the enteric mucosa, whereas an anti-rTsSerp antibody impeded larval invasion; the promotion and obstruction roles were dose-dependently related to rTsSerp and the anti-rTsSerp antibodies, respectively. Vaccination of mice with rTsSerp elicited a remarkable humoral immune response (high levels of serum IgG, IgG1/IgG2a, IgE and IgM), and it also triggered both systemic (spleen) and local intestinal mucosal mesenteric lymph node (MLN) cellular immune responses, as demonstrated by a significant elevation in Th1 cytokines (IFN-γ) and Th2 cytokines (IL-4) after the spleen and MLN cells from vaccinated mice were stimulated with rTsSerp. Anti-TsSerp antibodies participated in the killing and destruction of newborn larvae via ADCC. The mice vaccinated with rTsSerp exhibited a 48.7% reduction in intestinal adult worms and a 52.5% reduction in muscle larvae. These results indicated that TsSerp participates in T. spiralis invasion and development in the host and might be considered a potential candidate target antigen to develop oral polyvalent preventive vaccines against Trichinella infection.

Vaccination of Mice with a Novel Trypsin from Trichinella spiralis Elicits the Immune Protection against Larval Challenge.

Trichinella spiralis is a major foodborne parasite and has a serious threat to meat safety. Development of anti-Trichinella vaccines is prospective to eliminate Trichinella infection in food animal. The aim of this study was to assess the biological properties of a novel T. spiralis trypsin (TsT) and its elicited immune protection against larval challenge. The cDNA sequence of TsT gene was cloned and expressed. Western blotting showed rTsT was identified by infection serum and anti-TsT serum. RT-PCR results revealed that TsT gene was transcribed at diverse T. spiralis lifecycle stages. The IIFT results showed that natural TsT was principally expressed at epicuticle of 5-6 day adult worms, indicating that TsT is a worm somatic antigen and adult-stage specific surface antigen. Vaccination of mice with rTsT triggered an evident humoral immune response (high levels of serum IgG, IgG1/IgG2a, and enteral sIgA), and it also induced the systemic and enteral local cellular immune response, demonstrated by an significantly elevation of cytokines IFN-γ and IL-4. The mice vaccinated with rTsT exhibited a 33.17% reduction of enteral adult worms and a 37.80% reduction of muscle larvae after larval challenge. The results showed that TsT might be considered as a candidate target antigen for anti-T. spiralis vaccines.

Immunoglobulin G4 Related Lung Disease

Immunoglobulin G4 related disease (IgG4-RD) is a relatively newly defined disease known for multiple organ involvement. Histopathologically, the disease is characterized by lymphoplasmatic inflammation, fibrosis, and enhanced levels of IgG4-positive plasma cells in tissues. IgG4-RD has been reported in almost every organ system. With pulmonary involvement, lesions have been described in the lung parenchyma, airways, pleura, and the mediastinum. Glucocorticoids are the first choice of treatment, but additional immunosuppressive drugs may be administered in refractory patients. In this article, we report a patient with IgG4 syndrome who had lung parenchyma, mediastinum, aorta wall, and pancreatic involvement. Histopathological findings and high serum IgG4 level established the diagnosis of IgG4-related disease. The patient was treated successfully with glucocorticoids.

Abstract PR02: Glyphosate as a potential carcinogen for multiple myeloma

Abstract Glyphosate is the most commercially successful and the most widely used herbicide in the United States and worldwide. It represents about 50% of United States herbicide usage at approximately 250 million pounds annually; the annual use of glyphosate worldwide is about 1.8 billion pounds. There has been considerable debate around the carcinogenicity of glyphosate. IARC labeled glyphosate as “probably carcinogenic to humans.” However, other agencies like the EPA have maintained that glyphosate is unlikely to pose a carcinogenic risk. In epidemiologic studies on the association of cancer and glyphosate, only multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) have a positive and statistically significant association with glyphosate. MM is a plasma cell neoplasm and the second most common hematologic malignancy in the United States. Virtually all MM cases are preceded by a precursor condition, monoclonal gammopathy of undetermined significance (MGUS). MM is regarded as a disease with environmental causes, yet its etiology and what prompts progression remain largely unclear. We employed the Vk*Myc mouse model of MM to assess the impact of glyphosate exposure on MM pathogenesis. In both wild-type and Vk*Myc mice, glyphosate induced splenomegaly and multiple peripheral blood abnormalities, including anemia and high serum IgG levels, hallmarks of MGUS and MM in humans. In Vk*Myc mice, glyphosate triggered bone lytic lesions, as well as renal damage, a phenomenon associated with human MM kidney disease. Most importantly, glyphosate upregulated Aicda, which encodes the activation-induced cytidine deaminase (AID) in the spleen and bone marrow of both wild-type and Vk*MYC mice. AID mediates somatic hypermutation and class-switch recombination of immunoglobulin genes in B cells to produce diverse immunoglobins in secretive forms. Our data indicate that glyphosate accelerates MGUS development and promotes progression to MM in genetically predisposed mice. Given that AID dysregulation is a key pathogenic driver in both MM and NHL, this work offers the first direct experimental evidence establishing glyphosate as an environmental risk factor for MM and NHL. This abstract is also being presented as Poster A50. Citation Format: Yong Li. Glyphosate as a potential carcinogen for multiple myeloma [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr PR02.

IgG4 plasma cell myeloma: Clinicopathological characteristics and diagnosis.

Plasma cell myeloma (PCM) is usually associated with the presence of M-protein in the serum and urine of patients, and about half of the PCM cases exhibit the IgG M-protein and increased gamma-globulin fraction on membrane electrophoresis. The IgG4 subclass is located in the beta-2 fraction on membrane electrophoresis. The aim of this study was to develop a method to evaluate IgG4-producing PCM (IgG4-PCM) and its clinicopathological characteristics. We found three cases of IgG4-PCM among 80 cases of IgG-producing PCM by membrane electrophoresis, which were confirmed by IgG4 immunostaining. None of the cases had a clinical history of IgG4-related disease, although they exhibited high levels of serum IgG4. A bone marrow aspiration specimen had an increased number of plasma cells with a relatively mature morphology. No cases exhibited lymphoplasmacytic inflammation, obliterative phlebitis or fibrosis. Immunohistochemistry revealed that tumor cells expressed CD138 and IgG4 and showed monoclonal expression of kappa. We revealed that IgG4-PCM might not be associated with IgG4-related disease and that the detection of M-protein with beta-globulin fraction by electrophoresis may be useful for screening IgG4-PCM.

Immunity and autoantibodies of a mouse strain with autistic-like behavior

Female and male mice of the BTBR T+Itpr3tf/J (BTBR) strain have behaviors that resemble autism spectrum disorder. In comparison to C57BL/6 (B6) mice, BTBR mice have elevated humoral immunity, in that they have naturally high serum IgG levels and generate high levels of IgG antibodies, including autoantibodies to brain antigens. This study focused on the specificities of autoantibodies and the immune cells and their transcription factors that might be responsible for the autoantibodies. BTBR IgG autoantibodies bind to neurons better than microglia and with highest titer to nuclear antigens. Two of the antigens identified were alpha-enolase (ENO1) and dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial (DLST). Surprisingly based on IgG levels, the blood and spleens of BTBR mice have more CD4+ and CD8+ T cells, but fewer B cells than B6 mice. The high levels of autoantibodies in BTBR relates to their splenic T follicular helper (Tfh) cell levels, which likely are responsible for the higher number of plasma cells in BTBR mice than B6 mice. BTBR mice have increased gene expression of interleukin-21 receptor (Il-21r) and Paired Box 5 (Pax5), which are known to aid B cell differentiation to plasma cells, and an increased Lysine Demethylase 6B (Kdm6b)/DNA Methyltransferase 1 (Dnmt1) ratio, which increases gene expression. Identification of gene expression and immune activities of BTBR mice may aid understanding of mechanisms associated with autism since neuroimmune network interactions have been posited and induction of autoantibodies may drive the neuroinflammation associated with autism.