Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated condition causing organ swelling and fibrosis. Rarely, it coexists with primary immune thrombocytopenia (ITP), characterized by low platelet count (< 100 × 106/L) without an underlying cause. We present a case of a 56-year-old woman diagnosed with ITP in 2005, successfully treated with dexamethasone and intravenous immunoglobulins (IVIG). In 2011, she was diagnosed with IgG4-RD, type I autoimmune pancreatitis, initially treated with steroids then azathioprine with no response. ITP relapses were managed with prednisone/IVIG, rituximab, and thrombopoietin-receptor agonist therapy. Fostamatinib provided temporary relief, but platelet count dropped again in 2023. Combination therapy with small doses of prednisone and mycophenolate showed a partial response, maintaining platelet count over 50 × 106/L. Further investigation is warranted to explore any correlation between these two conditions, especially considering the patient\'s prolonged response to immunosuppressors.

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.

IgG4-RD is a multisystem fibroinflammatory disease characterized by the infiltration of tissues by IgG4 plasma cells. Combined skin and biliary tract involvement in IgG4-RD has not been described. We present perhaps the most comprehensive analysis of lymphocyte subsets in the first case of IgG4-related generalized skin rash and first case of combined skin and biliary tract manifestations. A 55-year-old male presented with painful jaundice and generalized macular pigmented pruritic eruptions, and CT abdomen revealed biliary obstruction. Ampulla and skin biopsies were subjected to histology and immunostaining. Naïve, central memory (TCM), effector memory (TEM), terminally differentiated effector memory (TEMRA) subsets of CD4+ and CD8+ T cells, T follicular helper subsets, naïve, transitional, marginal zone (MZ), germinal center (GC), IgM memory, and class-switched memory (CSM) B cells, and T follicular regulatory, regulatory B cells, CD4 Treg, and CD8 Treg were analyzed. Serum IgG4 was elevated at 448 mg/dL. Ampula biopsy showed lamina propria fibrosis and increased IgG4-positive plasma cells. Skin punch biopsy showed lymphoplasmacytic infiltrates with a 67% ratio of IgG4+:IgG+ plasma cells. CD4+TN and CD4+TCM decreased, whereas CD4+TEM increased. Naïve B cells increased; transitional, MZ, CSM, GC B cells, and plasmablasts decreased compared to control. CD4 Treg increased, whereas CD8 Treg and Breg decreased. In conclusion, IgG-RD may present with combined biliary tract and generalized dermatological manifestations. Changes in regulatory lymphocytes suggest their role in the pathogenesis of IgG4-RD.

IgG4-related disease (IgG4-RD) is a rare, systemic immune-mediated fibro-inflammatory condition with an unclear etiology and pathophysiology, potentially affecting multiple organs. It presents with common clinical, radiological, and serological characteristics. This study aims to compare the latest two IgG4-RD classification and diagnostic criteria: Umehara-Okazaki 2011 and ACR/EULAR 2019.
In a retrospective cross-sectional study conducted across two centers from January 2010 to July 2023, we included patients suspected of having IgG4-RD from various hospital departments. Patients finally diagnosed with other pathologies were excluded. The remaining suspected IgG4-RD cases were evaluated using both Umehara-Okazaki 2011 and ACR/EULAR 2019 criteria.
Out of 34 patients with a clinical diagnosis of IgG4-RD, the Umehara-Okazaki 2011 classified 20 patients: 5 as definitive, 7 as probable, and 8 as possible cases. Applying the ACR/EULAR 2019 criteria to the same cohort resulted in the diagnosis of 9 patients. Notably, retroperitoneal fibrosis and aortitis were the most prevalent form of presentation, accounting for 25% and 22.2% of cases classified under the 2011 and 2019 criteria, respectively.
The more recent and stringent ACR/EULAR 2019 criteria focus on histopathology, various forms of presentation, and analytical data, allow for a more accurate classification of patients.

Immunoglobulin G4-related disease is a systemic immune-mediated disease with insidious evolution characterized by fibroinflammatory lesions over virtually any organ system. Despite the remarkable progression of knowledge, its etiology remains undefined. Due to its relapse-remitting pattern, it could accumulate irreversible damage, increasing comorbidities and mortality. This paper emphasizes key concepts for diagnosing and treating patients with this condition.

IgG4 subclass antibodies represent the rarest subclass of IgG antibodies, comprising only 3-5% of antibodies circulating in the bloodstream. These antibodies possess unique structural features, notably their ability to undergo a process known as fragment-antigen binding (Fab)-arm exchange, wherein they exchange half-molecules with other IgG4 antibodies. Functionally, IgG4 antibodies primarily block and exert immunomodulatory effects, particularly in the context of IgE isotype-mediated hypersensitivity reactions. In the context of disease, IgG4 antibodies are prominently observed in various autoimmune diseases combined under the term IgG4 autoimmune diseases (IgG4-AID). These diseases include myasthenia gravis (MG) with autoantibodies against muscle-specific tyrosine kinase (MuSK), nodo-paranodopathies with autoantibodies against paranodal and nodal proteins, pemphigus vulgaris and foliaceus with antibodies against desmoglein and encephalitis with antibodies against LGI1/CASPR2. Additionally, IgG4 antibodies are a prominent feature in the rare entity of IgG4 related disease (IgG4-RD). Intriguingly, both IgG4-AID and IgG4-RD demonstrate a remarkable responsiveness to anti-CD20-mediated B cell depletion therapy (BCDT), suggesting shared underlying immunopathologies. This review aims to provide a comprehensive exploration of B cells, antibody subclasses, and their general properties before examining the distinctive characteristics of IgG4 subclass antibodies in the context of health, IgG4-AID and IgG4-RD. Furthermore, we will examine potential therapeutic strategies for these conditions, with a special focus on leveraging insights gained from anti-CD20-mediated BCDT. Through this analysis, we aim to enhance our understanding of the pathogenesis of IgG4-mediated diseases and identify promising possibilities for targeted therapeutic intervention.

OBJECTIVE: IgG4-related disease (IgG4-RD) can affect nearly any organ and is often treated with glucocorticoids, which contribute to organ damage and toxicity. Comorbidities and healthcare utilization in IgG4-RD are poorly understood.
METHODS: We conducted a cohort study using claims data from a US managed care organization. Incident IgG4-RD cases were identified using a validated algorithm; general population comparators were matched by age, sex, race/ethnicity and index date. The frequency of 21 expert-defined clinical outcomes associated with IgG4-RD or its treatment and healthcare-associated visits and costs were assessed 12 months before and 36 months after the index date (date of earliest IgG4-RD-related claim).
RESULTS: There were 524 cases and 5240 comparators. Most cases received glucocorticoids prior to (64.0%) and after (85.1%) the index date. Nearly all outcomes, many being common glucocorticoid toxicities, occurred more frequently in cases vs comparators. During follow-up, the largest differences between cases and comparators were seen for gastroesophageal reflux disease (prevalence difference: +31.2%, P < 0.001), infections (+17.3%, P < 0.001), hypertension (+15.5%, P < 0.01) and diabetes mellitus (+15.0%, P < 0.001). The difference in malignancy increased during follow-up from +8.8% to +12.5% (P < 0.001). Some 17.4% of cases used pancreatic enzyme replacement therapy during follow-up. Over follow-up, cases were more often hospitalized (57.3% vs 17.2%, P < 0.01) and/or had an emergency room visit (72.0% vs 36.7%, P < 0.01); all costs were greater in cases than comparators.
CONCLUSIONS: Patients with IgG4-RD are disproportionately affected by adverse outcomes, some of which may be preventable or modifiable with vigilant clinician monitoring. Glucocorticoid-sparing treatments may improve these outcomes.

UNASSIGNED: IgG4-related cholangitis (IRC) is the hepatobiliary manifestation of IgG4-related disease. Anti-laminin 511-E8 autoantibodies have been identified in its pancreatic manifestation. Laminin 511-E8 promotes endothelial barrier function, lymphocyte recruitment, and cholangiocyte differentiation. Here, we investigate anti-laminin 511-E8 autoantibody presence in IRC, and mechanisms via which laminin 511 may contribute to cholangiocyte protection.
UNASSIGNED: Anti-laminin 511-E8 serum autoantibody positivity was assessed by ELISA. RNA sequencing and RT-qPCR were performed on human H69 cholangiocytes treated with recombinant laminin 511-E8. H69 cholangiocytes were subjected to shRNA knockdown targeting genes encoding laminin 511 (LAMA5, LAMB1, LAMC1) or treated with recombinant laminin 511-E8. Cholangiocellular bile acid influx was quantified radiochemically using 22,23-3H-glycochenodeoxycholic acid (GCDC). GCDC-induced apoptosis was determined by Caspase-3/7 assays. Cholangiocellular barrier function was assessed by FITC-Dextran permeability assays. Immunofluorescent staining of laminin 511 and claudin 1 was performed on extrahepatic bile duct tissue of control and anti-laminin 511-E8 positive individuals with IRC.
UNASSIGNED: Seven out of 52 individuals with IRC had autoantibodies against laminin 511-E8. Recombinant laminin 511-E8 led to differential expression of genes involved in secretion, barrier function, and inflammation. Knockdown of laminin 511 constituents increased toxic bile acid permeation and GCDC-induced apoptosis. Laminin 511-E8 treatment decreased toxic bile acid permeation and dose-dependently alleviated GCDC-induced apoptosis. LAMA5 and LAMC1 knockdown increased transepithelial permeability. Laminin 511-E8 treatment reduced transepithelial permeability and prevented T lymphocyte-induced barrier dysfunction. Laminin 511 and claudin 1 staining patterns appeared altered in anti-laminin 511-E8 positive individuals with IRC.
UNASSIGNED: Laminin 511-E8 is an autoantigen in subsets of individuals with IRC. Laminin 511 enhances cholangiocellular barrier function and protects cholangiocytes against T lymphocyte-induced barrier dysfunction, toxic bile acid permeation and bile acid-induced apoptosis.
UNASSIGNED: A subset of patients with IgG4-related cholangitis (IRC) has autoantibodies against laminin 511-E8. In human cholangiocytes, laminin 511 protects against (T lymphocyte-induced) epithelial barrier dysfunction and hydrophobic bile acids. Laminin 511 and claudin 1 staining may be altered in extrahepatic bile ducts of patients with IRC who are anti-laminin 511-E8 positive. This makes it tempting to speculate that a decreased epithelial barrier function with attraction of immune cells and impaired bicarbonate secretion as a result of dysfunction of laminin 511 by autoantibody binding could potentially be a common systemic pathogenic mechanism in a subset of patients with IgG4-RD.

Immunoglobulins are an essential part of the humoral immune response. IgG4 antibodies are the least prevalent subclass and have unique structural and functional properties. In this review, we discuss IgG4 class switch and B cell production. We review the importance of IgG4 antibodies in the context of allergic responses, helminth infections and malignancy. We discuss their anti-inflammatory and tolerogenic effects in allergen-specific immunotherapy, and ability to evade the immune system in parasitic infection and tumour cells. We then focus on the role of IgG4 autoantibodies and autoantigens in IgG4-autoimmune diseases and IgG4-related disease, highlighting important parallels and differences between them. In IgG4-autoimmune diseases, pathogenesis is based on a direct role of IgG4 antibodies binding to self-antigens and disturbing homeostasis. In IgG4-related disease, where affected organs are infiltrated with IgG4-expressing plasma cells, IgG4 antibodies may also directly target a number of self-antigens or be overexpressed as an epiphenomenon of the disease. These antigen-driven processes require critical T and B cell interaction. Lastly, we explore the current gaps in our knowledge and how these may be addressed.

Background and Objectives: Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized immune-mediated, systemic condition of unknown etiology, associated with fibroinflammatory lesions. Diagnosis is set in the presence of IgG4-positive plasma cell infiltration of the involved tissue and elevated serum IgG4 levels. However, approximately 30% of patients have normal serum IgG4 levels. IgG4-RD may affect several organs, including the pancreas, bile ducts, mesentery, retroperitoneum, and salivary glands, but the involvement of the gastrointestinal tract is uncommon. Materials and Methods: The case series of 4 patients with IgG4-RD involving the intestinal tract was observed in the period of 2017-2022. Colorectal and ileal biopsy specimens were stained with hematoxylin and eosin and immunohistochemical techniques using monoclonal antihuman IgG4 primary antibody. Diagnosis of IgG4-RD was based on the presence of >50 cells/ HPF and IgG4/IgG ratio >40 confirmed by two pathologists. Results: IgG4-RD was set in patients previously diagnosed as affected by Crohn\'s disease. Conclusions: Systematic IgG4 immunohistochemical staining should be considered in the diagnostic workup of patients with gastrointestinal strictures, mimicking Crohn\'s disease. The exact prevalence of the condition is likely more frequent than reported and should be defined by a large series of consecutive patients.