Elevated Serum IgG4 Research Articles

Enrichment of serum IgG4 in MuSK myasthenia gravis patients

Muscle-specific kinase (MuSK) myasthenia gravis (MG) is a neuromuscular autoimmune disease belonging to a growing group of IgG4 autoimmune diseases (IgG4-AIDs), in which the majority of pathogenic autoantibodies are of the IgG4 subclass. The more prevalent form of MG with acetylcholine receptor (AChR) antibodies is caused by IgG1–3 autoantibodies. A dominant role for IgG4 in autoimmune disease is intriguing due to its anti-inflammatory characteristics. It is unclear why MuSK autoantibodies are predominantly IgG4. We hypothesized that MuSK MG patients have a general predisposition to generate IgG4 responses, therefore resulting in high levels of circulating IgG4. To investigate this, we quantified serum Ig isotypes and IgG subclasses using nephelometric and turbidimetric assays in MuSK MG and AChR MG patients not under influence of immunosuppressive treatment. Absolute serum IgG1 was increased in both MuSK and AChR MG patients compared to healthy donors. In addition, only MuSK MG patients on average had significantly increased and enriched serum IgG4. Although more MuSK MG patients had elevated serum IgG4, for most the IgG4 serum levels fell within the normal range. Correlation analyses suggest MuSK-specific antibodies do not solely explain the variation in IgG4 levels. In conclusion, although serum IgG4 levels are slightly increased, the levels do not support ubiquitous IgG4 responses in MuSK MG patients as the underlying cause of dominant IgG4 MuSK antibodies.

S1787 Steroid-refractory IgG4-Related Disease Presenting as Sclerosing Cholangitis

Introduction: IgG4-related disease (IgG4-RD) is characterized by tumefactive infiltration of IgG4-bearing plasmablasts and other lymphocytes, along with storiform fibrosis, into one or multiple organs, with resultant organ enlargement, fibrosis, and dysfunction. Although initial reports of IgG4-RD concerned involvement of the pancreas, other organs such as the biliary tract can be involved. We present a case of steroid refractory IgG4- RD sclerosing cholangitis (IgG4-SC). Case Description/Methods: A 67-year-old man with hypertension presented with a 2-week history of unintentional weight loss, painless jaundice, and pruritus. Exam showed jaundice and scleral icterus. Laboratory revealed elevated liver tests with an obstructive pattern, with ALP, GGT, & Bilirubin of 431 U/L, 438 IU/L, 17.6mg/dL, respectively. MRCP, ERCP, and subsequent EUS demonstrated diffuse pancreatic parenchymal hypo-echogenicity, long segment strictures at the distal common bile duct with proximal duct dilation, dilated common hepatic duct, and multiple segmental intrahepatic biliary duct strictures. Biliary sphincterotomy and stent placement resolved symptoms. Biopsy of the Ampulla of Vater revealed chronic inflammation with ulceration. Further work-up uncovered an elevated serum IgG4 of 266 mg/dL with a negative ANA, SMA, AMA, and tumor markers. He was then diagnosed with IgG4-SC and completed a course of prednisone. Relapse of symptoms prompted a repeat ERCP which uncovered biliary tree pruning and irregularity, necessitating biliary stent replacement. Due to poor tolerance with rituximab infusion, he was treated with Mycophenolate Mofetil which accomplished a year of disease quiescence. Discussion: The prime gastrointestinal manifestations of IgG4-RD include type 1 Autoimmune Pancreatitis and less commonly, IgG4-SC. Management involves high dose steroids for 4 weeks with a slow taper over years to prevent permanent fibrosis. Patients are at highest risk of relapse during steroid taper or within 6 months of completion, with a relapse rate of 15-60%. Although our patient did not have the classic predictive factors of relapse, such as proximal strictures or serum IgG4 >280 mg/dL, he had a suboptimal response to steroids which prolonged his clinical course and exposed him to repeated procedures. There is still a need for further studies regarding the role for possible combination therapy (steroids & immunosuppressive therapy) to prevent relapse in high-risk individuals.

IGG4-RELATED DISEASE PRESENTING AS A PULMONARY INFLAMMATORY PSEUDOTUMOR

IGG4-RELATED DISEASE PRESENTING AS A PULMONARY INFLAMMATORY PSEUDOTUMOR

The role of serological biomarkers in the diagnosis and management of autoimmune pancreatitis

ABSTRACT Introduction Autoimmune pancreatitis (AIP) is a fibroinflammatory disease of the pancreas. Type 1 AIP is the pancreatic manifestation of a systemic IgG4-related disease and is associated with serum elevation of IgG4, tissue infiltration of IgG4-positive plasma cells, and multiorgan involvement. Although serum IgG4 elevation is considered a useful diagnostic tool, the concomitant presence of more diagnostic criteria is needed to achieve diagnosis. No other biomarkers have been approved in clinical practice in type 1 AIP. Type 2 AIP is a pancreatic-specific disease associated with inflammatory bowel disease. No specific biomarkers for type 2 AIP have been identified. Areas covered The role of serum IgG4 in the diagnosis, management and follow-up of patients with type 1 AIP. Moreover, data on other emerging biomarkers for type 1 and 2 AIP have been reported. Expert Opinion The diagnosis of AIP is challenging in clinical practice, especially for focal forms without multiorgan involvement, where distinction from pancreatic cancer can be difficult. Despite the strong association with type 1 AIP, serum IgG4 should only be measured when the suspicion for the disease is high, considering its limited sensitivity. New biomarkers with high diagnostic yield for both type 1 and type 2 AIP are needed.

The clinicopathological features of adult orbital xanthogranulomatous disease with lacrimal gland reactive lymphoid hyperplasia

Objective: To investigate the clinicopathological features of adult orbital xanthogranulomatous disease (AOXGD) with lacrimal gland reactive lymphoid hyperplasia. Methods: Retrospective case series study. The clinical and pathological data of AOXGD cases diagnosed and treated in Tianjin Eye Hospital from January 2002 to December 2021 was reviewed, and the clinical characteristics, radiologic findings and pathological characteristics of periocular and lacrimal gland lesions of 5 cases were retrospectively analyzed. The expression of IgG4 and IgG protein in periocular and lacrimal gland lesions was detected by immunohistochemical staining, and the role of IgG4 in AOXGD was preliminarily studied. Results: There were four females and one male with an average age of 53.8 years (39 to 77 years). Among the five AOXGD cases, there were three cases of adult-onset xanthogranuloma, one case of adult-onset asthma and periocular xanthogranuloma, and one case of necrobiotic xanthogranuloma. All cases involved both eyes. The swelling of eyelids was observed in five cases, and the yellow or pale yellow eyelid skin was found in two cases. Imaging examinations showed the tumor mainly involved the eyelids, subcutaneous tissues, anterior orbit and lacrimal gland. A large number of foam cells and typical Touton giant cells were found in the periorbital lesions, accompanied by different degrees of fibrosis. The fibrinoid necrosis was detected in one case of necrobiotic xanthogranuloma. The lacrimal gland lesions showed different types of reactive lymphoid hyperplasia, including IgG4-related disease in two cases, follicular lymphoid hyperplasia in two cases and focal lymphoid hyperplasia in one case. IgG4 levels of periorbital and lacrimal gland lesions were elevated in four cases. Asthma and elevated serum IgG4 were found in one case of adult-onset periocular xanthogranuloma. Three patients underwent surgical resection and adjuvant hormone or immunosuppressive therapy, and two patients underwent simple surgical resection. The patients were followed up for 1.5 to 10.0 years, one patient was lost, and four patients had no recurrence. Conclusions: AOXGD with lacrimal gland reactive lymphoid hyperplasia is a group of rare diseases. The periorbital lesions of that are characterized by proliferation of foamy histiocytes and Touton giant cells, and the lacrimal gland lesions of that manifest as IgG4-related disease in some cases.

Idiopathic Plasmacytic Lymphadenopathy Forms an Independent Subtype of Idiopathic Multicentric Castleman Disease.

Idiopathic multicentric Castleman disease (iMCD) is a type of Castleman disease that is not related to KSHV/HHV8 infection. Currently, iMCD is classified into iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) and iMCD-NOS (not otherwise specified). The former has been established as a relatively homogeneous disease unit that has been recently re-defined, while the latter is considered to be a heterogeneous disease that could be further divided into several subtypes. In 1980, Mori et al. proposed the concept of idiopathic plasmacytic lymphadenopathy (IPL), a disease presenting with polyclonal hypergammaglobulinemia and a sheet-like proliferation of mature plasma cells in the lymph nodes. Some researchers consider IPL to be a part of iMCD-NOS, although it has not been clearly defined to date. This is the first paper to analyze iMCD-NOS clinicopathologically, to examine whether IPL forms a uniform disease unit in iMCD. Histologically, the IPL group showed prominent plasmacytosis and the hyperplasia of germinal centers, while the non-IPL group showed prominent vascularity. Clinically, the IPL group showed significant thrombocytosis and elevated serum IgG levels compared to the non-IPL group (p = 0.007, p < 0.001, respectively). Pleural effusion and ascites were less common in the IPL group (p < 0.001). The IPL group was more likely to have an indolent clinical course and a good response to the anti-IL-6 receptor antibody, while the non-IPL counterpart frequently required more aggressive medical interventions. Thus, the IPL group is a clinicopathologically uniform entity that forms an independent subtype of iMCD.

Clinical Characteristics and Potential Mechanisms in Patients with Abnormal Liver Function Indices and Elevated Serum IgG4.

We analyzed the etiological classification and clinical characteristics of patients with abnormal liver function indices and elevated serum IgG4 levels and investigated the effects of intrahepatic follicular helper T cell (Tfh) infiltration and serum IL-21. Clinical data (age, sex, past history, clinical manifestations, laboratory tests, imaging, diagnosis, and treatment) and etiology of liver injury from 136 patients were analyzed. We compared the general condition, clinical characteristics, and laboratory tests of 19 AIH (autoimmune hepatitis) patients with elevated serum IgG4 levels with those of 20 AIH patients with normal serum IgG4 levels admitted at the same time. Five patients with AIH and elevated serum IgG4 levels and five AIH patients with normal IgG4 levels were matched by sex, age, and liver function, and Tfh infiltration in liver biopsy tissues of patients in both groups was determined by immunofluorescence staining. Five AIH patients with elevated serum IgG4 levels were selected for measurement of serum interleukin-21 (IL-21) levels by enzyme-linked immunosorbent assay (ELISA), seventeen AIH patients with normal serum IgG4 were matched by sex, age, and liver function indices, and 29 physically healthy individuals matched by sex and age were selected as the control group. The changes in patients with IgG4-RD and abnormal liver function before and after glucocorticoid treatment were measured. Patients (136) with abnormal liver function indices and elevated serum IgG4 levels were diagnosed with liver disease of different etiologies. IgG4-related disease was the most frequent, followed by AIH and malignancy. Abnormal liver function indices with high serum IgG4 were most commonly seen as elevated gamma glutamyl transferase (GGT). The AIH group with elevated serum IgG4 had increased intrahepatic levels of Tfh. IL-21 in AIH patients with elevated IgG4 was higher than in patients with normal IgG4 and healthy controls. Patients (n = 28) with abnormal liver function indices and IgG4-related disease received glucocorticoid therapy for six months, and ALT, AST, ALKP, GGT, TBil, DBil, IgG, IgG4, and IgE were significantly lower after treatment. Elevated serum IgG4 was seen in patients with abnormal liver function indices with diverse causes. Tfh infiltration and increased IL-21 production may be related to the pathogenesis of AIH with elevated serum IgG4. Glucocorticoid therapy is effective in patients with abnormal liver function indices and IgG4-related disease. Assessing immune function in patients with abnormal liver function indices and elevated serum IgG4 levels should facilitate diagnosis and treatment of the disease.

Evaluation of SARS-CoV-2 Serum Level in Patients Vaccinated With Sinopharm/BBIBP-CorV With Kidney Transplantation

BackgroundEvery year, a large number of people undergo kidney transplants because of various reasons leading to renal failure. These patients usually have low immunoglobulin levels due to the use of immunosuppressive drugs. In recent years, the COVID-19 pandemic has been a major global health risk. Patients who are immunocompromised or who have diabetes are especially at risk.MethodsIn this study, we enrolled 156 patients who had undergone kidney transplant and had received 2 doses of Sinopharm/BIBP-CorV. The serum antibody levels against COVID-19 spike glycoprotein (immunoglobulin [Ig] G and IgM) were measured using a sandwich enzyme-linked immunosorbent assay kit to evaluate whether different immunosuppressive drugs could affect the body's response to the said vaccine.ResultsWe found that only patients receiving Rapamune had increased IgM secondary to COVID-19 vaccine. None of the immunosuppressive drugs in this study have shown a positive correlation with increased IgG levels. The only factor that showed a significant effect on both IgM and IgG was a positive history of COVID-19, which was correlated with increased levels of serum IgG/M.ConclusionsOnly patients treated with Rapamune showed an acute immune reaction to the vaccine in the form of positive serum IgM levels, and no rise of serum IgM antibody was observed in COVID-19-naive patients. Patients who had a previous history of COVID-19 infection showed an elevated serum IgM and IgG level, suggesting that vaccines in general and Sinopharm/BIBP-CorV in particular are not enough to ensure immunity against COVID-19 in transplant recipients. We recommend further studies using different types of vaccines and immunosuppressive drugs.

Multi-System Langerhans Cell Histiocytosis as a Mimic of IgG4-Related Disease: A Case Report and Literature Review

Langerhans cell histiocytosis (LCH) is a rare disease characterized by the clonal accumulation and/or proliferation of specific dendritic cells resembling normal epidermal Langerhans cells (LCs). Clinical manifestations are variable, depending on the affected tissues or organs, however, LCH with elevated serum IgG4 has not been reported. Herein, we reported a 26-year-old Chinese female multi-system LCH (MS-LCH) who first presented with central diabetes insipidus (CDI), accompanied by panhypopituitarism and hepatic dysfunction. Diagnostic investigations were strongly suspicious of IgG4-RD because of elevated serum IgG4 levels during the process. Furtherly, thyroid and lymph node involvement and biopsy led to the diagnosis of MS-LCH; the strongly positive staining of CD1a, S100, CD207 (langerin), and Ki67 was found. Moreover, after systemic treatment with five cycles of chemotherapy, many lesions were greatly improved. Since both LCH and IgG4-RD are orphan diseases that can affect any organ, the differential diagnosis is challenging, especially when LCH is associated with unexplained serum IgG4 elevation. In this article, the case of a young woman suffering from MS-LCH that affected organs including the pituitary, thyroid, lymph node, and liver was summarized, and relevant literature was reviewed to better equip the diagnosis and treatment in its early stages.

Autoimmune Pancreatitis with Gastric Cancer: Some IgG4-related Diseases May Be Paraneoplastic Syndrome

A 70-year-old man was referred to our department for the treatment of early gastric cancer. Contrast-enhanced computed tomography (CT) incidentally showed diffuse enlargement of the pancreas with a capsule-like rim, and blood tests showed elevated serum IgG4 levels, leading to a diagnosis of autoimmune pancreatitis (AIP). Endoscopic treatment for gastric cancer was performed, and pathological findings showed adenocarcinoma with abundant IgG4-positive plasma cell infiltration. Thereafter, the serum IgG4 levels normalized, and the findings of AIP disappeared on CT without steroid treatment. These findings suggest that the gastric cancer activated an IgG4-related immune response, resulting in the development of AIP.

Risk factors for IgG4‐related disease relapse: A systematic review and meta‐analysis

AbstractIgG4‐related disease (IgG4‐RD) is an autoimmune disease involving multiple organs with unique pathological features and has high relapse rates after treatment. Identifying patients at high risk of disease relapse for targeted treatment with long‐term and low‐dose glucocorticoid maintenance therapy is crucial for formulating rational treatment strategies. In this study, we conducted a meta‐analysis of relevant articles to explore the risk factors for IgG4‐RD relapse. We searched the Medline (via PubMed), EMBASE, Web of Science and Cochrane Library databases and extracted the mean and standard deviation of continuous variables and true‐positive (TP), false‐positive (FP), false‐negative (FN) and true‐negative (TN) rates to construct a 2 × 2 contingency table from dichotomous variables, and hazard ratios (HRs) were calculated from univariate and multivariate analyses. Finally, we identified five indicators (elevated baseline serum IgG4 level, eosinophil count, increased multiple organ involvement, history of allergy and proximal bile duct stenosis) as risk factors for IgG4‐RD relapse. These results provide new ideas and directions for more researchers to study the relapse of IgG4‐RD and offer reasonable suggestions for clinicians to select IgG4‐RD patients for low‐dose glucocorticoid maintenance therapy to reduce their relapse rates.

IgG4-related disease is characterised by the overexpression of immunomodulatory proteins.

Immunoglobulin 4-related disease (IgG4-RD) is a multisystem disease, characterised by tumefactive lesions and a swift response to immunosuppressive therapy. Although elevated serum and tissue IgG4 are characteristic, T cells appear to be the primary driver of this immunologically mediated disease. The overarching goal was to examine the role of immunomodulatory cells in IgG4-RD. Biopsies from patients with IgG4-RD (n = 39) and mimics of this disease (n = 78) were evaluated for IgG4, IgG, CD8, programmed cell death ligand 1 (PD-L1) and a subset (n = 18) evaluated for CD4, purine rich box 1 (PU.1), forkhead box protein 3 (FoxP3), PD-L1, programmed cell death 1 (PD-1), indoleamine 2,3-dioxygenase 1 (IDO1) and lymphocyte-activation gene 3 (LAG3). Data pertaining to demographics and laboratory findings at baseline evaluation was extracted from electronic medical records. When compared to mimics, IgG4-RD showed increased numbers of PD-L1- (P = 0.0001), PD-1- (P = 0.001), IDO1- (P = 0.03), LAG3- (P = 0.04) and FoxP3- (P = 0.04)-positive immune cells. The PD-L1-positive cells were enriched within aggregates of CD4 and CD8-positive T cells. Thirty-one of 39 (80%) IgG4-RD cases showed greater than five PD-L1-positive cells per high-power field (HPF), while four of 78 (5%) mimics of this disease exceeded this cut-point. In IgG4-RD, PD-L1-positive macrophages correlated with PD-1- (P = 0.002), LAG3- (P = 0.001) and IDO1-positive cells (P = 0.001); a-positive correlation was also noted between IgG4/IgG ratio and PD-L1-, PD-1- and IDO1-positive cells. IgG4-RD shows expansion of mechanisms that maintain peripheral tolerance. The spatial and temporal relationship between T cells and the PD-L1-PD-1 axis and the up-regulation of multiple immunomodulatory proteins suggests that these immunoregulatory mechanisms play a significant role in IgG4-RD.

A Case of Hepatic Immunoglobulin G4-Related Disease Presenting as an Inflammatory Pseudotumor and Sclerosing Cholangitis.

An inflammatory pseudotumor is a benign disease characterized by tumor-like lesions consisting of inflammatory cells including plasma cells and fibrous tissue. Recently, some inflammatory pseudotumor cases proved to be a form of Immunoglobulin G4-related disease (IgG4-RD). This novel clinical entity, recognized as a fibroinflammatory condition, is characterized by lymphoplasmacytic infiltration with a predominance of IgG4-positive plasma cells, storiform fibrosis, and often elevated serum IgG4 concentrations. We report a case of IgG4-RD in the form of an inflammatory pseudotumor in the liver with combined sclerosing cholangitis. We recommend that for diagnosing IgG4-RD accurately, it is important to obtain adequate tissue samples and follow-up the lesion in clinical practice.

Hyperphosphatemia: A Clue to Diagnosis

Serum phosphate level reference range in adults is 2.5 mg/dL to 4.5 mg/dL and in children is 3 mg/dL to 6 mg/dL. The causes of hyperphosphatemia fall into four categories. These are decreased renal excretion of phosphorus, exogenous phosphorus administration, redistribution of phosphorus, and pseudohyperphosphatemia. We report a 69-year-old gentleman presented with the history of swelling of feet and facial puffiness of 1 month duration. He had renal failure with normal sized kidneys. Serum phosphorus was high. Advanced investigations revealed plasma cell proliferative disorder (clonal bone marrow plasma cells &gt;10%) on bone marrow examination, presence of M band at the junction of beta-2 and gamma region, and elevated serum IgG and serum beta-2 microglobulin. Hyperphosphatemia in multiple myeloma may be true, or pseudohyperphosphatemia. Diligent history, examination, and investigations have yielded the possibility of pseudohyperphosphatemia owing to multiple myeloma in our patient. The interference with the phosphomolybdate ultraviolet assay for serum phosphorus estimation is one of the reasons of pseudohyperphosphatemia in multiple myeloma. The other mechanism of pseudohyperphosphatemia could be the direct binding of paraprotein to phosphorus.

Immunoglobulin G4-related disease presenting with hypertrophy and sclerosis of the inferior turbinate.

Immunoglobulin G4-related disease (IgG4-RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4+ plasma cells.1 We report the case of a 56-year-old man who presented with nasal obstruction for 5 years. Rhinoscopy revealed hypertrophy and sclerosis of the inferior turbinate, whereas computed tomography revealed inflammation of the anterior ethmoid sinus and frontal sinuses. An endoscopic inferior turbinectomy was performed, and IgG4-RD was definitively diagnosed based on the histopathological features of the turbinate tissue. Prednisolone was administered postoperatively. IgG4-RD presenting with hypertrophy and sclerosis of the inferior turbinate is rare. Awareness of IgG4-RD originating in the sinonasal cavity is essential to avoid delayed diagnosis.

MO1033: Kidney and Bone Marrow Involvement in Ipex Syndrome with Atypical Presentation: the ‘Fil Rouge’ of Treg Between Ipex Features and Other Clinical Entities

Abstract BACKGROUND AND AIMS The transcription factor Forkhead box protein P3 (FOXP3) is central to the function of regulatory T cells (Treg). Mutations in the FOXP3 gene lead to a systemic disease called immune dysregulation, polyendocrinopathy and enteropathy, X-linked syndrome (IPEX). Some FOXP3 mutations were associated with atypical presentation including rare diseases such as IgG4 related disease (IgG4 RD) and autoimmune lymphoproliferative syndrome (ALPS). IgG4 RD is characterized by fibro-inflammatory tissue damage and often by elevated serum IgG4, whereas ALPS is presented by early-onset, chronic, nonmalignant lymphoproliferation, splenomegaly and autoimmune manifestations due to defective lymphocyte apoptosis, due mainly to mutation of genes involved in the apoptosis pathway. Kidney involvement in ALPS is uncommon, whereas in IPEX and IgG4 RD is more frequent, with different renal manifestations. METHOD We reported two atypical cases of IPEX characterized by the kidney and haematologic involvement. These cases are anecdotal for the wide spectrum of possible phenotypes associated with FOXP3 mutations. RESULTS Case 1. A 16-year male with clinical diagnosis of ALPS was treated with an mTOR inhibitor. Due to the onset of proteinuria until 650 mg/day and estimated glomerular filtration rate (eGFR) 66 mL/min, a kidney biopsy was performed and light microscopy showed a membranous pattern. The M-type phospholipase A2 receptor (PLA2R) on serum was negative as well as immunofluorescence (IF) on tissue. IgG-IgG4 immunohistochemical (IHC) staining was negative. We decided to re-evaluate the genetics of the patient, implementing the HPO (Human Phenotype Ontology) code. We found a mutation of the FOXP3 gene (NM_014009.3): c.779T &amp;gt; A (p.L260Q), never reported before on the GnomAD database and predicted to be ‘Likely Pathogenic’ by the suite of variant annotation. The patient does not present the classical triad of IPEX and Treg resulted normal. He was treated with steroids and continues mTOR inhibitor with good control of proteinuria and stable kidney function. Case 2. A 2-year boy was diagnosed with a trilinear bone marrow failure, genetic investigations were negative. He presented elevated serum levels of IgG4 subclass and kidney failure with tubular acidosis. A renal biopsy showed MGP associated with TIN. IF and IHC for PLA2R resulted positive. IHC staining for IgG4 showed overlapping positivity for IgG and IgG4. After the diagnosis of IgG4 RD, steroid therapy was started, without clinical response. Thereafter the patient underwent a bone marrow transplant from his brother (HLA-identical). In consideration of the rarity of IgG4 RD in children, we decided to perform a new genetic exam. A whole-exome sequencing on the proband and relatives was done. A hemizygous mutation of the FOXP3 gene (NM_014009.3), c.1087A &amp;gt; G (p.I363V), was found. This variant, inherited by the mother and found also in the proband's brother, was already described in the literature, thus a diagnosis of IPEX was done. Therefore, Treg resulted normal for brother and mother but not in our patient (0.3%). The patient underwent kidney transplantation, and after 1 year he presents normal kidney function. CONCLUSION MGP and IgG4 RD are rare in paediatrics, and they encouraged us to perform further investigations and reconsider the previous diagnosis. MGP pathogenesis in IPEX is consistent with recent evidence of unbalance of Th17/Treg in idiopathic MGP, with a significant reduction of Treg cell and FOXP3 expression. Th17/Treg may be implicated also in the pathogenesis of IgG4 RD as sources of cytokines production responsible for fibrosis and IgG4-producing B cells. FOXP3 + Treg and FAS-ligand are crucial for autoimmunity and self-tolerance. In ALPS patients a reduced expression of FOXP3 + Treg subsets but with the normal suppressive function was found. IPEX poses a diagnostic challenge considering the spectrum of different phenotypes, but to recognize kidney involvement, together with the growing use of wide genomic analysis, could play a central role.

Advances in gut microbiomes and immunology of IgG4-related hepatobiliary and pancreatic diseases

IgG4-related disease (IgG4-RD) is an immune-mediated condition associated with chronic fibroinflammatory lesions that can affect nearly any organ. IgG4-related hepatobiliary and pancreatic diseases are IgG4-RD involving the hepatobiliary and pancreatic system, which is characterized with elevated serum IgG4 concentrations, large numbers of IgG4 positive lymphoplasma cells infiltration in affected organs, storiform fibrosis, and imaging changes of organ morphology. Due to the lack of reliable biomarkers, histopathology is still an important basis for diagnosis. The pathogenesis of IgG4-related hepatobiliary and pancreatic diseases has not been clarified. This review focuses on the recent advances in intestinal microecology-immunology, host genetics-immunity and recurrence monitoring of IgG4-related hepatobiliary and pancreatic diseases.

IgG4-related prostatitis manifesting as urinary obstruction in a 28-year-old male

BackgroundImmunoglobulin G4-related disease (IgG4-RD) is a systemic lymphoproliferative disorder characterized by elevated serum IgG4 levels and tumefactive lesions that can involve nearly every organ system. Involvement of the prostate is rare but has been reported in limited cases.Case presentationA 28-year-old man of Asian descent with a history of sinusitis and priapism presented to hospital with rigors and voiding symptoms. He was diagnosed with IgG4-RD one month prior to presentation, following pathological analysis of a submandibular mass that demonstrated chronic sclerosing sialadenitis. On presentation, white blood cell count, C-reactive protein, and prostate serum antigen levels were all within normal limits. Examination was notable for a large, firm prostate, and a foley catheter was inserted. Contrast CT of the abdomen was unremarkable. Further workup revealed elevated serum IgG4 levels (9.22 g/L) and he was subsequently started on prednisone 35 mg daily. Imaging to screen for systemic IgG4-RD involvement demonstrated paravertebral soft tissue involvement and he was given rituximab 1000 mg IV × 2 doses. MRI revealed diffuse prostatitis. Five days after starting prednisone and one day after his first dose of rituximab, he successfully passed trial of void and was discharged home.ConclusionsIgG4-related prostatitis is a rare and underrecognized manifestation of IgG4-RD. Our case highlights the need to consider IgG4-related prostatitis as an etiology of urinary obstruction in young individuals. Resolution of symptoms following treatment with steroids may be diagnostic of IgG4-related prostatitis, and may potentially avoid the need for invasive diagnostic procedures such as prostate biopsy.

The Clinical Phenotype of Chinese Patients With Autoimmune Pancreatitis Differs Significantly From Western Patients

AimTo characterize the clinical features of autoimmune pancreatitis (AIP) in China and compare differences between our Chinese cohort and Western cohorts.MethodsThis was a retrospective study of patients with AIP that was carried out in the China-Japan Friendship Hospital between January 2010 and April 2021. We included a total of 50 patients (46 males and 4 females) aged between 27 and 86 years who fulfilled the international Consensus Diagnostic (ICD) Criteria. For comparative purposes, we included data from seven representative Western cohorts.ResultWhen comparing Chinese and Western patients, we found that obstructive jaundice was the most frequent initial symptom (68 vs. 43%, P < 0.001). Extra-pancreatic organ involvement was more common in Chinese patients (68 vs. 30%, P < 0.001). Sclerosing cholangitis was the most frequent extrapancreatic lesion (48 vs. 24%, P = 0.001). The elevation of serum IgG4 was more obvious in our cohort (86 vs. 49%, P < 0.001). Conversely, the rates of ANA-positivity were significantly higher in Western populations (17 vs. 50%, P = 0.006). With regards to imaging, diffuse swelling was significantly more common in China (44 vs. 27%, P = 0.021). Steroid therapy was used more frequently in our Chinese patients (84 vs. 59%, P = 0.001). The steroid-response rate was also significantly higher in our Chinese patients (85 vs. 54%, P = 0.001); However, the rate of resection was higher in Western cohorts (2 vs. 31%, P < 0.001). There was no significant difference between the two populations with regards to recurrence rate (33 vs. 33%, P = 1.000).ConclusionThis study identified significant differences between Chinese and Western populations of patients with AIP. Within the Chinese population, AIP was more likely to have jaundice and extra-pancreatic organ involvement, and elevated serum IgG4 levels. Chinese patients were also showed favorable responses to treatment with glucocorticoids.

Immunogenicity and protection of a Pasteurella multocida strain with a truncated lipopolysaccharide outer core in ducks

Pasteurella multocida infection frequently causes fowl cholera outbreaks, leading to huge economic losses to the poultry industry worldwide. This study developed a novel live attenuated P. multocida vaccine strain for ducks named PMZ2 with deletion of the gatA gene and first four bases of the hptE gene, both of which are required for the synthesis of the lipopolysaccharide (LPS) outer core. PMZ2 produced a truncated LPS phenotype and was highly attenuated in ducks with a > 105-fold higher LD50 than the wild-type strain. PMZ2 colonized the blood and organs, including the spleen, liver and lung, at remarkably reduced levels, and its high dose of oral infection did not cause adverse effects on body temperatures and body weights in ducks. To evaluate the vaccine efficacy of the mutant, ducklings were inoculated orally or intranasally with PMZ2 or PBS twice and subsequently subjected to a lethal challenge. Compared with the PBS control, PMZ2 immunization stimulated significantly elevated serum IgG, bile IgA and tracheal IgA responses, especially after the boost immunization in both the oral and intranasal groups, and the induced serum had significant bactericidal effects against the wild-type strain. Furthermore, the two PMZ2 immunization groups exhibited alleviated tissue lesions and significantly decreased bacterial loads in the blood and organs compared with the PBS group post-challenge. All the ducks in the PMZ2 oral and intranasal groups survived the challenge, while 70% of ducks in the PBS group succumbed to the challenge. Thus, the P. multocida mutant with mutation of the gatA gene and part of the hptE gene proved to be an effective live attenuated vaccine candidate for prevention of fowl cholera in ducks.