A Case Report of an Atypical Presentation of IgG4-Related Disease and Idiopathic CD4 Lymphocytopenia

Case Reports in Medicine ◽

10.1155/2015/512370 ◽

2015 ◽

Vol 2015 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Francesco Rapisarda ◽

Luca Zanoli ◽

Grazia Portale ◽

Salvo Scuto ◽

Pietro Castellino

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Plasma Cells ◽

Elevated Serum ◽

Serum Levels ◽

Temporal Association ◽

Related Disease ◽

Igg4 Related Disease ◽

First Case ◽

Idiopathic Cd4 Lymphocytopenia

The IgG4-related disease is a fibroinflammatory disease characterized by tumefactive lesions, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and, often but not always, elevated serum levels of IgG4. Idiopathic CD4 lymphocytopenia is a heterogenic and rare syndrome characterized by the detection of a persistent absolute CD4 T cells count <300 cells/mm3(or <20% of total T cells) in more than one occasion and no evidence of HIV infection in absence of immunodeficiency or therapy associated with depressed levels of CD4 T cells. We report the case of a 50-year-old man with a multiorgan IgG4-related disease presenting in a temporal association with a profound and symptomatic idiopathic CD4 lymphocytopenia. Both clinical pictures improved after steroid treatment. Idiopathic CD4 lymphocytopenia has been associated with a number of autoimmune conditions but, to the best of our knowledge, this is the first case in which an association with the IgG4-related disease is reported.

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Are Classification Criteria for IgG4-RD Now Possible? The Concept of IgG4-Related Disease and Proposal of Comprehensive Diagnostic Criteria in Japan

International Journal of Rheumatology ◽

10.1155/2012/357071 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 87

Author(s):

Kazuichi Okazaki ◽

Hisanori Umehara

Keyword(s):

Diagnostic Criteria ◽

Plasma Cells ◽

Elevated Serum ◽

Serum Levels ◽

Mikulicz’S Disease ◽

Related Disease ◽

Igg4 Related Disease ◽

Biopsy Specimens ◽

Organ Specific ◽

Low Sensitivity

Recent studies suggest simultaneous or metachronous lesions in multiorgans characterized by elevated serum levels of IgG4 and abundant infiltration of IgG4-positive plasma cells with various degrees of fibrosis. Two Japanese research committees for IgG4-RD, one from fibrosclerosis (Okazaki team) and the other from lymph proliferation (Umehara team) supported by the “Research Program for Intractable Disease” of the Ministry of Health, Labor, and Welfare of Japan, have agreed with the unified nomenclature as “IgG4-RD” and proposed the comprehensive diagnostic criteria (CDC) for IgG4-RD. Validation of the CDC demonstrated satisfactory sensitivity for the practical use of general physicians and nonspecialists but low sensitivity in the organs to be difficult in taking biopsy specimens such as type1 autoimmune pancreatitis (IgG4-related AIP), compared with IgG4-related sialadenitis/dacryoadenitis (Mikulicz's disease) and IgG4-related kidney disease. Although the diagnostic criteria covering all IgG4-RD are hard to be established, combination with the CDC and organ-specific diagnostic criteria should improve sensitivity.

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HIV Triggers Interleukin 21-Mediated Induction of Granzyme B-Secreting B Cells with Regulatory and Antiviral Potential

Blood ◽

10.1182/blood.v120.21.1042.1042 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1042-1042

Author(s):

Christof Kaltenmeier ◽

Ali Gawanbacht ◽

Stefanie Lindner ◽

Thamara Beyer ◽

Georg Haerter ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Hiv Infection ◽

Cd4 T Cells ◽

Plasma Cells ◽

Conflicts Of Interest ◽

Granzyme B ◽

Elevated Serum ◽

Serum Levels ◽

Cd40 Ligand

Abstract Abstract 1042 Certain regulatory lymphocyte subpopulations including plasmacytoid dendritic cells and regulatory T cells secrete granzyme B (GrB), thereby suppressing T cell expansion. Recently, we found that B cells can also produce GrB and acquire regulatory potential in response to interleukin (IL-)21. Since HIV has been shown to be associated with elevated serum IL-21 levels, we hypothesized that GrB-expressing B cells may be induced during HIV infection. Here, we show that infection of CD4+ T cells with HIV 1 (NL4-3), but not mock infection, induces strong expression of IL-21 without upregulation of CD40 ligand. Importantly, we further demonstrate that such IL-21+CD40Llow T cells induce GrB in cocultured B cells in an IL-21-dependent fashion, rather than supporting their differentiation into plasma cells. In support of these findings, serum levels of both IL-21 and GrB are significantly higher in HIV-infected patients before HAART as compared to healthy controls. Up to 60% of freshly isolated B cells (36.2% ± 12.9%) from patients infected with HIV, but not B cells isolated from healthy individuals, express GrB. Of note, coculture of HIV-infected CD4+ T cells with GrB+ B cells result in GrB transfer, and strongly suppresses both, proliferation of T cells and viral replication as indicated by significantly reduced p24 levels in coculture supernatants. The observed effects are enhanced by IL-21, and reduced by GrB inhibition. In summary, we demonstrate that HIV infection induces IL-21 in CD4+ T cells, thereby indirectly triggering the development of GrB-secreting B cells with antiretroviral properties. GrB-secreting B cells may play a so far unappreciated role in decelerating HIV expansion, particularly in the early phase of infection. On the other hand, induction of GrB in HIV-specific B cells may interfere with their terminal differentiation into plasma cells, which may explain the lack of an efficient anti-HIV humoral immune response in HIV-infected patients. Disclosures: No relevant conflicts of interest to declare.

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Orbital Pseudotumor: Uncommon Initial Presentation of IgG4-Related Disease

Case Reports in Rheumatology ◽

10.1155/2015/324365 ◽

2015 ◽

Vol 2015 ◽

pp. 1-4 ◽

Cited By ~ 1

Author(s):

Teresa Carbone ◽

Ricardo Azêdo Montes ◽

Beatriz Andrade ◽

Pedro Lanzieri ◽

Luis Mocarzel

Keyword(s):

Elderly Patient ◽

Plasma Cells ◽

Elevated Serum ◽

Lymphocytic Infiltration ◽

Serum Levels ◽

High Serum ◽

Orbital Pseudotumor ◽

Related Disease ◽

Igg4 Related Disease ◽

Serum Igg4

IgG4-related disease (IgG4-RD) encompasses a group of fibroinflammatory conditions recognized in recent times. The main clinical features include variable degrees of tissue fibrosis, tumorlike expansions, perivascular lymphocytic infiltration rich in IgG4-positive plasma cells, and elevated serum IgG4. A case has been reported of an elderly patient with an unexplained unilateral exophthalmia; biopsy was performed and revealed lymphocytic infiltration, suggesting IgG4-RD. High serum levels of IgG4, in association with a good response to steroid therapy and to the exclusion of other diagnoses, confirmed the hypothesis of orbital pseudotumor by IgG4-RD.

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Synergistic effect of IgG4 antibody and CTLs causes tissue inflammation in IgG4-related disease

International Immunology ◽

10.1093/intimm/dxz073 ◽

2019 ◽

Vol 32 (3) ◽

pp. 163-174

Author(s):

Takanori Sasaki ◽

Taiki Yajima ◽

Tatsuro Shimaoka ◽

Shuhei Ogawa ◽

Takashi Saito ◽

...

Keyword(s):

T Cells ◽

Synergistic Effect ◽

Plasma Cells ◽

Synergistic Effects ◽

Lymphoid Tissues ◽

Irreversible Damage ◽

Tissue Specific ◽

Related Disease ◽

Igg4 Related Disease ◽

Igg4 Antibody

Abstract IgG4-related disease (IgG4-RD) is characterized by multi-organ irreversible damage resulting from tissue-specific infiltration of IgG4+ plasma cells and cytotoxic T lymphocytes (CTLs). However, whether IgG4 antibody contributes to the inflammation remains unclear. In this study, we established a mouse model that enabled us to evaluate the pathogenic function of IgG4 antibodies in response to a tissue-specific autoantigen using recombinant ovalbumin (OVA)-specific human IgG4 monoclonal antibody (rOVA-hIgG4 mAb) and the mice expressing OVA of the pancreatic islets (RIP-mOVA mice). We found no inflammatory effect of rOVA-hIgG4 mAb transfer alone; however, co-transfer with OVA-specific CD8 CTLs (OT-I T cells) induced tissue damage with dense lymphocytic inflammation in the pancreas of RIP-mOVA mice. rOVA-hIgG4 mAb caused accumulation of conventional DC1 cells (cDC1s) in the lymphoid tissues, and the dendritic cells (DCs) activated the OT-I T cells via cross-presentation. We also revealed that the synergistic effects of CTLs and antibodies were observed in the other subclasses including endogenous antibodies if they recognized the same antigen. The transfer of OVA-specific CD4 helper T cells (OT-II T cells) into RIP-mOVA mice induced the production of anti-OVA antibody, which had a synergistic effect, through acquisition of a T follicular helper (TFH) phenotype. Moreover, using OT-II T cells deficient in Bcl6 caused lower anti-OVA antibody production and inflammation with OT-I T cells. Our results indicated that autoreactive IgG4 antibodies play an important role of the tissue-specific CTL response in IgG4-RD.

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Hyper IgG4-Related Disease Presenting with Orbital Tumor and Immune Deficiency

Case Reports in Immunology ◽

10.1155/2021/9260051 ◽

2021 ◽

Vol 2021 ◽

pp. 1-5

Author(s):

Caroline G. Olson ◽

Nancy Y. Olson

Keyword(s):

Plasma Cells ◽

Elevated Serum ◽

Pelvic Mass ◽

Lymphocytic Infiltration ◽

Orbital Mass ◽

Related Disease ◽

Igg4 Related Disease ◽

New Development ◽

Initial Improvement ◽

Functional Antibodies

We report a case of IgG4-RD in a patient with high IgG4 levels, low functional antibodies, and low IgM levels. He presented with bilateral orbital pseudotumors and, after initial improvement on corticosteroids, relapsed with recurrent pleural effusion and pelvic pseudotumor. He had a grossly elevated serum IgG (1905 mg/dl) with elevations in all IgG subclasses but marked elevation in IgG4 (412 mg/dl), low IgM, and low pneumococcal antibodies. Orbital mass biopsy showed polyclonal lymphocytic infiltration and increased IgG4 plasma cells. The patient was started on prednisone and tried several immunosuppressive medications including mycophenolate mofetil, methotrexate, hydroxychloroquine, and azathioprine with decrease in size of the orbital pseudotumor. During a period when the patient stopped his medications, the pseudotumor enlarged with new development of recurrent pleural effusions. He was also found to have a pelvic mass that was biopsy positive for IgG4 proliferation. This case with progression to multiorgan involvement highlights the importance of identifying patients with IgG4-related disease. In contrast to previous cases with normal-to-high IgM, the IgM was low with impaired functional antibodies.

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Urologic manifestations of IgG4-related disease

Revista Mexicana de Urología ◽

10.48193/rmu.v80i5.610 ◽

2020 ◽

Vol 80 (5) ◽

pp. 1-10

Author(s):

Benjamin Enrique Montaño Roca ◽

Davide Vanacore ◽

Gustavo Gallegos Sánchez ◽

César Eduardo Rosales Velázquez ◽

Guillermo Enrique Ruvalcaba Oceguera ◽

...

Keyword(s):

Plasma Cells ◽

Elevated Serum ◽

Aged Patients ◽

Related Disease ◽

Igg4 Related Disease ◽

Lymphoplasmacytic Infiltrate ◽

Urinary Tract Symptoms ◽

Serum Igg4 ◽

Inflammatory Pseudotumors ◽

Clinically Significant

IgG4-related disease (IgG4-RD) is a clinical entity characterized by elevated serum IgG4 and tumor-like inflammation, with tissue infiltration by IgG4 and plasma cells. IgG4-RD is rare, but clinically significant, and its urologic manifestations have been reported in the literature. The present review covers a broad spectrum, describing the pathologies related to the area of urology. In 2003, Terumi Kamisawa was the first to recognize IgG4-RD, characterized by multiorgan lesions in patients with autoimmune pancreatitis and classified as an inflammatory and fibrotic entity with a dense lymphoplasmacytic infiltrate, positive for IgG4.(1–3) It presents in middle-aged patients, between 59-68 years of age, with no clear distribution by sex, (4–6) and has different clinical presentations. The main urologic manifestations are inflammatory pseudotumors and lower urinary tract symptoms. The present article offers a clear, general overview of the disease, encompassing its pathophysiology, diagnosis, and treatment, from the perspective of urology.

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Elevated Serum sIL-2Ra Levels Facilitate IL-2 Signaling and Contribute to Impaired Tumor Immunity in B-Cell Non-Hodgkin Lymphoma (NHL).

Blood ◽

10.1182/blood.v114.22.281.281 ◽

2009 ◽

Vol 114 (22) ◽

pp. 281-281

Author(s):

Zhi-Zhang Yang ◽

Steven C. Ziesmer ◽

Anne J. Novak ◽

Thomas E. Witzig ◽

Stephen M. Ansell

Keyword(s):

T Cells ◽

Tumor Immunity ◽

Cd4 T Cells ◽

Culture Medium ◽

Interleukin 2 ◽

Elevated Serum ◽

Foxp3 Expression ◽

Serum Levels ◽

Poor Prognostic Factor ◽

The Mean

Abstract Abstract 281 Elevated serum levels of soluble interleukin-2 receptor alpha (sIL-2Ra) have been shown to be a poor prognostic factor in various malignancies and sIL-2Ra levels have generally correlated with tumor bulk and advanced stage of disease. In a clinical trial of single agent rituximab in previously untreated follicular lymphoma (FL) patients, we found that sIL-2Ra levels were elevated compared to controls and increased sIL-2Ra levels prior to treatment were associated with a poor outcome. The mean sIL-2Ra level (+/− standard deviation) in untreated FL patients (n=32) was 2.13 ng/ml (+/− 1.81) and 1.09 ng/ml (+/− 1.53) for normal controls (n=16). The time to progression for previously untreated FL patients after 4 doses of rituximab was 12 months for patients with sIL-2Ra levels above the mean compared to 40 months for patients with low sIL-2Ra levels (p=0.003) confirming that elevated sIL-2Ra is a poor prognostic factor in FL. To explore the mechanism by which sIL-2Ra may contribute to a poor prognosis, we determined the source of sIL-2Ra and whether sIL-2Ra facilitates interleukin-2 (IL-2) signaling. Based on our previous work showing that IL-2 induces Foxp3 expression, we particularly evaluated whether sIL-2Ra may bind IL-2 and contribute to impaired anti-tumor immunity by promoting Treg cell development. We found that sIL-2Ra could be detected by ELISA in the culture medium of IL-2Ra-expressing cell lines such as SuDHL1 and Karpas299 and that activation of these cells with PMA/Ionomycin significantly increased sIL-2Ra levels in the culture medium. Production of sIL-2Ra was associated with an attenuation of surface IL-2Ra expression on SuDHL1 and Karpas299 cells suggesting that surface IL-2Ra is the source of sIL-2Ra. Next, using histo-tagged sIL-2R, we tested whether the complex between sIL-2Ra and IL-2 was able to bind to IL-2R on the malignant cell. We found that sIL-2Ra bound IL-2 and that the complex could be detected on the surface of IL-2R-expressing cells. We then compared the signaling of the sIL-2Ra/IL-2 complex to that of IL-2 alone. As expected, we found that IL-2 stimulated cell proliferation, enhanced STAT5 phosphorylation and upregulated Foxp3 expression in CD4+ T cells in a dose-dependent manner. Administration of an anti-IL-2 antibody attenuated these effects. In contrast, sIL-2Ra alone had little effect on cell proliferation, STAT5 phosphorylation and Foxp3 expression. However, the addition of sIL-2Ra to IL-2 prior to incubation with IL-2R-expressing cells enhanced IL-2-mediated phosphorylation of STAT5 and Foxp3 expression in CD4+ T cells. Compared to IL-2 alone, treatment with sIL-2Ra (25ng/ml) and IL-2 (25ng/ml) increases the number of CD4+ T cells with phosphorylation of STAT5 from 7.9% to 17.4%. Taken together, these results indicate that sIL-2R plays an active biologic role in FL by binding IL-2 and promoting IL-2 signaling rather than depleting IL-2 and blocking its function. Given the findings that IL-2 strongly induces Foxp3 expression and promotes Treg cell development and that Treg cells suppress anti-tumor immunity, we conclude that elevated serum levels of sIL-2Ra facilitate IL-2 signaling and thereby contribute to a poor prognosis in FL. Disclosures: No relevant conflicts of interest to declare.

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IgG4-Related Disease: A Multispecialty Condition

Case Reports in Rheumatology ◽

10.1155/2014/723493 ◽

2014 ◽

Vol 2014 ◽

pp. 1-3

Author(s):

Iuri Usêda Santana ◽

Emanuela Pimenta da Fonseca ◽

Mittermayer Barreto Santiago

Keyword(s):

Plasma Cells ◽

Elevated Serum ◽

Diffuse Abdominal Pain ◽

Related Disease ◽

Igg4 Related Disease ◽

Lymphoplasmacytic Infiltrate ◽

Serum Igg4 ◽

Polyclonal Hypergammaglobulinemia ◽

History Of ◽

Systemic Condition

IgG4-related disease (IgG4-RD) is a recently recognized group of conditions, characterized by tumor-like swelling of involved organs, lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, variable degrees of fibrosis, and elevated serum IgG4 concentrations. Currently IgG4-RD is recognized as a systemic condition that can affect several organs and tissues. Herein we report the case of a 34-year-old male patient who was admitted to our hospital with diffuse abdominal pain, weight loss, and painful stiffness in his neck. He had a history of tumoral mass of the left maxillary region, right palpebral ptosis with protrusion of the eyeball, and chronic dry cough for about 6 years. Laboratory tests revealed polyclonal hypergammaglobulinemia and increased serum IgG4 levels. Immunohistochemical staining of the maxillary biopsy was compatible with IgG4-RD. He had an excellent response to corticosteroid therapy. This case highlights that IgG4-RD should be included in the differential diagnosis with multisystem diseases.

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Long-term effects of intensive B cell depletion therapy in severe cases of IgG4-related disease with renal involvement

Immunologic Research ◽

10.1007/s12026-020-09163-3 ◽

2020 ◽

Vol 68 (6) ◽

pp. 340-352

Author(s):

Giacomo Quattrocchio ◽

Antonella Barreca ◽

Andrea Demarchi ◽

Roberta Fenoglio ◽

Michela Ferro ◽

...

Keyword(s):

B Cells ◽

B Lymphocyte ◽

Plasma Cells ◽

Renal Involvement ◽

Elevated Serum ◽

Long Term Effects ◽

Related Disease ◽

Igg4 Related Disease ◽

Serum Igg4 ◽

Storiform Fibrosis

AbstractIgG4-related disease (IgG4-RD) is an immune-mediated disorder often showing elevated serum IgG4 concentrations, dense T and B lymphocyte infiltration, and IgG4-positive plasma cells and storiform fibrosis. We prospectively evaluated for 4 years 5 patients with histologically proven IgG4-RD of whom 3 had tubulointerstitial nephritis (TIN) and 2 had retroperitoneal fibrosis (RPF). They received an intensive B depletion therapy with rituximab. The estimated glomerular filtration rate of TIN patients after 1 year increased from 9 to 24 ml/min per 1.73 m2. IgG/IgG4 dropped from 3236/665 to 706/51 mg/dl, C3/C4 went up from 49/6 to 99/27 mg/dl, and the IgG4-RD responder index fell from 10 to 1. CD20+ B cells decreased from 8.7 to 0.5%. A striking drop in interstitial plasma cell infiltrate as well as normalization of IgG4/IgG-positive plasma cells was observed at repeat biopsy. Both clinical and immunological improvement persisted over a 4-year follow-up. Treating these patients who were affected by aggressive IgG4-RD with renal involvement in an effort to induce a prolonged B cells depletion with IgG4 and cytokine production decrease resulted in a considerable rise in eGFR, with IgG4-RD RI normalization and a noteworthy improvement in clinical and histological features. Furthermore, the TIN subgroup was shown not to need for any maintenance therapy.

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