Serum Levels of Selected Cytokines and Chemokines and IgG4 in Children With Recurrent Respiratory Tract Infections.

Background: Respiratory tract infections are a common health problem. Cytokines/chemokines play a critical role in the regulation of the immune system. Their defective production may predispose to recurrent respiratory tract infections (RRIs), and an excessive immune response may lead to chronic inflammation and cause damage to the respiratory tract. Another biomarker of respiratory infections may be immunoglobulin-IgG4. Its meaning has still been little explored. We wanted to assess the suitability of the levels of biomarkers tested: interleukin (IL)-17A, IL-18, IL-23, normal T cells expressed and secreted (RANTES), and induced protein (IP)-10, as well as immunoglobilun G4 (IgG4) to predict recurrent infections. Methods: The study group (SG) included a total of 130 children (68 girls, 62 boys) between 3 and 17 years of age with RRI. The control group (CG) included 86 healthy children with no symptoms of inflammatory or allergic diseases (44 girls and 42 boys) of the same age. Blood samples were collected in fasting state and then serum samples were frozen and stored until biomarker assay. Results: Serum RANTES, IL-18, IL-23, and IgG4 concentration were higher in all children with recurrent infections vs. those in the CG (p < 0001). Serum levels of IL-17A and IP-10 were also significantly higher in the SG than in the CG, but only in the youngest children. Among the six serum markers, RANTES demonstrated the highest area under the receiver operating characteristic curve (area under curve) value (0.998, 95% confidence interval [CI]: 0.98-1.0, p < 0.001) for the diagnosis of RRIs, followed by IL-23 (0.99, 95% CI 0.966-0,999, p < 0.001) and IL-18 (0.957, 95% CI 0.921-0.980, p < 0.001). Conclusions: RANTES, IL-23, and IL-18 could be strong predictors of respiratory infections recurrence in children.

Immunoglobulin G4-Related Disease Presenting as Recurrent Acute Pancreatitis.

Immunoglobulin G4-related disease (IgG4-RD) is a rare immune-mediated disease affecting multiple organs and tissues. There is often the presence of elevated serum Ig4 subtype with histological evidence of lymphoplasmacytic infiltration, fibrosis, and phlebitis. The mainstay of treatment is steroid therapy. This case report is based on a 24-year-old man with IgG4-related type 1 autoimmune pancreatitis (AIP) who also had elevated serum IgG4 subclass and histological features in keeping with IgG4-RD. The main complaints were dry cough, nasal congestion with sneezing, sore throat, and fever. Necessary investigations were performed and based on the International Consensus Diagnostic Criteria, the diagnosis of AIP type 1 was confirmed, which is a pancreatic manifestation of IgG4-RD. He was subsequently treated with prednisolone and azathioprine and is showing a good response to the treatment.

Humoral signatures of Caspr2-antibody spectrum disorder track with clinical phenotypes and outcomes.

BACKGROUND: Immunoglobulin (Ig) G4 auto-antibodies (Abs) against contactin-associated protein-like 2 (Caspr2), a transmembrane cell adhesion protein expressed in the central and peripheral nervous system, are found in patients with a broad spectrum of neurological symptoms. While the adoptive transfer of Caspr2-specific IgG induces brain pathology in susceptible rodents, the mechanisms by which Caspr2-Abs mediate neuronal dysfunction and translate into clinical syndromes are incompletely understood. METHODS: We use a systems-level approach combined with high-dimensional characterization of Ab-associated immune features to deeply profile humoral biosignatures in patients with Caspr2-Ab-associated neurological syndromes. FINDINGS: We identify two signatures strongly associated with two major clinical phenotypes, limbic encephalitis (LE) and predominant peripheral nerve hyperexcitability without LE (non-LE). Caspr2-IgG Fc-driven pro-inflammatory features, characterized by increased binding affinities for activating Fcγ receptors (FcγRs) and C1q, along with a higher prevalence of IgG1-class Abs, in addition to IgG4, are strongly associated with LE. Both the occurrence of Caspr2-specific IgG1 and higher serum levels of interleukin (IL)-6 and IL-15, along with increased concentrations of biomarkers reflecting neuronal damage and glial cell activation, are associated with poorer clinical outcomes at 1-year follow-up. CONCLUSIONS: The presence of IgG1 isotypes and Fc-mediated effector functions control the pathogenicity of Caspr2-specific Abs to induce LE. Biologics targeting FcR function might potentially restrain Caspr2-Ab-induced pathology and improve clinical outcomes. FUNDING: This study was funded by a German-French joint research program supported by the German Research Foundation (DFG) and the Agence Nationale de la Recherche (ANR) and by the Interdisciplinary Centre for Clinical Research (IZKF) Münster.

A rare pathology that mimics lung cancer: IgG4-related vasculitis.

Immunoglobulin-G4 (IgG4)-related disease is essentially a fibro-inflammatory disease that can affect any organ simultaneously or at different times. The disease usually presents with organ growth that mimics a tumour and can affect the lacrimal glands, major salivary glands, pancreas, bile ducts, retroperitoneal area, lungs, kidneys, aorta, meninges and thyroid gland. The immunopathogenesis behind this new disease has not yet been elucidated. Histopathological distinguishing features of the disease include dense lymphoplasmocytic infiltrates dominated by IgG4 positive plasma cells, storiform fibrosis and obliterative phlebitis. The likelihood of developing with immunoglobulin G4 (IgG4-RD) is a recently identified rare systemic fibroinflammatory disease with an estimated incidence of less than 1 in 100,000 people worldwide. We present our case, which was diagnosed with IGG4-related vasculitis by lung fine needle aspiration biopsy, which is very rare in the literature.

Isolated IgG4-related Infundibulo-hypophysitis.

A 72-year-old man presented with several months of weakness, poor appetite, and depressed moods. Laboratory tests indicated central hypocortisolism, hypothyroidism and hypogonadism, and mild hyperprolactinemia. Imaging indicated a homogenously enhancing solid suprasellar mass inseparable from the hypothalamus and contiguous with a thickened proximal infundibulum. Neuro-ophthalmological evaluation was normal. Symptoms improved with hydrocortisone, levothyroxine, and testosterone replacement. After 6 months, transsphenoidal biopsy was performed due to mass enlargement and revealed fibrosis, lymphoplasmacytic infiltration, and CD138 and IgG4 staining. The levels of serum IgG4, complement, inflammatory markers, protein electrophoresis, amylase, and lipase and imaging of the chest, abdomen, and thyroid were unremarkable. After 1 month of prednisone therapy (starting dose 40 mg/day), the mass significantly involuted and remained stable afterward. Prednisone was gradually tapered to 5 mg daily over 10 weeks. During 22 months of follow-up, no systemic IgG4 disease was detected. Glucocorticoid, thyroid, and testosterone replacement was continued. This case of isolated IgG4-related hypophysitis illustrates the variable presentation that may not entail vasopressin deficiency or clinical mass effect. This entity should be considered in the differential diagnosis of suprasellar masses even in the absence of IgG4 systemic disease or characteristic serology. Management entails multidisciplinary collaboration and long-term follow-up.

The 2023 revised diagnostic criteria for IgG4-related dacryoadenitis and sialadenitis.

OBJECTIVES: For the diagnosis of IgG4-related dacryoadenitis and sialadenitis, either revised comprehensive diagnostic criteria or organ-specific diagnostic criteria for IgG4-related dacryoadenitis and sialadenitis in 2008 were applied; however, the collected knowledge for IgG4-related dacryoadenitis and sialadenitis required us to revise the criteria for IgG4-related dacryoadenitis and sialadenitis. METHODS: The board member of Japanese Study Group for IgG4-related Dacryoadenitis and Sialadenitis revised the diagnostic criteria for IgG4-related dacryoadenitis and sialadenitis. We collected the clinical questions to be revised and performed a review of the literature. When the data were insufficient, additional data collection was performed. After the revision, public comments were collected. RESULTS: The three major points were revised. 1. Asymmetric or under two pairs of dacryoadenitis and sialoadenitis were included as IgG4-related dacryoadenitis and sialadenitis. 2. The thresholds of IgG4-positive cell infiltration were adjusted to an IgG4+/IgG+ ratio >0.4 and IgG4+ cells >10 per high power field. 3. The labial salivary gland biopsy was allowed to diagnose IgG4-related dacryoadenitis and sialadenitis. CONCLUSIONS: The revised diagnostic criteria for IgG4-related dacryoadenitis and sialadenitis solved several issues with the previous criteria. It will improve the early diagnosis of IgG4-related dacryoadenitis and sialadenitis, especially in situations without enough resources for a biopsy.

Immunoglobulin G4 in primary Sjögren's syndrome and IgG4-related disease - connections and dissimilarities.

Primary Sjögren's syndrome (pSS) is an autoimmune disease, with B cell hyperactivation and autoantibody production as its immunological hallmarks. Although the distinction between immunoglobulin G4-related disease (IgG4-RD) and pSS, based on the presence or absence of certain autoantibodies, seems easy to make, possibility of elevated serum IgG4 concentration and often similar organ involvement may lead to a misdiagnosis. The increased serum concentration of IgG4 in IgG4-RD is not clearly linked to the pathogenesis of IgG-RD and it has been suggested that it may constitute just an epiphenomenon. The aim of this article is to discuss the presence of IgG4 in pSS and IgG4-RD and its potential significance for these two diseases.

Küttner's Tumor and Autoimmune Pancreatitis as Metachronous Manifestations of IgG4-Related Disease.

Immunoglobulin G4-related disease (IgG4-RD) is a multiorgan, fibro-inflammatory condition that presents with painless organ swelling, lymphoplasmacytic infiltration, and obliterative phlebitis, often showing a favorable response to corticosteroid therapy. The most affected organs include the pancreas, kidneys, retroperitoneum, lacrimal glands, and salivary glands. Diagnosis relies on serological, imaging, and histopathological findings, with glucocorticoids as the primary treatment. Despite its reversible nature and good prognosis in many cases, long-term complications such as organ dysfunction or malignancy can still occur. International collaborative efforts have enhanced the understanding, diagnosis, and management of IgG4-RD, emphasizing the importance of comprehensive diagnostic criteria and appropriate therapeutic strategies. Herein, we present an interesting case of a geriatric male who was referred to our clinic because of concern for pancreatic cancer. We diagnosed the patient with autoimmune pancreatitis, a manifestation of IgG4-RD. The patient experienced a dramatic response to steroid therapy and is currently on maintenance therapy.

Multisystem diseases in the abdomen and pelvis: imaging manifestations and diagnostic roles of cross-sectional imaging.

Systemic diseases, such as IgG4-related disease, sarcoidosis, and amyloidosis, usually involve multiple systems or organs simultaneously or sequentially. The gastrointestinal tract, hepatobiliary system, and genitourinary tract are commonly involved in many multisystem diseases and can also be the first sites with disease involvement. Cross-sectional imaging, such as CT and MR, plays an important role in the diagnosis and management of multisystem diseases by aiding in the evaluation of multiorgan involvement. Here, common imaging features of frequently affected organs are reviewed in multisystem diseases that we often encounter in the abdomen and pelvis, and the diagnostic roles of cross-sectional imaging for these diseases are also discussed.

A rare case of IgG4-related aortitis in the thoracic aorta mimicking an intramural hematoma: navigating the diagnostic labyrinth.

A 54-year-old female presented with recurrent abdominal pain and new onset chest pain. Chest computed-tomography angiogram detected a thoracic aortic aneurysm with suspected Type A intramural hematoma (IMH) versus aortitis. Initially, conservative management was pursued while awaiting a definitive diagnosis. Differential workup was negative, while additional imaging modalities favored IMH, prompting expedited surgical intervention. During ascending aortic and hemiarch replacement, severe aortitis was unexpectedly discovered without evidence of IMH. Histopathological examination of the aortic specimens identified transmural aortic inflammation with lymphoplasmacytic infiltrate and irregular fibrosis. Numerous IgG4-positive plasma cells were present with IgG4/IgG ratio of 40-50% suggesting IgG4-related disease (IgG4-RD). Subsequent analysis revealed B cells positive for clonal IgH gene rearrangement, and bone marrow biopsy then revealed the same clonal B cells. She was ultimately diagnosed with CLL, the most common phenotype of monoclonal B-cell lymphocytosis, thought to account for the IgG4-predominant plasma cells causing aortitis. Although rare, this case highlights the importance of considering IgG4-related disease (IgG4-RD) as a cause of aortitis when assessing symptomatic patients with aortic pathologies, emphasizing the complexities involved in diagnosing due to a variety of imaging presentation, differentiating, and managing large-vessel vasculitides. Moreover, it underscores the importance of Multidisciplinary Aortic Team care and the use of multiple diagnostic modalities in evaluating ambiguous aortic pathologies.

Case Report: IgG4-Related Disease Presenting With Isolated Hypophysitis.

Background/Objective: IgG4-related disease (IgG4-RD) is an immune-mediated condition that affects multiple organs, including the pituitary gland. Here we present a patient with isolated pituitary involvement of IgG4-RD mimicking pituitary apoplexy. Case Report: A 49-year-old woman presented to the emergency department with abdominal pain, nausea, vomiting, and weight loss. Her blood pressure was low, and she appeared euvolemic with the rest of physical examination being noncontributory. Her electrolytes showed low serum sodium of 118 mmol/L (normal 135-145). Further investigations were significant for low morning cortisol of 20 nmol/L (N:100-500) and low adrenocorticotropic hormone. Magnetic resonant imaging of the pituitary fossa showed a pituitary macroadenoma with hemorrhagic transformation. She was started on glucocorticoids and levothyroxine before undergoing surgical removal of the pituitary tumor. The pathology was positive for IgG-4-related hypophysitis (IgG4-RH) with no evidence of pituitary tumor. Discussion: IgG4-RD is an immune-mediated condition that can affect many organs including the pituitary gland, in the form of hypophysitis. IgG4-RH can affect anterior, posterior, or both pituitary lobes. In 2011, Leporati et al developed a diagnostic criteria for IgG4-RH which includes the following: imaging, serology, histopathology, and response t glucocorticoids. The mainstay of treatment is glucocorticoids and hormone replacement therapy. Conclusion: IgG4-RH might be underestimated and should be suspected in those with hypophysitis or unknown cause of hypopituitarism. Moreover, pituitary macroadenoma with hemorrhagic transformation and panhypopituitarism should be considered as rare and unusual presentations of IgG4-RD.

IgG4-Related Disease Involving the Ear: A Case Report.

IgG4-related disease is a chronic inflammatory disease with widespread clinical presentation. It mimics various malignant, infectious, and inflammatory conditions, leading to confusion in diagnosis and management. Otological manifestations, though relatively rare, can lead to significant complications. A 45-year-old male with a recent history of ventilation tube placement in the right ear presented with a sensation of imbalance associated with profound hearing loss. He was managed in line of acute otitis media with labyrinthitis with steroids and antibiotics and removal of the ventilation tube. He returned in one week and presented with right-sided lower motor neuron-type facial paresis. Computed tomography images of the temporal bone showed a soft tissue density lesion in the right middle ear cavity extending to the mastoid antrum. He underwent a right cortical mastoidectomy with decompression of the facial nerve. Histopathology and immunohistochemistry of granulation tissues from the middle ear and the mastoid revealed evidence suggestive of probable IgG4 disease. IgG4-related disease is a relatively new entity, and its pathogenesis has not been properly understood. IgG4 subclass has been involved in this disease resulting in fibro-inflammatory conditions leading to tumor-like masses or fibrosis of the affected organs. Treatment includes glucocorticoids and immunosuppressant medications.

IgG4 serologic elevation in a patient with severe hidradenitis suppurativa: a case report and review of the literature.

Hidradenitis suppurativa (HS) is a chronic cutaneous and systemic inflammatory condition. Increasingly, reports have found that immunoglobulins play a role in the exaggerated immune response occurring in severe HS. It is important to recognize these implications as HS patients may present with laboratory abnormalities relating to chronic inflammation and immune activation. If these laboratory abnormalities are mistakenly associated with another disease process, it could lead to invasive workup and treatment, causing harm to patients. We describe the case of a 23-year-old woman with Hurley stage III HS who was hospitalized and found to have persistent immunoglobulin-G4 (IgG4) elevation. Upon discharge, the patient was diagnosed with IgG4-related disease (IgG4-RD) and started treatment with azathioprine. However, the biopsy ultimately was negative for IgG4-RD, and she presented to our clinic several months later with worsening HS disease during an active flare. Physical examination revealed actively draining nodules and sinus tracts in the bilateral axillae, inguinal folds, and mons pubis region. A confusing laboratory marker with HS was observed in this case. IgG4 has the potential to inhibit or activate inflammation depending on the context, and so IgG4 elevation has been noted in varying disease states. IgG4 elevation is observed in chronic inflammatory states and may represent a compensatory response by the body. While no other cases have reported the association between HS and IgG4 elevation, IgG levels have been found to reflect HS disease severity. Therefore, IgG4 could play a potential role in HS disease monitoring, and awareness of this association is important for providers when managing patients with HS.

Autoimmune Biliary Diseases: A Review of Primary Biliary Cholangitis, Primary Sclerosing Cholangitis, Immunoglobulin G4-Related Sclerosing Cholangitis, and Autoimmune Hepatitis.

Autoimmune and immune-mediated biliary diseases represent a small proportion of biliary disorders, but owing to their progressive nature, lead to end-stage liver disease, necessitating liver transplantation for definitive management.

Mechanisms and implications of IgG4 responses to SARS-CoV-2 and other repeatedly administered vaccines.

Vaccine-induced immunoglobulin G (IgG) profiles can vary with respect to the predominant subclasses that characterize the response. Among IgG subclasses, IgG4 is reported to have anti-inflammatory properties, but can also exhibit reduced capacity for virus neutralization and activation of Fc-dependent effector functions. Here, we review evidence that IgG4 subclass responses can be disproportionately increased in response to some types of vaccines targeting an array of diseases, including pertussis, HIV, malaria, and COVID-19. The basis for enhanced IgG4 induction by vaccines is poorly understood but may be associated with platform- or dose regimen-specific differences in antigen exposure and/or cytokine stimulation. The clinical implications of vaccine-induced IgG4 responses remain uncertain, though collective evidence suggests that proportional increases in IgG4 might reduce vaccine antigen-specific immunity. Additional work is needed to determine underlying mechanisms and to elucidate what role IgG4 may play in modifications of vaccine-induced immunity to disease.

Imaging of the Major Salivary Glands in Rheumatic Disease.

Salivary gland involvement is a common feature of rheumatologic disease. The authors review the anatomy of the major salivary glands and the uses of imaging modalities such as ultrasound, MRI, computed tomography, sialography, and scintigraphy in evaluating the major salivary glands in rheumatologic disease.

An Evasive Liver Mass in a Human Immunodeficiency Virus (HIV)-Positive Patient.

IgG4-related disease (IgG4-RD) is an autoimmune syndrome that is characterized by elevated levels of serum IgG4 and infiltration of various tissue types by IgG4 immunoreactive plasma cells. The IgG4-RD can result in systemic disease and the formation of inflammatory mass lesions, frequently addressed as pseudotumors. While IgG4-RD can manifest in various organs, liver involvement is rare, and because it is an immune-mediated inflammatory process, it is uncommon in patients who are immunocompromised. Furthermore, despite IgG4-RD responding well to immunosuppressive treatment, cases of spontaneous remission are exceedingly rare in the literature. In this report, we present the unique case of a self-resolving IgG4-RD lesion of the liver in a HIV positive patient.

Surgical treatment of chronic aortic dissection with liver dysfunction due to constrictive pericarditis caused by IgG4-related disease: a case report.

Background: Severe liver failure with ascites may be associated with cardiac disease and may be the primary manifestation of constrictive pericarditis or aortic dissection. We report a case of a patient with a chief complaint of ascites for whom close examination revealed that the liver injury was attributed to constrictive pericarditis and chronic aortic dissection, with immunoglobulin G4 (IgG4)-related disease (IgG4-RD) as the primary cause. Case summary: A 72-year-old man presented to the emergency department with scrotal oedema and ascites. Initially, the patient was hospitalized in the Department of Hepatology. However, computed tomography (CT) revealed aortic dissection (DeBakey type II), pericardial thickening, and impaired right ventricular dilatation. Therefore, we performed an ascending aortic replacement. IgG4 staining of the aortic wall revealed an IgG4/IgG-positive cell ratio of 35%. Pathological examination did not confirm the diagnosis of IgG4-related aortitis; however, the patient was diagnosed with IgG4-RD because of decreased blood IgG4 levels in response to steroid medication and the presence of heterogeneous thickened lesions in the pericardium. The patient took prednisolone 5 mg/day for 1 month post-operatively. His IgG4 level decreased but re-elevated above the baseline value after discontinuation of oral medication. Discussion: Liver cirrhosis was suspected given the ascites, although a CT scan on admission confirmed insufficiency of systemic circulation due to cardiac constrictive pericarditis with aortic dissection. Despite the complexity of various pathologies in this patient, collaborative efforts and effective communication within the medical team enabled successful aortic surgery, averting life-threatening complications.

Imaging of Benign Biliary Tract Disease.

This review article discusses the most common benign biliary disorders and the various radiological findings on multiple modalities. A broad spectrum of diseases including various congenital disorders, infective and parasitic etiologies, immunological pathologies such as primary sclerosing cholangitis, and immunoglobulin G4-related sclerosing cholangitis are discussed along with obstructive diseases and ischemic cholangitis. The article emphasized the imaging differential diagnosis of the above lesions as well as clinical correlates those that are most relevant to radiologists. The article briefly touched upon management and intervention where relevant.

IgG4-Related Disease in a 90-Year-Old Man with an 18-Year Disease Course: A Case Report.

IgG4-related disease (IgG4-RD) is a multi-organ inflammatory immune-mediated illness caused by IgG4-secreting plasma cells infiltrating the tissue. This condition usually affects elderly men. A 90-year-old Chinese male was diagnosed with IgG4-RD based on the new 2019 ACR/EULAR classification criteria, as he had multiple organ involvement. After receiving treatment with glucocorticoids, leflunomide, and gamma-globulin, the patient's clinical symptoms significantly improved, confirming the accuracy of the diagnosis. The patient had an 18-year medical history during which the disease progressively worsened due to delayed diagnosis and treatment. Although the relevant symptoms were alleviated with appropriate medication, the overall treatment process encountered challenges. Due to the patient's relative lack of adrenocortical function, he experienced symptoms such as nausea, exhaustion, and loss of appetite during the hormone reduction process. Therefore, timely intervention is especially crucial to address the side effects of hormone therapy.