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1
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Whitehair RM, Aguilera NS, Pramoonjago P, Craig JW. Increased IgG4+ plasma cells are common in excised lymph nodes from children and adolescents without IgG4-related disease. J Hematop 2023; 16:209-216. [PMID: 38175435 DOI: 10.1007/s12308-023-00565-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 10/30/2023] [Indexed: 01/05/2024] Open
Abstract
Lymphadenopathy is a common finding in patients with IgG4-related disease (IgG4-RD) and often associated with increased IgG4+ plasma cells in this setting. The histologic features of so-called IgG4-related lymphadenopathy (IgG4-LAD) have seldom been investigated in children and adolescents, and step-wise progression to extranodal IgG4-RD has not been described. This study was performed to further evaluate the frequency, pathologic features, and clinical significance of IgG4-LAD-like histologic changes in the pediatric setting. We analyzed 37 benign lymph nodes collected semi-consecutively from children aged 0-18 years at our institution for both absolute and relative IgG4+ plasma cell abundance and recurrent histomorphologic patterns associated with IgG4-LAD. The combination of IgG4+/IgG+ plasma cell ratio >40% and IgG4+ plasma cell count ≥50 were considered as IgG4-LAD-like per expert consensus guidelines. Seven cases (19%) met both diagnostic criteria. The dominant histomorphologic patterns were follicular hyperplasia (n = 6), interfollicular expansion (n = 3), and progressive transformation of germinal centers (n = 3). Extranodal manifestations of IgG4-RD were not identified in this cohort (38 months average follow-up). Instead, clinical and laboratory findings indicated that lymph node enlargement in most patients could likely be attributed to alternative processes including antecedent dentistry, concurrent infection, and incipient Crohn's disease. Our findings suggest that the histologic features of IgG4-LAD are likely much more common in children and adolescents than previously recognized, often existing in complex with common reactive lymphadenopathies. The diagnostic value of routine immunohistochemical assessment for IgG4+ plasma cells in benign lymph nodes from pediatric patients without established extranodal IgG4-RD and/or other supportive clinical and laboratory data is therefore uncertain.
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Affiliation(s)
- Rachel M Whitehair
- Department of Pathology, University of Virginia Health System, Charlottesville, VA, 22908-0904, USA
| | - Nadine S Aguilera
- Department of Pathology, University of Virginia Health System, Charlottesville, VA, 22908-0904, USA
| | - Patcharin Pramoonjago
- Department of Pathology, University of Virginia Health System, Charlottesville, VA, 22908-0904, USA
| | - Jeffrey W Craig
- Department of Pathology, University of Virginia Health System, Charlottesville, VA, 22908-0904, USA.
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2
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Onkanga IO, Sang H, Hamilton R, Ondigo BN, Jaoko W, Odiere MR, Ganley-Leal L. CD193
(
CCR3
) expression by B cells correlates with reduced
IgE
production in paediatric schistosomiasis. Parasite Immunol 2023; 45:e12979. [PMID: 36971331 DOI: 10.1111/pim.12979] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 02/21/2023] [Accepted: 03/15/2023] [Indexed: 03/29/2023]
Abstract
We demonstrate that CD193, the eotaxin receptor, is highly expressed on circulating B cells in paediatric schistosomiasis mansoni. CD193 plays a role in directing granulocytes into sites of allergic-like inflammation in the mucosa, but little is known about its functional significance on human B cells. We sought to characterize CD193 expression and its relationship with S. mansoni infection. We found that CD193+ B cells increased with the intensity of schistosome infection. In addition, a significant negative association was observed between CD193 expression by B cells and IgE production. Decreased IgE levels are generally associated with susceptibility to re-infection. B cell stimulation with eotaxin-1 increased CD193 levels whereas IL-4 led to a reduction. This was supported by plasma levels of eotaxin-1 correlating with CD193 levels on B cells and other cells. In contrast, CD193 expression was induced on naive B cells with a combination of IL-10 and schistosome antigens. Whereas T cells had a modest increase in CD193 expression, only B cell CD193 appeared functionally chemotactic to eotaxin-1. Thus, CD193+ B cells, which co-express CXCR5, may be enroute to sites with allergic-like inflammation, such as gastrointestinal follicles, or even to Th2 granulomas, which develop around parasite eggs. Overall, our results suggest that schistosome infection may promote CD193 expression and suppress IgE via IL-10 and other undefined mechanisms related to B cell trafficking. This study adds to our understanding of why young children may have poor immunity. Nonetheless, praziquantel treatment was shown to reduce percentages of circulating CD193+ B cells lending hope for future vaccine efforts.
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Affiliation(s)
- I O Onkanga
- Center for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya
- KAVI-Institute of Clinical Research, and Department of Medical Microbiology & Immunology, University of Nairobi, Nairobi, Kenya
| | - H Sang
- Center for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya
| | - R Hamilton
- Elegance Biotechnologies, LLC, Wayne, Pennsylvania, USA
| | - B N Ondigo
- Department of Biochemistry and Molecular Biology, Faculty of Science, Egerton University, Egerton, Kenya
| | - W Jaoko
- KAVI-Institute of Clinical Research, and Department of Medical Microbiology & Immunology, University of Nairobi, Nairobi, Kenya
| | - M R Odiere
- Center for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya
| | - L Ganley-Leal
- Elegance Biotechnologies, LLC, Wayne, Pennsylvania, USA
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3
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Bushara O, Escobar DJ, Weinberg SE, Sun L, Liao J, Yang GY. The Possible Pathogenic Role of IgG4-Producing Plasmablasts in Stricturing Crohn's Disease. Pathobiology 2022; 89:187-197. [PMID: 35026755 DOI: 10.1159/000521259] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 11/26/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Crohn's disease (CD) is a condition on the spectrum of inflammatory bowel disease that affects up to 20 people per 100,000 in the US annually, and with incidence increasing. One of the most significant sources of morbidity in CD is the formation of strictures, with resultant intestinal blockage a common indication for hospitalization and surgical intervention in these patients. The pathophysiology of stricture formation is not fully understood. However, the fibroplasia that leads to fibrostenotic stricture formation may have shared pathophysiology with IgG4-related fibrosis. SUMMARY Initial intestinal inflammation recruits innate immune cells, such as neutrophils, that secrete IL-1β and IL-23, which induces a type 17 CD4+ T-helper T-cell (Th17)-mediated adaptive immune response. These CD4+ Th17 T cells also contribute to inflammation by secreting proinflammatory cytokines such as IL-17 and IL-21. IL-21 recruits and stimulates CD4+ T follicular helper (Tfh) cells, which secrete more IL-21. This causes ectopic germinal center formation, recruiting and stimulating naïve B cells. The IL-17 and IL-21 produced by Th17 cells and Tfh cells also induce IgG4 plasmablast differentiation. Finally, these IgG4-producing plasmablasts secrete platelet-derived growth factor (PDGF), which activates local PDGF-receptor expressing fibroblasts and myofibroblasts, resulting in uncontrolled fibroplasia.
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Affiliation(s)
- Omar Bushara
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - David Joseph Escobar
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Samuel Edward Weinberg
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Leyu Sun
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Jie Liao
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Guang-Yu Yang
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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IgG4-related Lymphadenopathy: A Comparative Study of 41 Cases Reveals Distinctive Histopathologic Features. Am J Surg Pathol 2021; 45:178-192. [PMID: 32889888 DOI: 10.1097/pas.0000000000001579] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Lymphadenopathy is common in patients with immunoglobulin G4-related disease (IgG4-RD). However, the described histopathologic features of IgG4-related lymphadenopathy have been shown to be largely nonspecific. In an attempt to identify features specific for nodal IgG4-RD we examined the histopathologic features of lymph nodes from 41 patients with established IgG4-RD, with comparison to 60 lymph nodes from patients without known or subsequent development of IgG4-RD. An increase in immunoglobulin (Ig) G4-positive plasma cells >100/HPF and IgG4/IgG ratio >40% was identified in 51% of IgG4-RD cases and 20% of control cases. Localization of increased IgG4-positive plasma cells and IgG4/IgG ratio to extrafollicular zones was highly associated with IgG4-RD, particularly when identified in regions of nodal fibrosis (P<0.0001; specificity: 98.3%), or in the context of marked interfollicular expansion (P=0.022; specificity: 100%). Other features characteristic of IgG4-RD included frequent eosinophils associated with IgG4-positive plasma cells, phlebitis (P=0.06), and perifollicular granulomas (P=0.16). The presence of an isolated increase in intrafollicular IgG4-positive plasma cells and IgG4/IgG ratio was more frequently present in control cases than IgG4-RD (P<0.0001). This study confirms that increased IgG4-positive plasma cells and IgG4/IgG ratio are neither sensitive nor specific for the diagnosis of IgG4-related lymphadenopathy, and most described morphologic patterns are nonspecific. In contrast, nodal involvement by IgG4-rich fibrosis akin to extranodal IgG4-RD or diffuse interfollicular expansion by IgG4-positive plasma cells are highly specific features of true IgG4-related lymphadenopathy. Our findings provide for a clinically meaningful approach to the evaluation of lymph nodes that will assist pathologists in distinguishing IgG4-related lymphadenopathy from its mimics.
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IgG4-Related Sclerosing Cholangitis Involving the Intrahepatic Bile Ducts Diagnosed with Liver Biopsy. Case Rep Pathol 2018; 2018:2309293. [PMID: 30305974 PMCID: PMC6165622 DOI: 10.1155/2018/2309293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Revised: 07/15/2018] [Accepted: 08/14/2018] [Indexed: 11/18/2022] Open
Abstract
IgG4-related disease is characterized by lymphoplasmacytic inflammation and fibrosis, often leading to mass-forming lesions in different organs. When IgG4-related disease affects the bile ducts, it is called IgG4-related sclerosing cholangitis. A 74-year-old male complained of dysphagia and abdominal pain. Endoscopic retrograde cholangiography and magnetic resonance cholangiography revealed bile duct changes suspicious of a bile duct carcinoma or cholangitis. Liver biopsy showed storiform fibrosis, lymphoplasmacytic infiltration, obliterative phlebitis, and a portal-based inflammatory nodule with expansion of a portal tract. Hot spots revealed 339 IgG4-positive cells per high power field (HPF) and an IgG4/IgG ratio of 72%. Eight months earlier, an inguinal lymph node had been removed, showing expanded interfollicular zones and increased plasma cells. Hot spots revealed 593 IgG4-positive cells and an IgG4/IgG ratio of 92%. The serum IgG4 of the patient was elevated nearly 10 times upper limit of normal. The diagnosis of IgG4-related sclerosing cholangitis associated with IgG4-related lymphadenopathy was made. There was good response to treatment with prednisolone and azathioprine. The differentiation of IgG4-related sclerosing cholangitis from primary sclerosing cholangitis and bile duct carcinoma is often difficult. Liver biopsy only rarely contributes to this setting, but we describe and report in detail a case where liver biopsy showed a portal-based inflammatory nodule with the characteristic features of this disease.
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6
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Yu SC, Tang JL. Reactive Follicular Hyperplasia With Perifollicular Granulomas and Increased IgG4-Positive Plasma Cells. Int J Surg Pathol 2017; 25:698-699. [PMID: 28480769 DOI: 10.1177/1066896917708609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Shan-Chi Yu
- 1 Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - Jih-Luh Tang
- 1 Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
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7
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Liang L, Zhou J, Chen L. Perifollicular granulomas with IgG4 plasmacytosis: A case report and review of literature. World J Clin Cases 2015; 3:650-654. [PMID: 26244157 PMCID: PMC4517340 DOI: 10.12998/wjcc.v3.i7.650] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 04/13/2015] [Accepted: 05/18/2015] [Indexed: 02/05/2023] Open
Abstract
Perifollicular granuloma is a unique histologic feature and whether it is associated with immunoglobulin G4 (IgG4)-related disease is controversial. We report a case of a 38-year-old man who presented with worsening left eye pain, proptosis, tearing, gritty sensation, blurred vision and multiple lymphadenopathy. An axillary lymph node resection showed reactive follicular and interfollicular lymph node hyperplasia, and increased eosinophils and plasma cells (at least 80% of IgG+ plasma cells were positive for IgG4). A distinct feature was the presence of multifocal, perifollicular histiocytic granulomas, which formed a wreath around the entire follicles. The human herpes virus 8 was not detected by immunohistochemistry. In addition, an extensive panel of special stains, immunohistochemistry, and flow cytometry was negative for lymphoma, fungal, or mycobacterial infection. The findings were suggestive of IgG4-related sclerosing disease-associated lymphadenopathy. Further laboratory testing showed a significant increase of serum immunoglobulin E (> 23000 IU/mL) and slight increase of total IgG, but normal serum IgG4. Even though perifollicular granuloma is a nonspecific histopathologic feature and can be seen in other diseases, such as nodular lymphocyte predominant Hodgkin lymphoma, IgG4-related lymphadenopathy should be listed in the differential diagnoses of benign reactive lymph nodes, especially when perifollicular granuloma and plasmacytosis coexist.
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8
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Bateman AC, Ashton-Key MR, Jogai S. Lymph node granulomas in immunoglobulin G4-related disease. Histopathology 2015; 67:557-61. [DOI: 10.1111/his.12658] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Accepted: 01/20/2015] [Indexed: 12/24/2022]
Affiliation(s)
- Adrian C Bateman
- Department of Cellular Pathology; University Hospital Southampton NHS Foundation Trust; Southampton UK
| | - Margaret R Ashton-Key
- Department of Cellular Pathology; University Hospital Southampton NHS Foundation Trust; Southampton UK
| | - Sanjay Jogai
- Department of Cellular Pathology; University Hospital Southampton NHS Foundation Trust; Southampton UK
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