[Molecular allergen IgE tests show neosensitizaions occurring during house dust mite specific immunotherapy].

Objective:Neosensitizations may be occur during the allergen specific immunotherapy（AIT） due to the differences between allergen vaccine's content and a patient's molecular sensitization profile. This study investigates whether AIT with HDM extract changes the sensitization profile, whether de novo sensitization occurs, and the clinical importance of the neosensitization. Methods:Fifty-three patients with HDM allergic rhinitis ,with/without asthma, patients were received one year HDM subcutaneous AIT . Fourteen patients were recruited as control group and received only necessary medications. Serum samples were collected at baseline, 6thmoths and 12thof AIT, respectively. Serum samples were tested specific IgE against Der p, Der p 1/2/3 and Der f, Der f 1/2/3, as well as IgG4 against Der p, Der p 1/2 and Der f, Der f 1/2. VAS were collected at the time-points as well. Results:In AIT group, Der p, Der p 1/3, and Der f 1/3 specific IgE levels were significantly higher after one-year treatment, especially for Der p 3. There were 69.2%（18/26） patients whose Der p 3 specific IgE below 0.35 kU/L at baseline but became positive（>0.35 kU/L） after treatment, that is, neosensitization occurred. All tested allergen specific IgG4 level significantly increased after one year AIT treatment and the VAS declined dramatically. However, for patients with neosensitization and without neosensitization, there were no significantly changes concerning to IgG4 level and VAS. Conclusion:Patients undergoing AIT might have a risk of neosensitization to the allergen components in the vaccines. However, the clinical importance of the neosensitization remains unclear and warrants further studies.

IgG4-related disease with nasopharyngeal malignancy-like manifestations.

Background: IgG4-related disease (IgG4-RD) was characterized by single or multiple masses in organs, which may mimic various inflammatory and malignant diseases. Here, we summarize 4 patients with aggressive manifestations of IgG4-RD that mimic nasopharynx cancer to provide some new sights for the diagnosis of IgG4-RD. Case summary: Four patients were included in our series. The age ranged from 53 to 64 years old, and the duration of the disease ranged from 4 to 6 months. The chief complaints included headache, rhinorrhea, or diplopia. All patients had more than 10 IgG4+ plasma cells/HPF in immunohistochemistry with plasma lgG4 levels ranging from 218 mg/dL to 765 mg/dL. All of them met the diagnostic criteria of lgG4-RD. Conclusion: The described case is highly similar to the clinical manifestations of nasopharyngeal carcinoma. Although pathology is the gold standard, there are still limitations. Serological IgG4 can help confirm the diagnosis. Timely diagnosis of IgG4-RD is of great significance in preventing secondary organ damage in patients with active diseases.

Histiocytosis and adult-onset orbital xanthogranuloma in 2023: a review of the literature and mini case series.

PURPOSE: Within the large umbrella of histiocytosis are a few similar yet heterogenous entities involving the orbit and periocular tissues with or without systemic infiltration, termed adult onset xanthogranuloma or orbital xanthogranuloma. Due to rarity of these conditions, different classifications in use, diverse clinical presentations and still unknown etiology, the aim of this paper was to provide an up-to-date literature review of the actual understanding of histiocytosis and its subgroups involving the orbit and periocular area, diagnostic strategies and therapeutic modalities. METHODS: We present a review of literature and small case series comprising four patients diagnosed and treated in the period from 2001 until 2023 in our hospital. Clinical files of 4 patients with adult-onset xanthogranulomatous disease of the orbit and ocular adnexa (AOXGD) were reviewed retrospectively. Clinical, laboratory, radiological, histopathological, and immunohistochemical findings were reexamined. RESULTS: Reviewing medical records of our patients with AOXGD, we found significant overlap between histiocytosis and different immune disorders. A broad workup should be considered in these patients as they can harbour severe immune disfunctions and hematologic disorders. Preferred treatment modality depends on a histopathologic type of AOXGD, clinical presentation and systemic involvement and should be conducted multidisciplinary. CONCLUSION: The diagnosis is often delayed because of its rarity and diverse clinical findings. Development of molecular genetic tests, detection of BRAF V600E mutation and different types of kinase mutations, mutations in transcriptional regulatory genes as well as tyrosine kinase receptors have shed a new light on the etiopathogenesis and potential targeted treatment of histiocytosis.

A Rare Case of Retroperitoneal Tumefactive Fibroinflammatory Lesion Related to IgG4-Sclerosing Disease.

We present a unique case of a retroperitoneal tumefactive fibroinflammatory lesion related to IgG4-sclerosing disease; it is a rare manifestation of the IgG4-related disease, which usually causes diffuse fibrosis when located in the retroperitoneum, rather than mass-like lesions. A 49-year-old man presented to the emergency department complaining of abdominal pain and vomiting. Subsequent testing with abdominal ultrasound, CT, and MRI revealed a large retroperitoneal mass of unknown origin, heterogenous, with a concentric circles pattern best visualized in MRI. The lesion was resected, and the histological and immunohistochemical studies revealed an IgG4-related tumefactive fibroinflammatory lesion of the retroperitoneum.

Severity of papular urticaria in children is associated with specific IgG4 anti-salivary gland antigens from Aedes aegypti.

Summary: Background. Papular Urticaria (PU) is a cutaneous hypersensitivity disorder triggered by hematophagous arthropod bites. Despite being a common condition, especially in tropical environments, many knowledge gaps are observed for this disease. The main objective of this study was to investigate the patterns of humoral immune response to mosquito antigens in children with PU and establish a correlation between this response and the severity of clinical symptoms. Methods. An analytical cross-sectional observational study was carried out. Clinical and sociodemographic data and children's blood samples were collected to measure the specific antibodies from: 1. A. aegypti salivary gland antigens; 2. A. aegypti whole body antigens (both produced in the laboratory of the Center for Health Sciences at the Federal University of Rio de Janeiro). A PU severity score based on clinical data is proposed to correlate disease severity with antibody reactivity signatures. Results. According to the clinical data, 58.9% of children received high severity scores. A significant statistical correlation was found between patients with high PU severity score and the development of symptoms before the age of two (p = 0.0326) and high IgG4 anti-salivary gland antigens concentration (p less than 0.05). Conclusion. It is suggested that PU severity in children is associated with a high concentration of IgG4 anti-salivary gland antigens from Aedes aegypti. Further studies are recommended to deepen the understanding of the mechanisms involved.

Is systemic lupus erythematosus linked to Immunoglobulin G4 Autoantibodies?

Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder characterized by a hyperactive immune system with multiple abnormalities in B-cell proliferation, antibody production, T-cell regulation, and immune complex (IC) formation. In humans, Immunoglobulin (Ig) G is found in four subclasses. IgG1-IgG4, which are distinguished by both structural and biological differences. Fab-arm Exchange (FAE), specific biases in the IgG4 response repertoire, and a decreased capacity to induce effector functions mediated by interactions in the fragment crystallizable (Fc) region are just a few of the distinctive characteristics of IgG4. The recent finding of the presence of double-stranded DNA (dsDNA) and antinuclear antibody (ANA)-IgG4 has raised attention to this IgG subclass and its possible role in SLE. IgG4 was previously believed to just have anti-inflammatory effects by inhibiting immune responses, but recent studies have shown that these antibodies can also play a role in the onset and development of some clinical disorders. To consider the clinical effects of IgG4 presence, it is necessary to discuss its characteristics, which could underlie the potential role it can play in SLE. Therefore, this study aimed to comprehensively review the role of IgG4 in SLE to elucidate the collective incidence of high IgG4 levels reported in some SLE patients.

A case of IgG4-related disease manifesting as a spinal epidural mass.

IgG4-related disease is an immune-mediated fibroinflammatory condition. Isolated manifestation in the spine as hypertrophic pachymeningitis is very rare and the mass-like lesion on MRI often mimic tumour or infection. Patients would present with symptoms that result from mass effect or neurovascular compression. Studies showed that serum and CSF IgG4 levels are rarely informative, and therefore, tissue biopsy is crucial for accurate diagnosis. Apart from supporting the diagnosis, MRI is helpful in delineating the extent of disease and follow-up after treatment. A 18F-FDG PET/CT scan is useful in detecting systemic manifestations of IgG4-related disease. Although IgG4-related disease generally responds well to corticosteroid at inflammatory state, relapse is not uncommon. Current treatment strategies for IgG4-related hypertrophic pachymeningitis are high dose corticosteroid therapy and early decompressive surgery to avoid chronic neurological complications. We described a case of a 27-year-old gentleman complaining of lower limb weakness and numbness. MRI showed a mass-like epidural lesion at the thoracic spine causing cord compression. Open biopsy of the epidural mass demonstrated histopathological characteristics of IgG4-related disease. Patient responded well to early surgical decompression of the spinal cord and corticosteroid as evidenced by symptom improvement and resolving mass on subsequent MRI study. However, a follow-up MRI revealed disease recurrence years later.

Elevated polyclonal IgG4 mimicking a monoclonal gammopathy in IgG4-related disease-a case-based review.

IgG4-related diseases (IgG-RDs) are a group of fibroinflammatory diseases that affect a variety of tissues, resulting in tumour-like effects and/or organ dysfunction. Monoclonal gammopathies (MGPs) are a group of disorders characterized by clonal proliferation of plasma cells or lymphoid cells resulting in the secretion of a monoclonal immunoglobulin. Cases of MGPs in IgG4-RDs coexisting with plasma cell dyscrasias and lymphoid neoplasms have been reported over the past few years. Therefore, the results of examinations of M protein in IgG4-RD patients should be interpreted with caution. Herein, we report the case of a 58-year-old male with a history of type 2 diabetes who presented with submandibular masses, anosmia, swollen lymph nodes, proteinuria, and renal impairment. Laboratory tests revealed hyperglobulinemia and elevated levels of IgG4 (124 g/L) and serum-free light chains (sFLCs). Serum protein electrophoresis (SPEP) revealed an M spike of 5.6 g/dL, and immunofixation electrophoresis (IPE) revealed biclonal IgG-κ and IgG-λ. The patient underwent bone marrow, lymph node, and kidney biopsy, which ruled out plasma cell disorders and lymphoma. He was finally diagnosed with an IgG4-RD comorbid with diabetic nephropathy. The findings in this case highlight that significant activation of B cells in IgG4-RD patients, especially those with multiorgan involvement can lead to significant hyperglobulinemia and high sFLC and IgG4 levels, which are more pronounced in the setting of renal impairment. Relatively high concentrations of polyclonal IgG4 can give rise to a focal band bridging the ß and γ fractions, which may mimic the appearance of a monoclonal band on SPEP and monoclonal gammaglobulinemia in IFE. The patient experienced considerable improvement in his symptoms after rituximab combined with glucocorticoid therapy, and a monoclonal immunoglobulin was not detected.

Surgical Treatment for Giant Multiple Coronary Artery Aneurysms Caused by an IgG4-Related Disease.

Coronary artery aneurysms (CAAs) due to an immunoglobulin G4 (IgG4)-related disease (IgG4-RD) are relatively rare, and there is no consensus on the choice of treatment method. In the present study, we report the results of the surgical treatment for multiple giant CAAs caused by IgG4-RD. A 71-year-old man was diagnosed with severe aortic regurgitation and CAAs. A blood test showed high IgG4 levels, and computed tomography revealed four giant coronary artery aneurysms: two in the right coronary artery (RCA) (proximal RCA and posterior descending artery (PDA)), one in the left anterior descending (LAD), and one in the diagonal branch (Dx). We planned aortic valve replacement, coronary aneurysm resection, and coronary artery bypass grafting (CABG). After finishing aortic valve replacement, the CAAs in proximal RCA, LAD, and Dx were resected. The proximal and distal tracts of the aneurysm were closed with a pericardial bovine patch and ligation. However, since the distal PDA was too calcified to be anastomosed, and the PDA aneurysm was smaller than the others, it was decided to leave the PDA aneurysm. The anastomoses of SVG-RCA and Dx, as well as the left internal thoracic artery to LAD, were performed. Histopathological examination of the aneurysm wall showed a high IgG4-positive cell/IgG-positive cell ratio, and a diagnosis of IgG4-RD was made. In the treatment of CAAs due to IgG4-RD, it is essential to select a procedure that takes into account the size, location, and nature of the aneurysm, and comorbidities. To ensure resection of the aneurysm and blockade of blood flow, closure of the inflow and outflow tracts with a pericardial bovine patch and CABG are effective.

An immuno-DOT diagnostic assay for autoimmune nodopathy.

OBJECTIVES: Autoimmune nodopathy (AN) is a life-threatening peripheral neuropathy mediated by four autoantibodies targeting axoglial cell adhesion molecules at the nodes of Ranvier: Neurofascin-155 (Nfasc155), PanNeurofascin (PanNfasc), Contactin-1 (CNTN1), and Contactin-associated protein 1 (CASPR1). Antibody detection is a strong biomarker for AN diagnosis and treatment monitoring. The aim of this study was to develop an immuno-dot assay (immuno-DOT) compatible with routine implementation in medical laboratories. METHODS: This new approach was compared to standard techniques: indirect immunofluorescence assay, cell-based assay, and ELISA. Sensitivities (Se) and specificities (Sp) were calculated on a cohort composed of 58 patients diagnosed with AN, 50 seronegative patients with chronic inflammatory demyelinating polyradiculoneuropathy, 20 healthy controls, 30 patients with Guillain-Barré syndrome, 20 with monoclonal gammopathy and 20 with Charcot-Marie-Tooth disease. The patients were diagnosed with AN based on compatible electro-clinical arguments and at least two positive standard techniques. RESULTS: Immuno-DOT sensitivities and specificities were Se=91 %, Sp=97 % for anti-Nfasc155; Se=80 %, Sp=94 % for anti-PanNfasc; Se=93 %, Sp=98 % for anti-CNTN1; and Se=87 %, Sp=94 % for anti-CASPR1. Immuno-DOT allowed the diagnosis within 3 h and the accurate follow-up of the immune reactivity and isotype, and dot intensity correlated with antibody titers following treatments. A longitudinal study indicated that immuno-DOT yielded reliable results even after six months of storage at -20 °C. CONCLUSIONS: The diagnostic performance of immuno-DOT was satisfactory and compatible with routine implementation in medical laboratories.

Chronic Ileum Obstruction, Granulation, and Ulceration With IgG4-Positive Plasma Cell Infiltration in a Six-Year-Old Girl With 21trisomy.

Patients with 21trisomy often develop congenital or acquired gastrointestinal diseases, such as duodenal or anal atresia, celiac disease, intussusception, and constipation. In these patients, it is often challenging to diagnose gastrointestinal diseases because most patients have difficulty explaining their complaints in detail. Furthermore, these patients also possess immunological disorders, such as increased type I interferon activation, innate immune hypersensitivity, and polarization to autoimmune. Here, we present a girl with 21trisomy and constipation who developed severe anemia, occult blood and elevated levels of calprotectin in stool, and chronic ileum obstruction confirmed by computed tomography. The patient underwent surgical resection of the ileum and recovered without complications. Pathological examination demonstrated intussusception, ischemia, ulceration, inflammatory granulation, and massive IgG4-positive plasma cell infiltration. After the surgery, her fecal calprotectin levels were normalized. We assumed that the ileum inflammation caused by ileum dilation generated ulcers and granulation, which could be associated with immunological, gastrointestinal, and intellectual disorders in patients with 21trisomy.

Revealing the distinct clinical patterns and relapse risk factors in seronegative IgG4-RD patients: A retrospective cohort study over a decade.

OBJECTIVES: Our study aimed to investigate the distinct clinical patterns of seronegative IgG4-related disease (IgG4-RD) patients. METHODS: We retrospectively enrolled 698 treatment-naïve IgG4-RD patients in this study. Patients were divided into four different subgroups according to their baseline serum IgG4 levels. The distinct clinical patterns of seronegative IgG4-RD patients were revealed through the comparison of baseline clinical data and disease prognosis among the different subgroups. COX regression analyses were used to investigate the risk factors for disease relapse and to construct the nomogram model. RESULTS: Seronegative IgG4-RD patients account for a minority of IgG4-RD patients (49/698, 7.02%). The proportions of seronegative IgG-RD patients in our study and several Asian cohorts were significantly lower than those of the European and American cohorts. Seronegative IgG4-RD patients got lower serum IgG levels (p < 0.0001), lower eosinophil count (p < 0.0001), lower serum IgE levels (p < 0.0001)), lower IgG4-RD responder index (RI) scores (p < 0.0001), and fewer affected organ numbers (p < 0.0001) compared with other subgroups, whereas they were more likely to manifest fibrotic type with some special organ involvement. Younger age at onset, GCs monotherapy, elevated C-reactive protein level, and elevated erythrocyte sedimentation rate level are the risk factors for the disease relapse of seronegative IgG4-RD patients. An effective nomogram model predicting disease relapse of seronegative IgG4-RD patients was constructed. Seronegative IgG4-RD patients with scores >84.65 at baseline were susceptible to suffering from disease relapse. CONCLUSIONS: Distinct clinical features and multiple risk factors for disease relapse of seronegative IgG4-RD patients have been revealed in this study. A nomogram model was constructed to effectively predict disease relapse during the follow-up period.

Atypical lymphoplasmacytic and immunoblastic proliferation: A Systematic Review.

Atypical lymphoplasmacytic and immunoblastic proliferation (ALPIBP) was first reported in 1984 as characteristic histological findings in lymph nodes associated with autoimmune diseases, but it has not been clearly defined to date. To summarize the histological characteristics and clinical diagnoses associated with ALPIBP, we searched MEDLINE and EMBASE for all peer-reviewed articles using keywords including "atypical lymphoplasmacytic and immunoblastic lymphadenopathy" from their inception to December 27, 2023. We also summarized the courses of three cases with a pathological diagnosis of ALPIBP. Nine articles with 52 cases were included. Among the total of 55 cases, including the three from our institution, the median age of the cases was 63.5 years with a female predominance (69.5%). Lymphadenopathy was generalized in 65.6% and regional in 34.4% of cases. RA (24.4%), SLE (24.4%), and autoimmune hemolytic anemia (20.0%), were common clinical diagnoses. A combination of cytotoxic chemotherapy was used in 15.6% of cases due to the suspicion of malignancy. Nodal T-follicular helper cell lymphoma, angioimmunoblastic type, methotrexate-associated lymphoproliferative disorders, and IgG4-related diseases were listed as important diseases that need to be pathologically differentiated from ALPIBP. This review summarizes the current understanding of the characteristics of ALPIBP. Given that underrecognition of ALPIBP could lead to overdiagnosis of hematological malignancy and unnecessary treatment, increased awareness of the condition in pathologists and clinicians is crucial.

Risk of Misdiagnosis in Spinal Hypertrophic Pachymeningitis: A Report of Two Cases.

Hypertrophic pachymeningitis (HP) is a rare inflammatory disease of the central nervous system. It typically manifests in the cranium; cases involving the spinal cord are rare (8.6%). This report includes two cases of spinal HP encountered among 666 spinal operative cases. The purpose of this study is to present the initial imaging findings, final diagnosis, and course of treatment in these two cases of spinal HP and to present the possible risk of misdiagnosis with a literature review. In case 1, a 69-year-old female presented with back pain. The initial radiological diagnosis with magnetic resonance imaging (MRI) was a meningioma. However, her blood test showed a mild elevation of C-reactive protein level (3.16 mg/dL), with positive IgG4 and myeloperoxidase anti-neutrophil cytoplasmic antibody results, suggesting an autoimmune disease. We performed a biopsy of the thickened dura and an expansive duraplasty. Serological and pathological diagnosis suggested IgG4-related HP. In case 2, a 67-year-old male presented with bilateral thigh pain. MRI revealed a mass resembling a disc hernia at the L2/3 intervertebral level. The mass was surgically removed. Pathological examination and cerebrospinal fluid analysis confirmed the diagnosis of HP associated with IgG4-related disease. In both cases, immunosuppressive therapy was administered, and follow-up MRI scans revealed the disappearance of the mass. The study concludes that a spinal HP can potentially be misdiagnosed when its images resemble those of tumors or disc hernias owing to its rarity.

Transudative pleural effusion in pleuritis associated with immunoglobulin G4-related disease diagnosed by thoracoscopy under local anaesthesia.

Immunoglobulin G4 (IgG4)-related disease is a chronic inflammatory condition often characterized by exudative pleural effusions. However, transudative pleural effusions, like in the presented case of an 80-year-old man with multiple comorbidities, are less common but possible. Despite initial treatment with diuretics, the effusion persisted, prompting further investigation. Medical thoracoscopy revealed lymphatic follicle hyperplasia and an abundance of IgG4-positive plasmacytoid cells, confirming IgG4-related pleuritis. This case underscores the importance of considering inflammatory etiologies, such as IgG4-related disease, when faced with unresponsive transudative pleural effusions. Thoracoscopy serves as a valuable diagnostic tool in such scenarios, allowing for precise diagnosis and appropriate management.

Case report: Isolated immunoglobulin G4-related sclerosing cholangitis misdiagnosed as hilar cholangiocarcinoma.

Background: Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) is frequently accompanied with type 1 autoimmune pancreatitis (AIP). Isolated IgG4-SC which is not accompanied with AIP is uncommon in clinical practice, and its manifestations are similar to those of hilar cholangiocarcinoma. Case presentation: A 55-year-old male presented with persistent aggravation of icteric sclera and skin. He was initially diagnosed with hilar cholangiocarcinoma and underwent surgery. However, positive IgG4 plasma cells were found in the surgical specimens. Thus, a pathological diagnosis of IgG4-SC was established. After that, steroid therapy was given and initially effective. But he was steroid dependent, and then received rituximab therapy twice. Unfortunately, the response to rituximab therapy was poor. Conclusion: It is crucial to differentiate isolated IgG4-SC from hilar cholangiocarcinoma to avoid unnecessary surgery. Future studies should further explore effective treatment strategy in patients who do not respond to steroids therapy. It is also required to develop novel and accurate diagnostic approaches to avoid unnecessary surgical procedures.

Triggers for eosinophilic esophagitis (EoE): The intersection of food allergy and EoE.

Eosinophilic esophagitis and IgE-mediated food allergy are both food-triggered diseases that are increasing in prevalence. They share many clinical links, including significant comorbidity and similar food triggers, and as atopic diseases, they likely share upstream mechanisms related to barrier function and signals leading to TH2 skewing. In this review, we focus on links between eosinophilic esophagitis and IgE-mediated food allergy with an emphasis on what insights may be derived from overlapping food triggers and immune phenotypes. Through further investigation of these connections, we may be able to better understand not only IgE-mediated food allergy and eosinophilic esophagitis but also general atopic response to food proteins and evolution of allergic response to food.